PanelApp

Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
Mendeliome v1.2371 MEG3 Zornitza Stark gene: MEG3 was added
gene: MEG3 was added to Mendeliome. Sources: Literature
SV/CNV, non-coding gene tags were added to gene: MEG3.
Mode of inheritance for gene: MEG3 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: MEG3 were set to 33010492; 33746039; 33067531; 38212313
Phenotypes for gene: MEG3 were set to Kagami-Ogata syndrome, MIM# 608149
Review for gene: MEG3 was set to GREEN
Added comment: Small deletions of MAG3 reported in multiple patients as one of the mechanisms of disease.
Sources: Literature
Mendeliome v1.2369 CFAP54 Zornitza Stark edited their review of gene: CFAP54: Added comment: PMID 37725231: three probands from two families with PCD, supportive mouse models x2.; Changed rating: AMBER; Changed publications: 26224312, 36593121, 37725231; Changed phenotypes: Spermatogenic failure 98, MIM# 621124, HCiliary dyskinesia, primary, 54, MIM# 621125
Mendeliome v1.2368 CFAP54 Zornitza Stark gene: CFAP54 was added
gene: CFAP54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP54 were set to 26224312; 36593121
Phenotypes for gene: CFAP54 were set to Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation
Review for gene: CFAP54 was set to RED
Added comment: PMID 36593121: Three men identified with bi-allelic variants and multiple morphologic abnormalities of the flagella or non-obstructive azoospermia.

PMID: 26224312: Homozygous mice have PCD characterized by hydrocephalus, male infertility (spermatogenesis defects in flagella maturation), and mucus accumulation. Brain analysis showed mild dilatation of the lateral ventricles. Tracheal cilia beat frequency was significantly reduced. The gene was highest expressed in the testis and lungs
Sources: Literature
Mendeliome v1.2366 BUD13 Zornitza Stark reviewed gene: BUD13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-progeroid syndrome, MIM# 621123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 KIAA1549 Sangavi Sivagnanasundram gene: KIAA1549 was added
gene: KIAA1549 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: KIAA1549 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1549 were set to 30120214; 34027671
Phenotypes for gene: KIAA1549 were set to retinitis pigmentosa 86 MONDO:0032834
Review for gene: KIAA1549 was set to GREEN
Added comment: Classified as STRONG by ClinGen Retina GCEP on 18/02/2025 - https://search.clinicalgenome.org/CCID:008708

Reported in 5 probands with RP - Green according to PanelApp
Sources: ClinGen
Mendeliome v1.2363 IFT74 Sangavi Sivagnanasundram reviewed gene: IFT74: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 PIGW Sangavi Sivagnanasundram reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 34618440; Phenotypes: hyperphosphatasia with intellectual disability syndrome 5 MONDO:0014457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 MYL1 Sangavi Sivagnanasundram reviewed gene: MYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: congenital myopathy MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 DEF6 Sangavi Sivagnanasundram reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency 87 and autoimmunity MONDO:0030457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2363 SLC25A25 Zornitza Stark gene: SLC25A25 was added
gene: SLC25A25 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC25A25 were set to 34346195
Phenotypes for gene: SLC25A25 were set to Nephrolithiasis MONDO:0008171,SLC25A25 related
Penetrance for gene: SLC25A25 were set to Incomplete
Review for gene: SLC25A25 was set to RED
Added comment: SLC25A25 encodes mitochondrial ATP-Mg/Pi carrier 3

A single missense variant was reported in 2 families with renal stones in 2021 by Jabalameli et al (PMID: 3436195).
In family 1 there was 4 affected individuals who shared the same heterozygous variant NM_001330988.2 c.1083G>C|p.Gln361His, however this variant was also seen in 7 individuals in the family without stones
In family 2 there were 7 affected individuals who also had p.Gln361His however this variant was also seen in 3 family members without stones.

This variant is located within the mitochondrial carrier domain and functional studies were performed looking at uptake of radioactive ATP compared to wild type. These studies demonstrated the variant protein had approximately 21% activity compared to wild type.

The variant was proposed to have incomplete penetrance and it should be noted there is 4352 heterozygotes in gnomad 4.

At this time there is insufficient evidence for a gene disease association between SLC25A25 and nephrolithiasis.
Sources: Literature
Mendeliome v1.2360 ELF4 Bryony Thompson gene: ELF4 was added
gene: ELF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELF4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ELF4 were set to 38231408
Phenotypes for gene: ELF4 were set to autoinflammatory syndrome, familial, X-linked, Behcet-like 2 MONDO:0024770
Mendeliome v1.2359 ATP5A1 Chirag Patel Publications for gene: ATP5A1 were set to 23599390
Mendeliome v1.2355 SLC9A6 Zornitza Stark Publications for gene: SLC9A6 were set to 18342287; 19377476; 25044251; 33278113; 32569089; 31879735
Mendeliome v1.2354 SLC9A6 Zornitza Stark edited their review of gene: SLC9A6: Added comment: Multiple female carriers reported with adult-onset neurological phenotypes including neurodegerative disease and Parkinsonism. Some had affected sons with ID. Uncertain whether this is a separate entity or manifestation in female carriers of a XL condition.; Changed publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735, 35198730, 39810750, 35198730, 31192222; Changed phenotypes: Intellectual developmental disorder, X-linked syndromic, Christianson type MIM#300243, Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement, MIM# 301142
Mendeliome v1.2353 CFAP47 Zornitza Stark Publications for gene: CFAP47 were set to PMID: 33472045
Mendeliome v1.2352 BAG3 Chirag Patel reviewed gene: BAG3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37907725, 31853710, 30145633, 28754666; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant MONDO:0015362, Charcot-Marie-Tooth disease type 2 MONDO: 0018993; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2352 PPP2R5E Chirag Patel gene: PPP2R5E was added
gene: PPP2R5E was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP2R5E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R5E were set to PMID: 39284558
Phenotypes for gene: PPP2R5E were set to Mendelian neurodevelopmental disorder MONDO:0100500
Review for gene: PPP2R5E was set to RED
Added comment: One 20yrs old individual with learning issues, motor coordination disorders, hypotonia (myopathy on EMG), and behavioural issues (mood and emotional dysregulation). WES testing identified a de novo heterozygous missense variant (Glu191Lys) in PPP2R5E gene. The variant was not found in the 4 healthy brothers of the individual. The variant is located within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation.

Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures (e.g. PP2AR-1A, 2B, 3C, 5C, 5D).
Sources: Literature
Mendeliome v1.2351 CFAP47 Chirag Patel reviewed gene: CFAP47: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39698362; Phenotypes: Cystic kidney disease MONDO:0002473; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2348 CDO1 Zornitza Stark reviewed gene: CDO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, CDO1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2348 ATF6 Bryony Thompson reviewed gene: ATF6: Rating: AMBER; Mode of pathogenicity: None; Publications: 39570676; Phenotypes: hearing loss disorder MONDO:0005365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2346 PHACTR4 Zornitza Stark reviewed gene: PHACTR4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, PHACTR4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2345 MSX1 Sangavi Sivagnanasundram reviewed gene: MSX1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005439; Phenotypes: tooth agenesis, selective, 1 MONDO:0007129; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2344 SPOUT1 Bryony Thompson gene: SPOUT1 was added
gene: SPOUT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to complex neurodevelopmental disorder MONDO:0100038, SPOUT1-related
Review for gene: SPOUT1 was set to GREEN
Added comment: Biallelic SPOUT1 variants were identified in 28 individuals with a complex neurodevelopmental disorder from 21 unrelated families. Common phenotypes include microcephaly (18/21), seizures (20/28), intellectual disability (14/14), and varying degrees of developmental delays (28/28). Also, supporting zebrafish model. The suggested name of the disorder is SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature).
Sources: Literature
Mendeliome v1.2343 MRPS28 Sangavi Sivagnanasundram reviewed gene: MRPS28: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: combined oxidative phosphorylation deficiency 47, MONDO:0033537; Mode of inheritance: None
Mendeliome v1.2341 SIN3B Zornitza Stark reviewed gene: SIN3B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SIN3B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2341 PHACTR4 Sangavi Sivagnanasundram gene: PHACTR4 was added
gene: PHACTR4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHACTR4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHACTR4 were set to 40012205
Phenotypes for gene: PHACTR4 were set to Abnormality in embryonic development, MONDO:0019755
Review for gene: PHACTR4 was set to RED
Added comment: The association with human disease phenotype is not yet established - classified as Red.
Two affected individuals present with overlapping phenotypic features including some neurodevelopmental features. Both having de novo variants (p. Arg622Pro and p.Leu623Pro) located in the RPEL3 repeat domain.
p.Leu623Pro was present at 19% VAF in patient two.
Sources: Literature
Mendeliome v1.2341 C14orf80 Sangavi Sivagnanasundram gene: C14orf80 was added
gene: C14orf80 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C14orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf80 were set to 39979680; 38252227
Phenotypes for gene: C14orf80 were set to Primary microcephaly, MONDO:0016660
Review for gene: C14orf80 was set to AMBER
Added comment: New Gene Name: TEDC1
Only two families reported with biallelic variants in this gene - Reports of a supportive functional assay however rated as Amber given that one of the reported families are consanguineous

PMID: 39979680 - Male sibs from non-consanguineous parents presenting with a range of phenotypes including growth development abnormalities, microcephaly, DD, ID and endocrine insufficiency. The brothers were found to carry chet variants identified in trans [NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)].
Homozygous zebrafish model recapitulated the human phenotype and is supportive of the loss of function mechanism of disease.

PMID: 38252227 - Iranian consanguineous families identified with a rare biallelic missense variant (Gln269Arg). The affected brothers presented with a range of developmental phenotypes including cognitive impairment and microcephaly.
Sources: Literature
Mendeliome v1.2341 CDO1 Sangavi Sivagnanasundram gene: CDO1 was added
gene: CDO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDO1 were set to 39949058
Phenotypes for gene: CDO1 were set to Neurological Disorder MONDO:0100545
Review for gene: CDO1 was set to AMBER
Added comment: Three children with overlapping neurological features. Three missense de novo variants were identified and were clustered around exon 3 and exon 4.
The three missense variants identified p.(His147Arg, Ala131Val, Glu143Lys) were classified as VUS due to the insilicos and the lack of other reports and are all absent from gnomAD v4.1.
Sources: Literature
Mendeliome v1.2341 DDX39B Sangavi Sivagnanasundram gene: DDX39B was added
gene: DDX39B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX39B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX39B were set to 39918047
Phenotypes for gene: DDX39B were set to neurodevelopmental disorder MONDO:0700092, DDX39B-related
Review for gene: DDX39B was set to GREEN
Added comment: Established gene-disease association.

6 individuals from 5 families with variable neurological and developmental phenotypes including hypotonia, DD, ID and epilepsy.
4 de novo missense variants and 1 inherited splice variant were identified. All variants are absent from gnomAD v4.1.
In vivo functional assay using Drosophila transgenic flies was supportive of a loss of function phenotype.
Sources: Literature
Mendeliome v1.2340 SMARCA1 Zornitza Stark Publications for gene: SMARCA1 were set to 26740508; 26539891; 29249292
Mendeliome v1.2337 SMARCA1 Zornitza Stark reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37841849; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SMARCA1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2337 GNA13 Bryony Thompson Added comment: Comment on list classification: Only a single recurrent variant reported at this point.
Mendeliome v1.2336 GNA13 Bryony Thompson gene: GNA13 was added
gene: GNA13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNA13 were set to 39966435
Phenotypes for gene: GNA13 were set to Ito hypomelanosis MONDO:0010302
Mode of pathogenicity for gene: GNA13 was set to Other
Review for gene: GNA13 was set to AMBER
Added comment: 4 unrelated cases with a recurrent post-zygotic GNA13 variant (NM_006572.4:c.599G>A p.Arg200Lys) with a syndrome including hypomelanosis of Ito associated with developmental anomalies. The variant was identified in one patient via exome sequencing of paired tissue/blood and then targeted GNA13 testing of other cases. In vitro assays demonstrate a gain of function for the variant. Q226L was an artificial variant demonstrating a gain of function similar to R200K. The suggested mechanism of disease is through upregulation of the RHOA/ROCK pathway altering melanocyte function.
Sources: Literature
Mendeliome v1.2335 SPTAN1 Bryony Thompson reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40023774; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2335 NR5A1 Zornitza Stark Publications for gene: NR5A1 were set to 31513305
Mendeliome v1.2333 NR5A1 Zornitza Stark edited their review of gene: NR5A1: Added comment: Rare reports of sex reversal with biallelic variants (hmz). RED/AMBER for this MOI.; Changed publications: 31513305, 38650427, 20453312; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2333 MBTPS1 Sangavi Sivagnanasundram reviewed gene: MBTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008256; Phenotypes: spondyloepiphyseal dysplasia, kondo-fu type MONDO:0032721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2333 MBD5 Sangavi Sivagnanasundram reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005344; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2333 MARS2 Sangavi Sivagnanasundram reviewed gene: MARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005338; Phenotypes: mitochondrial disease MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2333 DUOX2 Bryony Thompson Publications for gene: DUOX2 were set to 35429653; 27373512; 26301257; 28683258
Mendeliome v1.2331 CNTN6 Bryony Thompson Publications for gene: CNTN6 were set to 30836150; 28641109; 29983269
Mendeliome v1.2328 CNTN6 Bryony Thompson reviewed gene: CNTN6: Rating: AMBER; Mode of pathogenicity: None; Publications: 38183624; Phenotypes: congenital hypothyroidism MONDO:0018612; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2327 DUOX1 Bryony Thompson Publications for gene: DUOX1 were set to 29650690
Mendeliome v1.2325 DUOX1 Bryony Thompson reviewed gene: DUOX1: Rating: RED; Mode of pathogenicity: None; Publications: 29650690, 28633507; Phenotypes: congenital hypothyroidism MONDO:0018612; Mode of inheritance: Unknown
Mendeliome v1.2325 DSTYK Bryony Thompson reviewed gene: DSTYK: Rating: AMBER; Mode of pathogenicity: None; Publications: 23862974, 37746849, 34608560; Phenotypes: congenital anomalies of kidney and urinary tract 1 MONDO:0012561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2325 DSPP Bryony Thompson Publications for gene: DSPP were set to
Mendeliome v1.2324 DSG3 Bryony Thompson Publications for gene: DSG3 were set to 30528827
Mendeliome v1.2322 DSG3 Bryony Thompson reviewed gene: DSG3: Rating: AMBER; Mode of pathogenicity: None; Publications: 26763450, 37850634, 30528827; Phenotypes: Blistering, acantholytic, of oral and laryngeal mucosa MONDO:0030986; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2322 DRD3 Bryony Thompson Publications for gene: DRD3 were set to 16650084; 16809426; 17339592
Mendeliome v1.2321 DRD3 Bryony Thompson Publications for gene: DRD3 were set to
Mendeliome v1.2320 DPYS Bryony Thompson Publications for gene: DPYS were set to
Mendeliome v1.2319 DPY19L2 Bryony Thompson Publications for gene: DPY19L2 were set to
Mendeliome v1.2317 DRD2 Bryony Thompson reviewed gene: DRD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36456191, 34145635, 33200438; Phenotypes: Combined dystonia, MONDO:0020065, DRD2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2311 C12orf66 Zornitza Stark Publications for gene: C12orf66 were set to
Mendeliome v1.2306 ZFHX3 Zornitza Stark edited their review of gene: ZFHX3: Added comment: PMID 38508705: 8 unrelated probands with biallelic variants and a phenotype consistent with DEE and childhood partial epilepsy. Also a supporting Drosophila Zfh2 knockdown model with seizure-like behaviour.; Changed publications: 37292950, 38508705; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related, developmental and epileptic encephalopathy MONDO:0100062, ZFHX3-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2303 ALG5 Monique Dunstan reviewed gene: ALG5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: k,jsvz k,ajwbSCNZ, jqHABWDSCZ, ,JHqabwmsc; Mode of inheritance: None
Mendeliome v1.2302 HAT1 Monique Dunstan gene: HAT1 was added
gene: HAT1 was added to Mendeliome. Sources: UKGTN
SV/CNV tags were added to gene: HAT1.
Mode of inheritance for gene: HAT1 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: HAT1 were set to PMID:716253
Phenotypes for gene: HAT1 were set to sajhavscz
Penetrance for gene: HAT1 were set to Complete
Mode of pathogenicity for gene: HAT1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HAT1 was set to AMBER
Added comment: mjsfgzdckz.x,n efks.dzjhk. liuksweF<KDCjz lukESABJFC
Sources: UKGTN
Mendeliome v1.2301 ABCA1 Katrina Bell reviewed gene: ABCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: X VX; Phenotypes: Campomelic dysplasia with autosomal sex reversal 114290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2301 ACBD6 Katrina Bell reviewed gene: ACBD6: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: SZ C; Phenotypes: CA; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2301 ABCB6 Katrina Bell reviewed gene: ABCB6: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: Campomelic dysplasia with autosomal sex reversal 114290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v1.2299 CLCA2 Bryony Thompson gene: CLCA2 was added
gene: CLCA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCA2 were set to 31326550
Phenotypes for gene: CLCA2 were set to heart conduction disease MONDO:0000992
Review for gene: CLCA2 was set to AMBER
Added comment: Only a single family reported. A missense (p.Trp575Cys) segregates with conduction disease in 5 individuals from a large Chinese family. Electrocardiogram monitoring of mice with missense introduced induced mild conduction block and ectopic pacemakers.
Sources: Literature
Mendeliome v1.2297 ARHGEF40 Zornitza Stark reviewed gene: ARHGEF40: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 SHROOM3 Chirag Patel reviewed gene: SHROOM3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39875538; Phenotypes: Craniofacial microsomia MONDO:0015397; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 C12orf66 Chirag Patel reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39824192; Phenotypes: Neurodevelopmental disorder MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2295 ARHGEF40 Chirag Patel gene: ARHGEF40 was added
gene: ARHGEF40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF40 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGEF40 were set to PMID: 39838643
Phenotypes for gene: ARHGEF40 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: ARHGEF40 was set to RED
Added comment: 2 individuals with global developmental delay, hypotonia, short stature, hearing impairment, nystagmus, feeding issues, and dysmorphism (bifid uvula, narrow mouth, high palate, micrognathia). Trio clinical whole exome sequencing identified de novo variants in the ARHGEF40 gene at position p.Arg225, which is fully conserved in mammals and located within the n-terminal keratin binding region (p.Arg225Trp and p.Arg225Gln). Of note, multiple additional probands with rare missense variants at the p.Arg225 residue have been identified by the same laboratory (but there was no consent for publication, providing further evidence of
the importance of this residue.

The ARHGEF40 gene (aka SOLO) is a member of the Rho guanine nucleotide exchange factor (Rho-GEF) family of proteins, which stimulate Rho signal transduction molecules by converting them from inactive GDP-bound form to the active GTP-bound state. No functional studies to characterise disease-gene relationship or disease mechanism.
Sources: Literature
Mendeliome v1.2293 HECTD1 Chirag Patel gene: HECTD1 was added
gene: HECTD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HECTD1 were set to PMID: 39879987
Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: HECTD1 was set to GREEN
Added comment: 14 unrelated individuals (identified through GeneMatcher) with 15 variants of uncertain significance (VUS) in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant). Of the 15 different variants in HECTD1, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. All variants were absent in gnomAD, and HECTD1 is highly intolerant to loss-of-function variation (loss-of-function-intolerant score of 1). Clinical presentation was variable developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy.

The one individual with compound heterozygous variants had growth impairment along with NDD. The variants were inherited from apparently healthy parents, suggesting that genetic or environmental modifiers may be required to develop the phenotype. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease.

HECT-domain-containing protein 1 (HECTD1) mediates developmental pathways, including cell signalling, gene expression, and embryogenesis. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of 2 missense variants and 1 nonsense variant in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms.
Sources: Literature
Mendeliome v1.2292 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812 to Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812; Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091
Mendeliome v1.2291 PDGFRB Zornitza Stark edited their review of gene: PDGFRB: Added comment: Single family reported with OPDKD phenotype characterised by aggressive circumferential ingrowth of conjunctiva beginning in early childhood that is resistant to treatment, ultimately covering the cornea and resulting in loss of vision. Digital keloid formation after minor trauma, which can become extensive and cause flexion contractures; hardened auricles. RED for this association.; Changed publications: 33450762; Changed phenotypes: Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091, Basal ganglia calcification, idiopathic, 4, MIM# 615007, Kosaki overgrowth syndrome, MIM# 616592, Myeloproliferative disorder with eosinophilia, MIM# 131440, Myofibromatosis, infantile, 1, MIM# 228550, Premature ageing syndrome, Penttinen type, MIM# 601812
Mendeliome v1.2291 TAF11 Bryony Thompson gene: TAF11 was added
gene: TAF11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF11 were set to 39727181
Phenotypes for gene: TAF11 were set to cleft lip MONDO:0004747
Review for gene: TAF11 was set to RED
Added comment: 2 individuals in a single Chinese family with nonsyndromic cleft lip segregating with the missense p.Leu48Phe. The missense has an AF of 1.8% (including 15 homozygotes) in gnomAD v4 in the East Asian population, which is too common for an autosomal dominant disease—also, a supporting zebrafish model with craniofacial abnormalities (however the genetic evidence for this GDA is lacking).
Sources: Literature
Mendeliome v1.2289 PTPMT1 Bryony Thompson gene: PTPMT1 was added
gene: PTPMT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645; 37672386
Phenotypes for gene: PTPMT1 were set to inborn mitochondrial metabolism disorder MONDO:0004069
Review for gene: PTPMT1 was set to GREEN
Added comment: 6 cases from 3 independent families with biallelic variants in PTPMT1 (a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis). All cases presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome including developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Supporting knockout zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2287 NR6A1 Bryony Thompson gene: NR6A1 was added
gene: NR6A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 39606382
Phenotypes for gene: NR6A1 were set to Craniofacial microsomia MONDO:0015397
Review for gene: NR6A1 was set to GREEN
Added comment: 6 unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) with incomplete penetrance and variable expressivity. Colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities characterised the phenotype of the families. Also, supporting zebrafish model. Loss of function is the expected mechanism of disease.
Sources: Literature
Mendeliome v1.2285 MRAP2 Zornitza Stark gene: MRAP2 was added
gene: MRAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAP2 were set to 23869016; 31700171; 27474872; 26795956
Phenotypes for gene: MRAP2 were set to Susceptibility to obesity, MIM#615457
Review for gene: MRAP2 was set to AMBER
Added comment: Multiple studies supporting association between rare variants and obesity; however ?monogenic vs susceptibility alleles.
Sources: Literature
Mendeliome v1.2283 ITGAV Zornitza Stark gene: ITGAV was added
gene: ITGAV was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITGAV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAV were set to 39526957
Phenotypes for gene: ITGAV were set to Syndromic disease, MONDO:0002254, ITGAV-related
Review for gene: ITGAV was set to AMBER
Added comment: Three unrelated families reported: two with affected children (one hmz missense; other compound het LoF with missense) and one family with four affected fetuses. Clinical features included brain and eye anomalies and IBD/immune dysregulation. TGF-beta signalling pathway affected. The deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation.
Sources: Literature
Mendeliome v1.2281 RYBP Zornitza Stark gene: RYBP was added
gene: RYBP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RYBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYBP were set to 39891528
Phenotypes for gene: RYBP were set to Neurodevelopmental disorder, MONDO:0700092, RYBP-related
Review for gene: RYBP was set to GREEN
Added comment: Seven individuals with heterozygous de novo variants in RYBP reported. Clinical findings include severe developmental delay, dysmorphisms and multiple congenital anomalies. All the single nucleotide variants in RYBP localized to the N-terminal domain of the gene, which encodes the zinc finger domain and ubiquitin binding moiety. Further supportive in vitro and Drosophila functional data.
Sources: Literature
Mendeliome v1.2279 C1orf127 Zornitza Stark gene: C1orf127 was added
gene: C1orf127 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: C1orf127.
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy, visceral, MONDO:0018677, CIROZ-related
Review for gene: C1orf127 was set to GREEN
Added comment: 16 individuals from 10 families reported with bi-allelic variants in this gene and heterotaxy, including CHD. Supportive mouse model. CIROZ is absent or obsolete in select animals with motile cilia at their left-right organiser, including Carnivora, Atherinomorpha fish, or jawless vertebrates. Knockouts in zebrafish and Xenopus did not have observable LR anomalies. Approved HGNC name is CIROZ.
Sources: Literature
Mendeliome v1.2277 DAND5 Zornitza Stark gene: DAND5 was added
gene: DAND5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAND5 were set to 36316122; 34215651
Phenotypes for gene: DAND5 were set to Heterotaxy, visceral, 13, autosomal, MIM# 621079
Review for gene: DAND5 was set to AMBER
Added comment: Two individuals reported with bi-allelic LoF variants and heterotaxy.
Sources: Literature
Mendeliome v1.2274 SEL1L Zornitza Stark reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2274 PPA1 Zornitza Stark gene: PPA1 was added
gene: PPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPA1 were set to 37999237
Phenotypes for gene: PPA1 were set to Galactosaemia, MONDO:0018116
Review for gene: PPA1 was set to RED
Added comment: Homozygous missense variant detected in two siblings with increased galactose and galactose-related metabolites ascertained in neonatal screening. Some supportive functional data.
Sources: Literature
Mendeliome v1.2271 DMRT1 Zornitza Stark edited their review of gene: DMRT1: Added comment: DMRT1 gene exclusively expressed in male gonads. Thought not to affect ovarian development.
Gene included three international studies - see PMID: 28295047 supplemental article Fig 1 patient 19, 46XY with hypoplastic labia, uterus present had DMRT1 c.251A>G p.Tyr84Cys maternally inherited VOUS
PMID: 26005864: p.R111G also described in complete gonadal dysgenesis; Changed rating: AMBER; Changed publications: 31479588, 24934491, 29527098, 26005864, 28295047; Changed phenotypes: 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.2270 GUK1 Zornitza Stark reviewed gene: GUK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 21, MIM# 621071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2269 FLVCR1 Zornitza Stark reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MIM#621060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2268 MGA Zornitza Stark gene: MGA was added
gene: MGA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MGA were set to 39600096; 20044811; 39545409
Phenotypes for gene: MGA were set to Syndromic disease, MONDO:0002254, MGA-related; Premature ovarian failure 26, MIM# 621065
Review for gene: MGA was set to AMBER
Added comment: Association with syndromic disease: Three individuals with de novo LoF variants reported in individuals with ID and congenital anomalies. Zebrafish model supports role of this transcription factor in organogenesis. Note there are previous, less clear reports of association with NDD/CHD. Gene is constrained for LoF variants in gnomad v4; however, note there are ~30 individuals with LoF variants present. Borderline Green/Amber.

Association with POF: LoF variants enriched in a large POF cohort. Familial testing in a small number of families performed. Mouse model supportive. Also borderline Amber/Green.

Amber rating until phenotypes and mechanisms of disease for these two associations clarified.
Sources: Literature
Mendeliome v1.2266 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500; Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2265 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500, Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2263 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; Changed rating: GREEN; Changed publications: 32503408, 31423533, 35561741, 35712613, 39099563; Changed phenotypes: Familial primary hypomagnesemia, MONDO:0018100, TRPM7-related, {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth
Mendeliome v1.2262 TAOK2 Zornitza Stark Publications for gene: TAOK2 were set to 28385331; 29467497
Mendeliome v1.2258 INPP4A Chirag Patel reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39315527; Phenotypes: INPP4A-related neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2257 LRRC45 Zornitza Stark gene: LRRC45 was added
gene: LRRC45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 39638757
Phenotypes for gene: LRRC45 were set to Neurodevelopmental disorder MONDO:0700092, LRRC45-related
Review for gene: LRRC45 was set to AMBER
Added comment: Three individuals from two families reported with two homozygous variants, one splice site and the other missense. Features of a neurological ciliopathy with some supportive experimental evidence.
Sources: Literature
Mendeliome v1.2253 WASHC3 Zornitza Stark reviewed gene: WASHC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO:0700092, WASHC3 related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2252 NAV3 Zornitza Stark gene: NAV3 was added
gene: NAV3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAV3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAV3 were set to 39708122; 38977784
Phenotypes for gene: NAV3 were set to Neurodevelopmental disorder, MONDO:0700092, NAV3-related
Review for gene: NAV3 was set to GREEN
Added comment: 17 individuals from 11 families reported with bi-allelic variants and neurodevelopmental phenotypes, including DD/ID and behavioural abnormalities.
Sources: Literature
Mendeliome v1.2250 EEFSEC Zornitza Stark gene: EEFSEC was added
gene: EEFSEC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder, MONDO:0700092, EEFSEC-related
Review for gene: EEFSEC was set to GREEN
Added comment: Nine individuals from 8 unrelated families reported with bi-allelic variants in this gene and progressive neurodevelopmental disorder manifesting with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms.
Sources: Literature
Mendeliome v1.2248 DAP3 Zornitza Stark gene: DAP3 was added
gene: DAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Mitochondrial disease MONDO:0044970, DAP3-related
Review for gene: DAP3 was set to GREEN
Added comment: DAP3 encodes the mitoribosomal small subunit 29 (MRPS29). Five unrelated individuals reported with bi-allelic variants in DAP3 and variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants.
Sources: Literature
Mendeliome v1.2245 MYMX Chirag Patel reviewed gene: MYMX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39668186; Phenotypes: congenital myopathy MONDO:0019952, congenital myopathy with facial palsy, growth restriction, and dysmorphism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2244 DDX53 Chirag Patel gene: DDX53 was added
gene: DDX53 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX53 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DDX53 were set to PMID: 39706195
Phenotypes for gene: DDX53 were set to autism spectrum disorder MONDO:0005258
Review for gene: DDX53 was set to GREEN
Added comment: The DDX53 gene is a single-exon RNA helicase which lies intronic to PTCHD1-AS (a multi-isoform long noncoding RNA (lncRNA) at the Xp22.11 locus. It is thought to play a role in RNA decay, RNA processing, ribosome biogenesis, and translation initiation. 9 affected males and 3 affected females from 9 unrelated families with ASD and rare, predicted damaging or loss-of-function variants in DDX53 (including a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS). A further 26 individuals with ASD were identified (from Autism Speaks MSSNG and Simons Foundation Autism Research Initiative) with 19 rare, damaging DDX53 variations (mostly maternally inherited). No functional evidence.
Sources: Literature
Mendeliome v1.2239 CCT3 Zornitza Stark reviewed gene: CCT3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MIM# 621034; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 TCP1 Zornitza Stark reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with polymicrogyria and seizures, MIM# 621021; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 TAOK2 Achchuthan Shanmugasundram reviewed gene: TAOK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39737487; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257; Phenotypes: RBFOX2-related congenital heart disorder (MONDO:0100557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257); Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2237 LRRC8C Sangavi Sivagnanasundram changed review comment from: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature; to: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Supporting in vitro functional assay was conducted however further evidence is required to upgrade the gene classification.
Sources: Literature
Mendeliome v1.2237 EP400 Sangavi Sivagnanasundram gene: EP400 was added
gene: EP400 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EP400 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EP400 were set to 39708813
Phenotypes for gene: EP400 were set to neurodevelopmental disorder with or without early-onset generalized epilepsy - MONDO:0030930
Review for gene: EP400 was set to GREEN
Added comment: 6 unrelated probands presenting with epilepsy with NDD had compound heterozygous variants in EP400. They were confirmed in trans and inherited from their asymptomatic parents.

Knockdown of EP400 ortholog in Drosophila showed an increase in seizure-like susceptibility and abnormal neurological behaviour.
Sources: Literature
Mendeliome v1.2236 LDB1 Bryony Thompson gene: LDB1 was added
gene: LDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: Exome-wide significant enrichment of LDB1 protein-altering de novo variants (p = 1.11 x 10-15) in a large cerebral ventriculomegaly cohort (>2,697 parent-proband trios). 8 unrelated cases with ventriculomegaly, developmental delay, and dysmorphic features with de novo variants (7 LoF variants truncate LDB1's carboxy-terminal LIM interaction domain & 1 missense).
Sources: Literature
Mendeliome v1.2235 LRRC8C Sangavi Sivagnanasundram gene: LRRC8C was added
gene: LRRC8C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome MIM#621056
Mode of pathogenicity for gene: LRRC8C was set to Other
Review for gene: LRRC8C was set to RED
Added comment: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature
Mendeliome v1.2235 WASHC3 Sangavi Sivagnanasundram gene: WASHC3 was added
gene: WASHC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WASHC3 were set to DOI: https://doi.org/10.1016/j.gimo.2024.101915
Phenotypes for gene: WASHC3 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: WASHC3 was set to GREEN
Added comment: Three unrelated families with short stature, distinctive facies and neurodevelopmental abnormalities. Two different rare missense variants were identified between the three families (c.207A>C:p.L69F and c.1A>T, p.M1?).
In vitro functional assay was conducted on both variants showing impaired protein function supportive of disease mechanism.
Sources: Literature
Mendeliome v1.2235 SLC13A1 Sangavi Sivagnanasundram reviewed gene: SLC13A1: Rating: AMBER; Mode of pathogenicity: None; Publications: doi: https://doi.org/10.1016/j.gimo.2024.101958; Phenotypes: sulfation-related bone disorder MONDO:0019688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2234 RICTOR Bryony Thompson gene: RICTOR was added
gene: RICTOR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RICTOR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RICTOR were set to 39738822
Phenotypes for gene: RICTOR were set to Neurodevelopmental disorder MONDO:0700092, RICTOR-related
Review for gene: RICTOR was set to GREEN
Added comment: 8 unrelated cases presenting with ID and/or developmental delay with de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. Possible gain of function and loss of function mechanism of disease.
Sources: Literature
Mendeliome v1.2232 UBR5 Bryony Thompson gene: UBR5 was added
gene: UBR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to Neurodevelopmental disorder MONDO:0700092, UBR5-related
Review for gene: UBR5 was set to GREEN
Added comment: 29 individuals with a neurodevelopment syndrome (24 de novo variants) with a core phenotype characterised by developmental delay (26/28), autism (16/26), and intellectual disability (56%). Additionally, some individuals presented with epilepsy/seizures (11/27), movement disorders, and/or genital anomalies (35%). Loss of function is the expected mechanism of disease with functional experiments in C. elegans and in vitro ubiquitination assays.
Sources: Literature
Mendeliome v1.2230 MRUPAV_PLIN4 Bryony Thompson STR: MRUPAV_PLIN4 was added
STR: MRUPAV_PLIN4 was added to Mendeliome. Sources: Literature
STR tags were added to STR: MRUPAV_PLIN4.
Mode of inheritance for STR: MRUPAV_PLIN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: MRUPAV_PLIN4 were set to 32451610; 37145156; 36151849; 35499779
Phenotypes for STR: MRUPAV_PLIN4 were set to myopathy, distal, with rimmed vacuoles MONDO:0014945
Review for STR: MRUPAV_PLIN4 was set to GREEN
STR: MRUPAV_PLIN4 was marked as clinically relevant
Added comment: Expansion of 33-mer (33 amino acids, 99 bp) identified in coding exon 3 (exon 5) of PLIN4 via linkage analysis and long read sequencing in a large Italian cohort with progressive myopathy with specific pathology including rimmed ubiquitin-positive autophagic vacuolation.
Suggested disease name myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV). An additional 4 unrelated Chinese families/probands were reported. The repeat expansion is not detectable using short-read sequencing.
Normal PLIN4 alleles: 27-31 x 33-mer
Pathogenic: ≥39 x 33-mer
Sources: Literature
Mendeliome v1.2228 P2RY8 Zornitza Stark gene: P2RY8 was added
gene: P2RY8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: P2RY8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: P2RY8 were set to 34889940
Phenotypes for gene: P2RY8 were set to Systemic lupus erythematosus, MONDO:0007915, P2RY8-related
Review for gene: P2RY8 was set to AMBER
Added comment: One de novo variant, p.Leu257Phe, absent from gnomAD v4 identified in an individual with early-onset SLE.

Subsequent search for additional individuals in large cohorts identified:
p. Asn97Lys, inherited from mother, present in 19 individuals in gnomADv4.
p.Glu323Gly identified in 6 Chinese individuals, inheritance not determined, present in 51 individuals in gnomADv4.

Functional data support the role of the gene in immune tolerance. Role in contributing to the development of SLE is plausible, though not necessarily under a monogenic model.
Sources: Literature
Mendeliome v1.2227 PACSIN1 Zornitza Stark gene: PACSIN1 was added
gene: PACSIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PACSIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PACSIN1 were set to 36622335
Phenotypes for gene: PACSIN1 were set to Systemic lupus erythematosus, MONDO:0007915, PACSIN1-related
Review for gene: PACSIN1 was set to RED
Added comment: Single individual with de novo missense variant reported, supportive functional data.
Sources: Literature
Mendeliome v1.2224 CRYL1 Andrew Fennell reviewed gene: CRYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30455902; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2223 WNT7A Zornitza Stark Publications for gene: WNT7A were set to 21344627; 20949531; 16826533
Mendeliome v1.2222 WNT7A Zornitza Stark edited their review of gene: WNT7A: Changed publications: 19012338
Mendeliome v1.2222 WNT7A Zornitza Stark reviewed gene: WNT7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19012338]; Phenotypes: Santos syndrome, MIM# 613005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2221 FRYL Zornitza Stark reviewed gene: FRYL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2220 RFWD3 Bryony Thompson Publications for gene: RFWD3 were set to 28691929
Mendeliome v1.2218 RFWD3 Bryony Thompson reviewed gene: RFWD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 28691929, 38058754; Phenotypes: Fanconi anemia MONDO:0019391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2218 GNAT1 Sangavi Sivagnanasundram reviewed gene: GNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2218 ATG4A Bryony Thompson gene: ATG4A was added
gene: ATG4A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATG4A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATG4A were set to 33310865
Phenotypes for gene: ATG4A were set to infectious meningitis MONDO:0004796
Review for gene: ATG4A was set to RED
Added comment: Single case with recurrent HSV2 lymphocytic Mollaret’s meningitis heterozygous for a missense variant (p.Leu90Ile).
Sources: Expert list
Mendeliome v1.2217 IFNG Bryony Thompson Publications for gene: IFNG were set to 32163377
Mendeliome v1.2215 IFNG Bryony Thompson reviewed gene: IFNG: Rating: AMBER; Mode of pathogenicity: None; Publications: 32163377, 38363432; Phenotypes: inherited susceptibility to mycobacterial diseases MONDO:0019146; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2215 TMEM173 Bryony Thompson Publications for gene: TMEM173 were set to 25401470; 25029335
Mendeliome v1.2213 TMEM173 Bryony Thompson reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32673614, 36275728; Phenotypes: STING-associated vasculopathy with onset in infancy MONDO:0014405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2213 GTF3A Bryony Thompson gene: GTF3A was added
gene: GTF3A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GTF3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3A were set to 36399538
Phenotypes for gene: GTF3A were set to herpes simplex encephalitis MONDO:0012521
Review for gene: GTF3A was set to RED
Added comment: A single case is reported with common variable immunodeficiency and HSE, and some supporting functional assays.
Sources: Expert list
Mendeliome v1.2211 TLR4 Bryony Thompson Publications for gene: TLR4 were set to
Mendeliome v1.2209 TLR4 Bryony Thompson reviewed gene: TLR4: Rating: RED; Mode of pathogenicity: None; Publications: 32042729, 31442584; Phenotypes: Inflammatory bowel disease MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2208 RNASEL Bryony Thompson gene: RNASEL was added
gene: RNASEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNASEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEL were set to 36538032; 9351818
Phenotypes for gene: RNASEL were set to Multisystem inflammatory syndrome, MONDO:0035375, RNASEL-related
Review for gene: RNASEL was set to AMBER
Added comment: A single case reported with a homozygous variant reported and a supporting null mouse model.
Sources: Literature
Mendeliome v1.2206 OAS1 Bryony Thompson reviewed gene: OAS1: Rating: RED; Mode of pathogenicity: None; Publications: 36538032; Phenotypes: Multisystem inflammatory syndrome in children and adults MONDO:0035375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2203 RUNX1T1 Zornitza Stark Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Mendeliome v1.2199 CHUK Chirag Patel reviewed gene: CHUK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34533979; Phenotypes: Combined immunodeficiency, MONDO:0015131, CHUK-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2199 PDE12 Chirag Patel gene: PDE12 was added
gene: PDE12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to PMID: 39567835
Phenotypes for gene: PDE12 were set to Mitochondrial disease MONDO:0044970
Review for gene: PDE12 was set to GREEN
Added comment: 3 families (2 consanguineous) with 5 affected individuals with early onset mitochondrial disease presentation (3 liveborn, 2 intrauterine death).
-Family 1: 1 x infant death @3mths (no clinical information), 1 x 7yr old with neonatal respiratory and lactic acidosis, developmental delay, and mitochondrial respiratory chain deficiencies, and marked cytochrome c oxidase (COX) deficiency in muscle.
-Family 2: 1 x neonatal death @2days with metabolic acidosis and lactic acidosis, respiratory failure, lissencephaly, dysgenesis of the corpus callosum and extensive periventricular and subcortical cysts. Normal pyruvate dehydrogenase complex and electron
transfer chain activities in fibroblasts.
-Family 3: 2 x fetuses (13wks and 22wks) with increase nuchal translucency and reduced fetal movements. One had intra-uterine growth retardation, hydrops and cystic hygroma. The other had permanent flexion contractures of four limbs). Western blotting in fetal skeletal muscle showed absent respiratory chain complexes (I, IV, and V).

WES in all 3 families identified 3 different homozygous missense variants in PDE12 gene (p.Tyr155Cys, p.Gly372Glu, and p.Arg41Pro). All variants segregated with disease, were rare in gnomAD, and in silico pathogenicity prediction tools pointed towards a high likelihood of pathogenicity.

PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein.
Sources: Literature
Mendeliome v1.2197 RUNX1T1 Chirag Patel gene: RUNX1T1 was added
gene: RUNX1T1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RUNX1T1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Phenotypes for gene: RUNX1T1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: RUNX1T1 was set to GREEN
Added comment: RUNX1T1 encodes a transcription regulator for hematopoietic genes and is well-known for its involvement in hematologic malignancies. Germline RUNX1T1 variants may also play a role in human congenital neurodevelopmental disorders.

PMID: 39568205
3 unrelated individuals with developmental delay, learning disability, ASD, ADHD, and dysmorphism (1 x heart defects). Trio WES identified de novo variants in RUNX1T1 gene (1 x nonsense variant in 5' region [p.Gln36Ter], 2 x missense variants in C-terminus [p.Gly412Arg and p.His521Tyr]).

PMID: 19172993
1 individual with mild-moderate ID and congenital heart disease, and chromosome t(5;8)(q32;q21.3) translocation. Molecular characterization revealed that one of the break points was within the RUNX1T1 gene. Analysis of RUNX1T1 expression in human embryonic and fetal tissues suggests a role of RUNX1T1 in brain and heart development.

PMID: 22644616
1 individual with mild ID and dysmorphism, and de novo deletion exons 3-7 in RUNX1T1.

PMID: 31223340
1 individual with ID, anaemia, atrial septal defect, dysmorphism, and seizures. Found to have a 2.1 Mb deletion at 8q21.3q22.1 involving entire RUNX1T1 gene (and 2 adjacent genes - SLC26A7 and TRIQK), and a benign familial 4.3 Mb duplication at 1p22.1p21.3 (present in unaffected healthy brother).
Sources: Literature
Mendeliome v1.2196 CAPZA2 Zornitza Stark Publications for gene: CAPZA2 were set to 32338762
Mendeliome v1.2194 CAPZA2 Chris Ciotta reviewed gene: CAPZA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32338762, 38374166, 35856264; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CAPZA2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2193 CCT6A Ain Roesley gene: CCT6A was added
gene: CCT6A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to neurodevelopmental disorder MONDO:0700092, CCT6A-related
Penetrance for gene: CCT6A were set to Complete
Review for gene: CCT6A was set to GREEN
gene: CCT6A was marked as current diagnostic
Added comment: previously known as CCT6

5x individuals including 4x de novo
3x PTCS + 1x +5C>G + 1x missense

4/5 DD/ID
2/5 visual impairment
2/5 seizures
Sources: Literature
Mendeliome v1.2191 TCP1 Ain Roesley gene: TCP1 was added
gene: TCP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to neurodevelopmental disorder MONDO:0700092, TCP1-related
Penetrance for gene: TCP1 were set to Complete
Review for gene: TCP1 was set to GREEN
gene: TCP1 was marked as current diagnostic
Added comment: previously known as CCT1

8x individuals including 5x de novo
6x PTCs + 2x missense

6/8 DD/ID
2/8 visual impairment
6/8 seizures
6/8 polymicrogyria + 1x Ventriculomegaly, white matter hyperintensities
Sources: Literature
Mendeliome v1.2188 CCT3 Ain Roesley gene: CCT3 was added
gene: CCT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT3 were set to 39480921
Penetrance for gene: CCT3 were set to Complete
Review for gene: CCT3 was set to GREEN
gene: CCT3 was marked as current diagnostic
Added comment: 4x de novo - 3x PTCs and 1x missense

overlapping phenotypes:
4/4 ID/DD
3/4 visual impairment
2/4 seizures
4/4 Hypomyelination of white matter
Sources: Literature
Mendeliome v1.2187 CLASP1 Ain Roesley gene: CLASP1 was added
gene: CLASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLASP1 were set to 39040917
Phenotypes for gene: CLASP1 were set to neurodevelopmental disorder MONDO:0700092, CLASP1-related
Review for gene: CLASP1 was set to RED
gene: CLASP1 was marked as current diagnostic
Added comment: 3 siblings from a consanguineous family, homozygous for p.(Arg1481His)
at birth, all had low weight and microcephaly (< 3-4SD), profound dev delay, spasticity, seizures and lissencephaly

Arg1481His - 3 hets 0 Homs in v4
codon is highly conserved with a high REVEL score 0.83
Sources: Literature
Mendeliome v1.2186 GPATCH11 Zornitza Stark Publications for gene: GPATCH11 were set to
Mendeliome v1.2184 HMGCS1 Zornitza Stark gene: HMGCS1 was added
gene: HMGCS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS1 were set to 39531736
Phenotypes for gene: HMGCS1 were set to Rigid spine syndrome, MONDO:0019951, HMGCS1-related
Review for gene: HMGCS1 was set to GREEN
Added comment: Five individuals from four families reported. All individuals presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some; one individual died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.
HMGCS1 encodes a critical enzyme of the mevalonate pathway. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. Four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays
Sources: Literature
Mendeliome v1.2182 CMPK2 Zornitza Stark gene: CMPK2 was added
gene: CMPK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to 36443312
Phenotypes for gene: CMPK2 were set to bilateral striopallidodentate calcinosis, MONDO:0008947, CMPK2-related
Review for gene: CMPK2 was set to AMBER
Added comment: Three individuals from two unrelated families reported. One family (two sibs) with homozygous start loss variant, and the other family with compound het variants. Adult-onset neurodegenerative disorder. Extensive functional data including mouse model. Evidence of underlying mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.2177 CTGF Bryony Thompson Publications for gene: CTGF were set to 39506047
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 20534727
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 39414788
Mendeliome v1.2175 CTGF Bryony Thompson reviewed gene: CTGF: Rating: RED; Mode of pathogenicity: None; Publications: 39414788; Phenotypes: Spondyloepimetaphyseal dysplasia MONDO:0100510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2173 GUK1 Bryony Thompson gene: GUK1 was added
gene: GUK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome MONDO:0018158
Review for gene: GUK1 was set to GREEN
Added comment: 4 adult cases from 3 unrelated families with biallelic variants leading to GUK1 deficiency. Cases presented with ptosis, ophthalmoparesis, myopathic proximal limb weakness, variable hepatopathy, and altered T-lymphocyte profiles. Initial manifestations in childhood or adolescence and developed ptosis and skeletal myopathy. mtDNA depletion/deletions are present in muscle biopsies of reduced activities of mitochondrial respiratory chain enzymes in all 4 cases.
Sources: Literature
Mendeliome v1.2171 PPP2R2B Bryony Thompson Publications for gene: PPP2R2B were set to
Mendeliome v1.2168 PPP2R2B Bryony Thompson reviewed gene: PPP2R2B: Rating: AMBER; Mode of pathogenicity: None; Publications: 25356899, 39565297; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PPP2R2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2168 PPP2R2B Bryony Thompson edited their review of gene: PPP2R2B: Added comment: 5 cases with NDD and heterozygous missense (4/5 confirmed de novo): p.Thr246Lys (unknown inheritance), p.Asn310Lys (confirmed de novo), p.Glu37Lys (confirmed de novo, also had RNU4-2 path de novo Path variant), p.Ile427Thr (confirmed de novo, also had TAOK1 inherited Path variant), p.Arg149Pro (confirmed de novo). 5/5 with intellectual disability and developmental delay, 4/5 with seizures, 2/5 with hearing loss/auditory neuropathy. Study includes in vitro functional assays supporting a possible loss of function mechanism of disease. The 2 missense with additional diagnoses (E37K & I427T) demonstrated a partial reduction in PP2A holoenzyme assembly. Only 3 cases with a possible diagnosis that could be attributed to the PPP2R2B only, and only 2 were confirmed de novo.; Changed rating: AMBER; Changed publications: 25356899, 39565297; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2167 WDR47 Bryony Thompson gene: WDR47 was added
gene: WDR47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633; 35474353
Phenotypes for gene: WDR47 were set to Complex neurodevelopmental disorder MONDO:0100038, WDR47-related; Congenital heart disease MONDO:0005453
Review for gene: WDR47 was set to GREEN
Added comment: PMID: 39609633 - 7 cases from 5 unrelated families with biallelic variants and a complex neurodevelopmental syndrome. The most frequent phenotypes were corpus callosum dysgenesis (7/7), microcephaly (7/7), mild to severe intellectual disability (7/7), epilepsy (7/7). Additionally, mouse models recapitulate the human phenotype. Loss of function is the mechanism of disease. Heterozygous parents had no phenotype.

Limited evidence for mono allelic association with congenital heart defects
PMID: 35474353 - rare assumed de novo heterozygous variant (NM_014969.5:c.2056G>A p.(Val686Ile) - 10 hets in gnomAD v4.1) detected in a case with heterotaxy including AVCD, vena azygos continuation, artery lusoria, truncus bicaroticus and polysplenia. Screening of exams for 2,019 individuals with situs inversus totalis, heterotaxy, or isolated CHD detected 2 additional individuals with monoallelic rare missense variants. No functional assays or other supporting evidence. All variants are VUS
Sources: Literature
Mendeliome v1.2166 CTGF Sangavi Sivagnanasundram gene: CTGF was added
gene: CTGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia
Review for gene: CTGF was set to AMBER
Added comment: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent of missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature
Mendeliome v1.2166 GPATCH11 Sangavi Sivagnanasundram reviewed gene: GPATCH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 39572588; Phenotypes: early-onset retinal dystrophy with neurological impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2166 POLA2 Sangavi Sivagnanasundram gene: POLA2 was added
gene: POLA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLA2 were set to 39616267
Phenotypes for gene: POLA2 were set to Telomere biology disorders; Coats plus syndrome MONDO:0012815
Review for gene: POLA2 was set to GREEN
Added comment: New gene-disease association.

PMID: 39616267 - Five individuals from two unrelated swedish families presenting with clinical phenotype suggestive of a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Affected individuals also presented with shortened telomeres.

Compound heterozygous variants were identified in both families.
Family A (Ile96Thr;Pro424Leu) - Both variants are present in gnomAD v4.1 but FAF is rare enough for AR condition [c.287 T > C, p.(Ile96Thr) - FAF 0.002%; c.1271 C > T, p.(Pro424Leu) - FAF 0.0002 %]
Family B (Ile96Thr; intragenic SNV resulting in the deletion of the 5’ terminal and exon 1) - same missense as the other family along with an SNV.

In vitro assay using CRISPR/Cas9 genome engineering into HEK293T to assess whether the p.(Ile96Thr) would affect telomere length. The subclones carrying the missense variant showed telomeric shortening of ~4kb compared to the WT subclones.
Sources: Literature
Mendeliome v1.2166 FGF8 Zornitza Stark edited their review of gene: FGF8: Added comment: Association with CHD: Two individuals reported but extensive functional data. MODERATE by ClinGen.; Changed publications: 32664970, 7768185, 32664970, 10603341, 19509466, 9462741, 10603341, 12223415; Changed phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702, Hypoplastic femurs and pelvis, MIM#619545, Congenital heart disease MONDO:0005453, FGF8-related
Mendeliome v1.2164 RAB35 Bryony Thompson gene: RAB35 was added
gene: RAB35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB35 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: RAB35 were set to 38432637; 36928819
Phenotypes for gene: RAB35 were set to familial hypercholesterolemia MONDO:0005439; neurodevelopmental disorder MONDO:0700092
Review for gene: RAB35 was set to RED
Added comment: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6).
Sources: Literature
Mendeliome v1.2162 ARPC3 Bryony Thompson gene: ARPC3 was added
gene: ARPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC3 were set to 36928819; 26166300
Phenotypes for gene: ARPC3 were set to Charcot-Marie-Tooth disease MONDO:0015626
Review for gene: ARPC3 was set to AMBER
Added comment: Posterior probability association (PPA) 0.995 for Charcot-Marie Tooth disease under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 549 CMT cases and 54,856 controls used in BeviMed analysis. 5 rare variants (missense, splice region, a splice acceptor site) enriched in the CMT cohort (n=14).
Additionally, ArpC3 conditional knockout mice fail to ensheath axons causing axon dysfunction.
Sources: Literature
Mendeliome v1.2159 USP33 Bryony Thompson gene: USP33 was added
gene: USP33 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP33 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP33 were set to 36928819
Phenotypes for gene: USP33 were set to Renal hypertension MONDO:0001105
Review for gene: USP33 was set to AMBER
Added comment: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature
Mendeliome v1.2157 UCHL1 Bryony Thompson reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905, 35986737, 39030458; Phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2157 UCHL1 Bryony Thompson gene: UCHL1 was added
gene: UCHL1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: UCHL1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 23359680; 3340629; 28007905; 32656641; 29735986; 28007905; 35986737; 39030458
Phenotypes for gene: UCHL1 were set to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Mendeliome v1.2156 FMN1 Bryony Thompson Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Mendeliome v1.2154 FMN1 Bryony Thompson edited their review of gene: FMN1: Added comment: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); Changed publications: 20610440, 19383632, 15202026, 36928819; Changed phenotypes: Hearing loss disorder MONDO:0005365
Mendeliome v1.2154 PPP5C Lucy Spencer gene: PPP5C was added
gene: PPP5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP5C were set to 35361529; 25363768; 33057194
Phenotypes for gene: PPP5C were set to Neurodevelopmental disorder, MONDO:0700092, PPP5C-related
Review for gene: PPP5C was set to AMBER
Added comment: PMID: 35361529 - reported a de novo missense in a proband with microcephaly, developmental delay and epilepsy. However, after personal communication with the undiagnosed disease network this proband has since been found to have a different diagnosis with a nonsense and a missense in VARS1 identified, so unclear if the PPP5C variant is contributing to their phenotype.

3 more probands with de novo missense variants have been published in large autism or developmental disorder cohort with limited information (PMIDs: 25363768, 33057194)

An internal VCGS proband with intellectual disability and failure to thrive was also found to have a de novo missense variant in this gene.
Sources: Literature
Mendeliome v1.2153 MRVI1 Bryony Thompson gene: MRVI1 was added
gene: MRVI1 was added to Mendeliome. Sources: NHS GMS
new gene name tags were added to gene: MRVI1.
Mode of inheritance for gene: MRVI1 was set to Unknown
Publications for gene: MRVI1 were set to 30001348
Phenotypes for gene: MRVI1 were set to moyamoya syndrome
Review for gene: MRVI1 was set to RED
Added comment: A single report of a variant as a possible modifier of NF1-related Moyamoya disease. The SNP rs35857561 segregates co-occurring with NF1 in 2 families and Moyamoya disease. rs35857561 is a common SNP and IRAG1 (new gene name) hasn't been reported in association with Mendelian disease.
Sources: NHS GMS
Mendeliome v1.2152 DHDDS Zornitza Stark Publications for gene: DHDDS were set to 27343064; 29100083; 21295283; 34382076
Mendeliome v1.2151 DHDDS Zornitza Stark edited their review of gene: DHDDS: Added comment: Bi-allelic variants: ClinGen have lumped the CDG together with the RP -- likely represent a continuum of severity rather than distinct disorders.; Changed publications: 27343064, 29100083, 21295283, 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393
Mendeliome v1.2148 SLC35F1 Lucy Spencer reviewed gene: SLC35F1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SLC35F1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2147 ATP5A1 Lucy Spencer reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34483339, 34954817, 23599390, 23596069; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2146 NFATC2 Bryony Thompson reviewed gene: NFATC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35789258, 38427060; Phenotypes: Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2140 SH3KBP1 Bryony Thompson reviewed gene: SH3KBP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29636373, 21708930; Phenotypes: Immunodeficiency, common variable, 4 MONDO:0013284; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2140 RFC1 Bryony Thompson Publications for gene: RFC1 were set to 30926972; 33103729; 35883251
Mendeliome v1.2136 ZCCHC8 Zornitza Stark reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2135 PLA2G4A Sangavi Sivagnanasundram reviewed gene: PLA2G4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18451993, 23268370, 25102815; Phenotypes: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder MONDO:0018794; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RTTN Sangavi Sivagnanasundram reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008471; Phenotypes: microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ZCCHC8 Sangavi Sivagnanasundram reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31488579, 38375433; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2135 SLC18A2 Sangavi Sivagnanasundram reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008459; Phenotypes: brain dopamine-serotonin vesicular transport disease MONDO:0018130; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RFC1 Sangavi Sivagnanasundram reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251, 36478048, 36289003; Phenotypes: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome MONDO:0044720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 IQCB1 Sangavi Sivagnanasundram reviewed gene: IQCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008440; Phenotypes: ciliopathy MONDO:0005308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 WASHC5 Sangavi Sivagnanasundram reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006537, https://search.clinicalgenome.org/CCID:006538; Phenotypes: hereditary spastic paraplegia 8 MONDO:0011339, Ritscher-Schinzel syndrome 1 MONDO:0009073; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2135 G6PC Sangavi Sivagnanasundram reviewed gene: G6PC: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008420; Phenotypes: glycogen storage disease I MONDO:0002413; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 PYGL Sangavi Sivagnanasundram reviewed gene: PYGL: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008478; Phenotypes: glycogen storage disease VI MONDO:0009294; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CAMLG Sangavi Sivagnanasundram reviewed gene: CAMLG: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008383; Phenotypes: congenital disorder of glycosylation, type IIz MONDO:0859357; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CYP27A1 Sangavi Sivagnanasundram reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008400; Phenotypes: cerebrotendinous xanthomatosis MONDO:0008948; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 DEGS1 Sangavi Sivagnanasundram reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008468; Phenotypes: leukodystrophy, hypomyelinating, 18 MONDO:0032730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ANAPC1 Sangavi Sivagnanasundram reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008429; Phenotypes: Rothmund-Thomson syndrome type 1 MONDO:0016368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 COG3 Sangavi Sivagnanasundram reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008379; Phenotypes: congenital disorder of glycosylation MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2134 POU2AF1 Bryony Thompson reviewed gene: POU2AF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35603192, 33571536; Phenotypes: Agammaglobulinemia MONDO:0015977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2133 IGKC Bryony Thompson gene: IGKC was added
gene: IGKC was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IGKC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IGKC were set to https://search.clinicalgenome.org/CCID:005121
Phenotypes for gene: IGKC were set to recurrent infections associated with rare immunoglobulin isotypes deficiency MONDO:0013576
Review for gene: IGKC was set to AMBER
Added comment: Antibody Deficiencies GCEP classify gene-disease association as Limited (18/05/2021) - at least 6 probands https://search.clinicalgenome.org/CCID:005121
Sources: Expert list
Mendeliome v1.2131 FLT3LG Bryony Thompson reviewed gene: FLT3LG: Rating: AMBER; Mode of pathogenicity: None; Publications: 10828034, 38701783; Phenotypes: ?Immunodeficiency 125 MIM#620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2131 TNFSF9 Zornitza Stark gene: TNFSF9 was added
gene: TNFSF9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNFSF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF9 were set to 35657354
Phenotypes for gene: TNFSF9 were set to Hereditary susceptibility to infections, MONDO:0015979, TNFSF9-related
Review for gene: TNFSF9 was set to RED
Added comment: Fournier et al. described one patient with DiGeorge syndrome with a unique susceptibility to EBV with broad EBV infection and smooth muscle tumors. He was found to have a homozygous missense variant (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection.

They show that CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells.
Sources: Literature
Mendeliome v1.2129 APOA4 Zornitza Stark gene: APOA4 was added
gene: APOA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOA4 were set to 38096951
Phenotypes for gene: APOA4 were set to Hereditary amyloidosis, MONDO:0018634, APOA4-related
Review for gene: APOA4 was set to GREEN
Added comment: 5 families with autosomal dominant medullary amyloidosis. WGS/WES identified 2 different variants in the APOA4 gene (p.D33N in 3 families and p.L66V in 2 families). The variants were absent in gnomAD, located at the structurally flexible N-terminal domain of APOA4, and segregated with disease. There were 48 genotype +ve individuals with 44/48 having an eGFR <60. All clinically affected individuals presented with a bland urinary sediment, CKD, and no clinical evidence of systemic amyloidosis. Mean age of dialysis/transplantation was 58+/-11yrs. Routine kidney biopsies limited to the kidney cortex showed tubulointerstitial fibrosis and secondary glomerulosclerosis and no amyloid deposition. Four affected individuals were shown to have isolated medullary deposition of amyloid, with mass spectrometry showing the mutated Apoa4 as the primary constituent in 3 available cases. Plasma total ApoA4 levels were increased for patients (n=15) with ApoA4 mutations versus controls (n=49). They hypothesize that the amino acid substitutions alter the tertiary or quaternary structure of the mutated ApoA4, leading to increased plasma and primary urine concentrations and isolated medullary amyloid deposition.
Sources: Literature
Mendeliome v1.2128 TAPBP Bryony Thompson Publications for gene: TAPBP were set to 12149238
Mendeliome v1.2126 TAPBP Bryony Thompson reviewed gene: TAPBP: Rating: AMBER; Mode of pathogenicity: None; Publications: 38866210, 12149238; Phenotypes: MHC class I deficiency MONDO:0011476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2126 RHOH Bryony Thompson Publications for gene: RHOH were set to 22850876; 27574848
Mendeliome v1.2124 RHOH Bryony Thompson reviewed gene: RHOH: Rating: AMBER; Mode of pathogenicity: None; Publications: 38775840, 22850876; Phenotypes: epidermodysplasia verruciformis, susceptibility to, 4 MONDO:0032666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2123 PRIM1 Bryony Thompson reviewed gene: PRIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33060134, 38773012; Phenotypes: primordial dwarfism-immunodeficiency-lipodystrophy syndrome MONDO:0859276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2123 MAN2B2 Bryony Thompson Publications for gene: MAN2B2 were set to 31775018; 35637269
Mendeliome v1.2122 MAN2B2 Bryony Thompson reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 38622837, 35637269, 31775018; Phenotypes: Congenital disorder of glycosylation, MONDO:0015286, MAN2B2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2120 NUDCD3 Bryony Thompson gene: NUDCD3 was added
gene: NUDCD3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NUDCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD3 were set to 38787962
Phenotypes for gene: NUDCD3 were set to severe combined immunodeficiency MONDO:0015974
Mendeliome v1.2119 ATG9A Bryony Thompson gene: ATG9A was added
gene: ATG9A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG9A were set to 35838483
Phenotypes for gene: ATG9A were set to Autophagy-associated immune dysregulation and hyperplasia
Review for gene: ATG9A was set to RED
Added comment: A single case with compound heterozygous variants was reported. After infection with Epstein-Barr virus (EBV), the patient developed hyperplastic proliferation of T and B cells in the lung and brain and exhibited defects in lymphocyte memory cell populations. In vitro functional assays.
Sources: Literature
Mendeliome v1.2117 CCR2 Bryony Thompson Publications for gene: CCR2 were set to 34516427; 17504215; 15167933; 17604544
Mendeliome v1.2114 CCR2 Bryony Thompson reviewed gene: CCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38157855; Phenotypes: Polycystic lung disease MIM#219600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2113 ME2 Bryony Thompson gene: ME2 was added
gene: ME2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ME2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ME2 were set to 39401966
Phenotypes for gene: ME2 were set to inborn disorder of energy metabolism MONDO:0019243
Review for gene: ME2 was set to RED
Added comment: A single individual with a homozygous frameshift variant from a consanguineous family. The phenotype included developmental delay, microcephaly, mild brain atrophy, peripheral
hypotonia, subtle dysmorphic features, ectopic kidney, and mild lactate elevation. Deletion of yeast ortholog of the gene resulted in growth arrest (which could be rescued).
Sources: Literature
Mendeliome v1.2111 TSHZ3 Bryony Thompson gene: TSHZ3 was added
gene: TSHZ3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSHZ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TSHZ3 were set to 27668656; 34919690; 36553458; 39420202
Phenotypes for gene: TSHZ3 were set to congenital anomaly of kidney and urinary tract MONDO:0019719
Review for gene: TSHZ3 was set to AMBER
Added comment: More evidence for the gene-disease association is required
PMID: 27668656 - TSHZ3 is included in the region deleted in chromosome 19q13.11 Deletion Syndrome, which includes intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT)
PMID: 34919690 - haploinsufficient mouse model leads to kidney defects
PMID: 36553458 - heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in a case with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis.
PMID: 39420202 - 12 CAKUT patients from 9/301 (3%) families carried 5 different rare heterozygous TSHZ3 missense variants. However, 1 of the variants (p.Ser58Gly) present in 5 of the families is more common in gnomAD v4.1 than you would expect for a dominant disease including 5 homozygotes (1,408/1,612,114 alleles, 5 hom, AF=0.0008734). The authors state this is not unexpected in a condition, such as CAKUT. However, the different missense variants are inherited from unaffected parents in at least 2/9 families (there was no phenotype information available for an additional 3 parents).
Sources: Literature
Mendeliome v1.2109 WDR83OS Bryony Thompson Publications for gene: WDR83OS were set to 30250217
Mendeliome v1.2107 WDR83OS Bryony Thompson reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: None; Publications: 39471804, 30250217; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2106 GON4L Bryony Thompson gene: GON4L was added
gene: GON4L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GON4L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON4L were set to 39500882; 21937992; 31785789; 34011629; 33077954
Phenotypes for gene: GON4L were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: GON4L was set to GREEN
Added comment: 2 LoF variants in 4 cases from 3 unrelated consanguineous families, and supporting null zebrafish model
PMID: 39500882 - 2 homozygous truncating GON4L variants [NM_001282860.2: c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in 3 patients from 2 consanguineous families with prenatal-onset growth impairment, developmental delay, mild intellectual disability, speech impairment, progressive and disproportionate microcephaly, facial asymmetry, congenital heart anomaly, and brain structure abnormalities.
Null zebrafish model had distinct morphological and size abnormalities in the craniofacial cartilage of zebrafish larvae
Heterozygous carriers in biallelic families were unaffected
PMID: 21937992 - a case from Iran from a consanguineous family homozygous for c.5517+1G>A with syndromic ID. No other clinical details provided

Limited evidence for AD gene-disease association - heterozygous de novo variants identified in autism studies and a congenital hydrocephalus study. But, heterozygous carriers in families with biallelic LoF variants are healthy
PMID: 31785789 - 4 (3 NS & 1 Silent) de novo GON4L variants in cases with autism (n=3) & neurodevelopmental disorder
PMID: 34011629 - 2 cases with autism spectrum disorder and de novo missense
PMID: 33077954 - a de novo splice site variant identified in a single case with congenital hydrocephalus
Sources: Literature
Mendeliome v1.2105 SGSM3 Zornitza Stark Publications for gene: SGSM3 were set to PMID: 37833060
Mendeliome v1.2102 DALRD3 Zornitza Stark Publications for gene: DALRD3 were set to 32427860
Mendeliome v1.2100 UBTF Zornitza Stark Publications for gene: UBTF were set to 28777933; 29300972
Mendeliome v1.2099 UBTF Zornitza Stark edited their review of gene: UBTF: Added comment: PMID 39366741: 3 Chinese patients with global developmental delay, intellectual disability, social challenges and dysmorphism (wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip), but no neuroregression (but aged 1.8yrs-4.8yrs). WES with SNV/CNV analysis showed:
-nonsense variant c.1327C>T p. (Arg443Ter) - parental segregation not possible
-de novo ~46 kb deletion at 17q21.31 containing 7 genes but UBTF as only OMIM Morbid gene
-de novo ~106kb deletion at 17q21.31 containing 10 genes but UBTF as only relevant OMIM Morbid gene (other one was SLC4A1)

Propose haploinsufficiency presents with different phenotype to CONDBA which is due to GOF variant.

AMBER for this mechanism and phenotype.; Changed publications: 28777933, 29300972, 39366741; Changed phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701, Neurodevelopmental disorder, MONDO:0700092, UBTF-related
Mendeliome v1.2098 IRAK2 Zornitza Stark reviewed gene: IRAK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, MONDO:0957790, IRAK2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2098 DTNA Zornitza Stark Publications for gene: DTNA were set to 29118297; 11238270; 16427346
Mendeliome v1.2095 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259
Mendeliome v1.2094 CRACR2A Sangavi Sivagnanasundram reviewed gene: CRACR2A: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008378; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 DNAH9 Sangavi Sivagnanasundram reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008406; Phenotypes: ciliary dyskinesia, primary, 40 MONDO:0032664; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 FUK Sangavi Sivagnanasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008377; Phenotypes: congenital disorder of glycosylation with defective fucosylation 2 MONDO:0020777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 CTPS1 Sangavi Sivagnanasundram reviewed gene: CTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008376; Phenotypes: severe combined immunodeficiency due to CTPS1 deficiency MONDO:0014391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 SOX6 Sangavi Sivagnanasundram reviewed gene: SOX6: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008480; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2093 BHLHE22 Zornitza Stark gene: BHLHE22 was added
gene: BHLHE22 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092, BHLHE22-related
Review for gene: BHLHE22 was set to GREEN
Added comment: Four individuals with de novo missense variants within the highly conserved helix-loop-helix domain and seven individuals from five unrelated families with a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Individuals presented with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals had partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms.

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum.
Sources: Literature
Mendeliome v1.2091 MRPL49 Zornitza Stark gene: MRPL49 was added
gene: MRPL49 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 39417135
Phenotypes for gene: MRPL49 were set to Mitochondrial disease, MONDO:0044970, MRPL49-related
Review for gene: MRPL49 was set to GREEN
Added comment: Five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy and bi-allelic variants in this gene.
Sources: Literature
Mendeliome v1.2090 SATB1 Sangavi Sivagnanasundram reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008481; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 NT5C2 Sangavi Sivagnanasundram reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008372; Phenotypes: complex hereditary spastic paraplegia MONDO:0015150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 NPTX1 Sangavi Sivagnanasundram reviewed gene: NPTX1: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008403; Phenotypes: autosomal dominant cerebellar ataxia MONDO:0020380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 SLC24A1 Sangavi Sivagnanasundram reviewed gene: SLC24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008419; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 C1QTNF5 Sangavi Sivagnanasundram reviewed gene: C1QTNF5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008422; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 EPHB2 Sangavi Sivagnanasundram reviewed gene: EPHB2: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008367; Phenotypes: bleeding disorder, platelet-type, 22 MONDO:0032765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 F12 Sangavi Sivagnanasundram reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 HOXA11 Sangavi Sivagnanasundram reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832; Phenotypes: radioulnar synostosis with amegakaryocytic thrombocytopenia 1 MONDO:0024558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 CCDC115 Sangavi Sivagnanasundram reviewed gene: CCDC115: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008374; Phenotypes: CCDC115-CDG MONDO:0014789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 IRAK2 Chirag Patel changed review comment from: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature; to: PMID: 39299377
2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form.


Preprint paper:
2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly.

The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs.
Mendeliome v1.2089 WISP3 Sangavi Sivagnanasundram reviewed gene: WISP3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008442; Phenotypes: progressive pseudorheumatoid arthropathy of childhood MONDO:0008827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 WDR60 Sangavi Sivagnanasundram reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008443; Phenotypes: short-rib thoracic dysplasia 8 with or without polydactyly MONDO:0014214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 IRAK2 Chirag Patel gene: IRAK2 was added
gene: IRAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IRAK2 were set to PMID: 39299377
Phenotypes for gene: IRAK2 were set to Immunodeficiency, no OMIM #
Review for gene: IRAK2 was set to RED
Added comment: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature
Mendeliome v1.2087 MARK2 Chirag Patel gene: MARK2 was added
gene: MARK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to PMID: 39419027, 39436150
Phenotypes for gene: MARK2 were set to Neurodevelopmental disorder MONDO:0700092
Mode of pathogenicity for gene: MARK2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MARK2 was set to GREEN
Added comment: 31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears).

WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains.

The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD.
Sources: Literature
Mendeliome v1.2085 DTNA Chirag Patel reviewed gene: DTNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36799992; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis MONDO:0859322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2085 KAT2B Ain Roesley Phenotypes for gene: KAT2B were changed from steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related; cataract MONDO:0005129, KAT2B-related
Mendeliome v1.2084 ROCK2 Sangavi Sivagnanasundram gene: ROCK2 was added
gene: ROCK2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: ROCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROCK2 were set to 28554332, 30622330, 31941532
Phenotypes for gene: ROCK2 were set to congenital heart disease MONDO:0005453
Review for gene: ROCK2 was set to AMBER
Added comment: Reported in 4 unrelated individuals however classified as LIMITED by ClinGen Congenital Heart Disease GCEP on 03/09/2024 - https://search.clinicalgenome.org/CCID:008432
Sources: ClinGen
Mendeliome v1.2084 KAT2B Ain Roesley gene: KAT2B was added
gene: KAT2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KAT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KAT2B were set to 39366742
Phenotypes for gene: KAT2B were set to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related
Review for gene: KAT2B was set to RED
gene: KAT2B was marked as current diagnostic
Added comment: 1 family with 2 affected siblings homozygous for an NMD-predicted variant

both have steroid-resistant nephrotic syndrome and bilateral cataract
only 1 has FSGS
Sources: Literature
Mendeliome v1.2083 IKZF2 Ain Roesley reviewed gene: IKZF2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 39406892; Phenotypes: nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2083 ANKRD24 Ain Roesley gene: ANKRD24 was added
gene: ANKRD24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANKRD24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKRD24 were set to PMID: 39434538
Phenotypes for gene: ANKRD24 were set to sensorineural hearing loss disorder MONDO:0020678, ANKRD24-related
Review for gene: ANKRD24 was set to RED
gene: ANKRD24 was marked as current diagnostic
Added comment: 1 consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL

2 affecteds homozygous for c.1934_1937del; (p.Thr645Lysfs*52), which is NMD-predicted
Sources: Literature
Mendeliome v1.2082 DALRD3 Sangavi Sivagnanasundram reviewed gene: DALRD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39482881; Phenotypes: developmental and epileptic encephalopathy, 86 MONDO:0030054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2082 ZNF862 Ain Roesley gene: ZNF862 was added
gene: ZNF862 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF862 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF862 were set to PMID: 35142290
Phenotypes for gene: ZNF862 were set to hereditary gingival fibromatosis MONDO:0016070 , ZNF862 -related
Review for gene: ZNF862 was set to RED
gene: ZNF862 was marked as current diagnostic
Added comment: 13 individuals in a large multi-generational family with hereditary gingival fibromatosis

missense variant with 5 hets in gnomad v4, very low conservation and benign REVEL score
Sources: Literature
Mendeliome v1.2081 LSM7 Sangavi Sivagnanasundram reviewed gene: LSM7: Rating: AMBER; Mode of pathogenicity: None; Publications: 39420558; Phenotypes: leukodystrophy MONDO:0019046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2080 SGSM3 Sangavi Sivagnanasundram reviewed gene: SGSM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39390489; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), SGSM3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2080 GMNN Zornitza Stark changed review comment from: Three unrelated individuals reported, all variants in exon 2 (first coding exon).; to: Three unrelated individuals reported, all variants in exon 2 (first coding exon), leading to the expression of a stable truncated protein.
Mendeliome v1.2080 LINC01578 Zornitza Stark Publications for gene: LINC01578 were set to
Mendeliome v1.2079 LINC01578 Zornitza Stark edited their review of gene: LINC01578: Changed publications: 39442041
Mendeliome v1.2078 LINC01578 Zornitza Stark gene: LINC01578 was added
gene: LINC01578 was added to Mendeliome. Sources: Literature
SV/CNV, new gene name tags were added to gene: LINC01578.
Mode of inheritance for gene: LINC01578 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LINC01578 were set to Neurodevelopmental disorder, MONDO:0700092, CHASERR-related
Review for gene: LINC01578 was set to GREEN
Added comment: CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Three unrelated children reported with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis, indicating bidirectional dosage sensitivity in human disease.
Sources: Literature
Mendeliome v1.2076 RNU5B-1 Zornitza Stark gene: RNU5B-1 was added
gene: RNU5B-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related
Review for gene: RNU5B-1 was set to GREEN
Added comment: 20 individuals reported in two preprints with de novo variants in this gene and a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.2070 ZNF808 Zornitza Stark reviewed gene: ZNF808: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pancreatic agenesis 3, MIM# 620991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2069 AJAP1 Achchuthan Shanmugasundram gene: AJAP1 was added
gene: AJAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AJAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AJAP1 were set to 38985877
Phenotypes for gene: AJAP1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: AJAP1 was set to GREEN
Added comment: PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene and they presented with epilepsy, neurodevelopmental problems, or intellectual disability. There is also supporting functional evidence available.
Sources: Literature
Mendeliome v1.2067 MSL2 Zornitza Stark reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Karayol-Borroto-Haghshenas neurodevelopmental syndrome, MIM# 620985; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2065 BORCS8 Zornitza Stark reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram commented on gene: DHRSX: Note that this gene is located in the pseudoautosomal region 1.
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram gene: DHRSX was added
gene: DHRSX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRSX were set to 38821050
Phenotypes for gene: DHRSX were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: DHRSX was set to GREEN
Added comment: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2063 UFC1 Zornitza Stark reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth (MIM#618076); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2062 WFDC2 Zornitza Stark gene: WFDC2 was added
gene: WFDC2 was added to Mendeliome. Sources: Literature
founder tags were added to gene: WFDC2.
Mode of inheritance for gene: WFDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WFDC2 were set to 38626355
Phenotypes for gene: WFDC2 were set to bronchiectasis, MONDO:0004822, WFDC2-related
Review for gene: WFDC2 was set to GREEN
Added comment: 11 individuals from 10 families reported with bi-allelic variants in this gene and bronchiectasis and nasal polyps. p.Cys49Arg is recurrent and may be a founder variant.
Sources: Literature
Mendeliome v1.2059 BMP5 Zornitza Stark Publications for gene: BMP5 were set to
Mendeliome v1.2058 RELB Zornitza Stark Publications for gene: RELB were set to 7834753; 26385063
Mendeliome v1.2056 KLF1 Zornitza Stark Publications for gene: KLF1 were set to 21055716; 33339573; 32815883; 32221653; 32032242; 31818881
Mendeliome v1.2054 KLF1 Zornitza Stark edited their review of gene: KLF1: Added comment: Ten individuals reported with bi-allelic variants and congenital dyserythropoietic anaemia.; Changed publications: 21055716, 33339573, 32815883, 32221653, 32032242, 31818881, 24443441, 25724378, 28361594, 34554218; Changed phenotypes: Dyserythropoietic anaemia, congenital, type IV, MIM# 613673, MONDO:0013355, Anaemia, congenital dyserythropoietic, type IVb, MIM#620969; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2053 POLR3K Bryony Thompson Publications for gene: POLR3K were set to 30584594; 33659930
Mendeliome v1.2051 POLR3K Bryony Thompson reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1155/2024/8807171, 30584594; Phenotypes: POLR3-related leukodystrophy MONDO:0700282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2050 RELB Chirag Patel reviewed gene: RELB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39231201; Phenotypes: T-cell and B cell immunodeficiency, Immunodeficiency 53, OMIM #617585; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2049 BMP5 Chirag Patel edited their review of gene: BMP5: Changed publications: PMID: 39239663
Mendeliome v1.2048 BMP5 Chirag Patel gene: BMP5 was added
gene: BMP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Phenotypes for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Review for gene: BMP5 was set to RED
Added comment: 1 patient with skeletal dysostosis, atrioventricular septal defect, hypermobility, laryngo-tracheo-bronchomalacia and dysmorphic features (malar hypoplasia, short palpebral fissures, short nose, low nasal bridge, anteverted nares, long philtrum, small ears with abnormally folded antihelix). Skeletal survey showed mild thoracolumbar scoliosis, four sacral segments, absent ossification of the inferior pubic rami, and patellar aplasia. Trio WGS identified compound heterozygous loss of function variants in BMP5 (c.88_89del, p.(Gly30Argfs*11) and c.1104+2del, p.(?). Abnormal splicing was proven on the suspected splice variant using maternal fibroblasts. BMP5 expression is confined to specific parts of the skeleton and cartilage in mice and is tightly regulated by different enhancers. Previous studies of chicken embryonic heart development showed BMP5 expression in the endoderm underlying the precardiac mesoderm, the myocardium of the atrioventricular canal and outflow tract regions. Other bone morphogenetic proteins are linked to several genetic skeletal disorders.
Sources: Literature
Mendeliome v1.2046 IL7 Zornitza Stark gene: IL7 was added
gene: IL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL7 were set to 39352394
Phenotypes for gene: IL7 were set to Combined immunodeficiency, MONDO:0015131, IL7-related
Review for gene: IL7 was set to GREEN
Added comment: 6 indviduals from 4 kindreds with combined immune deficiency and recurrent infections. Extensive immunophenotyping revealing IL7 dependent and independent development of T cells.
Sources: Literature
Mendeliome v1.2043 LRRC7 Zornitza Stark reviewed gene: LRRC7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder (MONDO:0700092), LRRC7-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2042 RPL26 Zornitza Stark Publications for gene: RPL26 were set to 22431104
Mendeliome v1.2038 NHEJ1 Zornitza Stark Publications for gene: NHEJ1 were set to 30898087; 30666249; 28741180; 25288157; 24511403; 21721379; 21535335
Mendeliome v1.2037 NHEJ1 Zornitza Stark edited their review of gene: NHEJ1: Added comment: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1.; Changed publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335, 37580330; Changed phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650, Microphthalmia/coloboma, MIM# 13 620968
Mendeliome v1.2037 FLVCR1 Bryony Thompson edited their review of gene: FLVCR1: Added comment: A study with 30 patients from 23 unrelated families with biallelic ultra-rare missense and predicted loss-of-function variants in FLVCR1 with a novel FLVCR1-related phenotype characterised by severe developmental disorders with profound developmental delay, microcephaly, brain malformations, epilepsy, spasticity, and premature death. Optic disk atrophy, limb and digital malformations, and macrocytic anaemia can be present.; Changed publications: 21070897, 22279524, 21267618, 39306721; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177, neurodevelopmental disorder MONDO:0700092, FLVCR1-related
Mendeliome v1.2037 RPL26 Sangavi Sivagnanasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: Diamond-Blackfan anemia MONDO:0015253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2037 LRRC7 Sangavi Sivagnanasundram gene: LRRC7 was added
gene: LRRC7 was added to Mendeliome. Sources: Other,Literature
Mode of inheritance for gene: LRRC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC7 were set to 39256359
Phenotypes for gene: LRRC7 were set to neurodevelopmental disorder (MONDO:0700092)
Review for gene: LRRC7 was set to GREEN
Added comment: Well established gene-disease association.
Neurodevelopmental disorder with a clinical spectrum - symptoms include ID, ADHD, aggression and in many cases, hyperphagia associate obesity.
Heterozygous missense and LoF variants have been reported and functional assays were conducted on missense and truncating variants that support LoF mechanism of disease.
Sources: Other, Literature
Mendeliome v1.2030 ATAD2B Ain Roesley gene: ATAD2B was added
gene: ATAD2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATAD2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD2B were set to 39313616
Phenotypes for gene: ATAD2B were set to neurodevelopmental disorder MONDO:0700092, ATAD2B-related
Review for gene: ATAD2B was set to AMBER
gene: ATAD2B was marked as current diagnostic
Added comment: 3 families including 2 siblings
1 fam is hom for a highly conserved missense

Amber because of the lack of specific phenotypes:
Abnormality of the nervous system and Abnormality of the eye
Sources: Literature
Mendeliome v1.2028 ZDHHC16 Ain Roesley gene: ZDHHC16 was added
gene: ZDHHC16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZDHHC16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZDHHC16 were set to 39313616
Phenotypes for gene: ZDHHC16 were set to neurodevelopmental disorder MONDO:0700092, ZDHHC16-related
Review for gene: ZDHHC16 was set to AMBER
gene: ZDHHC16 was marked as current diagnostic
Added comment: 6 families including a pair of siblings

Amber because 5 of the families had non specific phenotypes listed
Abnormality of:
the nervous system, metabolism/homeostasis, head/neck, immune system, the integument, the digestive system, the respiratory system, the endocrine system, Growth abnormality the skeletal system, the musculature, the eye

Specific HPOs were provided for one individual (homoyzygous for a canonical splice)

Abnormality of the face; Cerebellar hypoplasia; Developmental regression; Encephalopathy; Hyperreflexia; Hypertonia; Hypotonia; Inguinal hernia; Laryngomalacia; Microcephaly; Motor delay; Optic atrophy; Seizure; Spastic paraparesis; Spasticity; Talipes equinovarus; Umbilical hernia
Sources: Literature
Mendeliome v1.2026 KBTBD2 Ain Roesley gene: KBTBD2 was added
gene: KBTBD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to neurodevelopmental disorder MONDO:0700092, KBTBD2-related
Review for gene: KBTBD2 was set to GREEN
gene: KBTBD2 was marked as current diagnostic
Added comment: 3 families - 2 compound hets and 1 hom

phenotypes include:
Microcephaly, hypotonia, failure to thrive, IUGR, delayed gross motor development, dysmorphism
Sources: Literature
Mendeliome v1.2024 EPB41L3 Bryony Thompson gene: EPB41L3 was added
gene: EPB41L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities MONDO:0030063
Review for gene: EPB41L3 was set to GREEN
Added comment: 6 cases from 5 unrelated consanguineous families (2nd & 3rd degree) with homozygous LoF variants and a neurodevelopmental condition, including ID and seizures. Epb41l3 shRNA-mediated downregulation in mouse oligodendroglia demonstrated impaired oligodendrocyte function.
Sources: Literature
Mendeliome v1.2022 PSKH1 Zornitza Stark gene: PSKH1 was added
gene: PSKH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to 39132680
Phenotypes for gene: PSKH1 were set to Cholestasis, progressive familial intrahepatic, 13, MIM# 620962
Review for gene: PSKH1 was set to GREEN
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Mendeliome v1.2020 CIAO1 Zornitza Stark reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple mitochondrial dysfunctions syndrome 10, MIM#620960; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2018 JPH1 Zornitza Stark reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 25, MIM# 620964; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Added comment: Comment on list classification: Comment on list classification: ClinGen HCVD GCEP has classified this gene as Limited for HCM on 13/09/2023 - https://search.clinicalgenome.org/CCID:006034
Mendeliome v1.2015 DNAH6 Seb Lunke reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34215651; Phenotypes: situs inversus, MONDO:0010029, transposition of the great arteries, MONDO:0000153; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 PHKG2 Sangavi Sivagnanasundram reviewed gene: PHKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031; Phenotypes: glycogen storage disease IXc MONDO:0013091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2013 PIH1D3 Sangavi Sivagnanasundram reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 28176794, 32170493, 38051289, 33106461, 38408845, 33635866; Phenotypes: ciliary dyskinesia, primary, 36, X-linked MONDO:0010517; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2013 IFIH1 Sangavi Sivagnanasundram reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 24686847, 24995871, 25620204, 30219631, 31898846; Phenotypes: IFIH1-related type 1 interferonopathy MONDO:0700262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 IRF4 Sangavi Sivagnanasundram reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36662884, 36917008, 29537367, 29408330; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 AICDA Sangavi Sivagnanasundram reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22992148, 12910268, 14564357, 15893695, 32423680, 35570134, 17560278; Phenotypes: hyper-IgM syndrome type 2 MONDO:0011528; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2011 B2M Bryony Thompson reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693999, 37223323, 24014031, 35575118, 32875920; Phenotypes: variant ABeta2M amyloidosis MONDO:0017810; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2010 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Mendeliome v1.2009 PNKP Shakira Heerah reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899, 20118933, 23224214, 29243230, 2578773, 27066567; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay, Charcot-Marie-Tooth disease, type 2B2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1998 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Mendeliome v1.1998 CAPN3 Sangavi Sivagnanasundram reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: muscular dystrophy, limb-girdle, autosomal dominant MONDO:0015151, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1998 BVES Sangavi Sivagnanasundram reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1996 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Mendeliome v1.1992 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Mendeliome v1.1990 COQ8B Zornitza Stark Publications for gene: COQ8B were set to 24270420
Mendeliome v1.1983 SPARCL1 Zornitza Stark gene: SPARCL1 was added
gene: SPARCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPARCL1 were set to 39169229
Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102
Review for gene: SPARCL1 was set to RED
Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits.

WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease.

SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium.
Sources: Literature
Mendeliome v1.1980 NDUFA7 Zornitza Stark reviewed gene: NDUFA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 ABL1 Sangavi Sivagnanasundram reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39155385, 38743093; Phenotypes: Human ABL1 Deficiency Syndrome (HADS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 GMPPB Sangavi Sivagnanasundram reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27147698; Phenotypes: myopathy caused by variation in GMPPB MONDO:0700084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis.
Sources: Other
Mendeliome v1.1980 PNPLA8 Chirag Patel reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39082157; Phenotypes: PNPLA8-related neurological diseases; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1979 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to 20036350; 20512146
Mendeliome v1.1978 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296, Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram gene: JPH1 was added
gene: JPH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy MONDO:0019952
Review for gene: JPH1 was set to GREEN
Added comment: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1977 PLEC Zornitza Stark Publications for gene: PLEC were set to 22144912
Mendeliome v1.1976 PLEC Zornitza Stark reviewed gene: PLEC: Rating: AMBER; Mode of pathogenicity: None; Publications: 39168815; Phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1976 GBF1 Ain Roesley reviewed gene: GBF1: Rating: RED; Mode of pathogenicity: None; Publications: 39110251; Phenotypes: autosomal dominant cataract MONDO:0022672, GBF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 TLN1 Ain Roesley reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39163585; Phenotypes: idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 COQ8B Bryony Thompson reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39226897, 25967120; Phenotypes: Retinitis pigmentosa MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1975 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Mendeliome v1.1974 ATP6V1C1 Ain Roesley gene: ATP6V1C1 was added
gene: ATP6V1C1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V1C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1C1 were set to 39210597
Review for gene: ATP6V1C1 was set to AMBER
gene: ATP6V1C1 was marked as current diagnostic
Added comment: 1x de novo missense p.Glu289Lys (absent in v4 gnomad). Manual inspection of IGV found the dad was mosaic 7% VAF and he shared some of the clinical features (minor digit anomalies).

Some functional studies using patient fibroblasts were performed, demonstrating similar effects as known pathogenic variants in ATP6V1B2.
- lysosomal morphology
- autophagic flux dysregulation
- increased acidification of lysosome

borderline red/amber
Sources: Literature
Mendeliome v1.1972 PLEKHM2 Bryony Thompson gene: PLEKHM2 was added
gene: PLEKHM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842
Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: PLEKHM2 was set to AMBER
Added comment: 2 unrelated families reported with DCM and supporting functional evidence
PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue

PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family

PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts

PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models
Sources: Literature
Mendeliome v1.1970 FLT3LG Zornitza Stark reviewed gene: FLT3LG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 125, MIM# 620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1969 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1968 LRP1 Zornitza Stark Publications for gene: LRP1 were set to
Mendeliome v1.1965 LRP1 Zornitza Stark reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36067312; Phenotypes: Developmental dysplasia of the hip 3, MIM# 620690; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1964 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108
Mendeliome v1.1962 RAB32 Zornitza Stark reviewed gene: RAB32: Rating: AMBER; Mode of pathogenicity: None; Publications: 38858457; Phenotypes: {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1961 VPS52 Bryony Thompson gene: VPS52 was added
gene: VPS52 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VPS52 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VPS52 were set to complex neurodevelopmental disorder with or without congenital anomalies MONDO:0100465
Review for gene: VPS52 was set to AMBER
Added comment: HGSA poster (P110) from Louise Bicknell's group at the University of Otago. 11 cases from 8 families (USA, NZ, Saudi Arabia) with a broad syndromic developmental delay phenotype with biallelic variants (both missense & truncating).
Sources: Other
Mendeliome v1.1958 CFAP57 Zornitza Stark Publications for gene: CFAP57 were set to
Mendeliome v1.1956 CFAP57 Zornitza Stark edited their review of gene: CFAP57: Added comment: PMID 36752199: 5 individuals from three families reported with biallelic LoF variants (two homozygous variants) and spermatogenic failure. Mouse model recapitulated the phenotype.; Changed rating: GREEN; Changed publications: 21574244, 32764743, 36752199; Changed phenotypes: Spermatogenic failure 95, MIM# 620917, Van der Woude Syndrome, Primary ciliary dyskinesia
Mendeliome v1.1954 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 23623387; 17572665; 21705420; 24878229; 18758830; 24598713
Phenotypes for gene: FIG4 were set to Yunis-Varon syndrome - MIM#216340; Polymicrogyria with epilepsy MIM# 612691; Charcot-Marie-Tooth disease, type 4J 611228; Amyotrophic lateral sclerosis 11, MIM# 612577
Review for gene: FIG4 was set to GREEN
Added comment: Associations between biallelic variants and CMT and Yunis Varon syndrome are well established.

Limited evidence for association with brain malformations and with ALS/FTD.
Sources: Expert Review
Mendeliome v1.1953 CSNK1G1 Rylee Peters reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33009664; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1952 REXO2 Zornitza Stark gene: REXO2 was added
gene: REXO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REXO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: REXO2 were set to 39107301
Phenotypes for gene: REXO2 were set to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related
Review for gene: REXO2 was set to AMBER
Added comment: Female infant of Chinese ancestry, presented at 2 years of age with whole-body rash with histological features of hyperkeratosis, parakeratosis and acanthosis with elongated rete ridges, focal liquefaction and degeneration of the basal layers of epidermis, vascular proliferation in the superficial dermis, infiltration of lymphocytes and eosinophils around small blood vessels in the dermis. She has recurrent infections (frequent and severe pneumonia). Extensive functional validation demonstrating heterozygous de novo mutation (p.T132A) impairs REXO2’s ability to cleave RNA leading to activation of the dsRNA sensor MDA5 leading to a Type 1 interferonopathy.
Sources: Literature
Mendeliome v1.1950 TMEFF1 Zornitza Stark gene: TMEFF1 was added
gene: TMEFF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEFF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEFF1 were set to 39048830
Phenotypes for gene: TMEFF1 were set to Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; HSV encephalitis
Review for gene: TMEFF1 was set to GREEN
Added comment: 2 unrelated patients with severe HSV encephalitis. Functional validation showing that human TMEFF1 encodes a type I IFN-independent, cortical neuron- and CNS-intrinsic restriction factor that is effective against HSV-1 that operates by impairing the entry of HSV-1 into cortical neurons.
Sources: Literature
Mendeliome v1.1948 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID:38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families identified through exome sequencing and subsequent gene-sharing efforts with biallelic missense CSMD1 variants. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs).

ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Mendeliome v1.1946 ZSCAN10 Zornitza Stark reviewed gene: ZSCAN10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Otofacial neurodevelopmental syndrome, MIM# 620910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1946 ACOX2 Zornitza Stark Publications for gene: ACOX2 were set to 27647924; 27884763
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.; to: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype; have calciuria. Likely polygenic susceptibility rather than Mendelian disorder.
Mendeliome v1.1943 ACOX2 Sangavi Sivagnanasundram reviewed gene: ACOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27647924, 27884763, 35395098; Phenotypes: congenital bile acid synthesis defect 6 MONDO:0015015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1943 PRPF4 Sangavi Sivagnanasundram reviewed gene: PRPF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24419317; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: None
Mendeliome v1.1942 FZD6 Zornitza Stark Publications for gene: FZD6 were set to 21665003; 23374899
Mendeliome v1.1941 FZD6 Zornitza Stark changed review comment from: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; to: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops. AMBER for this indication.
Mendeliome v1.1941 FZD6 Zornitza Stark edited their review of gene: FZD6: Added comment: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; Changed publications: 21665003, 23374899, 33082562, 26036949, 28425981
Mendeliome v1.1941 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350
Mendeliome v1.1939 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed publications: 24515783, 23687350, 36669495
Mendeliome v1.1936 C17orf53 Zornitza Stark edited their review of gene: C17orf53: Added comment: PMID 38105698: Additional family reported with two sibs and compound het LoF variants.

HGNC approved name is HROB.; Changed rating: GREEN; Changed publications: 34707299, 31467087, 38105698; Changed phenotypes: Ovarian dysgenesis 11, MIM# 620897
Mendeliome v1.1934 RINT1 Zornitza Stark Publications for gene: RINT1 were set to PMID: 31204009
Mendeliome v1.1933 RINT1 Zornitza Stark reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37463447, 38990652; Phenotypes: Hereditary spastic paraplegia, MONDO:0019064, RINT1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1932 HDAC3 Zornitza Stark gene: HDAC3 was added
gene: HDAC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HDAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HDAC3 were set to 39047730
Phenotypes for gene: HDAC3 were set to Neurodevelopmental disorder, MONDO:0700092, HDAC3-related
Review for gene: HDAC3 was set to GREEN
Added comment: Six individuals with de novo missense variants in this gene and variable NDD phenotypes, including ID, seizures. Supportive functional data.
Sources: Literature
Mendeliome v1.1930 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214; 24627108
Mendeliome v1.1928 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Changed publications: 32949214, 24627108, 36302985; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111, Combined immunodeficiency, MONDO:0015131, ITPR3-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1927 UNC93B1 Zornitza Stark Publications for gene: UNC93B1 were set to 16973841; 29768176
Mendeliome v1.1924 UNC93B1 Zornitza Stark edited their review of gene: UNC93B1: Added comment: PMID 38869500: Rare missense substitutions in UNC93B1 in probands from five unrelated kindreds presenting with early onset SLE (two probands) or CBL (three probands). Clinical, genetic, and functional in vitro and ex vivo data demonstrating changes in TLR7/8 signalling and trafficking.; Changed rating: GREEN; Changed publications: 29768176, 38869500; Changed phenotypes: Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 1, Autoinflammatory syndrome, MONDO:0019751, UNC93B1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1924 CD274 Zornitza Stark gene: CD274 was added
gene: CD274 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CD274 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD274 were set to 38634869
Phenotypes for gene: CD274 were set to Immune dysregulation, autoimmunity and auto inflammation, MONDO:0957790
Review for gene: CD274 was set to AMBER
Added comment: Two siblings, born to second-degree consanguineous parents of Moroccan descent, both developed neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk, respectively). One sibling was subsequently diagnosed with asthma at the age of 5 mo, auto-immune hypothyroidism at the age of 3 years, and growth hormone (GH) deficiency at the age of 10 years. He also had mild intellectual disability with delayed language development. By contrast, his sister had no clinical manifestations other than T1D.

Homozygous for splicing variant. This is the ligand of PD1, deficiency of which is also linked to immune dysregulation. Functional data.
Sources: Literature
Mendeliome v1.1922 OAS2 Zornitza Stark gene: OAS2 was added
gene: OAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OAS2 were set to 36538032
Phenotypes for gene: OAS2 were set to Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related
Review for gene: OAS2 was set to GREEN
Added comment: 3x unrelated patients with MIS-C after COVID infection. Patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C. Similar presentation to OAS1 and RNASEL. Functional data.
Sources: Literature
Mendeliome v1.1920 NFATC2 Zornitza Stark Publications for gene: NFATC2 were set to 35789258
Mendeliome v1.1919 NFATC2 Zornitza Stark reviewed gene: NFATC2: Rating: RED; Mode of pathogenicity: None; Publications: 38427060; Phenotypes: Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1918 IKBKE Zornitza Stark gene: IKBKE was added
gene: IKBKE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IKBKE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKBKE were set to 37937644
Phenotypes for gene: IKBKE were set to Encephalitis, acute, infection-induced, susceptibility to, MONDO:0800174, IKBKE-related
Review for gene: IKBKE was set to AMBER
Added comment: Single patient with recurrent HSV meningitis with supportive functional data.
Sources: Literature
Mendeliome v1.1917 SYCP2L Zornitza Stark Publications for gene: SYCP2L were set to 32303603
Mendeliome v1.1915 SYCP2L Zornitza Stark reviewed gene: SYCP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 38521400; Phenotypes: Premature ovarian failure 24, MIM# 620840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1912 PCBP2 Ain Roesley gene: PCBP2 was added
gene: PCBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCBP2 were set to 38965372
Phenotypes for gene: PCBP2 were set to neurodevelopmental disorder MONDO:0700092, PCBP2-related
Review for gene: PCBP2 was set to GREEN
gene: PCBP2 was marked as current diagnostic
Added comment: 3x individuals with de novo variants
Motor and speech delay and ASD
2x missense + 1x fs

There are 2 NMD variants with 9 and 8 hets respectively in gnomad v4, however the IGV looks to be low quality
Sources: Literature
Mendeliome v1.1910 LEO1 Ain Roesley gene: LEO1 was added
gene: LEO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LEO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEO1 were set to 38965372
Phenotypes for gene: LEO1 were set to neurodevelopmental disorder MONDO:0700092, LEO-1 related
Review for gene: LEO1 was set to AMBER
gene: LEO1 was marked as current diagnostic
Added comment: enrichment of a neurodev cohort
LEO1:
8x de novo – 6x missense + 2x PTC
1x pat splice
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature
Mendeliome v1.1908 KCNJ10 Zornitza Stark Publications for gene: KCNJ10 were set to 19289823; 19420365; 21849804; 11466414
Mendeliome v1.1906 KCNJ10 Zornitza Stark edited their review of gene: KCNJ10: Added comment: PMID 38979912: 11 individuals from 8 unrelated families reported with variants in this gene and paroxysmal dyskinesia. Notably one was the parent of a child with recessive SeSAME syndrome (established gene-disease association). Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes.; Changed publications: 19289823, 19420365, 21849804, 11466414, 38979912; Changed phenotypes: SESAME syndrome, MIM# 612780, Paroxysmal dyskinesia, MONDO:0015427, KCNJ10-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1906 SLC45A1 Zornitza Stark Publications for gene: SLC45A1 were set to 28434495
Mendeliome v1.1904 SLC45A1 Zornitza Stark edited their review of gene: SLC45A1: Added comment: PMID 39003656: additional individual with compound het missense variants and supportive functional data.; Changed rating: GREEN; Changed publications: 28434495, 39003656
Mendeliome v1.1903 HBS1L Bryony Thompson gene: HBS1L was added
gene: HBS1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HBS1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HBS1L were set to 38966981; 24288412; 30707697
Phenotypes for gene: HBS1L were set to Retinal disorder MONDO:0005283
Review for gene: HBS1L was set to AMBER
Added comment: A single case with biallelic variants reported with retinal dystrophy, poor growth and neurodevelopmental delay (originally reported in 2013). A hypomorph mouse model demonstrated defective development of photoreceptor cells.
Sources: Literature
Mendeliome v1.1901 SRPK3 Zornitza Stark Publications for gene: SRPK3 were set to 38429495
Mendeliome v1.1900 SRPK3 Zornitza Stark edited their review of gene: SRPK3: Added comment: PMID 39073169: 9 individuals from 5 unrelated families reported with 4 missense and 1 putative truncating variant and a neurodevelopmental phenotype. The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Supportive animal model data (mouse and zebrafish).; Changed publications: 38429495, 39073169
Mendeliome v1.1899 NDC1 Bryony Thompson gene: NDC1 was added
gene: NDC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDC1 were set to 39003500; 19782045
Phenotypes for gene: NDC1 were set to triple-A syndrome MONDO:0009279
Review for gene: NDC1 was set to GREEN
Added comment: 7 cases from 4 consanguineous families (3 different variants: 1 intronic variants that causes in-frame RNA splice impact, 2 missense) with a Triple-A-like syndrome (including ID and neuropathy). Supporting cellular localisation studies were conducted in patient cell lines with the splice variant. NDC1 is required to anchor ALADIN (encoded by AAAS, the gene that causes Triple-A syndrome) in the nuclear pore complex.
Sources: Literature
Mendeliome v1.1897 OPDM_ABCD3_GCC Bryony Thompson STR: OPDM_ABCD3_GCC was added
STR: OPDM_ABCD3_GCC was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: OPDM_ABCD3_GCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: OPDM_ABCD3_GCC were set to 39068203
Phenotypes for STR: OPDM_ABCD3_GCC were set to Oculopharyngodistal myopathy MONDO:0025193
Review for STR: OPDM_ABCD3_GCC was set to GREEN
STR: OPDM_ABCD3_GCC was marked as clinically relevant
Added comment: 35 OPDM individuals from 8 unrelated families from Australia, the UK, and France with an ABCD3 5’UTR CGG repeat. Affected individuals had repeat expansions ranging from 118-694 (n=19). 7 repeats is the median repeat size in non-neurological controls from the GE 100,000 Genome Project. 10 controls had estimated repeats >50, up to ~93. 50 repeats would be a safe cut-off for normal
Sources: Literature
Mendeliome v1.1895 RBBP5 Ain Roesley gene: RBBP5 was added
gene: RBBP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBBP5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBBP5 were set to 39036895
Phenotypes for gene: RBBP5 were set to neurodevelopmental disorder MONDO:0700092, RBBP5-related
Review for gene: RBBP5 was set to GREEN
gene: RBBP5 was marked as current diagnostic
Added comment: 5 individuals with de novo variants - 3x PTCs + 2x missense

2/5 short stature (> 3SD; 2x >=-2SD)
1/5 microcephaly (> 3SD; 3x >=-2SD)
4/5 dev delay/ID
2/5 SNHL
2/5 Seizures
3/5 hypotonia
Sources: Literature
Mendeliome v1.1894 BBS4 Andrew Coventry reviewed gene: BBS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11381270 12016587 10874630; Phenotypes: Bardet-Biedl syndrome 4 MIM#615982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1894 LDB3 Bryony Thompson Added comment: Comment on list classification: Monoallelic DCM association is still Amber
Mendeliome v1.1892 LDB3 Bryony Thompson reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36253531, 32922198; Phenotypes: dilated cardiomyopathy MONDO:0005021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1891 SNUPN Zornitza Stark reviewed gene: SNUPN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 29, MIM# 620793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1890 DCC Zornitza Stark Publications for gene: DCC were set to 20431009; 31697046; 21242494; 28250454; 28250456; 25763452
Mendeliome v1.1888 SLC7A5 Sangavi Sivagnanasundram gene: SLC7A5 was added
gene: SLC7A5 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SLC7A5 was set to Unknown
Publications for gene: SLC7A5 were set to 29884839
Phenotypes for gene: SLC7A5 were set to Large neutral amino acid transporter deficiency (MIM#600182)
Review for gene: SLC7A5 was set to RED
Added comment: Classified an inborn error of amino acid metabolism by IEMbase however more evidence is required to support the gene-disease association.
Sources: Other
Mendeliome v1.1886 ZNF483 Mark Cleghorn gene: ZNF483 was added
gene: ZNF483 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF483 was set to Unknown
Publications for gene: ZNF483 were set to 38951643
Phenotypes for gene: ZNF483 were set to primary ovarian failure MONDO:0005387
Review for gene: ZNF483 was set to AMBER
Added comment: PMID: 38951643, ESHG 2024 presentation
Large cohort assessing PRS for age of menarche
Noted rare PTVs in ZNF483 assoc w earlier menarche
No individual case information in this study
Sources: Literature
Mendeliome v1.1886 DDOST Achchuthan Shanmugasundram reviewed gene: DDOST: Rating: GREEN; Mode of pathogenicity: None; Publications: 34462534; Phenotypes: Congenital disorder of glycosylation, type Ir, OMIM:614507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1886 SENP7 Zornitza Stark Publications for gene: SENP7 were set to PMID: 37460201
Mendeliome v1.1884 SENP7 Zornitza Stark reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38972567, 37460201; Phenotypes: Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1883 MYZAP Zornitza Stark gene: MYZAP was added
gene: MYZAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYZAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYZAP were set to 34899865; 35840178; 38436102; 20093627
Phenotypes for gene: MYZAP were set to Cardiomyopathy, dilated, 2K, MIM# 620894
Review for gene: MYZAP was set to GREEN
Added comment: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. Note the MYZAP and GCOM1 genes are part of the GRINL1A complex transcription unit. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly.
Sources: Literature
Mendeliome v1.1880 RNU4-2 Zornitza Stark Publications for gene: RNU4-2 were set to 38645094
Mendeliome v1.1879 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Changed publications: 38991538
Mendeliome v1.1878 FDXR Zornitza Stark Publications for gene: FDXR were set to 30250212; 28965846
Mendeliome v1.1877 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Multiple reports of individuals with extra-ocular features, including ID and regression.; Changed publications: 30250212, 28965846, 29040572, 33348459, 37046037, 37481223; Changed phenotypes: Auditory neuropathy and optic atrophy, MIM#617717, Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887
Mendeliome v1.1876 SELENBP1 Sangavi Sivagnanasundram gene: SELENBP1 was added
gene: SELENBP1 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: SELENBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SELENBP1 were set to 29255262
Phenotypes for gene: SELENBP1 were set to extraoral halitosis due to methanethiol oxidase deficiency MONDO:0029144
Review for gene: SELENBP1 was set to GREEN
Added comment: 3 unrelated probands in one publication. All reported individuals had a “cabbage-like” breath odour due to the elevated levels of methanethiol and dimethylsulfide in their breath.
Knockout mouse model recapitulating the human phenotype including the biochemical characteristics.

Classified as Moderate by ClinGen Aminoacidopathy GCEP on 11/11/2022
https://search.clinicalgenome.org/CCID:006103
Sources: ClinGen
Mendeliome v1.1876 PRODH2 Sangavi Sivagnanasundram gene: PRODH2 was added
gene: PRODH2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: PRODH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRODH2 were set to 27139199
Phenotypes for gene: PRODH2 were set to hydroxyprolinemia MONDO:0009374
Review for gene: PRODH2 was set to RED
Added comment: PMID: 27139199
Variants reported in 6 individuals however only 2 cases presented with intermittant biochemical phenotype however the cause remains unclear. The rest of the individuals were asymptomatic suggesting that hydroxyprolinemia is a benign condition.

Classified as Limited by ClinGen Aminoacidopathy GCEP on 12/12/2022
https://search.clinicalgenome.org/CCID:005893
Sources: ClinGen
Mendeliome v1.1875 GAS2 Zornitza Stark gene: GAS2 was added
gene: GAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAS2 were set to 33964205
Phenotypes for gene: GAS2 were set to Deafness, autosomal recessive 125, MIM#620877
Review for gene: GAS2 was set to AMBER
Added comment: Single family reported with four affected brothers and a splicing variant. Supportive mouse model.
Sources: Literature
Mendeliome v1.1872 SREBF2 Zornitza Stark gene: SREBF2 was added
gene: SREBF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREBF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF2 were set to 38847193
Phenotypes for gene: SREBF2 were set to Neurocutaneous syndrome, MONDO:0042983, SREBF2-related
Review for gene: SREBF2 was set to AMBER
Added comment: Two individuals with de novo missense variants, presenting with neurological, cutaneous and skeletal features; supportive functional data.
Sources: Literature
Mendeliome v1.1868 PSMC5 Zornitza Stark Publications for gene: PSMC5 were set to 33057194
Mendeliome v1.1865 PSMF1 Zornitza Stark gene: PSMF1 was added
gene: PSMF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1
Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related
Review for gene: PSMF1 was set to GREEN
Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data.
Sources: Literature
Mendeliome v1.1863 POLD3 Zornitza Stark Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Mendeliome v1.1861 POLD3 Zornitza Stark reviewed gene: POLD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38099988; Phenotypes: Immunodeficiency 122, MIM# 620869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1860 TUBA4A Bryony Thompson reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 38884572, 37418012; Phenotypes: Hereditary ataxia MONDO:0100309, TUBA4A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1860 PSMC5 Rylee Peters reviewed gene: PSMC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38776958, 38293138; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), PSMC5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1859 SERPINA11 Ain Roesley gene: SERPINA11 was added
gene: SERPINA11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINA11 were set to 38831697
Review for gene: SERPINA11 was set to RED
gene: SERPINA11 was marked as current diagnostic
Added comment: 1 family with 2 fetuses.

1st fetus presented with isolated pericardial effusion and a TOP was opted.
post mortem:
mild subcutaneous edema with subtle facial dysmorphic features
small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces

2nd fetus also presented with pleural and pericardial effusion and a TOP was opted
post mortem findings were similar to fetus#1

homozygous nonsense variant in SERPINA11 was found p.(Tyr224*)

Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium
Sources: Literature
Mendeliome v1.1857 PSMD11 Bryony Thompson gene: PSMD11 was added
gene: PSMD11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMD11 were set to 38866022; 30733659
Phenotypes for gene: PSMD11 were set to Neurodevelopmental disorder, MONDO:0700092, PSMD11-related
Review for gene: PSMD11 was set to GREEN
Added comment: PMID: 38866022 - 10 unrelated children with early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity. Cognitive impairment is recapitulated in a drosophila model. Loss of function is the mechanism of disease

PMID: 30733659 - 4 probands with ID and different 17q11.2 deletions spanning PSMD11
Sources: Literature
Mendeliome v1.1855 VPS50 Ain Roesley reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis MIM#619685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1855 C10orf71 Sangavi Sivagnanasundram gene: C10orf71 was added
gene: C10orf71 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: C10orf71 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: C10orf71 were set to 38950288
Phenotypes for gene: C10orf71 were set to dilated cardiomyopathy MONDO:0005021
Review for gene: C10orf71 was set to GREEN
Added comment: Identified a frameshift variant in a large multigenerational family with 8 affected individuals.
Further identified four other loss of function variants in a large Chinese cohort of sporadic DCM cases. >50 unrelated individuals identified with loss of function variants.

c10orf71-Knockout mouse model recapitulating DCM human phenotype (impairs cardiac function) in the presence of the frameshift variant.
Sources: Other
Mendeliome v1.1855 PAK2 Ain Roesley Publications for gene: PAK2 were set to 33693784
Mendeliome v1.1853 PAK2 Ain Roesley reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38894571, 38712026; Phenotypes: Knobloch syndrome 2 MIM#618458; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1853 USP25 Sangavi Sivagnanasundram gene: USP25 was added
gene: USP25 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: USP25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP25 were set to 38875478
Phenotypes for gene: USP25 were set to USP25-related epilepsy (epilepsy, idiopathic generalized, MONDO:0005579)
Mode of pathogenicity for gene: USP25 was set to Other
Review for gene: USP25 was set to GREEN
Added comment: PMID: 38875478
5 heterozygous variants were identified in 8 individuals from 5 unrelated families all with clinical phenotypes associated with generalised epilepsy.

Knock-out mouse model showed increased seizure susceptibility compared to the WT.
Both loss of function and gain of function variants can be a mechanism of disease in individuals with USP25-related epilepsy.
Sources: Other
Mendeliome v1.1851 RBFOX3 Zornitza Stark gene: RBFOX3 was added
gene: RBFOX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBFOX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX3 were set to 35951651; 36117209; 24039908
Phenotypes for gene: RBFOX3 were set to Neurodevelopmental disorder (MONDO:0700092), RBFOX3-related
Review for gene: RBFOX3 was set to AMBER
Added comment: Reported as a candidate gene for epilepsy, particularly Rolandic epilepsy. Two supportive animal models.
Sources: Literature
Mendeliome v1.1850 GRXCR2 Zornitza Stark Publications for gene: GRXCR2 were set to 24619944
Mendeliome v1.1847 GRXCR2 Zornitza Stark edited their review of gene: GRXCR2: Added comment: PMID:33528103 reported another family and an unrelated individual from Cameroon with a different homozygous variant (c.251delC/ p.Ile85SerfsTer33).; Changed rating: GREEN; Changed publications: 24619944, 33528103
Mendeliome v1.1840 THRB Achchuthan Shanmugasundram reviewed gene: THRB: Rating: AMBER; Mode of pathogenicity: None; Publications: 37547476; Phenotypes: inherited retinal dystrophy, MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1840 SUMF1 Achchuthan Shanmugasundram reviewed gene: SUMF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38863195; Phenotypes: inherited retinal dystrophy, MONDO:0019118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. ; to: Craniosynostosis (MONDO:0015469), PRRX1-related
> 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

Agnathia-otocephaly complex, MIM# 202650
>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures.
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures.
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.
Mendeliome v1.1840 PRRX1 Melanie Marty reviewed gene: PRRX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37154149, 28366454, 34376651; Phenotypes: Craniosynostosis (MONDO:0015469), PRRX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1838 RDH14 Zornitza Stark gene: RDH14 was added
gene: RDH14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RDH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH14 were set to 34848785
Phenotypes for gene: RDH14 were set to Neurodevelopmental disorder, MONDO:0700092, RDH14-related
Review for gene: RDH14 was set to RED
Added comment: Two related individuals with ID and cerebellar atrophy and homozygous LoF variant reported.
Sources: Literature
Mendeliome v1.1837 HYKK Zornitza Stark gene: HYKK was added
gene: HYKK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYKK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYKK were set to 23242558
Phenotypes for gene: HYKK were set to inborn disorder of lysine and hydroxylysine metabolism MONDO:0017351
Review for gene: HYKK was set to RED
Added comment: No known gene-disease association as classified by ClinGen Aminoacidopathy GCEP on 14/07/2023 - https://search.clinicalgenome.org/CCID:005104 HYKK has been reported as a disorders of lysine, hydroxylysine, and tryptophan metabolism by ICIMD however there are no reported pathogenic variants in this gene to support the gene-disease association.
Sources: Literature
Mendeliome v1.1836 KMO Zornitza Stark gene: KMO was added
gene: KMO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KMO were set to 28187857; 24189070
Phenotypes for gene: KMO were set to pellagra MONDO:0019975
Review for gene: KMO was set to RED
Added comment: Classified as no known disease relationship by ClinGen Aminoacidopathy GCEP on 12/05/2023 - https://search.clinicalgenome.org/CCID:005248 Only two knock out mouse models have ben reported that exhibited behavioural changes including memory impairment and anxiety like behaviour. Not reported as disease causing in any affected individuals at this stage and no evidence of any inborn errors of amino acid metabolism.
Sources: Literature
Mendeliome v1.1834 FUZ Zornitza Stark Publications for gene: FUZ were set to 21840926
Mendeliome v1.1832 STK33 Zornitza Stark gene: STK33 was added
gene: STK33 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STK33 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK33 were set to 34155512; 29155043
Phenotypes for gene: STK33 were set to Spermatogenic failure 93, MIM#620849
Review for gene: STK33 was set to RED
Added comment: Four brothers with a homozygous variant and an animal model.
Sources: Literature
Mendeliome v1.1831 NAT6 Zornitza Stark gene: NAT6 was added
gene: NAT6 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: NAT6.
Mode of inheritance for gene: NAT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAT6 were set to 34805998
Phenotypes for gene: NAT6 were set to Auroneurodental syndrome, MIM# 620830
Review for gene: NAT6 was set to RED
Added comment: Case report of two brothers with homozygous missense variant and deafness, periodic hypotonia and dental anomalies.

HGNC approved name is NAA80.
Sources: Literature
Mendeliome v1.1827 MSL2 Zornitza Stark Publications for gene: MSL2 were set to 31332282; 33057194
Mendeliome v1.1824 HGF Zornitza Stark Publications for gene: HGF were set to 19576567
Mendeliome v1.1822 HGF Zornitza Stark edited their review of gene: HGF: Added comment: More than 10 families reported with childhood- to late-onset lymphoedema.; Changed publications: 19576567, 38676400, 38791500; Changed phenotypes: Deafness, autosomal recessive 39, MIM# 608265, Lymphoedema, MONDO:0019297, HGF-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1822 TKFC Zornitza Stark Phenotypes for gene: TKFC were changed from Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Inborn error of immunity, MONDO:0003778, TKFC-related
Mendeliome v1.1821 TKFC Zornitza Stark edited their review of gene: TKFC: Added comment: Single individual reported with homozygous variant and isolated immunodeficiency.; Changed publications: 32004446'38697782; Changed phenotypes: Triokinase and FMN cyclase deficiency syndrome, MIM#618805, Inborn error of immunity, MONDO:0003778, TKFC-related
Mendeliome v1.1819 FLT3LG Ain Roesley gene: FLT3LG was added
gene: FLT3LG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FLT3LG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLT3LG were set to 38701783
Phenotypes for gene: FLT3LG were set to Increased susceptibility to infections
Review for gene: FLT3LG was set to RED
gene: FLT3LG was marked as current diagnostic
Added comment: 3x sibs from a consanguineous family with a homozygous frameshift variant p.(Ser118Alafs*23)
recurrent infections and hypoplastic bone marrow with marked reduction in HPSCs
KO mice recapitulated BM findings

over a period of 5 (P1), 9 (P2), and 19 (P3) years of follow-up, all 3 were found to have moderate anaemia.
Total platelet counts and morphology decreased in 2 siblings.
Total WBC oscillated between low and normal
Eosinophils, basophils were in normal range
Neutrophils were in the lower part of the control range, ocassiannly lower
total lymphocyte counts were normal
Sources: Literature
Mendeliome v1.1818 TIE1 Ain Roesley Publications for gene: TIE1 were set to 32947856; 24764452
Mendeliome v1.1817 TIE1 Ain Roesley reviewed gene: TIE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38820174; Phenotypes: Lymphatic malformation 11, MIM# 619401; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1817 MSL2 Sangavi Sivagnanasundram reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38815585, 38702431; Phenotypes: MSL2-Related Developmental Disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1817 PISD Sangavi Sivagnanasundram reviewed gene: PISD: Rating: GREEN; Mode of pathogenicity: None; Publications: 38801004; Phenotypes: Liberfarb syndrome MONDO:0030045; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1816 ATXN7L3 Chirag Patel gene: ATXN7L3 was added
gene: ATXN7L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN7L3 were set to PMID: 38753057
Phenotypes for gene: ATXN7L3 were set to Neurodevelopmental disorder, MONDO_0100500
Review for gene: ATXN7L3 was set to GREEN
gene: ATXN7L3 was marked as current diagnostic
Added comment: This study reports 9 unrelated individuals with de novo heterozygous variants in ATXN7L3 identified through WES testing and GeneMatcher. Core clinical features included: global motor and language developmental delay, hypotonia, and dysmorphic features (hypertelorism, epicanthal folds, blepharoptosis, small nose, small mouth, and low-set posteriorly rotated ears). Variable features included: feeding difficulties, seizures, mild periventricular leukomalacia, and structural cardiac abnormalities.

A recurrent nonsense variant [p.(Arg114Ter)] was found in 5/9 individuals. The other variants were 1 frameshift [p.(Ser112LysfsTer12)] and 3 missense variants [p.(Ile71Thr), p.(Ser92Arg), and p.(Leu106Pro)]. They investigated the effects of the recurrent nonsense variant [p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired (as indicated by an increase in histone H2Bub1 levels). This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality.

Pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).
Sources: Literature
Mendeliome v1.1814 FAM177A1 Chirag Patel gene: FAM177A1 was added
gene: FAM177A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM177A1 were set to PMID: 38767059, 25558065
Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder, MONDO_0100500
Review for gene: FAM177A1 was set to GREEN
gene: FAM177A1 was marked as current diagnostic
Added comment: PMID: 38767059
5 individuals from 3 unrelated families reported with with biallelic loss of function variants in FAM177A1. Clinical features included: global developmental delay, intellectual disability, seizures, behavioural abnormalities, hypotonia, gait disturbance, and macrocephaly.

They showed that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.

PMID: 25558065
A study of 143 multiplex consanguineous families identified a homozygous frameshift variant in FAM177A1 in 1 family with 4 affected siblings with intellectual disability, dolicocephaly, obesity, and macrocephaly. The variant segregated with all 4 affected siblings and parents were confirmed heterozygous carriers.
Sources: Literature
Mendeliome v1.1813 ERF Chirag Patel reviewed gene: ERF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38824261; Phenotypes: Noonan syndrome-like with or without craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1813 SLC6A1 Sangavi Sivagnanasundram reviewed gene: SLC6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38781976; Phenotypes: myoclonic-atonic epilepsy MONDO:0014633; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1811 FUZ Chirag Patel reviewed gene: FUZ: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38702430, 29068549, 34719684; Phenotypes: Ciliopathy_MONDO_0005308, skeletal ciliopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1810 ANO4 Ain Roesley gene: ANO4 was added
gene: ANO4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANO4 were set to 38744284
Phenotypes for gene: ANO4 were set to neurodevelopmental disorder MONDO:0700092, ANO4-related
Review for gene: ANO4 was set to GREEN
gene: ANO4 was marked as current diagnostic
Added comment: aka TMEM16D

5x de novo + 2x inherited missense (73% penetrance + asymptomatic)

the ones with de novo variants:
all had ID, hypotonia
4x skeletal features (scoliosis, funnel chest, pet plants, hyper extensible joints)

all had epilepsy
all had abnormal MRI
Sources: Literature
Mendeliome v1.1808 KCND1 Ain Roesley gene: KCND1 was added
gene: KCND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCND1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: KCND1 were set to 38772379
Phenotypes for gene: KCND1 were set to neurodevelopmental disorder MONDO:0700092, KCND1-related
Review for gene: KCND1 was set to GREEN
gene: KCND1 was marked as current diagnostic
Added comment: 18 males from 17 families
2x de novo missense + 3x maternal NMDs + 12x maternal missense
Some functional studies were done

14x ID
4x delayed motor dev
7x muscular hypotonia
6x epilepsy
Sources: Literature
Mendeliome v1.1807 PPFIA3 Zornitza Stark Publications for gene: PPFIA3 were set to 37034625
Mendeliome v1.1806 PPFIA3 Zornitza Stark edited their review of gene: PPFIA3: Changed publications: 38723631
Mendeliome v1.1805 LRRC23 Zornitza Stark Publications for gene: LRRC23 were set to 37804054
Mendeliome v1.1803 LRRC23 Zornitza Stark reviewed gene: LRRC23: Rating: AMBER; Mode of pathogenicity: None; Publications: 38091523; Phenotypes: Spermatogenic failure 92, MIM# 620848; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1799 GABRA4 Zornitza Stark Publications for gene: GABRA4 were set to 35152403
Mendeliome v1.1797 GABRA4 Zornitza Stark edited their review of gene: GABRA4: Added comment: Three more novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile) reported.

The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells.

Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4).; Changed rating: GREEN; Changed publications: 35152403, 38565639; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, GABRA4-related
Mendeliome v1.1796 CCIN Zornitza Stark reviewed gene: CCIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 91, MIM# 620838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1796 DGCR8 Andrew Fennell reviewed gene: DGCR8: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 34821987; Phenotypes: Early-onset multinodular goiter and schwannomatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1794 LIG4 Santosh Varughese reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 11779494, 16088910, 15333585, 20133615; Phenotypes: LIG4 syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1792 RBBP8 Zornitza Stark Publications for gene: RBBP8 were set to 21998596
Mendeliome v1.1791 RBBP8 Zornitza Stark edited their review of gene: RBBP8: Added comment: Additional family reported with Jawad syndrome: prev reported founder variant, multi-generational family, abnormal splicing demonstrated.; Changed rating: GREEN; Changed publications: 34270086; Changed phenotypes: Jawad syndrome, MIM# 251255; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1790 ZNF41 Zornitza Stark gene: ZNF41 was added
gene: ZNF41 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: ZNF41.
Mode of inheritance for gene: ZNF41 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZNF41 were set to 14628291; 23871722
Phenotypes for gene: ZNF41 were set to non-syndromic X-linked intellectual disability MONDO:0019181
Review for gene: ZNF41 was set to RED
Added comment: DISPUTED by ClinGen.

Shoichet et al. (2003) described a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21) in whom they cloned the DNA fragment that contained the X chromosomal and the autosomal breakpoint. In silico sequence analysis demonstrated that the ZNF41 gene was disrupted. Expression studies indicated that ZNF41 transcripts were absent in the patient cell line, suggesting that the mental disorder in this patient resulted from loss of functional ZNF41. Screening of patients with mental retardation led to the identification of 2 other ZNF41 mutations that were not found in healthy control individuals. Based on their finding of the mutations in ZNF41 identified by Shoichet et al. (2003) in a total of 7 males in the NHLBI Exome Variant Server, and the additional finding of truncating ZNF41 variants in 1 male and 1 female in that database, Piton et al. (2013) classified the involvement of ZNF41 in mental retardation as highly questionable.
Sources: Expert Review
Mendeliome v1.1789 RBBP8 James The reviewed gene: RBBP8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:30561437, 34270086, 32379725; Phenotypes: Jawad syndrome, Pancreatic carcinoma, somatic, Seckel syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1787 AGTR2 Zornitza Stark changed review comment from: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review; to: DISPUTED by ClinGen:

Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1787 AGTR2 Zornitza Stark gene: AGTR2 was added
gene: AGTR2 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: AGTR2.
Mode of inheritance for gene: AGTR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: AGTR2 were set to X-linked complex neurodevelopmental disorder MONDO:0100148
Review for gene: AGTR2 was set to RED
Added comment: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1786 AVPR1A Zornitza Stark gene: AVPR1A was added
gene: AVPR1A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: AVPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AVPR1A were set to 24924430
Phenotypes for gene: AVPR1A were set to Autism spectrum disorder MONDO:0005258
Review for gene: AVPR1A was set to RED
Added comment: DISPUTED by ClinGen:

The Arginine Vasopressin Receptor 1A (AVPR1A) was considered a candidate gene in autism spectrum disorder (ASD) based on reports focused on linkage intervals and animal models. Additionally, experimental evidence showed that AVPR1A is possibly involved in social behaviors, including affiliation and attachment (PMID: 24924430). However, these association studies were underpowered—sequencing more individuals may have identified variants of functional significance. In two studies, transmission disequilibrium between AVPR1A microsatellites and autism were found but most were not statistically significant (PMID: 12082568, 16520824). In another study, investigators screened AVPR1A exons in 125 independent autistic probands (PMID: 15098001). However, the study did not demonstrate a disease-causing variant in the coding sequence, and the authors noted that differences in AVPR1A at the amino-acid level are unlikely to confer genetic vulnerability to autism. Experimental evidence is available, but, in the absence of human genetic evidence, such data were not utilized in the scoring. In summary, there is no valid genetic evidence to support an association between AVPR1A and autism spectrum disorder.
Sources: Expert list
Mendeliome v1.1783 LCP1 Zornitza Stark gene: LCP1 was added
gene: LCP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LCP1 were set to 38710235
Phenotypes for gene: LCP1 were set to Bone marrow failure syndrome, MONDO:0000159, LCP1-related
Review for gene: LCP1 was set to AMBER
Added comment: 3 individuals from single kindred presenting with fevers, recurrent infections ,lymphopenia, neutropenia and thrombocytopenia. Murine model with similar phenotype. heterozygous LCP1c.740 -1G>A splice site variant hypothesized to cause dominant negative mode of inheritance
Sources: Literature
Mendeliome v1.1782 UFSP2 Zornitza Stark Publications for gene: UFSP2 were set to 33473208; 26428751; 28892125; 32755715
Mendeliome v1.1781 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Added comment: PMID: 37214758:

Additional patient with spondyloepimetaphyseal dysplasia type Di Rocco:
- het missense Cys302Ser
- confirmed de novo in segregation analyses
- absent in gnomAD
- no functional studies on the missense.

Four AD missense reported in the literature so far are located in the C-term catalytic domain - 1x hip dysplasia, Beukes type and 3x spondyloepimetaphyseal dysplasia type Di Rocco.

The well reported AR missense (associated with neurodevelopmental anomalies and epilepsy) is located in the N-terminal domain possibly involved in substrate binding.; Changed publications: 33473208, 26428751, 28892125, 32755715, 37214758
Mendeliome v1.1778 KDM5A Zornitza Stark reviewed gene: KDM5A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: El Hayek-Chahrour neurodevelopmental syndrome, MIM# 620820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1778 KCNIP4 Ain Roesley gene: KCNIP4 was added
gene: KCNIP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNIP4 was set to Unknown
Publications for gene: KCNIP4 were set to 33826137
Phenotypes for gene: KCNIP4 were set to seizures; epilepsy
Review for gene: KCNIP4 was set to RED
gene: KCNIP4 was marked as current diagnostic
Added comment: single paper describing insertions of L1 retrotransposons in KCNIP4
samples were post-mortem of resected temporal cortex from individuals with idiopathic temporal lobe epilepsy

1x de novo insertion of L1 in KCNIP4 however ddPCR revealed that this did NOT alter KCNIP4 mRNA expression
Sources: Literature
Mendeliome v1.1777 CHRNA7 Ain Roesley gene: CHRNA7 was added
gene: CHRNA7 was added to Mendeliome. Sources: Literature
cnv tags were added to gene: CHRNA7.
Mode of inheritance for gene: CHRNA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA7 were set to 20979196; 21596161; 21290787
Phenotypes for gene: CHRNA7 were set to intellectual disability; seizures; hypotonia
Review for gene: CHRNA7 was set to RED
gene: CHRNA7 was marked as current diagnostic
Added comment: Homozygous deletion of 15q13.3, which includes CHRNA7, causes ID, hypotonia, seizures, encephalopathy
Sources: Literature
Mendeliome v1.1775 DNA2 Zornitza Stark Publications for gene: DNA2 were set to 24389050; 31045292; 23352259; 25635128; 28554558
Mendeliome v1.1774 DNA2 Zornitza Stark reviewed gene: DNA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 37133451; Phenotypes: Rothmund-Thomson syndrome, type 4, MIM# 620819; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 WDR36 Sangavi Sivagnanasundram reviewed gene: WDR36: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006545; Phenotypes: glaucoma 1, open angle, G MONDO:0012357; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 SPATA13 Sangavi Sivagnanasundram reviewed gene: SPATA13: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006261; Phenotypes: primary angle-closure glaucoma MONDO:0001868; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 C2orf71 Sangavi Sivagnanasundram reviewed gene: C2orf71: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005738; Phenotypes: PCARE-related retinopathy MONDO:0800404; Mode of inheritance: None
Mendeliome v1.1770 NTF4 Sangavi Sivagnanasundram reviewed gene: NTF4: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005684; Phenotypes: glaucoma 1, open angle, O MONDO:0013134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 FOXD3 Sangavi Sivagnanasundram reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004877; Phenotypes: aniridia MONDO:0019172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1770 ADAMTS18 Sangavi Sivagnanasundram gene: ADAMTS18 was added
gene: ADAMTS18 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ADAMTS18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS18 were set to https://search.clinicalgenome.org/CCID:004057
Phenotypes for gene: ADAMTS18 were set to microcornea-myopic chorioretinal atrophy (MONDO:0014195)
Review for gene: ADAMTS18 was set to GREEN
Added comment: Classified DEFINITIVE by ClinGen Retina GCEP on 02/03/20222 - https://search.clinicalgenome.org/CCID:004057
Sources: Other
Mendeliome v1.1770 TTC25 Sangavi Sivagnanasundram reviewed gene: TTC25: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005700; Phenotypes: primary ciliary dyskinesia 35 MONDO:0014910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 CCDC151 Sangavi Sivagnanasundram reviewed gene: CCDC151: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005699; Phenotypes: primary ciliary dyskinesia 30 MONDO:0014465; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 ARMC4 Sangavi Sivagnanasundram reviewed gene: ARMC4: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005698; Phenotypes: primary ciliary dyskinesia 23 MONDO:0014193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 DNAH8 Sangavi Sivagnanasundram reviewed gene: DNAH8: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004671; Phenotypes: primary ciliary dyskinesia (MONDO:0016575), spermatogenic failure 46 (MONDO:0033673); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 DNAH17 Sangavi Sivagnanasundram gene: DNAH17 was added
gene: DNAH17 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DNAH17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH17 were set to https://search.clinicalgenome.org/CCID:004669
Phenotypes for gene: DNAH17 were set to spermatogenic failure 39 (MONDO:0032845)
Review for gene: DNAH17 was set to GREEN
Added comment: Classified DEFINITIVE by ClinGen on 08/09/2022 - https://search.clinicalgenome.org/CCID:004669
Sources: Other
Mendeliome v1.1770 SLC52A1 Bryony Thompson Added comment: Comment on list classification: Moderate gene-disease classification by ClinGen - https://search.clinicalgenome.org/CCID:006192
Mendeliome v1.1769 SLC52A1 Bryony Thompson Publications for gene: SLC52A1 were set to 29122468; 17689999
Mendeliome v1.1768 SLC52A1 Bryony Thompson reviewed gene: SLC52A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37510312, 29122468, 21089064; Phenotypes: Maternal riboflavin deficiency MONDO:0014013, Disorders of riboflavin metabolism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1767 SLC6A20 Bryony Thompson Publications for gene: SLC6A20 were set to 24816252; 19033659
Mendeliome v1.1765 SLC6A20 Bryony Thompson reviewed gene: SLC6A20: Rating: RED; Mode of pathogenicity: None; Publications: 19033659, 36820062, 24816252; Phenotypes: Hyperglycinuria MONDO:0007677; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1765 BRWD1 Sangavi Sivagnanasundram reviewed gene: BRWD1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004289; Phenotypes: primary ciliary dyskinesia MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1763 DAGLA Zornitza Stark gene: DAGLA was added
gene: DAGLA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to 35737950
Phenotypes for gene: DAGLA were set to Neuroocular syndrome 2, paroxysmal type, MIM# 168885
Review for gene: DAGLA was set to GREEN
Added comment: 9 individuals from 8 families reported with daily paroxysmal spells characterized by eye deviation or nystagmus with abnormal head posturing apparent from birth or early infancy. The episodes tend to be triggered after sleeping, and most patients show improvement of the ocular symptoms over time. Affected individuals also have hypotonia, mild developmental delay, dysarthria, and gait ataxia; most have mildly impaired intellectual development. Seizures are not observed.
Sources: Literature
Mendeliome v1.1761 HOXD12 Zornitza Stark reviewed gene: HOXD12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Clubfoot (non-syndromic) MONDO:0007342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1761 PKHD1L1 Zornitza Stark Publications for gene: PKHD1L1 were set to
Mendeliome v1.1758 EPHX1 Lauren Rogers reviewed gene: EPHX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary lipodystrophy, MONDO:0020087, EPHX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1758 HOXD12 Sangavi Sivagnanasundram gene: HOXD12 was added
gene: HOXD12 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: HOXD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXD12 were set to 38663984
Phenotypes for gene: HOXD12 were set to Clubfoot (non-syndromic) MONDO:0007342
Mode of pathogenicity for gene: HOXD12 was set to Other
Review for gene: HOXD12 was set to GREEN
Added comment: Novel gene-disease association with non-syndromic clubfoot.

10 variants in HOXD12 have been reported in individuals with clubfoot (variants are predominantly missense variants however one rare deletion has been reported).

PMID: 38663984
Around 9 individuals from 4 unrelated families have been reported with clubfoot and the variants were shown to segregate.

N-terminal region and C-terminal homeobox domain of HOXD12 are known to be clusters for pathogenic variants related to clubfoot.
Loss of function variants are less likely to contribute to clubfoot pathogenesis therefore mechanism of disease is suggested as dominant negative but is not confirmed.
Sources: Other
Mendeliome v1.1758 PKHD1L1 Sangavi Sivagnanasundram edited their review of gene: PKHD1L1: Changed publications: 38459354
Mendeliome v1.1758 RAB32 Bryony Thompson gene: RAB32 was added
gene: RAB32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB32 were set to 38614108
Phenotypes for gene: RAB32 were set to Parkinson disease MONDO:0005180
Mode of pathogenicity for gene: RAB32 was set to Other
Review for gene: RAB32 was set to RED
Added comment: A single variant in RAB32 - c.213C>G p.(Ser71Arg) with a significant association with PD (odds ratio [OR] 13.17, 95% CI 2.15-87.23; p=0.0055, 6,043 PD cases and 62,549 controls). The variant cosegregated with autosomal dominant PD in 3 families (9 affected individuals), with incomplete penetrance. In vitro studies demonstrate that RAB32 Ser71Arg activates LRRK2 kinase. The variant is reported as a novel reduced penetrance PD risk factor. The 95% CI for the OR estimate are very wide. A confirmatory study is required for this variant.
Sources: Literature
Mendeliome v1.1756 CCDC91 Bryony Thompson gene: CCDC91 was added
gene: CCDC91 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC91 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCDC91 were set to 38627542
Phenotypes for gene: CCDC91 were set to Punctate palmoplantar keratoderma type III MONDO:0007047
Review for gene: CCDC91 was set to AMBER
Added comment: A single 3-generation Chinese acrokeratoelastoidosis family segregates c.1101 + 1 G > A (causes exon 11 skipping). In vitro knockdown experiments in cell lines demonstrated distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-human skin fibroblasts cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates
Sources: Literature
Mendeliome v1.1754 CYHR1 Bryony Thompson Publications for gene: CYHR1 were set to
Mendeliome v1.1752 CYHR1 Bryony Thompson reviewed gene: CYHR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38641995; Phenotypes: neurodevelopmental disorder MONDO:0700092, ZTRAF1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1749 IL27RA Ain Roesley gene: IL27RA was added
gene: IL27RA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL27RA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL27RA were set to 38509369
Phenotypes for gene: IL27RA were set to Epstein-Barr virus infection MONDO:0005111 , IL27RA-related
Review for gene: IL27RA was set to AMBER
gene: IL27RA was marked as current diagnostic
Added comment: 3 children from 2 families with severe acute EBV infection.

fam1: homozygous for p.(Gln96*) (NMD-pred)
fam2: chet for p.(Arg446Gly) and c.1142-2A>C

the splice variant in fam2 was found to to result in an in-frame deletion p.(Gln381_Ala395del)
the missense in fam2 is hypothesised to be a hypomorphic allele:
- out of 15 Homs in the Finnish database, 2 had hospital diagnoses of EBV IM
- expression of this variant on its own results in a weak but detectable IL-27RA expression associated with significant increase in STAT1/3 phosphorus in response to IL-27 stimulation

borderline amber/green due to functional studies performed
Sources: Literature
Mendeliome v1.1748 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790; 38562108; 29321670, 32703609
Mendeliome v1.1747 SHH Ain Roesley edited their review of gene: SHH: Changed publications: 38562108, 29321670, 32703609
Mendeliome v1.1747 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790,38562108, 29321670, 32703609
Mendeliome v1.1745 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790
Mendeliome v1.1744 SHH Ain Roesley reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 38562108, 29321670, 32703609; Phenotypes: Hypertelorism, ACC, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1741 PQLC2 Zornitza Stark Publications for gene: PQLC2 were set to PMID: 35486108; and online publication GiM Feb 2024
Mendeliome v1.1737 SLC4A7 Chirag Patel gene: SLC4A7 was added
gene: SLC4A7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A7 were set to PMID: 35486108, 32594822
Phenotypes for gene: SLC4A7 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: SLC4A7 was set to AMBER
Added comment: Total 4 individuals from 3 families (2 known to be from same ethnic origin: Oriental-Jewish) with adult onset retinitis pigmentosa. All individuals had same homozygous frameshift variant in SLC4A7 gene (p.P670Sfs*6). RNA seq analysis revealed retinal expression in human and mouse samples. Immunohistochemistry of human and mouse retina revealed relatively strong expression in various retinal layers. Western blot analysis in fibroblasts from 1 patient showed absence of encoded protein.
Sources: Literature
Mendeliome v1.1736 SLC39A12 Chirag Patel gene: SLC39A12 was added
gene: SLC39A12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC39A12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A12 were set to PMID: 35486108
Phenotypes for gene: SLC39A12 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: SLC39A12 was set to RED
Added comment: WES (with targeted analysis of SLC genes) in 913 cases from 785 families with inherited retinal dystrophy. They identified 1 homozygous variant in SLC39A12 in 1 individual with adult-onset mild widespread retinal degeneration with marked macular involvement. No functional data. RNA seq analysis revealed retinal expression in human samples. Immunohistochemistry of human and mouse retina revealed comprehensive expression in various retinal cells including retinal pigment epithelium.
Sources: Literature
Mendeliome v1.1734 PQLC2 Chirag Patel gene: PQLC2 was added
gene: PQLC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PQLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PQLC2 were set to PMID: 35486108; and online publication GiM Feb 2024
Phenotypes for gene: PQLC2 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: PQLC2 was set to GREEN
gene: PQLC2 was marked as current diagnostic
Added comment: HGNC Gene Symbol: SLC66A1
Total 8 individuals from 6 families.

Millo et al. (2022)(PMID: 35486108) -
WES (with targeted analysis of SLC genes) in 913 cases from 785 families with inherited retinal dystrophy. They identified 2 different homozygous variants in SLC66A1 in 3 individuals from 2 families with adult-onset retinal dystrophy. No functional data.


Olinger et al. (2024)(https://www.sciencedirect.com/science/article/pii/S2949774424009804) -
CNV analysis of trio and non-trio WGS data from Genomics England 100K genomes project. They identified homozygous 21kb deletion spanning nearly entire SLC66A1 gene in 2 siblings with adult-onset rod-cone dystrophy (parents HTZ carriers). Review of cohort data then identified homozygous LOF variants (1 nonsense, 2 frameshift) in another 3 individuals with rod-cone dystrophy.
Sources: Literature
Mendeliome v1.1733 SUPT7L Chirag Patel gene: SUPT7L was added
gene: SUPT7L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SUPT7L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPT7L were set to PMID: 38592547
Phenotypes for gene: SUPT7L were set to Lipodystrophy, MONDO:0006573
Review for gene: SUPT7L was set to RED
Added comment: 1 case with generalised lipodystrophy, growth retardation, congenital cataracts, severe developmental delay and progeriod features. Trio WGS identified compound heterozygous variants in SUPT7L (missense causing abnormal splicing + frameshift). Variants validated with Sanger. SUPT7L encodes a component of the core structural module of the STAGA complex - a nuclear multifunctional protein complex that plays a role in various cellular processes (e.g. transcription factor binding, protein acetylation, splicing, and DNA damage control). Immunolabelling in fibroblasts from patient showed complete absence of SUPT7L protein. Transcriptome data from individual revealed downregulation of several gene sets associated with DNA replication, DNA repair, cell cycle, and transcription.
Sources: Literature
Mendeliome v1.1732 PRMT9 Chirag Patel gene: PRMT9 was added
gene: PRMT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRMT9 were set to PMID: 38561334
Phenotypes for gene: PRMT9 were set to Neurodevelopmental disorder, MONDO:0100500
Review for gene: PRMT9 was set to RED
Added comment: A homozygous variant (G189R) in PRMT9 is reported based on large WGS study in 136 consanguineous families - unclear if only found in 1 family and no clinical information on case(s).

PMRTs (protein arginine methyltransferases) catalyse post translational modification via arginine methylation. Functional studies showed that the G189R variant abolishes PRMT9's methyltransferase activity - specifically at the R508 residue of SF3B2 RNA (exclusively methylated by PRMT9) - and leads to heavy PRMT9 ubiquitination, and abnormal splicing activity of SF3B2. Knock out mouse model showed PRMT9 loss in excitatory neurons leads to aberrant synapse development and impaired learning and memory.
Sources: Literature
Mendeliome v1.1730 JAK1 Zornitza Stark Publications for gene: JAK1 were set to 28111307; 28008925; 30671064
Mendeliome v1.1728 JAK1 Zornitza Stark edited their review of gene: JAK1: Added comment: PMID 38563820: 59 individuals presenting with autoimmunity, atopy, colitis, and/or dermatitis and one of four JAK1 variants.; Changed rating: GREEN; Changed publications: 28111307, 28008925, 30671064, 38563820; Changed phenotypes: Autoinflammatory syndrome, MONDO:0019751, JAK1-related, Eosinophilia, Eosinophilic enteritis, Thyroid disease, Poor growth, Viral infections, Susceptibility to mycobacteria and viruses, Autoinflammation, immunde dysregulation, and eosinophilia, MIM# 618999
Mendeliome v1.1727 SRPK3 Zornitza Stark gene: SRPK3 was added
gene: SRPK3 was added to Mendeliome. Sources: Literature
digenic tags were added to gene: SRPK3.
Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SRPK3 were set to 38429495
Phenotypes for gene: SRPK3 were set to Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related
Review for gene: SRPK3 was set to GREEN
Added comment: 33 individuals reported with SRPK3 variants but myopathy only occurred when TTN variant also present (most truncating). Zebrafish model supports digenic model of inheritance.
Sources: Literature
Mendeliome v1.1726 OTULIN Zornitza Stark Publications for gene: OTULIN were set to 27523608; 27559085; 35587511
Mendeliome v1.1725 OTULIN Zornitza Stark edited their review of gene: OTULIN: Added comment: Three individuals reported with de novo missense variants and auto inflammatory syndrome. Two had at the same variant, p.Cys129Ser. Experimental data supports dominant negative mechanism. Fourth individual with heterozygous variant in PMID 38129331 and severe fasciitis.; Changed publications: 27523608, 27559085, 35587511, 38630025, 38652464, 38129331
Mendeliome v1.1720 EHBP1L1 Zornitza Stark reviewed gene: EHBP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Non-immune hydrops fetalis, MONDO:0015193, EHBP1L1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1718 PACSIN3 Zornitza Stark gene: PACSIN3 was added
gene: PACSIN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PACSIN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PACSIN3 were set to 38637313
Phenotypes for gene: PACSIN3 were set to Myopathy, MONDO:0005336, PACSIN3-related
Review for gene: PACSIN3 was set to AMBER
Added comment: Two unrelated families with LoF variants, one homozygous. Muscle phenotype including raised CK. Supportive mouse model.
Sources: Literature
Mendeliome v1.1717 RNU4-2 Zornitza Stark Publications for gene: RNU4-2 were set to
Mendeliome v1.1716 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Changed publications: 38645094
Mendeliome v1.1715 FOSL2 Zornitza Stark reviewed gene: FOSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aplasia cutis-enamel dysplasia syndrome, MIM# 620789; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1715 KIAA1024L Achchuthan Shanmugasundram gene: KIAA1024L was added
gene: KIAA1024L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIAA1024L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1024L were set to 35727972
Phenotypes for gene: KIAA1024L were set to Deafness, autosomal recessive 120, OMIM:620238
Review for gene: KIAA1024L was set to GREEN
Added comment: New gene name - MINAR2

PMID:35727972 reported 13 patients from four unrelated families with non-syndromic sensorineural hearing loss. Four of these patients had prelingual onset of severe to profound, progressive bilateral hearing loss. The other nine patients had congenital onset of severe to profound bilateral hearing loss, which was not progressive on one patient, while data was not available for the other.

Three different homozygous variants (c.144G > A/ p.Trp48Ter, c.412_419delCGGTTTTG/ p.Arg138Valfs*10 and c.393G > T/ p.Lys131Asn) were identified in MINAR2/ KIAA1024L gene in these patients.

There is some functional evidence available for the p.Lys131Asn variant. In addition, mice with loss of function of the Minar2 protein present with rapidly progressive sensorineural hearing loss.

This gene has also been associated with relevant phenotype in OMIM (MIM #620238).
Sources: Literature
Mendeliome v1.1710 PMP2 Zornitza Stark reviewed gene: PMP2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26257172, 27009151, 30249361, 31412900, 26828946, 32277537; Phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1G, 618279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1710 ELANE Zornitza Stark Publications for gene: ELANE were set to 19036076
Mendeliome v1.1707 SHARPIN Zornitza Stark gene: SHARPIN was added
gene: SHARPIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHARPIN were set to 38609546
Phenotypes for gene: SHARPIN were set to Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related
Review for gene: SHARPIN was set to GREEN
Added comment: Two unrelated patients with homozygous frameshift variants presenting with: P1 - recurrent fever, parotitis, joint inflammation, colitis and chronic otitis media necessitating tympanoplasty P2 - recurrent fever episodes with lymphadenopathy and vomiting every 2–3 weeks. Extensive functional data and mouse model.
Sources: Literature
Mendeliome v1.1705 RTN2 Zornitza Stark Publications for gene: RTN2 were set to 22232211; 27165006
Mendeliome v1.1701 PTCRA Zornitza Stark reviewed gene: PTCRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, MONDO:0019751, PTCRA-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1700 CADM3 Zornitza Stark Publications for gene: CADM3 were set to PMID: 33889941
Mendeliome v1.1698 CADM3 Zornitza Stark edited their review of gene: CADM3: Added comment: Two additional families reported with a different variant, de novo in one family.; Changed rating: GREEN; Changed publications: 38074074
Mendeliome v1.1698 EMILIN1 Chern Lim reviewed gene: EMILIN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 10, MIM#620080, Aortic aneurysm, MONDO:0005160, EMILIN1-related, AR.; Mode of inheritance: None
Mendeliome v1.1697 ACBD6 Zornitza Stark reviewed gene: ACBD6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive movement abnormalities, MIM# 620785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1696 SLC37A3 Achchuthan Shanmugasundram gene: SLC37A3 was added
gene: SLC37A3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC37A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC37A3 were set to 28041643; 35486108
Phenotypes for gene: SLC37A3 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: SLC37A3 was set to GREEN
Added comment: Three unrelated cases reported with biallelic variants in SLC37A3 gene (One case in PMID:28041643 and two cases in PMID:35486108) and with autosomal recessive retinitis pigmentosa.
Sources: Literature
Mendeliome v1.1696 PTCRA Achchuthan Shanmugasundram gene: PTCRA was added
gene: PTCRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCRA were set to 38422122
Phenotypes for gene: PTCRA were set to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783
Review for gene: PTCRA was set to GREEN
Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds).

Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons.

Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available.
Sources: Literature
Mendeliome v1.1696 NAA60 Zornitza Stark Phenotypes for gene: NAA60 were changed from Basal ganglia calcification, MONDO:0008947, NAA60-related to Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786
Mendeliome v1.1695 NAA60 Zornitza Stark reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain, and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38527963; Phenotypes: distal hereditary motor neuropathy, MONDO:0018894; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1694 FAM58A Zornitza Stark reviewed gene: FAM58A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1694 TUBA8 Sangavi Sivagnanasundram reviewed gene: TUBA8: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006476; Phenotypes: polymicrogyria with optic nerve hypoplasia (MONDO:0013172); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1694 KIF1BP Sangavi Sivagnanasundram reviewed gene: KIF1BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1692 NSUN6 Zornitza Stark reviewed gene: NSUN6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 82, MIM# 620779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1691 CANVAS_ACAGG Bryony Thompson edited their review of STR: CANVAS_ACAGG: Added comment: Additional 4 unrelated cases homozygous for the (ACAGG)exp and one compound het with AAGGG/ACAGG expansion in a Japanese neuropathy cohort.; Changed rating: GREEN; Changed publications: 33103729, 36061987; Changed phenotypes: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome MONDO:0044720; Set clinically relevant: yes
Mendeliome v1.1689 PSMA5 Zornitza Stark gene: PSMA5 was added
gene: PSMA5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMA5 was set to Other
Publications for gene: PSMA5 were set to 37600812
Phenotypes for gene: PSMA5 were set to Inborn error of immunity, MONDO:0003778, PSMA5-related; PRAAS/CANDLE
Review for gene: PSMA5 was set to RED
Added comment: Single patient with heterozygous PSMB8 variant and de-novo PSMA5 truncating variant (p.Arg168*) with clinical features of CANDLE. Patient also had splice site variant in PSMC5. In silico modelling showing interaction of PSMB8 and PSMA5. PSMA5/a5 is a constitutive component of the 20S core proteasome, ? digenic model of disease.
Sources: Literature
Mendeliome v1.1687 SNF8 Zornitza Stark reviewed gene: SNF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 115, MIM#620783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1687 CNOT1 Sangavi Sivagnanasundram reviewed gene: CNOT1: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004485; Phenotypes: holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1687 CENPE Sangavi Sivagnanasundram reviewed gene: CENPE: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004413; Phenotypes: autosomal recessive primary microcephaly MONDO:0016660; Mode of inheritance: None
Mendeliome v1.1684 GALE Zornitza Stark Publications for gene: GALE were set to 27604308; 9700591
Mendeliome v1.1683 GALE Zornitza Stark reviewed gene: GALE: Rating: GREEN; Mode of pathogenicity: None; Publications: 30247636, 34159722, 36395340; Phenotypes: Thrombocytopenia 12, syndromic, MIM#620776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1682 BANF1 Zornitza Stark Publications for gene: BANF1 were set to 32783369; 21549337
Mendeliome v1.1680 BANF1 Zornitza Stark edited their review of gene: BANF1: Added comment: PMID 35982159: Single individual reported with a de novo variant, p.Ala87Thr, and a neurodevelopmental disorder.

PMID 36980188: Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related; Changed publications: 32783369, 21549337, 35982159, 36980188; Changed phenotypes: Nestor-Guillermo progeria syndrome, MIM# 614008, Neurodevelopmental disorder, MONDO:0700092, BANF1-related, Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1679 FILIP1 Zornitza Stark reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1676 YKT6 Zornitza Stark gene: YKT6 was added
gene: YKT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YKT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YKT6 were set to 38522068
Phenotypes for gene: YKT6 were set to Syndromic disease, MONDO:0002254, YKT6-related
Review for gene: YKT6 was set to AMBER
Added comment: Two individuals homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] exhibited normal prenatal course followed by failure to thrive, developmental delay and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] exhibited neurodevelopmental disorders and optic atrophy. Supportive functional data in Drosophila.

Amber rating due to homozygous missense variants and founder effect in two of the families.
Sources: Literature
Mendeliome v1.1674 SEPHS1 Zornitza Stark gene: SEPHS1 was added
gene: SEPHS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEPHS1 were set to 38531365
Phenotypes for gene: SEPHS1 were set to Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related
Review for gene: SEPHS1 was set to GREEN
Added comment: Nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo.
Sources: Literature
Mendeliome v1.1671 GLUL Zornitza Stark reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1670 SCA4_ZFHX3_GGC Bryony Thompson STR: SCA4_ZFHX3_GGC was added
STR: SCA4_ZFHX3_GGC was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: SCA4_ZFHX3_GGC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA4_ZFHX3_GGC were set to 38035881; 38197134
Phenotypes for STR: SCA4_ZFHX3_GGC were set to spinocerebellar ataxia type 4 MONDO:0010847
Review for STR: SCA4_ZFHX3_GGC was set to GREEN
STR: SCA4_ZFHX3_GGC was marked as clinically relevant
Added comment: PMID: 38035881 - repeat expansion is identified in 5 Swedish ataxia families that developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades.
PMID: 38197134 - Poly-glycine GGC expansion in the last coding exon of ZFHX3 was identified in the original SCA4 Utah pedigree (Swedish origin) in the region of high linkage identified on 16q22. The expansion was also identified in an Iowa ataxia pedigree of Swedish ancestry. The expansion wasn’t identified in 11,258 exomes, 7,650 WGS probands without neurological phenotype, or 803 individuals with ataxia. Grch38 chr16:72787695–72787758
Normal allele <30 repeats, 21 repeats is the most common (derived from 33,094 individuals)
Undefined pathogenic 30-48 repeats
Definitive pathogenicity 48+ repeats
Sources: Literature
Mendeliome v1.1668 GTF3C5 Bryony Thompson gene: GTF3C5 was added
gene: GTF3C5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C5 were set to 38520561; 35503477
Phenotypes for gene: GTF3C5 were set to neurodevelopmental disorder MONDO:0700092, GTF3C5-related
Review for gene: GTF3C5 was set to GREEN
Added comment: 4 families/probands with syndromic ID. Loss of function is the expected
PMID: 38520561 - Biallelic variants identified (3 missense & 1 stopgain) in 4 individuals from 3 families presenting with multisystem developmental syndrome including the features: growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Gene-disease relationship supported by: reduced protein expression in patient cells, yeast assays, and a zebrafish model
PMID: 35503477 - 1 proband with biallelic missense variants and hypomelanosis of Ito, seizures, growth retardation, abnormal brain MRI, developmental delay, and facial dysmorphism
Sources: Literature
Mendeliome v1.1666 MCOLN1 Zornitza Stark Publications for gene: MCOLN1 were set to
Mendeliome v1.1664 MCOLN1 Zornitza Stark edited their review of gene: MCOLN1: Added comment: PMID 37972748: 23 affected individuals from 13 families with Lisch epithelial corneal dystrophy. WGS in 2 families and then targeted Sanger sequencing in the other families identified 9 rare heterozygous loss of function variants in MCOLN1. Homozygous and compound-heterozygous state of 4 of 9 LECD-associated variants cause Mucolipidosis IV (MLIV), which comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. Six parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype. Heterozygous MCOLN1 variants can be associated with incomplete penetrance and variable expressivity of LECD with an estimated penetrance of 0.2% for MCOLN1 loss-of-function variants based on gnomAD.; Changed publications: 37972748; Changed phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653, Lisch epithelial corneal dystrophy, OMIM# 620763; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1662 TRPV5 Bryony Thompson Publications for gene: TRPV5 were set to PMID: 38528055
Mendeliome v1.1660 TRPV5 Sangavi Sivagnanasundram edited their review of gene: TRPV5: Changed publications: PMID: 38528055, 14679186
Mendeliome v1.1660 DOCK4 Sangavi Sivagnanasundram gene: DOCK4 was added
gene: DOCK4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DOCK4 were set to PMID: 38526744
Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder (MONDO:0060490)
Review for gene: DOCK4 was set to GREEN
Added comment: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Sources: Other
Mendeliome v1.1660 DISP1 Bryony Thompson Publications for gene: DISP1 were set to 19184110; 26748417; 23542665
Mendeliome v1.1657 DISP1 Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

; to: Gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

Mendeliome v1.1657 DISP1 Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).

Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function f DISP1 cause HPE as well.; to: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

Mendeliome v1.1656 FRYL Ain Roesley gene: FRYL was added
gene: FRYL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related
Review for gene: FRYL was set to GREEN
gene: FRYL was marked as current diagnostic
Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father)
5x missense + 8x fs/stopgain + 1x canonical splice

13/13 with ID/DD (1x deceased)
4/14 seizures
7/14 with cardiac anomalies such as PDA, TOF, VSD, dextrocardia

1x also has a de novo fs variant in SF3B4
1x also has a de novo stop gain variant in SDHA

functional studies using flies were performed
Sources: Literature
Mendeliome v1.1654 KCNB2 Ain Roesley gene: KCNB2 was added
gene: KCNB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder MONDO:0700092, KCNB2-related
Review for gene: KCNB2 was set to GREEN
gene: KCNB2 was marked as current diagnostic
Added comment: 7 individuals, all missense
1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature
Mendeliome v1.1652 MAP3K20 Zornitza Stark Publications for gene: MAP3K20 were set to 27816943; 26755636
Mendeliome v1.1650 MAP3K20 Zornitza Stark reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: 38451290; Phenotypes: Syndromic disease, MONDO:0002254, MAP3K20-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1649 PLXNB2 Chirag Patel gene: PLXNB2 was added
gene: PLXNB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to PMID: 38458752
Phenotypes for gene: PLXNB2 were set to Amelogenesis imperfecta MONDO:0019507, PLXNB2 -related; Sensorineural hearing loss disorder MONDO:0020678, PLXNB2 -related
Review for gene: PLXNB2 was set to GREEN
gene: PLXNB2 was marked as current diagnostic
Added comment: 8 individuals from 6 families with core features of amelogenesis imperfecta and sensorineural hearing loss. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. WES and WGS identified biallelic pathogenic variants in PLXNB2 (missense, nonsense, splice and a multiexon deletion variants). Variants segregated with disease.

PLXNB2 is a large transmembrane semaphorin receptor protein, and semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Plxnb2 expression was detected in differentiating ameloblasts in mice. Human phenotype overlaps with that seen in Plxnb2 knockout mice.
Sources: Literature
Mendeliome v1.1648 CEP295 Chirag Patel gene: CEP295 was added
gene: CEP295 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP295 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP295 were set to PMID: 38154379
Phenotypes for gene: CEP295 were set to Seckel syndrome 11, OMIM # 620767
Review for gene: CEP295 was set to GREEN
gene: CEP295 was marked as current diagnostic
Added comment: 4 children from 2 unrelated families with Seckel-like syndrome - severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes. WES identified biallelic pathogenic variants in CEP295 gene (p(Q544∗) and p(R1520∗); p(R55Efs∗49) and p(P562L)).

Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying mechanisms. Depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Loss of CEP295 caused extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts.
Sources: Literature
Mendeliome v1.1647 SASS6 Ain Roesley Publications for gene: SASS6 were set to 24951542; 30639237
Mendeliome v1.1646 SASS6 Ain Roesley reviewed gene: SASS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 38501757, 36739862; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1645 FANCI Ain Roesley reviewed gene: FANCI: Rating: AMBER; Mode of pathogenicity: None; Publications: 38483614; Phenotypes: primary ovarian failure MONDO:0005387, FANCI-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1644 CAPNS1 Zornitza Stark gene: CAPNS1 was added
gene: CAPNS1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CAPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPNS1 were set to 38230350
Phenotypes for gene: CAPNS1 were set to Hereditary pulmonary arterial hypertension MONDO:0017148, CAPNS1-related
Review for gene: CAPNS1 was set to AMBER
Added comment: Three individuals from two families reported with homozygous splice site variants.
Sources: Expert list
Mendeliome v1.1642 USP27X Zornitza Stark Publications for gene: USP27X were set to 25644381
Mendeliome v1.1640 USP27X Zornitza Stark edited their review of gene: USP27X: Added comment: Ten additional individuals and further experimental data reported.; Changed rating: GREEN; Changed publications: 25644381, 38182161; Changed phenotypes: Intellectual disability, X-linked 105, MIM#300984
Mendeliome v1.1639 ZNF143 Bryony Thompson reviewed gene: ZNF143: Rating: AMBER; Mode of pathogenicity: None; Publications: 27349184, 33845046, 9009278, 22268977, 27349184, 27349184; Phenotypes: methylmalonic aciduria and homocystinuria MONDO:0016826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1638 TCN1 Bryony Thompson gene: TCN1 was added
gene: TCN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TCN1 were set to 29764838; 19686235
Phenotypes for gene: TCN1 were set to transcobalamin I deficiency MONDO:0008659
Review for gene: TCN1 was set to AMBER
Added comment: Unclear if TC1 deficiency is associated with a clinical phenotype and only found 2 families with genetic findings. 1 confirmed chet (2 truncating variants) with severe TC 1 deficiency (depression and anxiety only reported symptoms, had sickle cell trait) & another family with 2 siblings that are presumed homozygous for a truncating variant (no plasma or serum TC 1 levels but no DNA available for genetic testing) which was found heterozygous in multiple first-degree relatives. Unclear if there is a clinical phenotype. Heterozygous individuals displayed mildly low or low-normal TC 1 serum levels. Also, 4 homozygotes were identified in a study of a loss-of-function variant associated with lower vitamin B12 concentration in African Americans but there was limited ability to assess the clinical impact of the recessive disease
Sources: Literature
Mendeliome v1.1636 FEM1B Zornitza Stark Publications for gene: FEM1B were set to PMID: 31036916
Mendeliome v1.1634 FEM1B Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications: 31036916, 38465576; Changed phenotypes: Syndromic disease MONDO:0002254, FEM1B-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1634 DISP1 Sangavi Sivagnanasundram reviewed gene: DISP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 38529886; Phenotypes: Holoprosencephaly (MONDO:0016296); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1634 TRPV5 Sangavi Sivagnanasundram gene: TRPV5 was added
gene: TRPV5 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TRPV5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPV5 were set to PMID: 38528055
Phenotypes for gene: TRPV5 were set to TRPV5-related hypercalciuria (MONDO:0009550)
Review for gene: TRPV5 was set to RED
Added comment: Not a well-established gene-disease association. Has only been reported in one consanguineous family.

PMID: 38528055
3 individuals from the same family affected with hypercalciuria.
Biallelic Met598Val variant was identified in the proband and his two affect sibs

Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used.
Sources: Other
Mendeliome v1.1633 USP14 Zornitza Stark gene: USP14 was added
gene: USP14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP14 were set to 38469793; 35066879
Phenotypes for gene: USP14 were set to Syndromic disease MONDO:0002254, USP14-related
Review for gene: USP14 was set to GREEN
Added comment: PMID 35066879: 3 fetuses from 2 different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11) in USP14, and sequencing of family members showed segregation with the phenotype. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human multiple congenital contractures phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay.

PMID 38469793: biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. The fetus and the newborn had extensive brain malformations.
Sources: Literature
Mendeliome v1.1630 PRDX1 Bryony Thompson gene: PRDX1 was added
gene: PRDX1 was added to Mendeliome. Sources: Literature
digenic tags were added to gene: PRDX1.
Mode of inheritance for gene: PRDX1 was set to Other
Publications for gene: PRDX1 were set to 29302025; 35190856
Phenotypes for gene: PRDX1 were set to methylmalonic aciduria and homocystinuria type cblC MONDO:0010184
Mode of pathogenicity for gene: PRDX1 was set to Other
Review for gene: PRDX1 was set to GREEN
Added comment: Only variants affecting the canonical splice acceptor site of intron 5 (e.g. c.515-1G-T, c.515-2A-T) that cause skipping of exon 6 and the polyA termination signal of PRDX1 produce an MMACHC epimutation. The resulting read-through transcript extends through the adjacent MMACHC locus in the antisense orientation. These PRDX1 exon 6 acceptor splice site variants cause disease through digenic inheritance with a pathogenic MMACHC on the other allele.
Sources: Literature
Mendeliome v1.1628 PSMB10 Zornitza Stark Publications for gene: PSMB10 were set to 31783057; 37600812
Mendeliome v1.1626 PSMB10 Zornitza Stark edited their review of gene: PSMB10: Added comment: PMID 38503300: Six individuals with three de novo missense variants. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.; Changed publications: 31783057, 37600812, 38503300; Changed phenotypes: Proteasome-associated autoinflammatory syndrome 5, MIM# 619175, Severe combined immunodeficiency, MONDO:0015974, PSMB10-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1625 CST3 Bryony Thompson reviewed gene: CST3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 38489591; Phenotypes: leukodystrophy MONDO:0019046, CST3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1623 EHHADH Bryony Thompson Publications for gene: EHHADH were set to 24401050
Mendeliome v1.1621 EHHADH Bryony Thompson reviewed gene: EHHADH: Rating: GREEN; Mode of pathogenicity: None; Publications: 35738466, 38310177, 24401050; Phenotypes: Fanconi renotubular syndrome 3 MONDO:0014275; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1621 RXFP2 Katie Ayers reviewed gene: RXFP2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37208861, 38430325; Phenotypes: Infertility, cryptorchidism, non-obstructive azoospermia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1617 SAMD7 Zornitza Stark reviewed gene: SAMD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Macular dystrophy with or without cone dysfunction, MIM# 620762; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1616 FHL2 Zornitza Stark gene: FHL2 was added
gene: FHL2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FHL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FHL2 were set to 36854411; 25358972
Phenotypes for gene: FHL2 were set to Cardiomyopathy, MONDO:0004994, FHL2-related
Review for gene: FHL2 was set to AMBER
Added comment: Emerging evidence that variants in this gene may be associated with cardiomyopathy.

Reports of HCM and DCM.

c.391C>T (p.Arg131Cys) may be recurrent in early-onset DCM.
Sources: Expert Review
Mendeliome v1.1615 ZFHX3 Zornitza Stark Publications for gene: ZFHX3 were set to
Mendeliome v1.1613 ZRSR2 Zornitza Stark gene: ZRSR2 was added
gene: ZRSR2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZRSR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZRSR2 were set to 38158857
Phenotypes for gene: ZRSR2 were set to Orofacialdigital syndrome MONDO:0015375, ZRSR2-related
Review for gene: ZRSR2 was set to GREEN
Added comment: Oral-facial-digital (OFD) syndrome with brain anomalies ranging from alobar holoprosencephaly to pituitary anomalies.
Six unrelated families with two truncating variants and functional studies:
- p.(Gly404GlufsTer23): detected in one family with 2x affected males
- p.(Arg403GlyfsTer24): 5 unrelated families, both de novo and inherited
Sources: Expert Review
Mendeliome v1.1610 BBS4 Bryony Thompson reviewed gene: BBS4: Rating: RED; Mode of pathogenicity: None; Publications: 37588201; Phenotypes: autosomal dominant polycystic liver disease MONDO:0000447; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1610 ZFHX3 Lucy Spencer reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38412861; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ZFHX3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1607 SLC4A10 Zornitza Stark reviewed gene: SLC4A10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, MIM# 620746; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1606 RGS6 Zornitza Stark Phenotypes for gene: RGS6 were changed from Cataract,MONDO:0005129; intellectual disability, MONDO:0001071; microcephaly, MONDO:0001149 to Neurodevelopmental disorder, MONDO:0700092, RGS6-related
Mendeliome v1.1603 CORIN Zornitza Stark Publications for gene: CORIN were set to 22437503
Mendeliome v1.1596 CIAO1 Paul De Fazio changed review comment from: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Sources: Literature; to: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. Muscle biopsy showed variation in fiber size and an increase in internalized nuclei, as well as scattered degenerating/regenerating fibers and a mild to minimal increase in endomysial fibrosis. Electron microscopy revealed morphologically abnormal mitochondria.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Mendeliome v1.1596 MMS19 Paul De Fazio gene: MMS19 was added
gene: MMS19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMS19 were set to 38411040
Phenotypes for gene: MMS19 were set to Neuromuscular disease, MMS19-related (MONDO:0019056)
Penetrance for gene: MMS19 were set to unknown
Review for gene: MMS19 was set to RED
gene: MMS19 was marked as current diagnostic
Added comment: Single patient reported with postnatal microcephaly, bilateral cataracts, failure to thrive, progressive spastic tetraparesis, scoliosis, myoclonic epilepsy and precocious puberty. Cerebral MRI at age 4 years showed pontocerebellar atrophy and white matter abnormalities. Patient died age 13 after recurrent respiratory tract infections. A homozygous in-frame deletion p.(Glu213del) was identified. Cell line studies supported pathogenicity of the variant. A zebrafish knockout model also showed a detrimental effect of Mms19 deficincy.
Sources: Literature
Mendeliome v1.1596 CIAO1 Paul De Fazio gene: CIAO1 was added
gene: CIAO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIAO1 were set to 38411040; 38196629
Phenotypes for gene: CIAO1 were set to Neuromuscular disease, CIAO1-related (MONDO:0019056)
Penetrance for gene: CIAO1 were set to unknown
Review for gene: CIAO1 was set to GREEN
gene: CIAO1 was marked as current diagnostic
Added comment: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Sources: Literature
Mendeliome v1.1595 THBS2 Ain Roesley Publications for gene: THBS2 were set to
Mendeliome v1.1593 THBS2 Chris Ciotta reviewed gene: THBS2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38433265; Phenotypes: connective tissue disorder MONDO:0003900, THBS2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1589 CORIN Daniel Flanagan reviewed gene: CORIN: Rating: RED; Mode of pathogenicity: None; Publications: 37913506, 15637153; Phenotypes: ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1588 UBAP1L Ee Ming Wong gene: UBAP1L was added
gene: UBAP1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBAP1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBAP1L were set to PMID: 38293907; 38420906
Phenotypes for gene: UBAP1L were set to Cone-rod dystrophy (MONDO:0015993), UBAP1L-related
Review for gene: UBAP1L was set to GREEN
gene: UBAP1L was marked as current diagnostic
Added comment: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy
- Reported variants included splice, nonsense, frameshift and in-frame del variants
- Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later.
Sources: Literature
Mendeliome v1.1587 CELSR3 Crystle Lee gene: CELSR3 was added
gene: CELSR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to PMID: 38429302
Phenotypes for gene: CELSR3 were set to Neurodevelopmental disorder (MONDO#0700092), CELSR3-related
Review for gene: CELSR3 was set to GREEN
Added comment: PMID: 38429302:12 affected individuals from 11 families reported with bi-allelic variants. Phenotype ranged from CNS anomalies (7/12), CNS and CAKUT (3/12) and CAKUT only (2/12). Only missense variants reported and 1 inframe variant. Functional studies done in zebrafish demonstrate similar structural anomalies of the developing pronephros and neuronal abnormalities to affected individuals

PMID: 34951123: 5 het missense variants reported in patients with febrile seizures (FS)/epilepsy. Arg3141Gln present in gnomAD (7 hets). No functional studies. Summarised as potentially associated with febrile seizures (FS)/epilepsy
Sources: Literature
Mendeliome v1.1587 ZSCAN10 Rylee Peters gene: ZSCAN10 was added
gene: ZSCAN10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZSCAN10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSCAN10 were set to PMID: 38386308
Phenotypes for gene: ZSCAN10 were set to syndromic disease MONDO:0002254
Review for gene: ZSCAN10 was set to GREEN
Added comment: Bi-allelic ZSCAN10 loss-of-function variants were identified in seven affected individuals from five unrelated families with syndromic neurodevelopmental disorder.

Highly consistent phenotypic features include global developmental delay, behavioural abnormalities, and variable facial asymmetry with outer and inner ear malformations leading to profound SNHL.

Facial asymmetry was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations.
Sources: Literature
Mendeliome v1.1586 SLC12A9 Zornitza Stark gene: SLC12A9 was added
gene: SLC12A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC12A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A9 were set to 38334070
Phenotypes for gene: SLC12A9 were set to Neurodevelopmental disorder, MONDO:0700092, SLC12A9-related
Review for gene: SLC12A9 was set to GREEN
Added comment: Three individuals from unrelated families with bi-allelic LoF variants and a neurodevelopment phenotype, skeletal and brain abnormalities, hypopigmentation, dysmorphic features.
Sources: Literature
Mendeliome v1.1585 SNF8 Chern Lim gene: SNF8 was added
gene: SNF8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to Neurodevelopmental disorder (MONDO:0700092), SNF8-related
Review for gene: SNF8 was set to GREEN
gene: SNF8 was marked as current diagnostic
Added comment: PMID: 38423010
- Nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8. In total, three putative LoF variants and four missense variants were identified.
- The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.
- Functional studies using fibroblasts derived from patients and zebrafish model showed LoF is the disease mech.
Sources: Literature
Mendeliome v1.1584 HSPG2 Dean Phelan reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38424183; Phenotypes: Dyssegmental dysplasia, Rolland-Desbuquois type (MONDO:0009139); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1584 SNUPN Suliman Khan gene: SNUPN was added
gene: SNUPN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNUPN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNUPN were set to PMID: 38413582; PMID: 38366623
Phenotypes for gene: SNUPN were set to autosomal recessive limb-girdle muscular dystrophy MONDO:0015152
Review for gene: SNUPN was set to GREEN
Added comment: PMID: 38413582: reported 18 children from 15 unrelated families with muscular phenotypes, including proximal upper limb weakness, distal upper and lower limb weakness, and myopathy (EMG) with elevated serum creatinine kinase level. Exome sequencing revealed nine hypomorphic biallelic variants in the SNUPN gene, predominantly clustered in the last coding exon. Functional studies showed that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts.

PMID: 38366623: reported five individuals from two unrelated families with limb-girdle muscular dystrophy.
Sources: Literature
Mendeliome v1.1584 APOLD1 Lucy Spencer gene: APOLD1 was added
gene: APOLD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOLD1 were set to 35638551
Phenotypes for gene: APOLD1 were set to Bleeding disorder, vascular-type (MIM#620715)
Review for gene: APOLD1 was set to AMBER
Added comment: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.
Sources: Literature
Mendeliome v1.1584 RGS6 Seb Lunke gene: RGS6 was added
gene: RGS6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RGS6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS6 were set to 38332109; 25525169
Phenotypes for gene: RGS6 were set to Cataract,MONDO:0005129; intellectual disability, MONDO:0001071; microcephaly, MONDO:0001149
Review for gene: RGS6 was set to RED
Added comment: Original paper from 2015 describes single consanguineous with two siblings affected by cataract, developmental delay, and microcephaly >3SD. A homozygous canonical splice variant predicted to lead to NMD in RGS6 was identified by WGS and linkage (rather than full WGS analysis). The 2024 paper speculates that the phenotype is driven by a change in RGS6 isoform balance rather than LoF using a knock-out mouse model. It is noted that the mice did not have microcephaly, and ID was assessed using social interaction. No mention of cataract in the mice.
Sources: Literature
Mendeliome v1.1583 TOGARAM2 Naomi Baker gene: TOGARAM2 was added
gene: TOGARAM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOGARAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM2 were set to PMID:38374469
Phenotypes for gene: TOGARAM2 were set to Nonsyndromic genetic hearing loss (MONDO:0019497), TOGARAM2-related
Review for gene: TOGARAM2 was set to RED
Added comment: Paper reports one individual with bilateral profound hearing loss with a homozygous TOGARAM2 nonsense variant and demonstrated reduced mRNA expression in transfected cells.
Sources: Literature
Mendeliome v1.1583 DIP2C Melanie Marty gene: DIP2C was added
gene: DIP2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DIP2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DIP2C were set to PMID: 38421105
Phenotypes for gene: DIP2C were set to Neurodevelopmental disorder (MONDO#0700092), DIP2C-related
Review for gene: DIP2C was set to GREEN
Added comment: PMID: 38421105 - Twenty three patients with het DIP2C variants (10 de novo).
All patients had developmental delays affecting expressive language and speech, most had mild dev delay and ID. Four patients had seizures. Additional phenotypic findings were non-specific but recurrent anomalies did include a high anterior hair-line, prominent forehead, and a broad nasal tip. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects,and bicuspid aortic valve)
Sources: Literature
Mendeliome v1.1581 TUBA4A Sarah Pantaleo gene: TUBA4A was added
gene: TUBA4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA4A were set to PMID: 38413182
Phenotypes for gene: TUBA4A were set to Congenital myopathy MONDO:0019952
Review for gene: TUBA4A was set to AMBER
Added comment: One novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy.

Identified candidate genes using laser capture micro dissection, proteomics, WES, clinical data, myopathological changes, electrophysiological exams and thigh muscle MRIs.

The variant is de novo in both patients, c.679C>T, p.(Leu227Phe). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiqution-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of Leu227Phe resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

Patient 1 is 14yo and had delayed motor development milestones since infancy. Myopathic face, high-arched palate, waddling gait, winged scapula and muscle weakness in four limbs with lower extremities and proximal muscle more severely affected. Follow up at 14yo showed slight improvement in motor function compared with 3yo.

Patient 2 is 6yo and presented with motor retardation since birth. At 3yo, presented with mild ptosis and ophthalmoparesis, high-arched palate and muscle weakness involving both proximal and distal in all limbs.

No likely pathogenic variants in 116 other protein-encoding genes. Variants confirmed by Sanger sequencing and absent from gnomAD. ACMG predicts likely pathogenic classification.
Sources: Literature
Mendeliome v1.1581 DENND5B Elena Savva Publications for gene: DENND5B were set to
Mendeliome v1.1580 NIT1 Paul De Fazio gene: NIT1 was added
gene: NIT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NIT1 were set to 38430071
Phenotypes for gene: NIT1 were set to Cerebrovascular disorder, NIT1-related (MONDO:0011057)
Penetrance for gene: NIT1 were set to unknown
gene: NIT1 was marked as current diagnostic
Added comment: 5 unrelated families reported with recessively inherited cerebral small vessel disease had compound hetereozygous or homozygous variants in NIT1. 1 family (3 siblings) had p.(Ala68*) in trans with p.(Arg243Trp), the remaining 4 families (1 individual each) were all homozygous for p.(Arg243Trp).

Patients presented in mid-adulthood with progressive movement disorders (e.g. dystonia, chorea, bradykinesia and tremor, gait disturbance, dysarthria) and had abnormal brain MRI findings (honeycomb appearance of the basal ganglia-thalamus complex, due to numerous strongly dilated PVS). 3 patients had non-lobar intracerebral hemorrhage. Slowly progressive cognitive decline was also a key feature.

Metabolic analysis in urine confirmed loss of NIT1 enzymatic function.

Note p.(Arg243Trp) has 1 homozygote in gnomAD v4, but permitted due to later presentation in reported patients.
Sources: Literature
Mendeliome v1.1580 DENND5B Elena Savva reviewed gene: DENND5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38387458; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), DENND5B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1580 RREB1 Zornitza Stark Publications for gene: RREB1 were set to 32938917
Mendeliome v1.1578 RREB1 Zornitza Stark edited their review of gene: RREB1: Added comment: PMID 38332451: de novo LoF variant in an individual with phenotype consistent with the previous reports.; Changed rating: AMBER; Changed publications: 32938917, 38332451; Changed phenotypes: Rasopathy, MONDO:0021060, RREB1-related
Mendeliome v1.1578 FEZF2 Ain Roesley gene: FEZF2 was added
gene: FEZF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEZF2 were set to 38425142
Phenotypes for gene: FEZF2 were set to neurodevelopmental disorder MONDO:0700092, FEZF2-related
Review for gene: FEZF2 was set to GREEN
gene: FEZF2 was marked as current diagnostic
Added comment: - 7 indiv but 1 has whole gene deletion and 6x SNV (4x PTCs and 2x same missense Arg344Cys)
- of the 6x SNV, 4x de novo + 1x from affected father
- all have ID/ASD
- 1x seizures
- 1x hypotonia
- 1x motor coordination disorder
- 2x enuresis after 7yo
Sources: Literature
Mendeliome v1.1576 ZFX Zornitza Stark gene: ZFX was added
gene: ZFX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZFX were set to 26350204; 26740508; 38325380
Phenotypes for gene: ZFX were set to Neurodevelopmental disorder, MONDO:0700092, ZFX-related
Review for gene: ZFX was set to GREEN
Added comment: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.
Sources: Literature
Mendeliome v1.1571 NLRP12 Bryony Thompson Publications for gene: NLRP12 were set to 18230725; 21360512; 24064030; 27633793
Mendeliome v1.1568 APPL1 Bryony Thompson Publications for gene: APPL1 were set to 26073777
Mendeliome v1.1566 APPL1 Bryony Thompson edited their review of gene: APPL1: Added comment: PMID: 36208030 - a study using the UK Biobank comparing individuals with and without diabetes found LoF variants in APPL1 were ‘Inconsistent’ with being high penetrant for diabetes (failed both statistical criteria - enrichment & comparison to maximum credible allele frequency). Refutes previous study.; Changed rating: RED; Changed publications: 26073777, 36208030
Mendeliome v1.1566 KLF11 Bryony Thompson Publications for gene: KLF11 were set to 15774581; 26248217; 23589285; 31124255
Mendeliome v1.1565 KLF11 Bryony Thompson Added comment: Comment on list classification: Association with monogenic diabetes now Refuted
Classification - 02/08/2023. ClinGen Monogenic Diabetes GCEP - https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b1e38a49-7c12-4514-a2a1-109e04da146f-2023-02-08T170000.000Z?page=1&size=25&search=
Mendeliome v1.1564 KLF14 Hali Van Niel gene: KLF14 was added
gene: KLF14 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KLF14 was set to Unknown
Publications for gene: KLF14 were set to 33389382; 35081256; 24486580
Phenotypes for gene: KLF14 were set to diabetes mellitus MONDO:0005015
Review for gene: KLF14 was set to RED
Added comment: PMID: 33389382
Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes

PMID: 35081256
Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity

PMID: 24486580
Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population)
Sources: Other
Mendeliome v1.1564 PCSK2 Hali Van Niel gene: PCSK2 was added
gene: PCSK2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: PCSK2 was set to Unknown
Publications for gene: PCSK2 were set to 26607656; 7698505; 17618154
Phenotypes for gene: PCSK2 were set to diabetes mellitus MONDO:0005015
Review for gene: PCSK2 was set to RED
Added comment: Cannot find any evidence of association with mendelian disease

PMID: 26607656

10 SNPs genotyped, genetic polymorphisms responsible for glucose homeostasis and incidental diabetes

PMID: 7698505
DNA polymorphism found in 11% of non insulin dependent diabetes patients (out of 152 japanese patients) vs 4% in health population (out of 102 japanese patients).

PMID: 17618154
29 SNPS analysed across PCSK2, 4 SNPS associated type 2 diabetes in african american population
Sources: Other
Mendeliome v1.1564 ACO2 Zornitza Stark Publications for gene: ACO2 were set to 22405087; 25351951; 30689204; 32519519; 25351951
Mendeliome v1.1562 YEATS2 Elena Savva gene: YEATS2 was added
gene: YEATS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YEATS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YEATS2 were set to PMID: 22713812; 31539032
Phenotypes for gene: YEATS2 were set to ?Epilepsy, myoclonic, familial adult, 4 MIM#615127
Review for gene: YEATS2 was set to RED
Added comment: PMID: 22713812 - 13 members of a single family with Benign Adult Familial Myoclonic Epilepsy (BAFME). The average age of onset was 19.5 (range 10–33) years for tremor and 25 (range 19–33) years for seizures.
PMID: 31539032 - Expansions of TTTTA and insertions of TTTCA repeats in intron 1 of YEATS2 segregated in the same family ^.
Sources: Literature
Mendeliome v1.1557 STAB1 Zornitza Stark reviewed gene: STAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperferritinemia, MIM# 620729; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1556 PUM1 Zornitza Stark Publications for gene: PUM1 were set to 29474920; 25768905; 30903679; 31859446
Mendeliome v1.1555 ACO2 Rylee Peters reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34056600; Phenotypes: Optic atrophy 9, MIM# 616289; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1553 NEK1 Zornitza Stark Publications for gene: NEK1 were set to 21211617; 22499340; 25492405; 28123176; 33445179
Mendeliome v1.1552 NEK1 Zornitza Stark edited their review of gene: NEK1: Added comment: PMID 27530628: two brothers with OFD phenotype.; Changed publications: 21211617, 22499340, 25492405, 28123176, 27530628; Changed phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520, Orofaciodigital syndrome II , MIM# 252100, Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892
Mendeliome v1.1551 LCP2 Achchuthan Shanmugasundram reviewed gene: LCP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37211057; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1549 TMTC2 Zornitza Stark Publications for gene: TMTC2 were set to 29671961; 27311106
Mendeliome v1.1547 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Single family reported with bi-allelic variants.

Mouse model.; Changed publications: 29671961, 27311106, 37943620, 30188326; Changed phenotypes: Deafness, autosomal recessive 122, MIM# 620714; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1547 TMLHE Bryony Thompson Added comment: Comment on list classification: ClinGen Disputed gene-disease association Classification - 03/02/2021 by ID & Autism GCEP: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a780ea6-ad4e-417a-a596-27188e327aad-2021-03-02T050000.000Z?page=1&size=25&search=
Mendeliome v1.1546 ANKZF1 Zornitza Stark reviewed gene: ANKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302725, 36857589; Phenotypes: Infantile-onset inflammatory bowel disease, MONDO:0005265, ANKZF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1545 CARD8 Zornitza Stark edited their review of gene: CARD8: Added comment: Additional individual reported with JRA and IBD.; Changed rating: AMBER; Changed publications: 29408806, 37724393
Mendeliome v1.1543 ONECUT1 Bryony Thompson gene: ONECUT1 was added
gene: ONECUT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ONECUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ONECUT1 were set to 37639628; 34663987; 10825208
Phenotypes for gene: ONECUT1 were set to Neonatal diabetes mellitus MONDO:0016391
Review for gene: ONECUT1 was set to GREEN
Added comment: 3 unrelated neonatal diabetes cases with homozygous variants & supporting iPSC/mouse models
PMID: 37639628 - UK biobank study of ONECUT1 variants in neonatal diabetes mellitus (NDM), MODY, and type 2 diabetes. Identified a case with syndromic NDM with a homozygous frameshift (p.Met289Argfs*8). Rare heterozygous variants were not enriched in individuals with suspected MODY (n=484). Heterozygous null variants were significantly associated with type 2 diabetes (p=0.006) as a potential susceptibility gene.

PMID: 34663987 - 2 consanguineous families with homozygous variants (Glu231Ter or Glu231Asp) in cases with syndromic ND. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation.

PMID: 10825208 - Hnf6 (old gene name) null mice have diabetes
Sources: Literature
Mendeliome v1.1541 HSPA1L Zornitza Stark reviewed gene: HSPA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1539 TNRC6A Elena Savva gene: TNRC6A was added
gene: TNRC6A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNRC6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNRC6A were set to PMID: 29507423; 33040085
Phenotypes for gene: TNRC6A were set to ?Epilepsy, familial adult myoclonic, 6 MIM#618074
Review for gene: TNRC6A was set to RED
Added comment: PMID: 29507423;33040085 - intronic expansion in a cohort with familial myoclonic epilepsy, also observed in controls but enriched in the affect cohort.

Gene was listed in the Oliver list
Sources: Literature
Mendeliome v1.1538 FBXO31 Lucy Spencer reviewed gene: FBXO31: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1538 SIRT1 Achchuthan Shanmugasundram gene: SIRT1 was added
gene: SIRT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIRT1 were set to 23473037
Phenotypes for gene: SIRT1 were set to autoimmune disease, MONDO:0007179
Review for gene: SIRT1 was set to RED
Added comment: PMID:23473037 reported the identification of a missense SIRT1 variant (p.Leu107Pro) in five members of a single family and all five of them had autoimmune disorder, four had type I diabetes and one had ulcerative colitis.
Sources: Literature
Mendeliome v1.1538 SCGN Achchuthan Shanmugasundram gene: SCGN was added
gene: SCGN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCGN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCGN were set to 31663849
Phenotypes for gene: SCGN were set to ulcerative colitis, MONDO:0005101
Review for gene: SCGN was set to AMBER
Added comment: PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.
Sources: Literature
Mendeliome v1.1538 HSPA1L Achchuthan Shanmugasundram gene: HSPA1L was added
gene: HSPA1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HSPA1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPA1L were set to 28126021
Phenotypes for gene: HSPA1L were set to inflammatory bowel disease, MONDO:0005265
Review for gene: HSPA1L was set to GREEN
Added comment: PMID:28126021 reported the identification of a heterozygous de novo variant (p.Ser277Leu) in HSPA1L in a patient with inflammatory bowel disease. In addition, five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) were identified in six patients from a cohort of 136 IBD patients with WES data.

Functional studies showed that all six HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.
Sources: Literature
Mendeliome v1.1537 PRDM8 Zornitza Stark gene: PRDM8 was added
gene: PRDM8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRDM8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM8 were set to 2296154; 35034233
Phenotypes for gene: PRDM8 were set to Epilepsy, progressive myoclonic, 10 MIM#616640
Review for gene: PRDM8 was set to RED
Added comment: - PMID:22961547, 3 individuals from one family, all with myoclonic epilepsy, all had the Phe261Leu variant. This variant is absent from gnomAD V4.
- PMID: 35034233, Two individuals from one family, no clinical seizures but presented with myoclonus and abnormal EEG (generalised epileptiform charges), these individuals had the Ala230Gly missense change, which has currently been reported as a VUS.
Sources: Expert list
Mendeliome v1.1536 PRIMA1 Zornitza Stark gene: PRIMA1 was added
gene: PRIMA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRIMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIMA1 were set to 26339676
Phenotypes for gene: PRIMA1 were set to Frontal Lobe Epilepsy MONDO:0002612
Review for gene: PRIMA1 was set to RED
Added comment: - 2/3 siblings from unaffected parents in PMID: 26339676 were diagnosed with nocturnal frontal lobe epilepsy, which was confirmed by EEG. The affected siblings were homozygous for the c.93+2T>C variant canonical splice site variant. This variant was demonstrated by mini-gene assay to skip exon 2 of PRIMA1. Overall 1 family, 2 individuals with epilepsy and high impact variants in PRIMA1.
Sources: Expert list
Mendeliome v1.1534 PLXNC1 Zornitza Stark gene: PLXNC1 was added
gene: PLXNC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PLXNC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLXNC1 were set to 36808730
Phenotypes for gene: PLXNC1 were set to Malformations of cortical development
Review for gene: PLXNC1 was set to RED
Added comment: This gene was included in the genes4epilepsy resource (PMID:36808730) and was reported as being associated with the clinical phenotype "malformations of cortical development". There are no current PubMed articles linking this gene with epilepsy however
Sources: Expert list
Mendeliome v1.1532 CASZ1 Zornitza Stark gene: CASZ1 was added
gene: CASZ1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 28099117; 36293425; 31268246
Phenotypes for gene: CASZ1 were set to Dilated cardiomyopathy, MONDO:0005021, CASZ1-related; left ventricular non compaction
Review for gene: CASZ1 was set to GREEN
Added comment: Rare cause of paeditric onsent DCM. at least 3 papers report LoF variants, 2 of which each report a novel de novo frameshift variant in children diagnosed with DCM less than 1 and who died at 11 mths ( PMID: 31268246; Guo 2019) and 22mths (PMID: 36293425, Orlova 2022). Another paper (PMID: 28099117, Qiu 2017) reported a nonsense variant that segregated with DCM in a family in an AD fashion (full text not available).
Sources: Expert list
Mendeliome v1.1531 SMC3 Zornitza Stark Publications for gene: SMC3 were set to 18996922; 25655089; 31334757
Mendeliome v1.1530 NDUFB9 Zornitza Stark Publications for gene: NDUFB9 were set to 22200994
Mendeliome v1.1529 NDUFB9 Zornitza Stark edited their review of gene: NDUFB9: Added comment: PMID: 38129218: Thr144Met, listed as ACMG-P, hom in 1x pt with mito complex I deficiency and leukodystrophy, no functional studies, both parents are het.

However, this variant has 2 homozygotes in gnomADv4 so unlikely pathogenic.; Changed publications: 22200994, 38129218
Mendeliome v1.1529 DNM2 Bryony Thompson reviewed gene: DNM2: Rating: RED; Mode of pathogenicity: None; Publications: 23092955; Phenotypes: fetal akinesia-cerebral and retinal hemorrhage syndrome MONDO:0014149; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1528 SMC3 Bryony Thompson reviewed gene: SMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38297832; Phenotypes: Cornelia de Lange syndrome MONDO:0016033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1524 ASCC3 Zornitza Stark Publications for gene: ASCC3 were set to 21937992; https://doi.org/10.1016/j.xhgg.2021.100024
Mendeliome v1.1523 ASCC3 Zornitza Stark reviewed gene: ASCC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 81, MIM# 620700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1521 RIC1 Zornitza Stark Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to Cleft lip/palate MONDO:0016044, RIC1-related; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Mendeliome v1.1520 RIC1 Zornitza Stark Publications for gene: RIC1 were set to 31932796
Mendeliome v1.1516 ACACA Zornitza Stark reviewed gene: ACACA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36709796; Phenotypes: Acetyl-CoA carboxylase deficiency, MIM# 613933; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1515 NUP160 Zornitza Stark Publications for gene: NUP160 were set to 30179222
Mendeliome v1.1513 NUP160 Melanie Marty reviewed gene: NUP160: Rating: GREEN; Mode of pathogenicity: None; Publications: 30910934, 30179222, 33456446, 38224683; Phenotypes: Steroid-resistant nephrotic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1511 SP9 Suliman Khan gene: SP9 was added
gene: SP9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SP9 were set to PMID: 38288683
Phenotypes for gene: SP9 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: SP9 was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1511 CCDC88C Rylee Peters reviewed gene: CCDC88C: Rating: AMBER; Mode of pathogenicity: None; Publications: 38173219; Phenotypes: monogenic epilepsy MONDO:0015653, CCDC88C-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1510 RHOXF1 Chris Ciotta gene: RHOXF1 was added
gene: RHOXF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RHOXF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RHOXF1 were set to PMID: 38258527
Phenotypes for gene: RHOXF1 were set to Spermatogenic failure, MONDO:0004983, RHOXF1-related
Review for gene: RHOXF1 was set to AMBER
Added comment: In a cohort of 1,201 men from China with oligozoospermia and azoospermia, hemizygous RHOXF1 variants were identified in 4 unrelated individuals.

Three of these variants were missense variants (V130M, A91V & A156V), all were absent from gnomAD (including version 4) and had deleterious in silicos.

The one other variant was a nonsense variant (R160X) which is predicted to escape NMD and truncate the protein. This is seen in gnomAD version 4 in 1 heterozygote female, and absent in other versions.

In vitro functional evidence for these variants was provided, the V130M, A156V and R160X mutants demonstrated impaired protein localisation with an increase in the protein in the cytoplasm and impaired nuclear entry, the A91V mutant protein did not share these localisation defects.

Further, The V130M mutant protein decreased DMRT1 promotor activity, DMRT1 is considered essential for testicular development and spermatogenesis. However, the R160X variant demonstrated increased activation, three times higher than WT. The two other missense variants had no effect.
Sources: Literature
Mendeliome v1.1509 PRDM6 Elena Savva gene: PRDM6 was added
gene: PRDM6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRDM6 were set to 38071433; 27716515; 27181681
Phenotypes for gene: PRDM6 were set to Patent ductus arteriosus 3 MIM#617039
Review for gene: PRDM6 was set to GREEN
Added comment: Gene is established for patent ductus arteriosus. Only missense reported but supported by functional studies suggesting LOF.

PMID: 38071433 - Two families (3 affected, 6 affected) with patent ductus arteriosus with/without additional coarctation of the aorta. Family 1 had a missense, family 2 had a PTC - both regarded as VUSs

Additional papers PMID: 27716515;27181681 describe nonsyndromic patent ductus arteriosus for the first time
Sources: Literature
Mendeliome v1.1507 MEI4 Lisa Norbart gene: MEI4 was added
gene: MEI4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MEI4 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: MEI4 were set to 38252283
Phenotypes for gene: MEI4 were set to Infertility disorder, MONDO:0005047, MEI4-related
Review for gene: MEI4 was set to GREEN
Added comment: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype.

In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis.
Sources: Literature
Mendeliome v1.1506 WDR44 Andrew Fennell gene: WDR44 was added
gene: WDR44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WDR44 were set to PMID: 38191484
Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related
Review for gene: WDR44 was set to GREEN
Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development.
WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model.
The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients.
Sources: Literature
Mendeliome v1.1504 SH2B3 Ain Roesley Publications for gene: SH2B3 were set to 26457647; 23908464; 31102422; 31173385
Mendeliome v1.1502 SH2B3 Ain Roesley reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37206266, 23908464, 38152053; Phenotypes: Myeloproliferation and multi-organ autoimmunity, juvenile myelomonocytic leukemia MONDO:001190, SH2B3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1502 SAMD7 Paul De Fazio gene: SAMD7 was added
gene: SAMD7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SAMD7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SAMD7 were set to 38272031
Phenotypes for gene: SAMD7 were set to Macular dystrophy, retinal, SAMD7-related MONDO:0031166
Review for gene: SAMD7 was set to GREEN
gene: SAMD7 was marked as current diagnostic
Added comment: Five biallelic variants were identified in eight individuals from six families with macular dystrophy with or without cone dysfunction. Three families were consanguineous. Mean age at first presentation was 34.8 years, range 14 to 51.

Four variants affected splicing, while one missense variant impaired the repressive activity of SAMD7. All functional work was performed using in vitro assays.
Sources: Literature
Mendeliome v1.1501 CAMK2D Elena Savva gene: CAMK2D was added
gene: CAMK2D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMK2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK2D were set to 38272033
Phenotypes for gene: CAMK2D were set to Neurodevelopmental disorder (MONDO#0700092), CAMK2D-related
Added comment: PMID: 38272033
- 8 patients (5/8 de novo) with mostly missense and a single splice site variant, ages range from 5 weeks to 20 years old
- Most variants functionally shown to have a GOF mechanism causing addition DCM phenotype, LOF is only neurological
- Phenotypes include dev delay (mild-severe) (7/7 patients), skeletal anomalies (7/8, scoliosis, kyphosis, involving spine/hands/feet/palate), DCM (6/8), seizures (3/8), visual anomalies (astigmatism, cortical vision impairment, myopia, strabismus 5/5), enlarged brain ventricles (3/5)
Sources: Literature
Mendeliome v1.1499 ERG Zornitza Stark edited their review of gene: ERG: Changed rating: AMBER; Changed publications: s://ash.confex.com/ash/2023/webprogram/Paper191986.html; Changed phenotypes: Myelodysplasia syndrome, MONDO:0018881, ERG-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1498 RBMX Zornitza Stark Publications for gene: RBMX were set to 25256757; 34260915
Mendeliome v1.1497 RBMX Zornitza Stark edited their review of gene: RBMX: Added comment: PMID 37277488: In-frame deletion reported in a large multiplex Swedish family; Changed publications: 25256757, 34260915, 37277488; Changed phenotypes: Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238, Gustavson syndrome, MIM# 309555
Mendeliome v1.1492 MEIOB Zornitza Stark Publications for gene: MEIOB were set to 34794894; 24068956; 31000419; 28206990
Mendeliome v1.1491 MEIOB Zornitza Stark reviewed gene: MEIOB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35991565, 34392356, 31000419; Phenotypes: Premature ovarian failure 23, MIM# 620686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1491 NEPRO Zornitza Stark Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Mendeliome v1.1489 NEPRO Zornitza Stark reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: None; Publications: 37294112; Phenotypes: Anauxetic dysplasia 3, MIM618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1489 RNF213 Zornitza Stark Publications for gene: RNF213 were set to
Mendeliome v1.1480 COQ4 Zornitza Stark Publications for gene: COQ4 were set to 25658047; 26185144; 33704555
Mendeliome v1.1479 COQ4 Zornitza Stark edited their review of gene: COQ4: Added comment: PMIDs 36047608;38014483;38013626: more than 10 families reported with more limited spastic ataxia phenotype, onset from infancy to adulthood.; Changed publications: 25658047, 26185144, 33704555, 36047608, 38014483, 38013626; Changed phenotypes: Coenzyme Q10 deficiency, primary, 7, MIM# 616276, Spastic ataxia 10, autosomal recessive, MIM# 620666
Mendeliome v1.1478 SEC61A1 Zornitza Stark Publications for gene: SEC61A1 were set to 27392076; 32325141; 28782633
Mendeliome v1.1477 SEC61A1 Zornitza Stark edited their review of gene: SEC61A1: Added comment: PMID 32325141: single individual with de novo missense and phenotype primarily characterised by severe neutropenia.; Changed publications: 27392076, 32325141, 28782633, 32325141
Mendeliome v1.1472 KCNAB3 Elena Savva Publications for gene: KCNAB3 were set to PMID: 32990398
Mendeliome v1.1471 KCNAB3 Elena Savva reviewed gene: KCNAB3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 37396552, 32990398, 36345448; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), KCNAB3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1468 PPFIA3 Zornitza Stark gene: PPFIA3 was added
gene: PPFIA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPFIA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPFIA3 were set to 37034625
Phenotypes for gene: PPFIA3 were set to Neurodevelopmental disorder, MONDO:0700092, PPFIA3-related
Review for gene: PPFIA3 was set to GREEN
Added comment: 19 individuals with mono-allelic variants presenting with features including developmental delay, intellectual disability, hypotonia, micro/macrocephaly, autism, and epilepsy.

One individual with compound het variants: insufficient evidence for bi-allelic variants causing disease.
Sources: Literature
Mendeliome v1.1467 SLC13A3 Zornitza Stark Publications for gene: SLC13A3 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200101 (No PMID)
Mendeliome v1.1464 MAX Zornitza Stark Publications for gene: MAX were set to 21685915
Mendeliome v1.1459 CACHD1 Zornitza Stark reviewed gene: CACHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: syndromic complex neurodevelopmental disorder MONDO:0800439; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1459 SLC13A3 Daniel Flanagan gene: SLC13A3 was added
gene: SLC13A3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC13A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A3 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200101 (No PMID)
Phenotypes for gene: SLC13A3 were set to Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (MIM# 618384)
Review for gene: SLC13A3 was set to GREEN
Added comment: Seven patients reported with biallelic SLC13A3 variants, causing acute reversible leukoencephalopathy and α-ketoglutarate accumulation. Patients presented with acute neurological deterioration after a febrile illness. 5/7 with ataxia, 4/7 had seizures, 1/7 developmental delay.
Sources: Expert list
Mendeliome v1.1459 MAX Rylee Peters reviewed gene: MAX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38141607; Phenotypes: Syndromic disease (MONDO:0002254), MAX-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1457 CACHD1 Suliman Khan gene: CACHD1 was added
gene: CACHD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACHD1 were set to PMID: 38158856
Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder MONDO:0800439
Penetrance for gene: CACHD1 were set to unknown
Review for gene: CACHD1 was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1457 SPIN4 Belinda Chong gene: SPIN4 was added
gene: SPIN4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPIN4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SPIN4 were set to 36927955
Phenotypes for gene: SPIN4 were set to Lui-Jee-Baron syndrome MIM#301114
Review for gene: SPIN4 was set to AMBER
Added comment: PMID 36927955
* Single family, hemizygous frameshift variant (NM_001012968.3, c.312_313AGdel) identified in a male individual with generalized overgrowth of prenatal onset, variant also present in the mother and grandmother (both had adult heights 2 SDS greater than their midparental heights).
* In vitro shows loss of function and mice studies recapitulated the human phenotype with
generalized overgrowth, including increased longitudinal bone growth.
Sources: Literature
Sources: Literature
Mendeliome v1.1457 SOX8 Paul De Fazio gene: SOX8 was added
gene: SOX8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SOX8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOX8 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200088
Phenotypes for gene: SOX8 were set to Neurodevelopmental disorder (MONDO:0700092), SOX8-related
Review for gene: SOX8 was set to RED
gene: SOX8 was marked as current diagnostic
Added comment: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces.

Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Functional studies on patient fibroblasts showed misregulation of downstream SOX8 targets.
Sources: Literature
Mendeliome v1.1457 BORCS8 Lauren Rogers gene: BORCS8 was added
gene: BORCS8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to Neurodevelopmental disorder (MONDO#0700092), BORCS8-related
Review for gene: BORCS8 was set to GREEN
Added comment: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Mendeliome v1.1457 GTPBP1 Lucy Spencer gene: GTPBP1 was added
gene: GTPBP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related
Review for gene: GTPBP1 was set to GREEN
Added comment: PMID: 38118446- Cohort of individuals with variants in GTPBP2 (which has been previously described) and GTPBP1 (new) who have an identical neurodevelopmental syndrome. 4 homozygous individuals from 3 consanguineous families. 2 families have different NMD-predicted nonsense variants and the third has a missense, all are absent from gnomad v4.

The shared cardinal features of GTPBP1 and 2 related disease are microcephaly, profound neurodevelopmental impairment, and distinctive craniofacial features. Epilepsy was present in 10 of 20 individuals but its not clear if those individuals had GTPBP1 or 2 variants.
Sources: Literature
Mendeliome v1.1455 RAPGEF2 Belinda Chong gene: RAPGEF2 was added
gene: RAPGEF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAPGEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAPGEF2 were set to 37021642; 30351492; 29507423
Phenotypes for gene: RAPGEF2 were set to ?Epilepsy, familial adult myoclonic, 7 MIM# 618075
Review for gene: RAPGEF2 was set to RED
Added comment: Heterozygous 5-bp repeat expansion (TTTCA(n)) in intron 14 of RAPGEF2 gene. Two individuals previously reported (PMID: 30351492 and 29507423) with seizures
Sources: Literature
Mendeliome v1.1455 ALG8 Zornitza Stark Publications for gene: ALG8 were set to 26066342; 28375157; 15235028
Mendeliome v1.1453 PRICKLE2 Zornitza Stark Publications for gene: PRICKLE2 were set to 34092786
Mendeliome v1.1451 PRICKLE2 Zornitza Stark reviewed gene: PRICKLE2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34092786, 21276947, 26942291, 26942292; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PRICKLE2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1448 ERI1 Zornitza Stark reviewed gene: ERI1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hoxha-Aliu syndrome, MIM# 620662, Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1448 ALG8 Rylee Peters reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 35716054; Phenotypes: Congenital disorder of glycosylation, type Ih, MIM# 608104; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1446 GPT2 Zornitza Stark edited their review of gene: GPT2: Added comment: 10 families reported.; Changed publications: 27601654, 25758935, 31471722
Mendeliome v1.1445 POLD1 Zornitza Stark Publications for gene: POLD1 were set to 23770608; 33618333; 33369179; 32826474; 30023403; 29199204; 28791128
Mendeliome v1.1442 LCK Zornitza Stark edited their review of gene: LCK: Added comment: Additional cases:
PMID 38100037: Description of a second unrelated patient with novel biallelic missense LCK c.1393T>C, p.C465R variant in a patient from a consanguineous Syrian family with profound T-cell immune deficiency characterized by complete LCK protein expression deficiency and ensuing proximal TCR signaling-and CD4 and CD8-co-receptor-mediated functional and phenotypical defects.

PMID: 27087313 reported 3 siblings of a consanguineous family presenting with recurrent pneumonia and severe viral skin disease leading to malignant transformation. The patients had an intronic LCK c.188-2A>G splice site variant resulting in skipping of exon 3 and mRNA decay. Clinical data alongside with CD4+ T-cell lymphocytopenia suggested a hypomorphic LCK deficiency.; Changed rating: GREEN; Changed publications: 22985903, 1579166, 11021796, 27087313, 38100037
Mendeliome v1.1440 CASP2 Zornitza Stark reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, MIM# 620653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1439 RBFOX1 Zornitza Stark Publications for gene: RBFOX1 were set to 24664471
Mendeliome v1.1436 MAP1LC3B2 Zornitza Stark gene: MAP1LC3B2 was added
gene: MAP1LC3B2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAP1LC3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1LC3B2 were set to 35748970; 33310865
Phenotypes for gene: MAP1LC3B2 were set to Hereditary susceptibility to infection, MONDO:0015979, MAP1LC3B2 -related; Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2
Review for gene: MAP1LC3B2 was set to RED
Added comment: PMID: 35748970 Affects CNS (resident cells and fibroblasts) Impaired autophagy induction after HSV2 infection - increased viral replication and apoptosis of patient fibroblasts.

PMID: 33310865 one affected individual with heterozygous variant in MAP1LC3B2 (p.L109M)
Sources: Expert Review
Mendeliome v1.1434 CAPRIN1 Zornitza Stark Publications for gene: CAPRIN1 were set to 35979925
Mendeliome v1.1433 CAPRIN1 Zornitza Stark edited their review of gene: CAPRIN1: Added comment: Two individuals reported with the same de novo c.1535C > T (p.Pro512Leu) variant and a progressive course.; Changed rating: AMBER; Changed publications: 36136249
Mendeliome v1.1432 CAPRIN1 Zornitza Stark reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1431 MANF Zornitza Stark gene: MANF was added
gene: MANF was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MANF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MANF were set to 26077850; 33500254; 34815294
Phenotypes for gene: MANF were set to Diabetes, deafness, developmental delay, and short stature syndrome, MIM# 620651
Review for gene: MANF was set to AMBER
Added comment: Two individuals reported with homozygous variants. Mouse model recapitulates deafness phenotype.
Sources: Expert Review
Mendeliome v1.1428 GABRA4 Zornitza Stark gene: GABRA4 was added
gene: GABRA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRA4 were set to 35152403
Phenotypes for gene: GABRA4 were set to Developmental and epileptic encephalopathy MONDO:0100062, GABRA4-related
Review for gene: GABRA4 was set to RED
Added comment: Single individual with de novo missense variant reported, supportive functional data.
Sources: Literature
Mendeliome v1.1426 RBFOX1 Dean Phelan reviewed gene: RBFOX1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37962958; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), RBFOX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1425 MGP Zornitza Stark Publications for gene: MGP were set to 9916809; 15810001; 33996798
Mendeliome v1.1422 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932; 36018820
Mendeliome v1.1421 KIF5B Zornitza Stark edited their review of gene: KIF5B: Added comment: Four additional patients with three distinct de-novo missense variants and features consistent with osteogenesis imperfecta. All variants are in the Kinesin motor domain (~50% of the protein). Functional data in C. Elegans and cell lines shows impaired protein function. Not clear what distinguishes OI causing variants from other phenotypes for this gene at this stage. Dominant negative effect proposed but not conclusively proven.; Changed publications: 37934770; Changed phenotypes: Skeletal dysplasia, MONDO:0018230, osteogenesis imperfecta, MONDO:0019019
Mendeliome v1.1415 RAB1A Zornitza Stark gene: RAB1A was added
gene: RAB1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB1A were set to 37924809
Phenotypes for gene: RAB1A were set to neurodevelopmental disorder MONDO:0700092, RAB1A-related
Review for gene: RAB1A was set to AMBER
Added comment: Four families and 5 individuals, 2/5 have speech delay and 4/5 have motor delay. Anxiety in 3/5 and autism in 2/5. Microcephaly in only one individual, spastic paraplegia observed in 2 individuals from one family. In 2 families variants were inherited from an affected parent.
Sources: Literature
Mendeliome v1.1414 CRELD1 Zornitza Stark Publications for gene: CRELD1 were set to 22740159
Mendeliome v1.1413 FUK Zornitza Stark Publications for gene: FUK were set to 30503518
Mendeliome v1.1411 FUK Zornitza Stark edited their review of gene: FUK: Added comment: PMID: 35718084: Reporting on 3 unrelated patients from literature and 1 new patient. All reported to have mild-severe intellectual disability, developmental delay and brain abnormalities, and 3/4 present with seizures. Phenotypes are childhood onset. Homozygous and compound heterozygous variants have been reported.

PMID: 36426412: Reporting on new 1 patient (homozygous missense). Not affected by intellectual disability, developmental delay, or brain abnormalities. Presents with seizures. Loss of function suggested due to depletion of the FUK gene expression.; Changed rating: GREEN; Changed publications: 30503518, 35718084, 36426412
Mendeliome v1.1409 SV2A Zornitza Stark reviewed gene: SV2A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SV2A-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1408 CEP192 Chern Lim gene: CEP192 was added
gene: CEP192 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP192 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CEP192 were set to 37981762
Phenotypes for gene: CEP192 were set to microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size
Review for gene: CEP192 was set to RED
gene: CEP192 was marked as current diagnostic
Added comment: PMID: 37981762:
- In one family, chet missense p.His638Tyr and p.Asn1917Ser segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size in two affected siblings. Both sibs also fulfilled dx for mosaic variegated aneuploidy (MVA) syndrome and have tetraploidy.
- A lower but substantial proportion of MVA/tetraploidy cells was observed in II-1, II-2, and II-4 (who are het for one of the variants).

- In the same family, each variants in heterozygous state segregated with infertility and/or reduced testicular size in the proband’s father and maternal uncle.
- Variant screening of CEP192 coding regions performed for 1264 unrelated males with idiopathic infertility.
- Asn1917Ser was also detected in three additional unrelated infertile males with reduced testicular volumes.
- Two other missense and two synonymous variants were repeatedly detected in infertile males.

- qPCR showed CEP192 expression was decreased in individuals with c.1912C>T His638Tyr, mini-gene assay showed that c.1912C>T His638Tyr led to the skipping of exon 14, predicted to result in NMD.
- Epithelial cells cultured in vitro from patients with biallelic variants showed the number of cells arrested during the prophase increased because of the failure of spindle formation.

- Embyronic mouse lethality in Cep192-/- (hom for His638Tyr), Cep192M/M (hom for Asn1917Ser) and Cep192-/M (chet).
- Embryos of Cep192M/M mice had significant increase of MVA and tetraploidy cells.
- Number of apoptotic cells increased in Cep192M/M embryos compared with that of Cep192+/+, similar result in Cep192-/- embryos.
- Male mice with Cep192 heterozygous variants replicated infertility

Conclusions:
- Association of this gene with autosomal recessive disease has not been established.
- Association of monoallelic variants in this gene with infertility is not well established:
- Two variants with some supportive evidence from mouse model.
Sources: Literature
Mendeliome v1.1408 CRELD1 Naomi Baker reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37947183; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), CRELD1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1405 DDX17 Melanie Marty gene: DDX17 was added
gene: DDX17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX17 were set to https://www.medrxiv.org/search/DDX17
Phenotypes for gene: DDX17 were set to Neurodevelopmental disorder (MONDO#0700092), DDX17-related
Review for gene: DDX17 was set to GREEN
Added comment: https://www.medrxiv.org/search/DDX17 (pre-print)
11 patients with het de novo variants in DDX17 (5 NMD, 6 missense). Patient's phenotype included mild-moderate intellectual disability, delayed speech and language development and global developmental delay. 64% had dysmorphic facial features. Some patients also have gross and fine motor delay, generalized hypotonia, stereotypy, and evidence of autism spectrum disorder.

Knockdown of Ddx17 in newborn mice showed impaired axon outgrowth and reduced axon outgrowth and branching was observed in primary cortical neurons in vitro. This result was replicated in Crispant Xenopus tadpoles, which had clear functional neural defects and showed an impaired neurobehavioral phenotype.
Sources: Literature
Mendeliome v1.1405 SV2A Karina Sandoval gene: SV2A was added
gene: SV2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SV2A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SV2A were set to PMID: 37985816
Phenotypes for gene: SV2A were set to Epilepsy, MONDO:0005027
Review for gene: SV2A was set to GREEN
Added comment: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature
Mendeliome v1.1403 ACBD6 Lucy Spencer edited their review of gene: ACBD6: Changed publications: 37951597, 36457943, 21937992, 35446914
Mendeliome v1.1402 SLC19A1 Paul De Fazio reviewed gene: SLC19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36517554, 36745868; Phenotypes: Combined immunodeficiency, SLC19A1-related MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1402 KCNJ3 Daniel Flanagan gene: KCNJ3 was added
gene: KCNJ3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNJ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ3 were set to PMID: 37963718
Phenotypes for gene: KCNJ3 were set to Epilepsy (MONDO#0005027), KCNJ3-related
Review for gene: KCNJ3 was set to AMBER
Added comment: Two de novo missense variants, p.(Leu333Ser) and p.(Arg313Gln), were identified in two unrelated probands with epilepsy. 1/2 had developmental delay. Whole-cell patch-clamp functional studies showed a significantly reduction in current amplitude and density.

Kcnj3-knockout mice display hyperactivity and decreased anxiety, while a knock-in mouse line displays spontaneous seizure-like activity.
Sources: Expert list
Mendeliome v1.1402 RNF213 Seb Lunke reviewed gene: RNF213: Rating: GREEN; Mode of pathogenicity: None; Publications: 37924258; Phenotypes: Leigh syndrome, MONDO:0009723, pediatric arterial ischemic stroke, MONDO:0018585, Moyamoya disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1401 MARK4 Rylee Peters changed review comment from: Missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature; to: Heterozygous missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature
Mendeliome v1.1401 PLA2G16 Lauren Rogers gene: PLA2G16 was added
gene: PLA2G16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLA2G16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLA2G16 were set to PMID: 37919452
Phenotypes for gene: PLA2G16 were set to Lipodystrophy (MONDO:0006573)
Review for gene: PLA2G16 was set to GREEN
Added comment: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy.

Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
Sources: Literature
Mendeliome v1.1401 MARK4 Rylee Peters gene: MARK4 was added
gene: MARK4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MARK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK4 were set to PMID: 38041405
Phenotypes for gene: MARK4 were set to neurodevelopmental disorder (MONDO:0700092), MARK4-related
Mode of pathogenicity for gene: MARK4 was set to Other
Review for gene: MARK4 was set to AMBER
gene: MARK4 was marked as current diagnostic
Added comment: Missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature
Mendeliome v1.1401 SEL1L Sarah Pantaleo gene: SEL1L was added
gene: SEL1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to PMID: 37943610; PMID: 37943617
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder, MONDO:0700092, SEL1L-related
Penetrance for gene: SEL1L were set to Complete
Added comment: Wang paper PMID: 37943610

SEL1L protein is involved in the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation.

Report two biallelic missense variants in SEL1L in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia (termed ERAD-associated neurodevelopment disorder with onset in infancy (ENDI). The variants were hypomorphic and impaired ERAD function.

Identified by WES. Parents heterozygous and asymptomatic. P.(Gly585Asp) in Patient 1, p.(Met528Arg) in Patients 2 and 3 (siblings).

All variants cause substrate accumulation. The extent of substrate accumulation in knockin cells was modest compared to those in knockout cells, pointing to a hypomorphic nature.

They also had a variant in HRD1.



Weis paper PMID: 37943617

Third variant p.(Cys141Tyr), biallelic, causing premature death in five patients from a consanguineous family with early-onset neurodevelopmental disorders and agammaglobulinaemia due to severe SEL1L-HRD1 ERAD dysfunction.

This variant appears to have a more severe outcome, exhibiting B cell depletion and agammaglobulinaemia, causing the most severe dysfunction among all of the variants described by this group so far. They postulate that functionality of SEL1L-HRD1 ERAD is inversely correlated with disease severity in humans.

Their symptoms were dev delay, neurological disorder and agammaglobulinaemia in childhood. Along with severe axial hypotonia, short stature and microcephaly.

“Not a complete loss-of-function variant”.
Sources: Literature
Mendeliome v1.1401 FOXL1 Lilian Downie gene: FOXL1 was added
gene: FOXL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXL1 were set to PMID: 34633540
Phenotypes for gene: FOXL1 were set to Otosclerosis 11 #MIM620576
Review for gene: FOXL1 was set to RED
Added comment: Single paper with variant in large AD family from Newfoundland with otosclerosis, hearing loss onset varied from late teens onwards. Segregation not completely convincing, 1 person with the deletion without otosclerosis. Conductive HL, sometimes mixed, not isolated SNHL. Second family with common haplotype and same 15bp deletion with otosclerosis. Functional studies. High population frequency and 3x homozygotes.
Sources: Literature
Mendeliome v1.1401 PPID Elena Savva gene: PPID was added
gene: PPID was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPID was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPID were set to 37977818
Phenotypes for gene: PPID were set to Stutter disorder, (MONDO:0000723), PPID-related
Review for gene: PPID was set to RED
Added comment: PMID: 37977818 - a large family (10 affected confirmed to have the variant) with stuttering/language disorder and a het missense (p.(Pro270Ser)). Mouse K/I model showed microstructural changes in the corticospinal tract
Sources: Literature
Mendeliome v1.1400 ACBD6 Lucy Spencer edited their review of gene: ACBD6: Added comment: PMID: 37951597
Much larger cohort with - 45 individuals from 28 families with a neurodevelopmental syndrome with complex and progressive movement disorder phenotype. 18 PTCs and splice, 1 missense 1 in frame insertion.

Phenotypes: weight was >50th percentile in 20/34 patients, all mod-severe GDD, facial dysmorphism in 38/40, mild cerebellar ataxia 35/41, limb spasticity/hypertonia 31/41, gait abnormalities in 33/35.; Changed publications: 37951597
Mendeliome v1.1400 PRPF19 Dean Phelan gene: PRPF19 was added
gene: PRPF19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRPF19 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRPF19 were set to PMID: 37962958
Phenotypes for gene: PRPF19 were set to Neurodevelopmental disorder (MONDO:0700092), PRPF19-related
Review for gene: PRPF19 was set to GREEN
Added comment: PMID: 37962958
Six unrelated individuals with de novo variants. Five had speech language motor delay, four had formal diagnosis of autism, three hypotonia and one fetus with multiple congenital abnormalities.
Sources: Literature
Mendeliome v1.1400 MGP Andrew Fennell reviewed gene: MGP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37675773; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1399 COL17A1 Zornitza Stark Publications for gene: COL17A1 were set to 27309958; 29708937; 25676728; 20301304
Mendeliome v1.1398 COL17A1 Zornitza Stark reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37979963; Phenotypes: Amelogenesis imperfecta MONDO:0019507, COL17A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1398 GRIA3 Zornitza Stark Publications for gene: GRIA3 were set to 32977175; 17989220
Mendeliome v1.1396 GRIA3 Zornitza Stark edited their review of gene: GRIA3: Added comment: New manuscript describing ~40 individuals with variants in GRIA3, including affected females. Some variants demonstrated to be LoF and others GoF. LoF variants generally caused a milder phenotype.; Changed publications: 32977175, 17989220, 38038360; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1395 WBP4 Zornitza Stark Publications for gene: WBP4 were set to
Mendeliome v1.1394 WBP4 Zornitza Stark reviewed gene: WBP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 37963460; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, WBP4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1393 MRPL39 Zornitza Stark reviewed gene: MRPL39: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency-59 (COXPD59), MIM#620646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1392 CNTN2 Zornitza Stark Publications for gene: CNTN2 were set to 23518707; 34120799; 34691156
Mendeliome v1.1391 CNTN2 Zornitza Stark edited their review of gene: CNTN2: Added comment: Additional family, consanguineous, homozygous variants segregated in 3 affected sibs and was not homozygous in unaffected sib. Seizures later childhood onset and mild ID.; Changed rating: GREEN; Changed publications: 23518707, 37359369; Changed phenotypes: Epilepsy, MONDO:0015653, CNTN2-related
Mendeliome v1.1391 FA2H Zornitza Stark Publications for gene: FA2H were set to 29423566
Mendeliome v1.1390 FA2H Zornitza Stark edited their review of gene: FA2H: Changed publications: 29423566, 31135052, 18463364, 19068277, 20104589
Mendeliome v1.1390 FA2H Zornitza Stark changed review comment from: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.
Sources: Expert Review; to: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.

PubMed: 31135052 – 19 patients from 16 families consistent with a complicated form of SPG.
PubMed:18463364 – 7 individuals identified from a large consanguineous family with SPG.
PubMed: 19068277 – 7 patients from 2 unrelated consanguineous middle eastern families
PubMed: 20104589– Multiple affected individuals in an Omani family. Findings indicated that an abnormal hydroxylation of myelin galactocerebroside lipid components can lead to the progression of a severe phenotype.

Sources: Expert Review
Mendeliome v1.1389 FA2H Zornitza Stark gene: FA2H was added
gene: FA2H was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to 29423566
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive, MIM#611026
Review for gene: FA2H was set to GREEN
Added comment: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.
Sources: Expert Review
Mendeliome v1.1385 PHLDB1 Zornitza Stark reviewed gene: PHLDB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, type XXIII, MIM# 620639; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1381 KDR Zornitza Stark edited their review of gene: KDR: Added comment: PMID 34113005: Exome sequencing in a family with two siblings affected by ToF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants.

Rare variant burden analysis conducted in a set of 1,569 patients of European descent with ToF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). At this stage MOI unclear and insufficient evidence for either MOI.; Changed publications: 31980491, 29650961, 18931684, 34113005; Changed phenotypes: Pulmonary hypertension, Haemangioma, capillary infantile, somatic 602089, Tetralogy of Fallot, MONDO:0008542; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1380 DOT1L Zornitza Stark gene: DOT1L was added
gene: DOT1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOT1L were set to 37827158
Phenotypes for gene: DOT1L were set to Neurodevelopmental disorder, MONDO:0700092, DOT1L-related
Mode of pathogenicity for gene: DOT1L was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: DOT1L was set to GREEN
Added comment: Nine individuals reported with seven de novo missense variants.

All had DD/ID and variable patterns of associated congenital anomalies.

Variants demonstrated to be GoF and lead to increased H3K79 methylation levels in flies and human cells.
Sources: Literature
Mendeliome v1.1376 ARPC5 Zornitza Stark reviewed gene: ARPC5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 133 with autoimmunity and autoinflammation, MIM# 620565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1376 RRAGC Zornitza Stark Publications for gene: RRAGC were set to 27234373
Mendeliome v1.1374 SLCO1B3 Zornitza Stark Publications for gene: SLCO1B3 were set to 33860121
Mendeliome v1.1372 SLCO1B3 Zornitza Stark edited their review of gene: SLCO1B3: Added comment: Five additional individuals reported.; Changed rating: GREEN; Changed publications: 33860121, 36964102
Mendeliome v1.1372 SLCO1B1 Zornitza Stark Publications for gene: SLCO1B1 were set to 30250148; 24918167; 33860121
Mendeliome v1.1371 SLCO1B1 Zornitza Stark edited their review of gene: SLCO1B1: Changed publications: 36964102, 33860121
Mendeliome v1.1370 SLCO1B1 Zornitza Stark edited their review of gene: SLCO1B1: Added comment: Five additional individuals reported.; Changed publications: 33860121, 33860121
Mendeliome v1.1370 KCNA3 Zornitza Stark Publications for gene: KCNA3 were set to
Mendeliome v1.1369 KCNA3 Zornitza Stark reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37964487; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, KCNA3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1366 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309 to Optic atrophy 15, MIM# 620583
Mendeliome v1.1365 MCAT Zornitza Stark Publications for gene: MCAT were set to 31915829
Mendeliome v1.1364 MCAT Zornitza Stark edited their review of gene: MCAT: Added comment: Second individual reported in PMID 33918393; Changed publications: 33918393
Mendeliome v1.1364 MCAT Zornitza Stark edited their review of gene: MCAT: Changed phenotypes: Optic atrophy 15, MIM# 620583
Mendeliome v1.1363 MDM4 Bryony Thompson gene: MDM4 was added
gene: MDM4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MDM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MDM4 were set to 32300648; 33104793
Phenotypes for gene: MDM4 were set to bone marrow failure syndrome MONDO:0000159, MDM4-related
Review for gene: MDM4 was set to AMBER
Added comment: A single family was reported to segregate a missense variant (p.Thr454Met) with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. A mouse model of p.Thr454Met showed increased p53 activity, decreased telomere length, and bone marrow failure.
Sources: Other
Mendeliome v1.1362 THOC6 Ling Sun reviewed gene: THOC6: Rating: AMBER; Mode of pathogenicity: None; Publications: 35426486, 30476144; Phenotypes: VSD/ASD, severe aortic and left ventricular hypoplasia, Mild dilation of the right chambers and a mild myocardial hypertrophy secondary to a chronic hypertension, ventriculomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1361 DAW1 Zornitza Stark reviewed gene: DAW1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, with or without heterotaxy, MIM#620570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1361 TCIRG1 Achchuthan Shanmugasundram reviewed gene: TCIRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753205, 35573728; Phenotypes: severe congenital neutropenia, MONDO:0018542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1360 PSMB10 Zornitza Stark Publications for gene: PSMB10 were set to 31783057
Mendeliome v1.1358 PSMB10 Zornitza Stark edited their review of gene: PSMB10: Added comment: PMID 37600812: 3 additional unrelated patients with compound heterozygous variants with structural modelling of proteasome assembly.; Changed rating: GREEN; Changed publications: 31783057, 37600812
Mendeliome v1.1357 FYB1 Zornitza Stark gene: FYB1 was added
gene: FYB1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FYB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FYB1 were set to 25516138; 25876182
Phenotypes for gene: FYB1 were set to Thrombocytopenia 3, MIM# 273900
Review for gene: FYB1 was set to GREEN
Added comment: Two families with LoF variants and segregation reported in the literature. Aware of two additional cases through clinical testing (Prevention Genetics).

Good functional evidence, including mouse models.

Moderate by ClinGen, though note score was in 'Strong' range and downgraded due to two families in the literature only.
Sources: Expert Review
Mendeliome v1.1355 MCTS1 Zornitza Stark gene: MCTS1 was added
gene: MCTS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCTS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCTS1 were set to 37875108
Phenotypes for gene: MCTS1 were set to Inherited susceptibility to mycobacterial diseases, MONDO:0019146, MCTS1-related
Review for gene: MCTS1 was set to GREEN
Added comment: 6 male subjects from 5 kindreds with LOF MCTS-1 variants with MSMD.
Extensive ex-vivo functional validation and mouse model.
Sources: Literature
Mendeliome v1.1351 FMNL2 Achchuthan Shanmugasundram gene: FMNL2 was added
gene: FMNL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FMNL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FMNL2 were set to 34043722
Phenotypes for gene: FMNL2 were set to inflammatory bowel disease, MONDO:0005265
Mode of pathogenicity for gene: FMNL2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: FMNL2 was set to AMBER
Added comment: A patient was reported with a de novo heterozygous FMNL2 variant (p.Leu136Pro) and with severe very early onset inflammatory bowel disease (IBD). The functional characterisation of this variant showed that FMNL2 L136P protein displayed subcellular mislocalisation and deregulated protein autoinhibition indicating gain-of-function mechanism (PMID:34043722).
Sources: Literature
Mendeliome v1.1351 HIST1H4J Zornitza Stark Publications for gene: HIST1H4J were set to 31804630
Mendeliome v1.1345 MYO9B Melanie Marty reviewed gene: MYO9B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36260368; Phenotypes: Charcot-Marie-Tooth disease type 2 (MONDO:0018993), MYO9B-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1342 ELP1 Ain Roesley Publications for gene: ELP1 were set to 11179008; 32296180
Mendeliome v1.1341 MAN2B2 Zornitza Stark Publications for gene: MAN2B2 were set to 31775018
Mendeliome v1.1340 ELP1 Ain Roesley reviewed gene: ELP1: Rating: RED; Mode of pathogenicity: None; Publications: 36864284; Phenotypes: neurodevelopmental disorder, MONDO:0700092, ELP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1340 CCDC66 Anna Ritchie gene: CCDC66 was added
gene: CCDC66 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC66 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCDC66 were set to PMID: 37852749
Review for gene: CCDC66 was set to RED
Added comment: Nonsense variant (c.172C>T, p.Q58X) segregating in family with 5 affected members with high myopia (HM). Additionally, one family member with the variant displayed no symptoms, hinting at possible incomplete penetrance. Six other rare variants were identified in 200 sporadic high myopia patients that could potentially be linked to HM. A deficiency in CCDC66 might disrupt cell proliferation by influencing the mitotic process during retinal growth, leading to HM.
Sources: Literature
Mendeliome v1.1339 MIEF1 Seb Lunke Added comment: Comment on list classification: Two patients but both missense and one with a few too many hets. Functional data not quite strong enough.
Mendeliome v1.1338 SGSM3 Dean Phelan gene: SGSM3 was added
gene: SGSM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SGSM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSM3 were set to PMID: 37833060
Phenotypes for gene: SGSM3 were set to Neurodevelopmental disorder (MONDO:0700092), SGSM3-related
Review for gene: SGSM3 was set to AMBER
Added comment: PMID: 37833060
- 13 patients from 8 families of Ashkenazi Jewish origin all had the same homozygous frameshift variant (c.981dup). Predicted to cause NMD. The variant co-segregated with disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. Considered a founder variant (1 in 52 Ashkenazi Jews carry the variant). Also present in other populations but no homozygotes in gnomAD.
Sources: Literature
Mendeliome v1.1335 AGPAT3 Ee Ming Wong gene: AGPAT3 was added
gene: AGPAT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT3 were set to 37821758
Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related
Review for gene: AGPAT3 was set to GREEN
gene: AGPAT3 was marked as current diagnostic
Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa
- All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant
- Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis
- KO AGPAT3 mouse demonstrated impaired neuronal migration
Sources: Literature
Mendeliome v1.1335 HEPHL1 Naomi Baker gene: HEPHL1 was added
gene: HEPHL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEPHL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEPHL1 were set to PMID: 31125343; 31293895
Phenotypes for gene: HEPHL1 were set to Abnormal hair, joint laxity, and developmental delay (MIM#261990)
Review for gene: HEPHL1 was set to RED
Added comment: PMID: 31125343 - Single patient reported with biallelic variants (missense and splice) that presented with abnormal hair and early cognitive delays. Authors also created a knockout mouse, with homozygotes having short, curled whiskers while heterozygotes did not have this phenotype.

PMID: 31293895 - Report of curly whiskers (cw) mouse model that has a spontaneous variant (frame shifting single base insertion) in Hephl1.
Sources: Literature
Mendeliome v1.1335 CD81 Zornitza Stark Publications for gene: CD81 were set to 20237408
Mendeliome v1.1333 DLG2 Elena Savva gene: DLG2 was added
gene: DLG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLG2 were set to PMID: 37860969
Phenotypes for gene: DLG2 were set to Intellectual disability (MONDO#0001071), DLG2-related
Review for gene: DLG2 was set to AMBER
Added comment: PMID: 37860969 - 13 patients from 10 families with neurodevelopmental disorders, dysmorphic features and intragenic deletions including both exonic (minimal affect all transcripts) and UTR regions.
Majority of variants were inherited, some de novo. But many NMD PTCs in gnomAD (some looking messy, in noncanonical transcript etc.)
Sources: Literature
Mendeliome v1.1330 LRRC23 Belinda Chong gene: LRRC23 was added
gene: LRRC23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC23 were set to 37804054
Phenotypes for gene: LRRC23 were set to Non-syndromic male infertility due to sperm motility disorder MONDO:0017173
Review for gene: LRRC23 was set to RED
Added comment: PMID 37804054: A homozygous nonsense mutation in LRRC23 (c.376C>T: p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection.
Sources: Literature
Mendeliome v1.1330 MIEF1 Lucy Spencer gene: MIEF1 was added
gene: MIEF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIEF1 were set to 33632269
Phenotypes for gene: MIEF1 were set to Optic atrophy 14 (MIM#620550)
Review for gene: MIEF1 was set to AMBER
Added comment: PMID: 33632269
Inherited optic neuropathies cohort from france with nothing found in OPA1, OPA3 and WFS1 or mtDNA. 2 individuals (55 and 47yo) found to have missense variant in MIEF1, p.Arg146Trp has 35 hets 0 homs in gnomad, p.Tyr240Asn is absent. Both have non-syndromic late onset inherited optic neuropathies characterized by initial loss of peripheral visual fields.

Functional studies in HeLa cells- both missense localised to the mitochondria and formed oligomers similar to WT. MIEF1 normally regulates mitochondrial fission dynamics and causes an increase in mitochondrial fusion events, however both missense variants caused a significantly decreased mitochondrial fusion events.
Sources: Literature
Mendeliome v1.1330 CASP2 Lisa Norbart gene: CASP2 was added
gene: CASP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP2 were set to 37880421
Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related
Penetrance for gene: CASP2 were set to Complete
Review for gene: CASP2 was set to GREEN
gene: CASP2 was marked as current diagnostic
Added comment: 7 patients from 5 families
4 families hom for PTCs, 1 family Chet for splice+PTC
RNA studies done for the splice to indicate usage of two cryptic splice donor sites

5/5 have ID/dev delay
1/5 has seizures
2/5 hypotonia
3/5 lissencephaly (pachygyria and cortical thickening)
Sources: Literature
Mendeliome v1.1330 MAN2B2 Achchuthan Shanmugasundram reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35637269; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1330 CD81 Achchuthan Shanmugasundram reviewed gene: CD81: Rating: GREEN; Mode of pathogenicity: None; Publications: 35849269; Phenotypes: Immunodeficiency, common variable, 6, OMIM:613496; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1328 AXL Zornitza Stark reviewed gene: AXL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1327 ELANE Michelle Torres reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 33968054, 3124897; Phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1327 AXIN1 Zornitza Stark changed review comment from: Mouse data only.; to: Caudal duplication: Mouse data only.
Mendeliome v1.1327 AXIN1 Zornitza Stark edited their review of gene: AXIN1: Added comment: PMID: 37582359
- four families (7 individuals) with three homozygous truncating variants.
- all variant shown to result in reduced protein, though 1/3 would be NMD predicted
- Probands had macrocephaly (4/6), GDD (3/7), hip dysplasia (5/6), cardiac anomalies eg. VSD/ASD (3/7), cranial hyperostosis and vertebral endplate sclerosis; Changed rating: GREEN; Changed publications: 37582359; Changed phenotypes: Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1327 AXIN1 Zornitza Stark Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related to Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558
Mendeliome v1.1324 SAT1 Chirag Patel reviewed gene: SAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.1323 GPR156 Zornitza Stark reviewed gene: GPR156: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 121, MIM# 620551; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1320 KDM5B Lauren Rogers reviewed gene: KDM5B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), KDM5B-related, Intellectual developmental disorder, autosomal recessive 65 (MIM#618109); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1320 PTPN4 Bryony Thompson Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Mendeliome v1.1319 PTPN4 Bryony Thompson edited their review of gene: PTPN4: Changed publications: 17953619, 25424712, 30238967, 34527963
Mendeliome v1.1319 PTPN4 Bryony Thompson changed review comment from: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature; to: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
PMID: 34527963 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Mendeliome v1.1318 ZFHX3 Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related
Mendeliome v1.1318 SMG8 Zornitza Stark Publications for gene: SMG8 were set to PMID: 31130284
Mendeliome v1.1317 EPHA2 Zornitza Stark Publications for gene: EPHA2 were set to 19005574; 19649315; 19306328; 33671840
Mendeliome v1.1316 EPHA2 Zornitza Stark Phenotypes for gene: EPHA2 were changed from cataract 6 multiple types MONDO:0007288 to cataract 6 multiple types MONDO:0007288; microphthalmia, MONDO:0021129, EPHA2-related
Mendeliome v1.1313 COG3 Zornitza Stark reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIbb, MIM# 620546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1312 ADAMTS15 Zornitza Stark reviewed gene: ADAMTS15: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, distal, type 12, MIM# 620545; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1311 DNAJB2 Lauren Rogers reviewed gene: DNAJB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881); Mode of inheritance: None
Mendeliome v1.1311 EPHA2 Sarah Leigh reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33671840, 35918037; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1311 SMG8 Sarah Leigh reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34761517; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1309 COQ7 Zornitza Stark Publications for gene: COQ7 were set to 26084283; 31240163; 33215859; 28409910
Mendeliome v1.1308 COQ7 Zornitza Stark reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36758993, 36759155; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 9, MIM# 620402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1306 ZFHX3 Chirag Patel reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37292950; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1302 IL23R Zornitza Stark Publications for gene: IL23R were set to 30578351; 35829840
Mendeliome v1.1300 IL23R Zornitza Stark edited their review of gene: IL23R: Added comment: PMID 36763636: Six individuals from four unrelated Iranian kindreds with AR complete IL-23R deficiency presenting MSMD with complete penetrance. Also some patients with susceptibility to CMC with incomplete penetrance.; Changed rating: GREEN; Changed publications: 30578351, 35829840, 36763636; Changed phenotypes: Immunodeficiency disease, MONDO:0021094, Inherited susceptibility to mycobacterial disease, MONDO:0019146, IL23R-related
Mendeliome v1.1299 IRF1 Zornitza Stark Publications for gene: IRF1 were set to
Mendeliome v1.1296 IRF1 Zornitza Stark edited their review of gene: IRF1: Added comment: PMID 36736301: Two unrelated children with recurrent early-onset life-threatening mycobacterial diseases due to multiple mycobacteria (BCG, M. avium). Homozygous LoF vairiants with extensive supporting functional data.; Changed rating: GREEN; Changed publications: 36736301; Changed phenotypes: Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1295 IRF4 Zornitza Stark Publications for gene: IRF4 were set to 29537367; 29408330
Mendeliome v1.1293 IRF4 Zornitza Stark edited their review of gene: IRF4: Added comment: PMID 36662884: Seven individuals with profound CID from six kindreds of diverse ethnic origins (Fig. 1A). All affected individuals suffered with early onset (<1 year of age) recurrent sinopulmonary infections, with the opportunistic pathogen Pneumocystis jirovecii causing pneumonia in most individuals. p.T95R variant found in all patients. Extensive functional data including knockout mouse model. The heterozygous IRF4T95R variant found in multiple unrelated families caused a fully penetrant, severe very early-onset immunodeficiency characterized by greatly enhanced susceptibility to opportunistic pathogens such as P. jirovecii and weakly pathogenic mycobacteria.; Changed rating: GREEN; Changed publications: 29537367, 36662884; Changed phenotypes: Combined immunodeficiency, MONDO:0015131, IRF4-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1293 MCM9 Zornitza Stark Publications for gene: MCM9 were set to 25480036; 26771056; 33538981; 33095795
Mendeliome v1.1291 CR2 Zornitza Stark Publications for gene: CR2 were set to 22035880; 26325596
Mendeliome v1.1289 CR2 Zornitza Stark edited their review of gene: CR2: Added comment: PMID:28499783 reported two siblings from consanguineous parents, both with a homozygous frameshift variant in CR2 and with recurrent respiratory infections and hypogammaglobulinaemia.; Changed rating: GREEN; Changed publications: 22035880, 26325596, 28499783
Mendeliome v1.1289 HMOX1 Zornitza Stark Publications for gene: HMOX1 were set to 21088618; 9884342; 20844238
Mendeliome v1.1287 HMOX1 Zornitza Stark edited their review of gene: HMOX1: Added comment: PMID:33066778 provides a third case in support of promoting HMOX1 to green rating. This third case is a boy born to nonconsanguineous parents who presented with early onset asplenia, recurrent infections, and associated flares with bone marrow histiocyte activation with worsening interstitial lung disease and joint pain. This boy harboured compound heterozygous variants (p.L89Sfs*24 and p.Ala88Profs*51).; Changed rating: GREEN; Changed publications: 21088618, 9884342, 20844238, 33066778
Mendeliome v1.1286 HYOU1 Zornitza Stark edited their review of gene: HYOU1: Added comment: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anemia, thrombocytopenia and severe panleukopenia and immunodeficiency.; Changed rating: GREEN; Changed publications: 27913302, 35822684, 35549617
Mendeliome v1.1286 KCNH5 Zornitza Stark reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36307226; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1283 ERLIN2 Zornitza Stark reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 18A, autosomal dominant, MIM# 620512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1283 MCM9 Natalie Tan reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26806154, 34556653, 32841224, 32613604, 37378315); Phenotypes: Primary ovarian insufficiency, Lynch-like syndrome/colorectal cancer; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1267 SRP68 Zornitza Stark gene: SRP68 was added
gene: SRP68 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SRP68 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP68 were set to 32273475
Phenotypes for gene: SRP68 were set to Neutropenia, severe congenital, 10, autosomal recessive, MIM# 620534
Review for gene: SRP68 was set to AMBER
Added comment: Single individual reported with bi-allelic LoF variants and presenting with infantile-onset severe neutropenia and recurrent infections. Multiple lines of functional evidence provided.
Sources: Expert list
Mendeliome v1.1265 PLS3 Zornitza Stark Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Mendeliome v1.1263 PLS3 Zornitza Stark edited their review of gene: PLS3: Added comment: PMID 37751738: 8 unrelated families with affected males with an X-linked condition characterised by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. All were missense variants. A mouse knock in model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Gain-of-function is a suggested mechanism.; Changed publications: 32655496, 25209159, 29736964, 29884797, 28777485, 24088043, 37751738; Changed phenotypes: Bone mineral density QTL18, osteoporosis - MIM#300910, congenital diaphragmatic hernia MONDO:0005711, PLS3-related; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1261 MYCN Elena Savva Publications for gene: MYCN were set to 21224895; 8470948; 30573562
Mendeliome v1.1255 EFCAB7 Melanie Marty gene: EFCAB7 was added
gene: EFCAB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB7 were set to PMID: 37684519
Phenotypes for gene: EFCAB7 were set to Polydactyly (MONDO:0021003), EFCAB7-related
Review for gene: EFCAB7 was set to AMBER
Added comment: PMID: 37684519: two homozygous frameshift variants were identified by exome sequencing in four consanguinous Pakistani families, 3 families with p.(Gly277Valfs*5) and 1 family with p.(Asn451Phefs*2). Variants segregated with disease and het carriers were unaffected. Counting as 2 families to be conservative.
Sources: Literature
Mendeliome v1.1254 CFAP20 Sarah Pantaleo gene: CFAP20 was added
gene: CFAP20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP20 were set to PMID:36329026
Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200)
Review for gene: CFAP20 was set to GREEN
Added comment: CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development.

Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy (retinitis pigments). Hence, CFAP20 functions within a structural./functional hub centred on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associaetd domains or macromolecular complexes.

Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin.

Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate.
Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5)
Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly).
Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys)

For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old).

Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues.
Sources: Literature
Mendeliome v1.1252 MYCN Naomi Baker reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:37710961; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), MYCN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1251 CDC23 Michelle Torres gene: CDC23 was added
gene: CDC23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC23 were set to 37768355
Phenotypes for gene: CDC23 were set to inherited oocyte maturation defect MONDO#0014769, CDC23-related
Review for gene: CDC23 was set to GREEN
Added comment: Two missense variants, p.(Y329C) and p.(R330C), detected in three unrelated homozygous infertile females characterised by oocyte maturation defects.

In vitro studies using HeLa cells showed either decreased protein levels (Y329C) or impaired localisation (R330C). In vivo studies in mice homozygous for Y329C reproduced patient’s phenotype.
Sources: Literature
Mendeliome v1.1251 GPRASP1 Paul De Fazio gene: GPRASP1 was added
gene: GPRASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPRASP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPRASP1 were set to 37787182
Phenotypes for gene: GPRASP1 were set to Arteriovenous hemangioma/malformation, GPRASP1-related, MONDO:0001256
Penetrance for gene: GPRASP1 were set to unknown
Review for gene: GPRASP1 was set to AMBER
gene: GPRASP1 was marked as current diagnostic
Added comment: Two hemizygous germline missense variants, p.Arg1167Trp and p.Trp553Cys, were identified in three male patients presenting with spinal AVM, Cobb syndrome, or scalp AVM. The variants were inherited from unaffected heterozygous mothers. Note that p.Arg1167Trp has hemizygous (>70) and homozygous individuals reported in gnomAD.

The variants were found to result in LoF in endothelial cells. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral hemorrhage, AVMs, and exhibited vascular anomalies in multiple organs.
Sources: Literature
Mendeliome v1.1251 COG3 Daniel Flanagan gene: COG3 was added
gene: COG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to PMID: 37711075
Phenotypes for gene: COG3 were set to Neurodevelopmental disorder (MONDO#0700092), COG3-related
Review for gene: COG3 was set to AMBER
Added comment: Two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings.
Sources: Expert list
Mendeliome v1.1250 ATP2B2 Zornitza Stark Publications for gene: ATP2B2 were set to 30535804; 15829536
Mendeliome v1.1249 MAST4 Ain Roesley gene: MAST4 was added
gene: MAST4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Penetrance for gene: MAST4 were set to Complete
Review for gene: MAST4 was set to GREEN
gene: MAST4 was marked as current diagnostic
Added comment: PMID: 36910266 - 4 families with 4 affecteds, all de novo missense

2x borderline microcephaly (-2SD)
2x gross motor delay
2x dysmorphism
4x ID + seizures
3x abnormal brain MRI findings

PMID: 33057194 - 5x de novos, 4x missense + 1x PTC
Cohort of individuals with severe developmental disorder
individual phenotypic information not provided


Recurrent variants are Thr1471Ile (3x) and Ser1181Phe)
Sources: Literature
Mendeliome v1.1247 ZBTB47 Elena Savva gene: ZBTB47 was added
gene: ZBTB47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Review for gene: ZBTB47 was set to GREEN
Added comment: PMID 37743782:
- 5 patients with de novo missense, 4/5 have a recurring p.Gly477Lys. Probands have intellectual disability (5/5), seizures (5/5), hypotonia (5/5), gait abnormalities, and variable movement abnormalities (5/5).
- Missense variants are positioned close to His and Cys residues involved in forming C2H2 zinc fingers.
- No functional studies performed
- Minimal PTCs in gnomAD
Sources: Literature
Mendeliome v1.1245 ATP2B2 Andrew Fennell reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 37675773; Phenotypes: Neurodevelopmental Disorder, MONDO:0700092, ATP2B2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1245 KIF4A Lucy Spencer reviewed gene: KIF4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31616463; Phenotypes: Taurodontism, microdontia, and dens invaginatus (MIM#313490); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1229 CASP4 Zornitza Stark gene: CASP4 was added
gene: CASP4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CASP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP4 were set to 37647624
Phenotypes for gene: CASP4 were set to Hereditary susceptibility to infection, MONDO:0015979, CASP4-related; Susceptibility to meliodiosis
Review for gene: CASP4 was set to RED
Added comment: Single patient with severe disease secondary to B. pseudomallei requiring ECMO. Adjunctive IFN-γ administration as replacement for its failed induction by IL-18 promptly led to clearance of B. pseudomallei and subsequent weaning of support. Novel homozygous missense mutation in CASP4, at exon 7 c.1030C > T. Peripheral blood mononuclear cells (PBMC) of the patient and her parents showed reduced IFN-γ production, notably to IL-12 stimulation, and decreased IL-18 in response to LPS and increased IL-1B. Cloned cells show impacts on CASP4 activation and pyroptosis.
Sources: Expert Review
Mendeliome v1.1226 IL36RN Zornitza Stark edited their review of gene: IL36RN: Added comment: Monoallelic disease: Multiple patients with systemic inflammation with monoallelic variants in IL36RN suggesting a gene dosage effect whereby GPP onset is significantly delayed in subjects with monoallelic mutations but still at high risk of systemic inflammation.; Changed publications: 21848462, 21839423, 22903787, 23648549, 25458002; Changed phenotypes: Psoriasis 14, pustular, MIM# 614204, Autoinflammatory syndrome, MONDO:0019751, IL36RN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1210 ASTN2 Zornitza Stark Publications for gene: ASTN2 were set to 28940097
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed publications: 28940097, 34412080, 27138430
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Added comment: Rare CNVs also reported.; Changed publications: 28940097, 34412080
Mendeliome v1.1189 MCCC1 Bryony Thompson Publications for gene: MCCC1 were set to 27604308; 11170888; 31730530
Mendeliome v1.1188 MCCC1 Bryony Thompson reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36822454, 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1182 AKR1E2 Zornitza Stark Phenotypes for gene: AKR1E2 were changed from congenital cataracts to Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1181 AKR1E2 Zornitza Stark edited their review of gene: AKR1E2: Changed phenotypes: Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1180 AKNA Zornitza Stark reviewed gene: AKNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, AKNA-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1177 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, AGMO-related; Mode of inheritance: None
Mendeliome v1.1174 SEMA3E Zornitza Stark Publications for gene: SEMA3E were set to 15235037; 31691538; 31464029
Mendeliome v1.1173 SEMA3E Lucy Spencer reviewed gene: SEMA3E: Rating: AMBER; Mode of pathogenicity: None; Publications: 15235037, 31691538, 31464029, 35628442, 32441320; Phenotypes: CHARGE syndrome MONDO:0008965, SEMA3E-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1172 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fliedner-Zweier syndrome, MIM#620511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1171 NR2F2 Zornitza Stark Publications for gene: NR2F2 were set to 24702954; 29478779; 31687637; 27363585; 29222010; 29663647
Mendeliome v1.1170 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37500725; Phenotypes: Syndromic disease, MONDO:0002254, NR2F2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1168 KLK11 Zornitza Stark gene: KLK11 was added
gene: KLK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK11 were set to 36689511; 37212630
Phenotypes for gene: KLK11 were set to Ichthyosis with erythrokeratoderma, MIM# 620507
Review for gene: KLK11 was set to GREEN
Added comment: Four families reported: one multiplex with variant segregating with disease in 4 affected and 4 unaffected individuals. Three additional families with de novo variants.
Sources: Literature
Mendeliome v1.1166 FTCD Bryony Thompson Publications for gene: FTCD were set to 27604308; 12815595
Mendeliome v1.1165 FTCD Bryony Thompson edited their review of gene: FTCD: Changed publications: http://iembase.com/disorder/47
Mendeliome v1.1165 FTCD Bryony Thompson changed review comment from: Well-established gene-disease association (see OMIM entry). Glutamate formiminotransferase deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism.
Sources: NHS GMS; to: Glutamate formiminotransferase deficiency is classified as a benign form of folate metabolism disorder and an inborn error of amino acid metabolism without clinically significant phenotype (http://iembase.com/disorder/47).
Mendeliome v1.1163 GJA4 Zornitza Stark gene: GJA4 was added
gene: GJA4 was added to Mendeliome. Sources: Expert Review
somatic tags were added to gene: GJA4.
Mode of inheritance for gene: GJA4 was set to Other
Publications for gene: GJA4 were set to 33912852
Phenotypes for gene: GJA4 were set to Cavernous hemangioma, MONDO:0003155, GJA4-related
Review for gene: GJA4 was set to GREEN
Added comment: Recurrent somatic GJA4 c.121G>T (p.Gly41Cys) mutation as a driver of hepatic (n=12) and cutaneous (n=3) vascular malformations. Induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation, in lentiviral transduction of primary human endothelial cells.
Sources: Expert Review
Mendeliome v1.1161 COL4A3BP Zornitza Stark Publications for gene: COL4A3BP were set to 25533962
Mendeliome v1.1158 DBR1 Zornitza Stark edited their review of gene: DBR1: Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Total of 7 affected children. WES done for one proband from each family.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed publications: 29474921, 37656279; Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem, Ichthyosis (MONDO#0019269), DBR1-related
Mendeliome v1.1157 APOO Zornitza Stark Publications for gene: APOO were set to 32439808
Mendeliome v1.1156 APOO Zornitza Stark edited their review of gene: APOO: Added comment: PMID: 37649161
1 family, 2 individuals (male & female) with same NMD variant c.532G>T (p.E178*), maternally inherited (mother unaffected).

Both died before 18 months of age with partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies.
Other phenotypes included partial syndactyly of the 2nd and 3rd toes, wrinkled palm, and sole skin.

Functional studies included site directed mutagenesis. This mutation resulted in a highly unstable and degradation
prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and
interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells.; Changed publications: 37649161; Changed phenotypes: Mitochondrial disease, MONDO:0044970, APOO-related, Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour
Mendeliome v1.1156 RAB5C Rylee Peters changed review comment from: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature; to: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1156 DBR1 Chern Lim reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37656279; Phenotypes: Ichthyosis (MONDO#0019269), DBR1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1155 CAP2 Zornitza Stark Publications for gene: CAP2 were set to 30518548
Mendeliome v1.1153 CAP2 Zornitza Stark reviewed gene: CAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30518548, 33083013, 34862840; Phenotypes: Cardiomyopathy, dilated, 2I (MIM#620462); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1153 COL4A3BP Ee Ming Wong reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36976648; Phenotypes: Intellectual developmental disorder 34 (MIM#616351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1152 RAB5C Rylee Peters gene: RAB5C was added
gene: RAB5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to PMID: 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Penetrance for gene: RAB5C were set to Complete
Review for gene: RAB5C was set to GREEN
gene: RAB5C was marked as current diagnostic
Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1152 AXIN1 Elena Savva Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864 to Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related
Mendeliome v1.1152 AXIN1 Elena Savva Publications for gene: AXIN1 were set to 9335612
Mendeliome v1.1148 PPP1R3F Andrew Fennell gene: PPP1R3F was added
gene: PPP1R3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Review for gene: PPP1R3F was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1148 LAMA3 Bryony Thompson Publications for gene: LAMA3 were set to 7633458; 8530087; 11810295; 10366601
Mendeliome v1.1147 FTH1 Bryony Thompson Publications for gene: FTH1 were set to 11389486; 36778397
Mendeliome v1.1145 FTH1 Bryony Thompson Added comment: Comment on list classification: Article describing the gene-disease association with neuroferritinopathy now published in HGG advances
Mendeliome v1.1143 C3 Ain Roesley Publications for gene: C3 were set to 15781264; 1944729; 11813855; 26847111
Mendeliome v1.1142 SLC30A7 Zornitza Stark reviewed gene: SLC30A7: Rating: RED; Mode of pathogenicity: None; Publications: 36821639; Phenotypes: Ziegler-Huang syndrome, MIM# 620501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1141 SOX11 Zornitza Stark Publications for gene: SOX11 were set to 29459093; 24886874
Mendeliome v1.1140 SOX11 Zornitza Stark edited their review of gene: SOX11: Added comment: Over 40 additional individuals reported, e.g. PMID 35341651. The phenotype that has emerged over time is distinct from patients with mutations in ARID1B (614556) and Coffin-Siris syndrome-1 (135900). Patients with IDDMOH tend to be microcephalic and have ocular motor apraxia, abnormal eye morphology, or hypogonadotropic hypogonadism.; Changed publications: 29459093, 24886874, 33086258, 33785884, 35642566, 35341651
Mendeliome v1.1139 PTCD3 Zornitza Stark Publications for gene: PTCD3 were set to 30607703; 19427859
Mendeliome v1.1137 PTCD3 Zornitza Stark edited their review of gene: PTCD3: Added comment: Three additional families reported.; Changed rating: GREEN; Changed publications: 30607703, 19427859, 36450274
Mendeliome v1.1135 MRM2 Zornitza Stark edited their review of gene: MRM2: Added comment: Two additional families reported.; Changed rating: GREEN; Changed publications: 28973171, 36002240; Changed phenotypes: Mitochondrial DNA depletion syndrome 17, MIM# 618567
Mendeliome v1.1135 COX5A Zornitza Stark Publications for gene: COX5A were set to 2824752
Mendeliome v1.1133 COX5A Zornitza Stark edited their review of gene: COX5A: Added comment: Second family reported, albeit hmz missense.; Changed rating: AMBER; Changed publications: 35246835, 28247525
Mendeliome v1.1127 SRSF1 Zornitza Stark reviewed gene: SRSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 620489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1125 THPO Zornitza Stark edited their review of gene: THPO: Added comment: 5 families reported with bi-allelic variants and thrombocytopenia with progression to pancytopenia, aplastic anemia, and bone marrow failure.; Changed publications: 9425899, 10583217, 32150607, 28466964, 24085763, 28559357, 29191945, 36226497; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478, Amegakaryocytic thrombocytopenia, congenital, 2, MIM# 620481; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1125 NEUROG1 Achchuthan Shanmugasundram gene: NEUROG1 was added
gene: NEUROG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Phenotypes for gene: NEUROG1 were set to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Review for gene: NEUROG1 was set to GREEN
Added comment: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be added with green rating in the intellectual disability panel.

PMID:23419067 - A homozygous micro deletion of NEUROG1 was identified in a six year-old boy presenting with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild global developmental delay. His IQ was normal.

PMID:26077850 - A homozygous NEUROG1 variant (p.Arg116Leu) was identified in a 12 year-old boy presented with syndromic corneal opacity, mild intellectual disability and absent corneal reflex.

PMID:33439489 - A homozygous loss-of-function variant (p.Glu68Ter) was identified in a 12 year-old boy presenting with hypotonia, global developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. This patient had a global IQ of 62 at the age of ten.

PMID:36647078 - A female proband was identified with a novel homozygous truncating frameshift variant (p.Thr78ProfsTer122 and was reported with profound global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her sister also had a similar, but less severe phenotype and also harboured the same variant at homozygous state.

This gene has been associated with relevant phenotypes in OMIM (MIM #620469), but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.1123 PPOX Zornitza Stark Publications for gene: PPOX were set to 12357337; 32247286; 23324528; 27982422
Mendeliome v1.1121 PPOX Zornitza Stark edited their review of gene: PPOX: Added comment: Bi-allelic variants cause childhood onset disease.; Changed publications: 12357337, 32247286, 23324528, 27982422, 9811936, 11286631, 33159949; Changed phenotypes: Porphyria variegata , MIM#176200, Variegate porphyria, childhood-onset, MIM# 620483; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1120 THPO Zornitza Stark Publications for gene: THPO were set to 9425899; 10583217
Mendeliome v1.1119 THPO Zornitza Stark edited their review of gene: THPO: Added comment: Thrombocytopenia: 5 unrelated families reported.; Changed publications: 9425899, 10583217, 32150607, 28466964; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478
Mendeliome v1.1118 ACTB Zornitza Stark reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombocytopenia 8, with dysmorphic features and developmental delay, MIM# 620475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1117 APOL1 Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021
Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2.
PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance.
PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN
rs73885319 (G1) OR 9.66, p=9.97E-25
rs60910145 (G1) OR 9.75, p=9.04E-24
rs71785313 (G2) OR 5.69, p=3.39E-06
2 APOL1 risk alleles OR 18.31, p=3.31E-58
PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease
G1:
p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes)
p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes)
G2:
p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes

AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER
Mendeliome v1.1117 GOSR2 Achchuthan Shanmugasundram reviewed gene: GOSR2: Rating: RED; Mode of pathogenicity: None; Publications: 37074134; Phenotypes: hearing loss, autosomal recessive, MONDO:0019588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1116 DDRGK1 Ain Roesley gene: DDRGK1 was added
gene: DDRGK1 was added to Mendeliome. Sources: Literature
founder tags were added to gene: DDRGK1.
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type (MIM#602557)
Review for gene: DDRGK1 was set to GREEN
gene: DDRGK1 was marked as current diagnostic
Added comment: RNA and protein studies performed for the splice variant. These two variants likely represents founder variants

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).
Sources: Literature
Mendeliome v1.1113 FBXO31 Zornitza Stark Publications for gene: FBXO31 were set to 24623383; 32989326
Mendeliome v1.1111 FBXO31 Ain Roesley reviewed gene: FBXO31: Rating: AMBER; Mode of pathogenicity: None; Publications: 35019165, 24623383; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1111 TBL1XR1 Achchuthan Shanmugasundram reviewed gene: TBL1XR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28687524, 37010288; Phenotypes: Pierpont syndrome, OMIM:602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1111 NEB Achchuthan Shanmugasundram reviewed gene: NEB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12207937, 21798101, 33376055, 37010288; Phenotypes: Arthrogryposis multiplex congenita 6, OMIM:619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 ECEL1 Achchuthan Shanmugasundram reviewed gene: ECEL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30131190, 37010288; Phenotypes: Arthrogryposis, distal, type 5D, OMIM:615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 CCT5 Bryony Thompson edited their review of gene: CCT5: Added comment: Now two families reported with two different missense variants (Leu224Val and His147Arg).; Changed publications: 16399879, 25124038, 25345891, 33076433, 37237456
Mendeliome v1.1108 HNRNPC Zornitza Stark gene: HNRNPC was added
gene: HNRNPC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189
Phenotypes for gene: HNRNPC were set to Neurodevelopmental disorder (MONDO:0700092), HNRNPC-related
Review for gene: HNRNPC was set to GREEN
Added comment: 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five had an identical in-frame deletion of nine amino acids in the extreme C terminus. Supportive functional data; haploinsufficiency is the mechanism.
Sources: Literature
Mendeliome v1.1107 PSMC3 Zornitza Stark Phenotypes for gene: PSMC3 were changed from Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354 to neurodevelopmental disorder, MONDO:0700092, PSMC3-related; Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v1.1106 PSMC3 Zornitza Stark Publications for gene: PSMC3 were set to 32500975
Mendeliome v1.1103 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Added comment: PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.; Changed rating: GREEN; Changed publications: 32500975, 37256937; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, PSMC3-related, Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1103 EMC1 Zornitza Stark Publications for gene: EMC1 were set to 26942288; 29271071
Mendeliome v1.1101 EMC1 Chern Lim reviewed gene: EMC1: Rating: ; Mode of pathogenicity: None; Publications: 35234901, 26942288; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1101 RELA Zornitza Stark Publications for gene: RELA were set to 28600438; 29305315
Mendeliome v1.1099 RELA Zornitza Stark edited their review of gene: RELA: Added comment: Additional 6 individuals from two families reported.; Changed rating: GREEN; Changed publications: 28600438, 29305315, 37273177; Changed phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias
Mendeliome v1.1097 DPP9 Zornitza Stark Publications for gene: DPP9 were set to 36112693
Mendeliome v1.1095 DPP9 Zornitza Stark edited their review of gene: DPP9: Added comment: Amber for mono-allelic association:

de novo monoallelic dominant-negative mutation in DPP9 (c.755G>C, R252P) presenting with HLH at ~2m. Functional data supporting dominant negative mechanism.; Changed publications: 36112693, 37544411; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1095 PDGFD Zornitza Stark gene: PDGFD was added
gene: PDGFD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PDGFD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFD were set to 33187088; 33971972
Phenotypes for gene: PDGFD were set to Pulmonary arterial hypertension MONDO:0015924, PDGFD-related
Review for gene: PDGFD was set to RED
Added comment: Rated as LIMITED by ClinGen. 10 unique variants (all missense) that have been reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. 9 of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). Gelinas et al. also reported a missense PDGFD variant in a proband with IPAH (PMID:33187088). There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans.
Sources: Expert list
Mendeliome v1.1093 FBLN2 Zornitza Stark gene: FBLN2 was added
gene: FBLN2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBLN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBLN2 were set to 33971972
Phenotypes for gene: FBLN2 were set to Pulmonary arterial hypertension MONDO:0015924, FBLN2-related
Review for gene: FBLN2 was set to RED
Added comment: LIMITED by ClinGen. Out of a cohort of 1647 idiopathic PAH cases, 3 rare predicted deleterious missense variants were identified in 6 unrelated individuals with one variant recurrent in four individuals. Gene-disease association also supported by tissue expression data.
Sources: Expert list
Mendeliome v1.1091 AQP1 Zornitza Stark Publications for gene: AQP1 were set to PMID:22683574; 29650961
Mendeliome v1.1089 AQP1 Zornitza Stark reviewed gene: AQP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37007933, 35627312; Phenotypes: Pulmonary arterial hypertension MONDO:0015924, AQP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1088 TET2 Zornitza Stark Publications for gene: TET2 were set to 30890702; 31827242; 32330418
Mendeliome v1.1087 TET2 Zornitza Stark edited their review of gene: TET2: Added comment: Association with PAH:
MODERATE by ClinGen. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.; Changed publications: 30890702, 31827242, 32330418, 32518946, 32192357; Changed phenotypes: Dementia, Lymphoma/myeloid malignancy, Immunodeficiency-75 (IMD75), MIM#619126, Pulmonary arterial hypertension MONDO:0015924, TET2-related
Mendeliome v1.1084 PRDM10 Zornitza Stark reviewed gene: PRDM10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Birt-Hogg-Dube syndrome 2, MIM# 620459; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1083 IL1R1 Zornitza Stark gene: IL1R1 was added
gene: IL1R1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IL1R1 were set to 37315560
Phenotypes for gene: IL1R1 were set to Chronic recurrent multifocal osteomyelitis 3, MIM# 259680
Review for gene: IL1R1 was set to RED
Added comment: Single individual reported with de novo missense variant in this gene and a phenotype of chronic recurrent multifocal osteomyelitis, auto inflammatory in nature. Some functional data presented.
Sources: Literature
Mendeliome v1.1079 SMARCA4 Zornitza Stark Publications for gene: SMARCA4 were set to 22426308
Mendeliome v1.1074 EZH1 Zornitza Stark gene: EZH1 was added
gene: EZH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EZH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EZH1 were set to 37433783
Phenotypes for gene: EZH1 were set to Neurodevelopmental disorder (MONDO:0700092), EZH1-related
Review for gene: EZH1 was set to GREEN
Added comment: PMID: 37433783
Variants were identified 19 individuals from 14 unrelated families, all sharing a clinical phenotype of a neurodevelopmental disorder manifested early in life as global motor, speech and cognitive delay leading to intellectual disability, usually non-progressive and co-occurring with dysmorphic facial features.

Functional studies have shown that some missense EZH1 variants lead to GOF with increased methyltransferase activity and recessive variants impair EZH1 expression causing loss of function effects.
Sources: Literature
Mendeliome v1.1071 CANVAS Dean Phelan reviewed STR: CANVAS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37450567; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (MIM:614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1071 PHF5A Daniel Flanagan gene: PHF5A was added
gene: PHF5A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF5A were set to PMID: 37422718
Phenotypes for gene: PHF5A were set to Neurodevelopmental disorder (MONDO#0700092), PHF5A-related
Review for gene: PHF5A was set to GREEN
Added comment: Nine subjects with congenital malformations, including hypospadias, growth abnormalities, and developmental delay who had de novo PHF5A variants. Prenatally, six subjects had intrauterine growth retardation. All subjects had motor and speech delay and developmental delay. Congenital abnormalities comprised hypospadias in three of four male subjects, and heart defects (3/9), inguinal hernia (3/9), and sacral dimple (3/9). Six of the nine subjects had short stature. Craniofacial dysmorphism is variable in the nine subjects, high forehead and preauricular skin tag(s) in five subjects.
Sources: Expert list
Mendeliome v1.1071 TBC1D31 Lilian Downie gene: TBC1D31 was added
gene: TBC1D31 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBC1D31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D31 were set to PMID: 37468454
Phenotypes for gene: TBC1D31 were set to congenital anomaly of kidney and urinary tract MONDO:0019719
Review for gene: TBC1D31 was set to RED
Added comment: Single paper with homozygous mutations in 3 sibs with CAKUT from consanguineous family
Sources: Literature
Mendeliome v1.1071 AQP4 Lucy Spencer gene: AQP4 was added
gene: AQP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AQP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AQP4 were set to 37143309
Phenotypes for gene: AQP4 were set to ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448
Review for gene: AQP4 was set to AMBER
Added comment: PMID: 37143309
Cohort of patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Missense variant in AQP4 seen homozygous in 2 siblings and het in the parents. Patients had macrocephaly, developmental delay, hypotonia, epilepsy, and cognitive deficit.

Western blots on generated MDCK cell lines showed no detectable expression of AQP4 protein from the cells with the patients variant. Immunofluorescence also showed no membrane expression. Overexpression studies in HEK293T cells showed WT was seen as mainly monomers or dimers where as variant protein formed large aggregates- likely due to the saturation of protein degradation pathways because of the overexpression.
Sources: Literature
Mendeliome v1.1071 GPRC5B Lucy Spencer gene: GPRC5B was added
gene: GPRC5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPRC5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPRC5B were set to 37143309
Phenotypes for gene: GPRC5B were set to Megalencephalic leukoencephalopathy with subcortical cysts 3 620447
Review for gene: GPRC5B was set to GREEN
Added comment: PMID: 37143309
Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). 3 unrelated patients had variants in GPRC5B, 2 have the same inframe dup Ile175dup and the third has an in frame dup of Ala177. All 3 were de novo and unaffected siblings did not have the variants. All patients have macrocephaly, delayed motor development, seizures, all had varying degrees of cognitive deficits. 2 also had spasticity, ataxia and dystonia. MRI showed MLC, abnormal and swollen cerebral white matter.

Patient cell lines showed reduced regulatory volume decrease, and western blot showed a strong increase in GRPC5B levels in patient lymphoblasts. Together, these findings indicate disturbed volume regulation in lymphoblasts from patients with GPRC5B variants, potentially due to increased GPRC5B levels. Transfected cells caused increased volume-regulated anion channel activity.
Sources: Literature
Mendeliome v1.1069 PTPA Zornitza Stark Publications for gene: PTPA were set to 36073231
Mendeliome v1.1068 MAMDC2 Belinda Chong gene: MAMDC2 was added
gene: MAMDC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAMDC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAMDC2 were set to 37503746
Phenotypes for gene: MAMDC2 were set to Muscular Dystrophy MONDO:0020121, MAMDC2-related
Review for gene: MAMDC2 was set to AMBER
Added comment: 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease.
Sources: Literature
Mendeliome v1.1064 COX18 Naomi Baker gene: COX18 was added
gene: COX18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to PMID:37468577
Phenotypes for gene: COX18 were set to Mitochondrial disease (MONDO:0044970), COX18-related
Review for gene: COX18 was set to RED
Added comment: Paper reports a single patient with a homozygous COX18 missense variant, with a neonatal form of mitochondrial hypertrophic cardiomyopathy, lactic acidosis, failure to thrive and neurological involvement associated with severe skeletal muscle COX deficiency. Functional studies demonstrated COX deficiency which could be partially rescued with over-expression of COX18.
Sources: Literature
Mendeliome v1.1064 TUFM Ain Roesley reviewed gene: TUFM: Rating: RED; Mode of pathogenicity: None; Publications: 37461298; Phenotypes: Inherited primary ovarian failure MONDO:0019852, TUFM-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1064 STAT4 Elena Savva Publications for gene: STAT4 were set to
Mendeliome v1.1064 STAB1 Chern Lim gene: STAB1 was added
gene: STAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAB1 were set to 37490907; 28052375
Phenotypes for gene: STAB1 were set to Iron metabolism disease (MONDO:0002279), STAB1-related
Review for gene: STAB1 was set to GREEN
gene: STAB1 was marked as current diagnostic
Added comment: PMID: 37490907
- Biallelic variants identified in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.
- Homozygous/compound heterozygous variants: missense, frameshift, stopgain, inframe del of 3 AAs, one synonymous.
- Samples from three of the patients from two families showed no immunoreactivity with anti-stabilin-1 compared to control liver where high signal was detected in the liver sinusoids (immunohistochemistry analysis).
- Patients’ peripheral monocytes and monocyte-derived macrophages showed very little expression of stabilin-1 on CD14+ monocytes and macrophages compared to control subjects (flow cytometry analysis).
- These families have also been published in PMID: 28052375.
Sources: Literature
Mendeliome v1.1063 PTPA Ee Ming Wong reviewed gene: PTPA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37448355; Phenotypes: Intellectual disability, MONDO: 36073231, PTPA-related, Parkisonism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1062 SMARCA4 Paul De Fazio reviewed gene: SMARCA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 37399313; Phenotypes: Otosclerosis MONDO:0005349, SMARCA4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.1062 NAA30 Sarah Pantaleo gene: NAA30 was added
gene: NAA30 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAA30 was set to Unknown
Publications for gene: NAA30 were set to PMID: 37387332
Penetrance for gene: NAA30 were set to unknown
Added comment: Report a de novo heterozygous NAA30 nonsense variant c.244C>T, p.(Gln82*) in a 5yo boy with GDD, ASD, hypotonia, seizures, tracheal cleft and recurrent respiratory infections. Seizures resolved after two weeks of life. Family history of ASD in older sister. Epilepsy in mother, childhood onset.

Biochemical studies performed to assess the functional impact of the premature stop codon on catalytic activity. The variant was found to completely disrupt N-terminal acetyltransferase activity using an in vitro acetylation assay.

Variant de novo, “in a gene sensitive to loss of heterozygosity”. Limitation of study - have not established whether this gene variant acts in a dominant or recessive manner.
Sources: Literature
Mendeliome v1.1062 PIP5K1C Elena Savva Publications for gene: PIP5K1C were set to 17701898
Mendeliome v1.1061 PEX14 Lilian Downie reviewed gene: PEX14: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37493040; Phenotypes: peroxisome biogenesis disorder due to PEX14 defect MONDO:0100268; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1060 STAT4 Melanie Marty reviewed gene: STAT4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 37256972; Phenotypes: Disabling pansclerotic morphea, inflammatory disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1060 SENP7 Elena Savva gene: SENP7 was added
gene: SENP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SENP7 were set to PMID: 37460201
Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related
Review for gene: SENP7 was set to AMBER
Added comment: PMID: 37460201
- 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically.
- Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome.
- Additional studies performed supporting downstream proteins expression being affected
- Neutropenia observed in 2/3 patients
Sources: Literature
Mendeliome v1.1059 STX5 Ain Roesley Publications for gene: STX5 were set to
Mendeliome v1.1057 SLC4A10 Krithika Murali gene: SLC4A10 was added
gene: SLC4A10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A10 were set to PMID: 37459438
Phenotypes for gene: SLC4A10 were set to Neurodevelopmental disorderMONDO:0700092, SLC4A10-related
Review for gene: SLC4A10 was set to GREEN
Added comment: PMID: 37459438 Fasham et al 2023 (Brain) report 10 affected individuals from 5 unrelated families with biallelic LoF variants in this gene with a novel neurodevelopmental disorder.

Phenotypic features include hypotonia in infancy, delayed psychomotor development, typically severe ID, progressive postnatal microcephaly, ASD traits, corpus callosal abnormalities and 'slit-like' lateral ventricles. These phenotypic features were recapitulated in knockout mice with additional supportive functional studies.

Isolated seizures was reported in 2/10 cases.
Sources: Literature
Mendeliome v1.1056 KDM4B Sarah Pantaleo reviewed gene: KDM4B: Rating: ; Mode of pathogenicity: None; Publications: PMID: 37526414; Phenotypes: Intellectual developmental disorder, autosomal dominant 65, MIM#619320; Mode of inheritance: None
Mendeliome v1.1056 STX5 Ain Roesley edited their review of gene: STX5: Changed publications: 34711829
Mendeliome v1.1056 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645; 36847845
Mendeliome v1.1054 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Additional individual with isolated, early-onset dystonia reported.

It is likely these clinical presentations are part of a spectrum.; Changed rating: GREEN; Changed publications: 34542157, 29178645, 36847845, 37475611
Mendeliome v1.1052 TEP1 Zornitza Stark gene: TEP1 was added
gene: TEP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TEP1 were set to 34543729
Phenotypes for gene: TEP1 were set to Cerebral palsy, MONDO:0006497, TEP1-related
Review for gene: TEP1 was set to AMBER
Added comment: Wang et al. screened a large cohort of more than 600 CP patients from China and found several variants in TEP1, 11 of which were LoF, while no LoF variant was found in the control cohort. These children all had spastic CP. Among these 11 children, 6 children had birth asphyxia and neonatal encephalopathy. Compared to the total group with birth asphyxia (71/667), 6 patients with TEP1 LOF mutations had a significantly greater risk of birth asphyxia. They confirmed TEP1 as a risk factor for CP by cytological and animal models.

Uncertain if these are risk alleles vs indicative of a monogenic disorder. Note LoF variants in gnomad. As this was a cohort study, inheritance of these variants is unknown.
Sources: Literature
Mendeliome v1.1049 TINF2 Sangavi Sivagnanasundram reviewed gene: TINF2: Rating: AMBER; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.xhgg.2023.100225; Phenotypes: Multiple Primary Melanomas (MPM); Mode of inheritance: Unknown
Mendeliome v1.1049 LAMA3 Sangavi Sivagnanasundram reviewed gene: LAMA3: Rating: AMBER; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.xhgg.2023.100227; Phenotypes: Ebstein’s anomaly (MIM#224700); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1049 DUSP7 Sangavi Sivagnanasundram gene: DUSP7 was added
gene: DUSP7 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DUSP7 was set to Unknown
Publications for gene: DUSP7 were set to https://doi.org/10.1155/2023/4348290
Phenotypes for gene: DUSP7 were set to Acute Myeloid Leukemia (AML)
Review for gene: DUSP7 was set to RED
Added comment: New gene with an association in AML prognosis.

Gao (2023) - Recruitment from three public AML cohorts - GSE71014, TARGET-AML, and TCGA-AML.
The study results suggest that with an DUSP7 may affect AML progression in individuals by affecting the recruitment of local immune cells.
Sources: Other
Mendeliome v1.1045 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Mendeliome v1.1045 DHX9 Achchuthan Shanmugasundram gene: DHX9 was added
gene: DHX9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37467750
Phenotypes for gene: DHX9 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Charcot-Marie-Tooth disease, MONDO:0015626
Review for gene: DHX9 was set to GREEN
Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old). The three cases with CMT presented with adult-onset axonal neuropathy.
Sources: Literature
Mendeliome v1.1045 MCOLN1 Achchuthan Shanmugasundram reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17239335, 25156245, 33965501, 35205297; Phenotypes: Mucolipidosis IV, OMIM:252650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1044 KLK1 Zornitza Stark Publications for gene: KLK1 were set to
Mendeliome v1.1042 KLK1 Zornitza Stark edited their review of gene: KLK1: Added comment: Association with PAH:

PMID: 31727138
screening of the biobank - 12 individuals with genetic variant in KLK1 relevant to PAH (not all were found to be hereditary). Assay showed that carriers of variants in KLK1 are less clinically severe compared to those who carry variants in BMPR2.

PMID: 17573418
Functional study using sensitive and specific type ELISAs to assay multiple panels of human tissue. KLK1 tissue was abundantly expressed in the pancreas and salivary gland and moderately expressed in the lungs.

Reviewed by ClinGen Pulmonary Hypertension GCEP on 30/8/2022 with LIMITED evidence supporting gene-disease validity; Changed publications: 31727138, 17573418; Changed phenotypes: [Kallikrein, decreased urinary activity of] 615953, Pulmonary arterial hypertension MONDO:0015924; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1028 TSPOAP1 Zornitza Stark reviewed gene: TSPOAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 22, MIM# 620453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1027 NAA60 Zornitza Stark Phenotypes for gene: NAA60 were changed from Basal ganglia calcification to Basal ganglia calcification, MONDO:0008947, NAA60-related
Mendeliome v1.1019 COL4A6 Zornitza Stark Publications for gene: COL4A6 were set to 23714752; 12784310
Mendeliome v1.1016 SLC4A3 Zornitza Stark Publications for gene: SLC4A3 were set to PMID: 29167417; 34557911
Mendeliome v1.1013 PLCG1 Zornitza Stark gene: PLCG1 was added
gene: PLCG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272
Phenotypes for gene: PLCG1 were set to Autoinflammatory syndrome, MONDO:0019751, PLCG1-related; Immune dysregulation
Mode of pathogenicity for gene: PLCG1 was set to Other
Review for gene: PLCG1 was set to AMBER
Added comment: Single 7yo proband presented with thrombocytopaenia and lymphadenopathy. De Novo , c.3062C>T, p.S1021F with functional testing supportive of GOF mechanism of disease
Sources: Expert Review
Mendeliome v1.1010 TBX6 Chirag Patel reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36112137, 36161696; Phenotypes: Mayer-Rokitansky-Küster-Hauser syndrome, Combined skeletal-kidney dysplasia syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1007 KDM2A Chirag Patel gene: KDM2A was added
gene: KDM2A was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder
Review for gene: KDM2A was set to GREEN
gene: KDM2A was marked as current diagnostic
Added comment: ESHG 2023:
14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense)
Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism.

Functional studies:
-patient blood showed aberrant genome wide methylation profile - potential episignature
-HEK293T cells showed altered subcellular localisation of KDM2A
-Drosophila models showed variants caused neurotoxicity
Sources: Other
Mendeliome v1.1005 PIP5K1C Chirag Patel reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder and microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1004 NSUN6 Chirag Patel reviewed gene: NSUN6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1003 INTS13 Chirag Patel gene: INTS13 was added
gene: INTS13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS13 were set to PMID: 36229431
Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome
Review for gene: INTS13 was set to GREEN
gene: INTS13 was marked as current diagnostic
Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies.
Sources: Literature
Mendeliome v1.1002 TUBB4B Chirag Patel reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1002 PTCH1 Chirag Patel reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bladder exstrophy and epispadias complex (BEEC); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.999 PMVK Zornitza Stark Publications for gene: PMVK were set to 26202976
Mendeliome v1.997 PMVK Zornitza Stark edited their review of gene: PMVK: Added comment: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; Changed publications: 26202976, 37364720, 36410683; Changed phenotypes: Porokeratosis 1, multiple types, MIM# 175800, Autoinflammatory syndrome, MONDO:0019751, PMVK-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.996 RIPK3 Zornitza Stark gene: RIPK3 was added
gene: RIPK3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RIPK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK3 were set to 37083451
Phenotypes for gene: RIPK3 were set to Hereditary susceptibility to infections, MONDO:0015979, RIPK3-related; Recurrent HSV encephalitis
Review for gene: RIPK3 was set to AMBER
Added comment: Single female patient with independent episodes of HSE at 6 and 17 months of age and with autoimmune encephalitis 1 month after the second episode of HSE with two heterozygous mutations of RIPK3 predicted to be loss of function (pLOF): p. Arg422* (c.1264 C > T, MAF 0.001568, CADD 35) and p. Pro493fs9* (c.1475 C > CC, MAF 0.002611, CADD 24.2). Extensive supportive functional data including RIPK3 knockout human pluripotent stem cell–derived cortical neurons.
Sources: Expert Review
Mendeliome v1.994 ANO1 Zornitza Stark Publications for gene: ANO1 were set to 32487539
Mendeliome v1.992 ANO1 Zornitza Stark edited their review of gene: ANO1: Added comment: PMID 37253099: screening analysis of Moyamoya disease (MMD) cohort revealed 8 individuals with variants in the ANO1 gene. Two families had the same rare variant p.Met658Val. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Amber rating due to somewhat conflicting segregation and functional data presented.; Changed publications: 37253099; Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease, MONDO:0016820, ANO1 related
Mendeliome v1.989 NAA60 Chirag Patel reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary familial brain calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.989 NAA60 Chirag Patel gene: NAA60 was added
gene: NAA60 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NAA60 were set to Basal ganglia calcification
Review for gene: NAA60 was set to GREEN
gene: NAA60 was marked as current diagnostic
Added comment: ESHG 2023:
10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift).
All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations).

NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain).
Sources: Other
Mendeliome v1.974 VGLL2 Chirag Patel gene: VGLL2 was added
gene: VGLL2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VGLL2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VGLL2 were set to Syngnathia
Review for gene: VGLL2 was set to GREEN
gene: VGLL2 was marked as current diagnostic
Added comment: ESHG 2023:
4 families/7 affected individuals with isolated unilateral/bilateral syngnathia
biallelic truncating variants in VGLL2
But not phenotype in KO mouse or zebrafish models
Sources: Other
Mendeliome v1.972 ITFG2 Chirag Patel reviewed gene: ITFG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.972 COL4A6 Ain Roesley reviewed gene: COL4A6: Rating: AMBER; Mode of pathogenicity: None; Publications: 33840813; Phenotypes: Deafness, X-linked 6 MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v1.972 RDH11 Elena Savva reviewed gene: RDH11: Rating: AMBER; Mode of pathogenicity: None; Publications: 24916380, 15634683, 30731079, 18326732, 34988992; Phenotypes: Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.972 SLC4A3 Chern Lim reviewed gene: SLC4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36806574; Phenotypes: Short QT syndrome 7, MIM#620231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.972 C1GALT1C1 Zornitza Stark reviewed gene: C1GALT1C1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37216524; Phenotypes: Haemolytic uraemic syndrome, atypical, 8, with rhizomelic short stature, MIM# 301110; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.971 ZMYM3 Zornitza Stark reviewed gene: ZMYM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 112, MIM# 301111; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.969 SMAD1 Bryony Thompson Added comment: Comment on list classification: Disputed gene-disease validity curation by ClinGen PH VCEP 21/11/2022 - Only two probands reported to have PAH and SMAD1 variants. The variants are missense variants without functional data at the time of curation. Thus, SMAD1 is classified as disputed for PAH based upon insufficient genetic evidence over multiple years of research.
Mendeliome v1.967 ZNF808 Krithika Murali Added comment: Comment on list classification: Green in Genomics England PanelApp neonatal diabetes panel with both of these papers cited in their review. Note that De Franco et al has not been peer-reviewed, however, the evidence provided is strong and from a reputable source.
Mendeliome v1.966 ZNF808 Hazel Phillimore gene: ZNF808 was added
gene: ZNF808 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF808 were set to PMID: 37308312
Phenotypes for gene: ZNF808 were set to non-syndromic neonatal diabetes; MONDO:0016391
Review for gene: ZNF808 was set to GREEN
Added comment: PMID: 37308312; Alqahtani, MA. et al. (2023) Clin Genet. doi: 10.1111/cge.14389.
Three siblings in one consanguineous Saudi Arabian family with non-syndromic neonatal diabetes, all with a homozygous frameshift variant, NM_001321425.2:c.1448dupA, p.(Tyr483*), in ZNF808. (Same nucleotide and amino acid numbering as for the MANE SELECT transcript, NM_001039886.4).
This variant has been entered as likely pathogenic in ClinVar by this group.
This variant occurs in the last exon of the gene and is therefore not NMD-predicted. Instead it is predicted to cause a truncated protein.
This paper shows a diagram with several other truncating variants in this exon, which were reported in the paper by De Franco, E. et al. (2021).
(These patients also had low vitamin D levels, suggesting an association, and is consistent with other studies looking into loci that are associated with vitamin D).

De Franco, E. et al. (2021) medRxiv 08.23.21262262. (Exeter, UK):
Firstly, this group found a homozygous variant NM_001039886.3:c.637del, p.(Leu213*) that is predicted to cause a truncated protein, and also a homozygous CNV Chr19(GRCh37):g.53057128_53100968del (predicted to cause a deletion of exons 4 and 5) in two unrelated affected individuals. These patients had pancreatic agenesis, defined as insulin-dependent diabetes in the first 6 months of life (neonatal diabetes) and exocrine pancreatic insufficiency. Both were from consanguineous families. Parents were subsequently tested and shown to be heterozygous carriers.
They then investigated 232 additional patients who had been diagnosed with neonatal diabetes before the age of 6 months and found ten more homozygous ZNF808 variants. Six were nonsense: p.(Gln194*), p.(Cys233*), p.(Tyr427*), p.(Lys458*), p.(Tyr528*) and p.(Arg727*), and three were frameshift variants: p.(Ala379Valfs*157), p.(Leu588Profs*118), p.(Asn770Ilefs*98) and one was a whole-gene deletion.
All the frameshift and nonsense variants occurred in the last exon of the gene, which contains all 23 zinc finger domains; and therefore all of these variants are predicted to result in truncated proteins, and removal of some, if not all, those domains.
This group also carried out functional studies using an in vitro model of pancreas development and showed an aberrant activation of many transposable elements (mostly MER11 elements) that would be normally be repressed during early pancreas development.
Sources: Literature
Mendeliome v1.965 SART3 Daniel Flanagan gene: SART3 was added
gene: SART3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SART3 were set to PMID: 37296101
Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related
Review for gene: SART3 was set to GREEN
Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG.

Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro.
Sources: Expert list
Mendeliome v1.962 NUDCD2 Ee Ming Wong gene: NUDCD2 was added
gene: NUDCD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD2 were set to 37272762
Phenotypes for gene: NUDCD2 were set to Multiple congenital anomalies (MONDO:0019042), NUDCD2-related
Penetrance for gene: NUDCD2 were set to unknown
Review for gene: NUDCD2 was set to AMBER
gene: NUDCD2 was marked as current diagnostic
Added comment: - Two unrelated probands, each biallelic for two variants in NUDCD2 (total 3x LoF variants, 1x missense variant)
- Immunoblotting of proteins extracted from the primary fibroblasts of one proband with 2x LoF variants demonstrated markedly reduced NUDCD2 levels compared to healthy individuals
Sources: Literature
Mendeliome v1.961 ARPC5 Paul De Fazio gene: ARPC5 was added
gene: ARPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARPC5 were set to 37349293; 37382373
Phenotypes for gene: ARPC5 were set to Combined immunodeficiency, ARPC5-related MONDO:0015131
Review for gene: ARPC5 was set to GREEN
gene: ARPC5 was marked as current diagnostic
Added comment: 4 individuals from 3 families reported with homozygous LoF variants. All had recurrent and severe infections. Other developmental anomalies were present but seemed variable.

PMID:37349293 reports 2 unrelated patients. Both had scoliosis. One had neurodevelopmental delay and brain atrophy. Patient 1 died at 15yo after a sudden episode of hemoptysis and hematochezia. Patient 2 died at 1yo because of progressive neurologic and respiratory disease; an autopsy was not performed.

PMID:37382373 reports 2 patients from the same family. One had multiple congenital anomalies including a congenital heart defect (CHD) (patent foramen ovale), cleft palate, and hypoplastic corpus callosum. The sibling also had CHD (moderate pulmonary stenosis and atrial septal defect).

Functional studies and a mouse model were supportive of the disease association.
Sources: Literature
Mendeliome v1.958 DCAF13 Michelle Torres gene: DCAF13 was added
gene: DCAF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DCAF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF13 were set to 36797467
Phenotypes for gene: DCAF13 were set to Neuromuscular disease (MONDO#0019056), DCAF13-related
Review for gene: DCAF13 was set to RED
Added comment: One consanguineous family, 4x individuals homozygous NM_015420.7(DCAF13)c.907 G > A; p.(Asp303Asn) (3x via WES and 1x via Sanger) with a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy.

In silicos analysis of mutant DCAF13 suggests that the amino acid change is deleterious and affects a ß-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Functional studies were not performed.

Previously, a heterozygous variant in DCAF13 with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder.
Sources: Literature
Mendeliome v1.957 ERI1 Elena Savva gene: ERI1 was added
gene: ERI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related
Review for gene: ERI1 was set to GREEN
Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families
- Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly
- Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly
- Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive

- Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells
- K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense

More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy
with ERI1, staying bound to those RNA molecules"
Sources: Literature
Mendeliome v1.956 RAB34 Sarah Pantaleo gene: RAB34 was added
gene: RAB34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB34 were set to PMID: 37384395
Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies
Penetrance for gene: RAB34 were set to Complete
Review for gene: RAB34 was set to GREEN
Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS.

Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher).

Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects.

RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function.

Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands.

In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth.

All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities.

All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance.
Sources: Literature
Mendeliome v1.956 DRG1 Dean Phelan gene: DRG1 was added
gene: DRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DRG1 were set to PMID: 37179472
Phenotypes for gene: DRG1 were set to Neurodevelopmental disorder (MONDO:0700092), DRG1-related
Review for gene: DRG1 was set to GREEN
Added comment: PMID: 37179472
- Biallelic variants were identified in four affected individuals from three distinct families with neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature and craniofacial anomalies. Functional studies show the variants result in a loss of function.
Sources: Literature
Mendeliome v1.956 RPH3A Lucy Spencer gene: RPH3A was added
gene: RPH3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPH3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPH3A were set to 37403762; 29441694
Phenotypes for gene: RPH3A were set to Neurodevelopmental disorder (MONDO#0700092), RPH3A-related
Review for gene: RPH3A was set to GREEN
Added comment: PMID: 37403762- 6 patients with RPH3A variant. All 6 have ID, 4 have epilepsy, 2 with obesity, 1 with dysmorphic features. All 6 have missense variants, 3 shown to be de novo, the other 3 parents were not available for testing. I patient also had language and motor impairment, breathing issues and mixed hypo/hypertonia- he also had variants in CUL4B, PRKAG2, SCN4A, none of these genes cause seizures (which he had).

Patch clamp studies on 2 of the missense showed they increased either the number of NMDA receptors on neuron membrane surface or increased their conductance. Study suggests that the variants interrupt the normal role of RPH3A activity at the synaptic NMDAR complex which is needed for the induction of synaptic plasticity and NMDAR-dependant behaviours

Previously this gene was reported in PMID: 29441694- 1 girl with learning disabilities, tremors, ataxia, hyperglycemia and muscle fatigability. Chet for 2 RPH3A missense. Functional analysis showed strong and marginal impairment of protein binding for each variant. this is the only biallelic report currently.
Sources: Literature
Mendeliome v1.956 MIR204 Chern Lim gene: MIR204 was added
gene: MIR204 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR204 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR204 were set to 26056285; 37321975
Phenotypes for gene: MIR204 were set to Retinal dystrophy and iris coloboma with or without cataract (MIM#616722)
Mode of pathogenicity for gene: MIR204 was set to Other
Review for gene: MIR204 was set to GREEN
gene: MIR204 was marked as current diagnostic
Added comment: PMID: 26056285
- Bilateral coloboma and rod-cone dystrophy with or without cataract in nine individuals of a five-generation family.
- Heterozygous n.37C>T segregates with the disease in all affected individuals.
- Functional analysis including transcriptome analysis showed this variant resulted in significant alterations of miR-204 targeting capabilities. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family.
- Authors suggested gain of function is the likely disease mechanism.

PMID: 37321975
- Four members of a three-generation family with early-onset chorioretinal dystrophy, heterozygous for n.37C>T.
- Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants.
- Haplotype analysis excluded relatedness with the family reported in PMID: 26056285.
- In silico analysis of the MIR204 n.37C>T variant reveals profound changes to its target mRNAs and suggests a gain-of-function mechanism of miR 204 variant.
Sources: Literature
Mendeliome v1.955 CD2AP Bryony Thompson Publications for gene: CD2AP were set to 30612599; 17713465; 10997929; 12764198; 15951437
Mendeliome v1.954 CD2AP Bryony Thompson Publications for gene: CD2AP were set to 30612599; 17713465
Mendeliome v1.952 CD2AP Bryony Thompson Added comment: Comment on list classification: Definitive gene-disease assessment by ClinGen Glomerulopathy GCEP - classified 13/12/2021
Mendeliome v1.946 UBE3B Achchuthan Shanmugasundram reviewed gene: UBE3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 23200864, 23687348, 37010288; Phenotypes: Kaufman oculocerebrofacial syndrome, OMIM:244450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.946 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 3, OMIM:614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 NOTCH2 Achchuthan Shanmugasundram reviewed gene: NOTCH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 9188663, 30329210, 37010288; Phenotypes: Hajdu-Cheney syndrome, OMIM:102500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 AUTS2 Achchuthan Shanmugasundram reviewed gene: AUTS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31788251, 37010288; Phenotypes: Intellectual developmental disorder, autosomal dominant 26, OMIM:615834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ARID1A Achchuthan Shanmugasundram reviewed gene: ARID1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram edited their review of gene: ZC4H2: Changed publications: 31206972, 37010288; Changed phenotypes: Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram reviewed gene: ZC4H2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.945 EWSR1 Bryony Thompson Added comment: Comment on list classification: Disputed gene-disease validity assessment by ClinGen ALS spectrum disorders GCEP - 11/10/2022
Mendeliome v1.944 STAG2 Achchuthan Shanmugasundram reviewed gene: STAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28296084, 29263825, 30158690, 31334757, 33014403, 37010288; Phenotypes: Holoprosencephaly 13, X-linked, OMIM:301043, Mullegama-Klein-Martinez syndrome, OMIM:301022; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.944 SMARCA4 Achchuthan Shanmugasundram reviewed gene: SMARCA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 4, OMIM:614609; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 POGZ Achchuthan Shanmugasundram changed review comment from: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders panel'.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.; to: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders' panel.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.
Mendeliome v1.943 POGZ Achchuthan Shanmugasundram reviewed gene: POGZ: Rating: AMBER; Mode of pathogenicity: None; Publications: 26739615, 31782611, 37010288; Phenotypes: White-Sutton syndrome, OMIM:616364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 PGAP3 Achchuthan Shanmugasundram reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28390064, 37010288; Phenotypes: Hyperphosphatasia with impaired intellectual development syndrome 4, OMIM:615716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.943 KMT2A Achchuthan Shanmugasundram reviewed gene: KMT2A: Rating: AMBER; Mode of pathogenicity: None; Publications: 25929198, 30305169, 31710778, 37010288; Phenotypes: Wiedemann-Steiner syndrome, OMIM:605130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 GLI2 Achchuthan Shanmugasundram reviewed gene: GLI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24744436, 37010288; Phenotypes: Culler-Jones syndrome, OMIM:615849, Holoprosencephaly 9, OMIM:610829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 FGFR3 Achchuthan Shanmugasundram reviewed gene: FGFR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 22565872, 29150894, 37010288; Phenotypes: Muenke syndrome, OMIM:602849, Hypochondroplasia, OMIM:146000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.942 SPTSSA Zornitza Stark reviewed gene: SPTSSA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 90B, autosomal recessive , MIM# 620417, Spastic paraplegia 90A, autosomal dominant, MIM# 620416; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.941 VWA8 Zornitza Stark reviewed gene: VWA8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 97, MIM#620422; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram changed review comment from: There are at least three unrelated cases with monoallelic variants in ARID1B gene reported with either cleft palate, cleft uvula or bifid uvula. Hence, this gene can be added with green rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

One patient with ARID1B variant (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients with ARID1B variants (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula in DECIPHER database.; to: Although there are more than three unrelated cases with ARID1B monoallelic variants reported with either cleft palate, cleft uvula or bifid uvula, clefting isn not consistently present in patients with ARID1B variants. Hence, this gene can be added with amber rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

Of >100 patients with ARID1B variants in the DECIPHER database, only one patient (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula.
Mendeliome v1.941 CNTNAP1 Achchuthan Shanmugasundram reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29511323, 29882456, 37010288; Phenotypes: Hypomyelinating neuropathy, congenital, 3, OMIM:618186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30349098, 37010288; Phenotypes: Coffin-Siris syndrome 1, OMIM:135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.941 TUFT1 Zornitza Stark Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Mendeliome v1.940 TUFT1 Zornitza Stark edited their review of gene: TUFT1: Changed publications: 36689522
Mendeliome v1.939 CHD4 Achchuthan Shanmugasundram reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31388190, 37010288; Phenotypes: Sifrim-Hitz-Weiss syndrome, OMIM:617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.938 KLHL9 Bryony Thompson gene: KLHL9 was added
gene: KLHL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL9 were set to 20554658
Phenotypes for gene: KLHL9 were set to distal myopathy MONDO:0018949
Review for gene: KLHL9 was set to AMBER
Added comment: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Sources: Literature
Mendeliome v1.936 MYMX Bryony Thompson gene: MYMX was added
gene: MYMX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYMX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYMX were set to 35642635
Phenotypes for gene: MYMX were set to Carey-Fineman-Ziter syndrome MONDO:0009700
Review for gene: MYMX was set to AMBER
Added comment: Single family, two siblings with weakness of the facial musculature, hypomimic face, increased overbite, micrognathia, and facial dysmorphism with homozygous p.Arg46*. The phenotype resembles CFZ syndrome. The variant prevents fusion of myoblasts from patient-derived iPSCs. Mouse model recapitulates a lethal CFZS-like phenotype.
Sources: Literature
Mendeliome v1.934 NOP10 Zornitza Stark Publications for gene: NOP10 were set to 17507419; 32554502
Mendeliome v1.932 NOP10 Zornitza Stark edited their review of gene: NOP10: Added comment: PMID 32139460: large multiplex family with 4 affected individuals segregating a heterozygous variant.; Changed rating: AMBER; Changed publications: 17507419, 32139460; Changed phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9, MIM# 620400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.931 RHOBTB2 Zornitza Stark Publications for gene: RHOBTB2 were set to 29276004; 29768694
Mendeliome v1.928 RHOBTB2 Zornitza Stark reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Epileptic encephalopathy, early infantile, 64, MIM#618004; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.927 NFATC1 Zornitza Stark gene: NFATC1 was added
gene: NFATC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC1 were set to 37249233
Phenotypes for gene: NFATC1 were set to Inborn error of immunity, MONDO:0003778, NFATC1-related; Combined Immune deficiency
Review for gene: NFATC1 was set to AMBER
Added comment: 3 individuals from a multigenerational consanguineous pedigree with early-onset sinopulmonary infections and bronchiectasis, recurrent viral (warts) and bacterial (folliculitis and abscesses) skin infections, hypogammaglobulinemia, lower CD4+/CD8+ T-cell ratio and lower recent thymic emigrants compared with the age-matched controls. Lymphocyte proliferation responses to PHA and CD3/CD28 stimulations were defective.

Single pedigree with supportive functional studies.
Sources: Literature
Mendeliome v1.925 CNTN1 Bryony Thompson Publications for gene: CNTN1 were set to 19026398
Mendeliome v1.923 CNTN1 Bryony Thompson reviewed gene: CNTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19026398, 10595523, 22242131, 32779773; Phenotypes: Compton-North congenital myopathy MONDO:0012929, fetal akinesia deformation sequence MONDO:0008824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.921 MRPL50 Zornitza Stark reviewed gene: MRPL50: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disease, MONDO: 004470, MRPL50-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.918 HMGCR Zornitza Stark Publications for gene: HMGCR were set to 18354102; 29480216
Mendeliome v1.915 MOS Melanie Marty gene: MOS was added
gene: MOS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MOS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOS were set to PMID: 34779126; PMID: 34997960; PMID: 36403623; PMID: 35670744
Phenotypes for gene: MOS were set to Early embryonic arrest and fragmentation; infertility
Review for gene: MOS was set to GREEN
Added comment: PMID: 34779126: 3 x females with infertility with biallelic MOS variants identified. Using oocyte-specific Erk1/2 knockout mice, they verified that MOS-ERK signal pathway inactivation in oocytes caused early embryonic arrest and fragmentation.

PMID: 34997960: 2 x females with biallelic MOS variants. Functional studies showed a reduction of protein for two of these variants (missense and frameshift). Functional studies also showed these variants reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase 1/2.

PMID: 35670744 1 x additional family (twins) with infertility and abnormal oocyte morphology with large first polar body. Functional studies showed the MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, functional studies also showed when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1.

PMID: 36403623 1 x female with primary infertility, patient’s oocytes had a large polar body and poor embryonic development, hom missense variant in MOS identified.
Sources: Literature
Mendeliome v1.915 TAPT1 Elena Savva Publications for gene: TAPT1 were set to 26365339
Mendeliome v1.911 TAPT1 Paul De Fazio reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36697720, 36652330; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.909 RNH1 Ain Roesley Publications for gene: RNH1 were set to PMID: 36935417
Mendeliome v1.908 PRSS8 Lucy Spencer gene: PRSS8 was added
gene: PRSS8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRSS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRSS8 were set to 36715754
Phenotypes for gene: PRSS8 were set to ichthyosis MONDO:0019269, PRSS8-related
Review for gene: PRSS8 was set to AMBER
Added comment: PMID: 36715754
1 family with 3 affected sons with congenital ichthyosis, consanguineous parents. All 3 affected members are homozygous for a canonical splice in PRSS8, quantitative RT-PCR showed a significant reduction in normal PRSS8 transcript.

A second family with 4 affected members (proband and 3 cousins) with ichthyosis (3 also had autism), also consanguineous. Only the proband was tested who is homozygous for a missense in PTSS8. However this patient also had a TAAR1 missense (no disease association, but the paper suggests this could be responsible for the autism phenotype- KO mice have abnormal learning behaviour).
Sources: Literature
Mendeliome v1.908 RNH1 Dean Phelan reviewed gene: RNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37191094; Phenotypes: encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.906 NSUN6 Michelle Torres gene: NSUN6 was added
gene: NSUN6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN6 were set to 37226891
Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related
Review for gene: NSUN6 was set to AMBER
Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants:
- p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested.
- p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers.
- p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers.
Sources: Literature
Mendeliome v1.906 HMGCR Naomi Baker reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37167966, 36745799; Phenotypes: autosomal recessive limb-girdle muscular dystrophy (MONDO: 0015152), HMGCR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.906 UNC79 Krithika Murali gene: UNC79 was added
gene: UNC79 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC79 were set to PMID:37183800
Phenotypes for gene: UNC79 were set to Neurodevelopmental disorderMONDO:0700092
Review for gene: UNC79 was set to AMBER
Added comment: PMID:37183800 Bayat et al 2023 report 6 unrelated patients with heterozygous NMD-predicted LoF variants in UNC79 - x1 canonical splice site variant, x5 nonsense/frameshift. 5 were confirmed de novo, 1 not identified in mother - father unavailable for testing. All variants absent in gnomAD and v2 pLI score for UNC79 is 1.

Patients with UNC79 variants were identified through GeneMatcher or an international network of Epilepsy and Genetics departments. x1 patient underwent duo exome sequencing, remaining had trio exome sequencing - no other causative variants identified.

Phenotypic features included:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal to bilateral tonic-clonic seizures)
- 5/6 hypotonia

unc79 knockdown drosophila flies exhibited significantly higher rate of seizure-like behaviour than controls. unc79 haploinsufficiency shown to lead to significant reduction in protein levels of both unc79 and unc80 in mouse brains. Unc79 haploinsufficiency associated with deficiency in hippocampal-dependent learning and memory in mice.

Authors have reviewed their own evidence in relation to the gene-disease criteria detailed by Strande et al 2017 and note that their clinical and experimental data provides moderate-level evidence supporting the association between UNC79 and a neurodevelopment disorder including ASD.

Amber association favoured due to clinical phenotypic range reported between affected individuals and their lack of specificity.
Sources: Literature
Mendeliome v1.906 U2AF2 Elena Savva Publications for gene: U2AF2 were set to 34112922; 37092751; 36747105; 37134193
Mendeliome v1.905 U2AF2 Elena Savva Publications for gene: U2AF2 were set to 33057194
Mendeliome v1.903 MRPL50 Anna Ritchie gene: MRPL50 was added
gene: MRPL50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL50 were set to PMID: 37148394
Phenotypes for gene: MRPL50 were set to Mitochondrial disease, MONDO: 004470, MRPL50-related
Added comment: A homozygous missense variant (c.335T>A; p.Val112Asp) shared by twin sisters presenting with premature ovarian insufficiency, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction.
Quantitative proteomics data demonstrated a significant reduction in abundance of MRPL50 protein when compared with controls.
Patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. This data supports a biochemical phenotype associated with MRPL50 variants.
Knockdown/knockout of mRpL50 in Drosophila, resulted abnormal ovarian development.
Sources: Literature
Mendeliome v1.901 MCM6 Zornitza Stark Publications for gene: MCM6 were set to
Mendeliome v1.898 NPR1 Lilian Downie gene: NPR1 was added
gene: NPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPR1 were set to PMID: 37080586
Phenotypes for gene: NPR1 were set to Genetic hypertension MONDO:0015512
Review for gene: NPR1 was set to GREEN
Added comment: 4 sibs with systemic hypertension in the neonatal period - presenting with cardiogenic shock, with homozygous variants (consanguineous parents), parents confirmed heterozygotes. 3/4 infants had increased NT (>3.5) in utero
RT-PCR shows dramatic reduction of RNA levels
2 sibs in a second family, normal NT and pregnancy, neonatal systematic hypertension presenting with cardiogenic shock,
Sources: Literature
Mendeliome v1.898 POU3F2 Sarah Pantaleo gene: POU3F2 was added
gene: POU3F2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POU3F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU3F2 were set to PMID: 37207645
Phenotypes for gene: POU3F2 were set to Autism spectrum disorder, NDD, and adolescent-onset obesity
Penetrance for gene: POU3F2 were set to unknown
Mode of pathogenicity for gene: POU3F2 was set to Other
Review for gene: POU3F2 was set to GREEN
Added comment: We associate ultra-rare variants in POU3F2, encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopment delay in 12 individuals. Demonstrate variant pathogenicity through in vitro analysis. Used exome sequencing, GeneMatcher and Genomics England 100,000 Genomes Project rare disease database.

Both truncating and missense variants in over 10 individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity (may have had other features eg. CAKUT in 2 individuals, diabetes in two) . Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperplasia during childhood. With the exception of an early truncating variant, the variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promoter activation.

Variants absent from population and clinical databases. Almost all constituted putatively non-inherited de novo variants (8/10).

Functional studies provide evidence for loss of function in eight and gain of function in one obesity-associated POU3F2 variant. One variant did not impact POU3F2-promoter activation, leaving the possibility for further path-mechanisms.
Sources: Literature
Mendeliome v1.897 ACBD6 Lucy Spencer gene: ACBD6 was added
gene: ACBD6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 36457943; 21937992; 35446914
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder (MONDO#0700092), ACBD6-related
Review for gene: ACBD6 was set to GREEN
Added comment: PMID: 36457943
2 siblings with a neurodevelopmental disorder: severely delayed development, obesity, pancytopenia, diabetes, liver cirrhosis, intravertebral disc herniation, mild brain atrophy. Consanguineous family both siblings found to have a homozygous frameshift.

This paper also mentioned 3 other reported variants in 6 individuals (only 3 unrelated) all homozygous, 2 frameshift, 1 canonical splice. All reported to have a neurodevelopmental disorder, some with limited information but one family also has obesity, spasticity, and dysmorphism. PMIDs: 21937992, 35446914
Sources: Literature
Mendeliome v1.896 U2AF2 Paul De Fazio reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34112922, 37092751, 36747105, 37134193; Phenotypes: Neurodevelopmental disorder, U2AF2-related (MONDO:0700092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.896 MAP4K4 Zornitza Stark edited their review of gene: MAP4K4: Added comment: 26 individuals from 21 families reported with Rasopathy-like phenotype, comprising ID/DD, dysmorphic features and congenital anomalies.; Changed rating: GREEN; Changed publications: 37126546; Changed phenotypes: RASopathy, MONDO:0021060, MAP4K4-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.896 CHRM5 Elena Savva gene: CHRM5 was added
gene: CHRM5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHRM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRM5 were set to 37213061
Phenotypes for gene: CHRM5 were set to Congenital anomaly of kidney and urinary tract, (MONDO:0019719), CHRM5-related
Review for gene: CHRM5 was set to RED
Added comment: PMID: 37213061
- homozygous missense p.(Q184R) in a proband with neurogenic bladder and CAKUT. Additional features were small trabeculated urinary bladder, bilateral severe hydronephrosis, grade V VUR right, chronic kidney disease (stage 4).
- Radioligand binding experiments were inconclusive - the missense variant had no effect on receptor expression or binding affinity.
- ACh binding assay did show a 2-fold increase (borderline significant), but no effect in secondary messenger accumulation.
- Transfected CHO line showed no effect on receptor expression
- Described a mouse K/O as having a bladder overactivity

No hom PTCs in gnomAD
Sources: Literature
Mendeliome v1.895 SLC26A1 Ain Roesley reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: 36719378; Phenotypes: perichondritis, hyposulphatemia, renal sulphate wasting; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.895 MCM6 Suliman Khan reviewed gene: MCM6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37198333; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, MCM6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.892 AMFR Zornitza Stark reviewed gene: AMFR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.891 ATP11A Zornitza Stark edited their review of gene: ATP11A: Added comment: PMID 35278131 reports three additional families with deafness, including segregation in a large pedigree.; Changed rating: GREEN; Changed publications: 35278131
Mendeliome v1.889 OXGR1 Zornitza Stark reviewed gene: OXGR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.887 GIGYF2 Bryony Thompson Publications for gene: GIGYF2 were set to PMID: 18358451, 19449032
Mendeliome v1.885 GIGYF2 Bryony Thompson reviewed gene: GIGYF2: Rating: RED; Mode of pathogenicity: None; Publications: 18358451, 33239198, 25279164, 20060621, 19250854, 26152800; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.885 NDUFA13 Lucy Spencer reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.883 UNC13A Ain Roesley reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO#0700092, UNC13A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.881 RANBP2 Bryony Thompson Publications for gene: RANBP2 were set to
Mendeliome v1.880 GATAD2A Bryony Thompson Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Mendeliome v1.879 GATAD2A Bryony Thompson edited their review of gene: GATAD2A: Changed publications: 37181331, 17565372
Mendeliome v1.878 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.878 ZNF292 Michelle Torres reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, MIM#619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.877 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.877 ARFGEF3 Ain Roesley reviewed gene: ARFGEF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.877 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy; cataract to Dilated cardiomyopathy (MONDO:0005021), RRAGC-related
Mendeliome v1.874 RECQL4 Zornitza Stark Publications for gene: RECQL4 were set to
Mendeliome v1.873 RECQL4 Zornitza Stark reviewed gene: RECQL4: Rating: RED; Mode of pathogenicity: None; Publications: 35025765; Phenotypes: RECON progeroid syndrome, MIM# 620370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.872 ATP5O Zornitza Stark Publications for gene: ATP5O were set to 34954817
Mendeliome v1.870 ATP5O Zornitza Stark reviewed gene: ATP5O: Rating: GREEN; Mode of pathogenicity: None; Publications: 35621276; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.869 SLITRK2 Zornitza Stark reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 111, MIM# 301107; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.869 AMFR Yetong Chen gene: AMFR was added
gene: AMFR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Hereditary spastic paraplegia, MONDO:0019064
Review for gene: AMFR was set to GREEN
Added comment: PMID 37119330 reports 20 individuals harbouring AMFR variants from 8 unrelated, consanguineous families. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Mendeliome v1.868 POLD3 Bryony Thompson gene: POLD3 was added
gene: POLD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Phenotypes for gene: POLD3 were set to Severe combined immunodeficiency MONDO:0015974
Review for gene: POLD3 was set to AMBER
Added comment: Homozygous missense variant (NM_006591.3; p.Ile10Thr) identified in a single Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency with neurodevelopmental delay and hearing loss. POLD3 as well as POLD1 and POLD2 expression was abolished in the patient's cells. Null mouse models are embryonic lethal and demonstrate Pold3 is essential for DNA replication in murine B cells.
Sources: Literature
Mendeliome v1.866 POLD2 Bryony Thompson Publications for gene: POLD2 were set to 31449058
Mendeliome v1.864 POLD2 Bryony Thompson reviewed gene: POLD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31449058, 36528861; Phenotypes: Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145; Mode of inheritance: None
Mendeliome v1.863 SLC4A2 Zornitza Stark gene: SLC4A2 was added
gene: SLC4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A2 were set to 34668226; 20507629
Phenotypes for gene: SLC4A2 were set to Osteopetrosis, autosomal recessive 9, MIM# 620366
Review for gene: SLC4A2 was set to AMBER
Added comment: Single individual reported with homozygous missense variant. However, cattle and mouse models support gene-disease association.
Sources: Literature
Mendeliome v1.860 NOP10 Bryony Thompson Publications for gene: NOP10 were set to 17507419
Mendeliome v1.858 NOP10 Bryony Thompson reviewed gene: NOP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 17507419, 32554502; Phenotypes: Telomere syndrome MONDO:0100137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.857 ACD Bryony Thompson Publications for gene: ACD were set to 25205116; 25233904
Mendeliome v1.855 ACD Bryony Thompson reviewed gene: ACD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807141, 31515401, 30995915, 27528712, 25205116, 24316971, 30064976, 33446513, 25233904; Phenotypes: telomere syndrome MONDO:0100137, dyskeratosis congenita, autosomal dominant 6 MONDO:0014690, Hoyeraal-Hreidarsson syndrome MONDO:0018045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.855 RRAGC Naomi Baker reviewed gene: RRAGC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:37057673, 27234373, 33057194; Phenotypes: Dilated cardiomyopathy (MONDO:0005021), RRAGC-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.855 MCAT Zornitza Stark reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.855 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mendeliome v1.853 DNAH7 Zornitza Stark reviewed gene: DNAH7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.853 RARA Zornitza Stark commented on gene: RARA: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.
Mendeliome v1.852 RARA Zornitza Stark Publications for gene: RARA were set to 31343737
Mendeliome v1.850 RARA Zornitza Stark edited their review of gene: RARA: Added comment: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.; Changed rating: AMBER; Changed publications: 31343737, 37086723; Changed phenotypes: Craniosynostosis - MONDO:0015469, Syndromic chorioretinal coloboma; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.849 PMEPA1 Zornitza Stark reviewed gene: PMEPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.848 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Expert list
Mendeliome v1.847 PMEPA1 Hazel Phillimore changed review comment from: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature; to: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.842 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to PMID: 37057675
Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: LHX2 was set to GREEN
Added comment: PMID: 37057675

Case series of 19 individuals across 18 families.
1 whole gene deletion, 7 missense, 10 predicted LoF variants.
Proposed loss-of-function mechanism.
Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features.
Microcephaly in 7 individuals.
1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo.
Sources: Literature
Mendeliome v1.841 PMEPA1 Hazel Phillimore gene: PMEPA1 was added
gene: PMEPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to PMID: 36928819
Phenotypes for gene: PMEPA1 were set to Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome
Mode of pathogenicity for gene: PMEPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.839 CBX1 Daniel Flanagan gene: CBX1 was added
gene: CBX1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBX1 were set to PMID: 37087635
Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related
Review for gene: CBX1 was set to GREEN
Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin.
Sources: Expert list
Mendeliome v1.839 MCAT Seb Lunke Classified gene: MCAT as Amber List (moderate evidence)
Mendeliome v1.839 MCAT Seb Lunke Gene: mcat has been classified as Amber List (Moderate Evidence).
Mendeliome v1.838 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mendeliome v1.837 DNAH7 Chern Lim gene: DNAH7 was added
gene: DNAH7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH7 were set to 34476482; 35543642
Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related
Review for gene: DNAH7 was set to GREEN
gene: DNAH7 was marked as current diagnostic
Added comment: PMID: 34476482 (Wei et al 2021):
- Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms.
- Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased.

PMID: 35543642 (Gao et al 2022):
- One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous.
- Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient.
Sources: Literature
Mendeliome v1.836 SRSF1 Paul De Fazio gene: SRSF1 was added
gene: SRSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092
Review for gene: SRSF1 was set to GREEN
gene: SRSF1 was marked as current diagnostic
Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS.

Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms.

Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17).
Sources: Literature
Mendeliome v1.834 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Mendeliome v1.834 GPR156 Anna Ritchie gene: GPR156 was added
gene: GPR156 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID: 36928819
Phenotypes for gene: GPR156 were set to Sensorineural hearing loss, MONDO:60700002, GPR156-related
Review for gene: GPR156 was set to GREEN
Added comment: Eight affected individuals from three unrelated families with congenital nonsyndromic bilateral sensorineural hearing loss. Homozygous or compound heterozygous loss of function variants were reported in these families.
Sources: Literature
Mendeliome v1.834 DPP9 Sarah Pantaleo reviewed gene: DPP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 36112693; Phenotypes: Hatipoglu immunodeficiency syndrome MIM#620331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.834 MRPL39 Lilian Downie gene: MRPL39 was added
gene: MRPL39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to PMID: 37133451
Phenotypes for gene: MRPL39 were set to Leigh syndrome MONDO:0009723
Added comment: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 INTS11 Melanie Marty reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37054711; Phenotypes: Global developmental delay, launguage delay, intellectual disability, impaired motor development, brain atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.834 ERG Ain Roesley Publications for gene: ERG were set to
Mendeliome v1.831 ERG Ain Roesley reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: 36928819; Phenotypes: primary lymphoedema MONDO#0019175, ERG-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.830 GATAD2A Bryony Thompson gene: GATAD2A was added
gene: GATAD2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to GREEN
Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.829 RNF212B Bryony Thompson Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Mendeliome v1.826 YWHAE Zornitza Stark gene: YWHAE was added
gene: YWHAE was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: YWHAE.
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 10 patients with YWHAE variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1) who have mild to severe intellectual disability. 3 individuals with SNVs. Mouse model supports gene-disease association.
Sources: Literature
Mendeliome v1.825 OXGR1 Bryony Thompson Publications for gene: OXGR1 were set to PMID:35671463
Mendeliome v1.823 KPNA7 Zornitza Stark Publications for gene: KPNA7 were set to 24045845; 32179771
Mendeliome v1.821 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36647821; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram gene: INTS11 was added
gene: INTS11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Review for gene: INTS11 was set to GREEN
Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association.

PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature
Mendeliome v1.816 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.815 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043
Mendeliome v1.814 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Six individuals from two unrelated families reported with SPG.; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280, Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.811 DNAJB4 Zornitza Stark Publications for gene: DNAJB4 were set to PMID: 36264506
Mendeliome v1.808 DNAJB4 Zornitza Stark reviewed gene: DNAJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 21 with early respiratory failure, MIM# 620326; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.807 C16orf62 Chirag Patel reviewed gene: C16orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36113987; Phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.807 DNAJB4 Bryony Thompson reviewed gene: DNAJB4: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36512060; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.807 TSPAN7 Ain Roesley reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 26350204, 36625203; Phenotypes: Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.807 KDM5A Achchuthan Shanmugasundram gene: KDM5A was added
gene: KDM5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KDM5A were set to 21937992; 33350388
Phenotypes for gene: KDM5A were set to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Review for gene: KDM5A was set to GREEN
Added comment: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Sources: Literature
Mendeliome v1.806 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530; 33270637; 28402530; 35348658
Mendeliome v1.805 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed publications: 28286008, 30692597, 35227688, 35348658, 28592524, 30530901, 33270637, 28402530
Mendeliome v1.804 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; Changed publications: 28592524, 30530901, 30692597, 33270637, 28402530, 35348658; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400
Mendeliome v1.802 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.801 RYR3 Zornitza Stark Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Mendeliome v1.797 LYN Zornitza Stark Publications for gene: LYN were set to
Mendeliome v1.794 LYN Zornitza Stark reviewed gene: LYN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36932076, 36122175; Phenotypes: Vasculitis, MONDO:0018882, LYN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.793 MAP3K3 Zornitza Stark gene: MAP3K3 was added
gene: MAP3K3 was added to Mendeliome. Sources: Literature
somatic tags were added to gene: MAP3K3.
Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774
Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related
Mode of pathogenicity for gene: MAP3K3 was set to Other
Review for gene: MAP3K3 was set to GREEN
Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies).
Sources: Literature
Mendeliome v1.789 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.788 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.787 POLR1A Zornitza Stark Publications for gene: POLR1A were set to 25913037; 28051070
Mendeliome v1.783 BIN1 Bryony Thompson Publications for gene: BIN1 were set to 17676042
Mendeliome v1.782 BIN1 Bryony Thompson Added comment: Comment on mode of inheritance: ClinGen Definititive for semidominant for centronuclear myopathy by the Congenital myopathy GCEP - Classification - 04/27/2020
Mendeliome v1.781 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.781 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Mendeliome v1.776 CRIPT Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Mendeliome v1.776 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Mendeliome v1.776 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942
Review for gene: ACTC1 was set to GREEN
Added comment: ClinGen definitive association with HCM, moderate for DCM
5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405)
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy
facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge
All missense variants
Sources: Literature
Mendeliome v1.776 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.775 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28051070, 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.775 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.774 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Mendeliome v1.774 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis. No antenatal features reported.
Sources: Literature
Mendeliome v1.774 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.773 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.773 DAAM2 Zornitza Stark Publications for gene: DAAM2 were set to 33232676
Mendeliome v1.771 DAAM2 Zornitza Stark edited their review of gene: DAAM2: Added comment: AIS: 6 unrelated individuals with extensive functional data.; Changed publications: 33232676, 36972684; Changed phenotypes: Nephrotic syndrome, type 24, MIM# 619263, Steroid-resistant nephrotic syndrome (SRNS), Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.769 MB Elena Savva gene: MB was added
gene: MB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MB were set to 35527200; 30918256
Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286
Mode of pathogenicity for gene: MB was set to Other
Review for gene: MB was set to GREEN
Added comment: PMID: 30918256:
- Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy.
- Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin.
- GOF hypothesised
- 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms.

PMID: 35527200:
- single adult patient with myoglobinopathy
- same recurring p.His98Tyr variant
Sources: Literature
Mendeliome v1.768 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Mendeliome v1.767 PKDCC Zornitza Stark Publications for gene: PKDCC were set to PMID:30478137; 19097194
Mendeliome v1.765 PKDCC Zornitza Stark reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 36896672; Phenotypes: Rhizomelic limb shortening with dysmorphic features 618821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Mendeliome v1.763 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.763 PPCDC Bryony Thompson gene: PPCDC was added
gene: PPCDC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPCDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPCDC were set to 36564894
Phenotypes for gene: PPCDC were set to dilated cardiomyopathy MONDO:0005021
Review for gene: PPCDC was set to RED
Added comment: Single family reported with two siblings with a fatal cardiac phenotype including dilated cardiomyopathy with biallelic variants p.Thr53Pro and p.Ala95Val. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant.
Sources: Literature
Mendeliome v1.757 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.757 RNF212B Sangavi Sivagnanasundram gene: RNF212B was added
gene: RNF212B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047
Review for gene: RNF212B was set to AMBER
Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family).

Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs.

Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries.
Sources: Other
Mendeliome v1.757 RYR3 Chern Lim reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25262651; Phenotypes: developmental and epileptic encephalopathy (MONDO:0100062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.752 PRDM10 Achchuthan Shanmugasundram gene: PRDM10 was added
gene: PRDM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM10 were set to 36440963
Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086
Review for gene: PRDM10 was set to RED
Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family.

Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.751 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.
Sources: Expert list
Mendeliome v1.750 LCP2 Zornitza Stark Publications for gene: LCP2 were set to 33231617
Mendeliome v1.748 LCP2 Zornitza Stark edited their review of gene: LCP2: Added comment: PMID 36474126: second individual reported. Functional data.; Changed rating: GREEN; Changed publications: 33231617, 36474126
Mendeliome v1.747 STX4 Zornitza Stark Publications for gene: STX4 were set to
Mendeliome v1.744 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Mendeliome v1.740 MS4A1 Zornitza Stark Publications for gene: MS4A1 were set to 20038800
Mendeliome v1.736 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.728 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.727 ACTA1 Zornitza Stark reviewed gene: ACTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Mendeliome v1.724 FTH1 Zornitza Stark Publications for gene: FTH1 were set to 11389486
Mendeliome v1.721 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838
Mendeliome v1.719 DPYSL2 Zornitza Stark gene: DPYSL2 was added
gene: DPYSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related
Review for gene: DPYSL2 was set to AMBER
Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Mendeliome v1.717 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related
Review for gene: RBSN was set to GREEN
Added comment: Four unrelated families reported, consistent feature is ID.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Mendeliome v1.715 SRPRA Zornitza Stark gene: SRPRA was added
gene: SRPRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to 36223592
Phenotypes for gene: SRPRA were set to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Review for gene: SRPRA was set to AMBER
Added comment: De novo variant; zebrafish model. Schwachman-Diamond like.
Sources: Literature
Mendeliome v1.713 SRP19 Zornitza Stark gene: SRP19 was added
gene: SRP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to 36223592
Phenotypes for gene: SRP19 were set to Neutropenia, MONDO:0001475, SRP19-related
Review for gene: SRP19 was set to AMBER
Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Sources: Literature
Mendeliome v1.712 ATP5B Zornitza Stark Publications for gene: ATP5B were set to 36860166
Mendeliome v1.711 ATP5B Zornitza Stark edited their review of gene: ATP5B: Changed publications: 36860166, 36239646
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. Particularly, Eph overexpressed flies had a poorer performance compared to controls in negative geotaxis assay. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36130215; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram gene: EPHA10 was added
gene: EPHA10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPHA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA10 were set to 36048850
Phenotypes for gene: EPHA10 were set to postlingual non-syndromic genetic hearing loss, MONDO:0016298
Mode of pathogenicity for gene: EPHA10 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: EPHA10 was set to RED
Added comment: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.710 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature
Mendeliome v1.709 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645
Mendeliome v1.708 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Fourth family reported in PMID 36847845 with hypotonia and paroxysmal dyskinesia.; Changed publications: 34542157, 29178645, 36847845
Mendeliome v1.708 YWHAZ Zornitza Stark gene: YWHAZ was added
gene: YWHAZ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members. In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Mendeliome v1.707 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932
Mendeliome v1.705 PLXND1 Zornitza Stark Publications for gene: PLXND1 were set to 26068067
Mendeliome v1.703 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Literature
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram reviewed gene: PLXND1: Rating: ; Mode of pathogenicity: None; Publications: 35396997; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.702 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: ; Mode of pathogenicity: None; Publications: 36018820; Phenotypes: dilated cardiomyopathy, MONDO:0005021, ophthalmoplegia, MONDO:0003425, myopathy, MONDO:0005336, Hypotonia, HP:0001252, Seizure, HP:0001250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.701 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)
Sources: Expert Review
Mendeliome v1.700 TLN1 Achchuthan Shanmugasundram reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 35861643; Phenotypes: thrombocytopenia, MONDO:0002049, lymphopenia, MONDO:0003783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.699 PCK2 Bryony Thompson reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: Peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.699 FTH1 Paul De Fazio reviewed gene: FTH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36778397; Phenotypes: Neuroferritinopathy (MONDO:0011638); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.698 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Mendeliome v1.698 TRPV1 Krithika Murali reviewed gene: TRPV1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 36454632, PMID: 36472910; Phenotypes: Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mendeliome v1.696 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Mendeliome v1.695 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Mendeliome v1.694 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36751037; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.694 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400; 34164801
Mendeliome v1.691 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400 ( all de novos)

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes
Mendeliome v1.691 LGR4 Elena Savva Publications for gene: LGR4 were set to 32493844
Mendeliome v1.689 LGR4 Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).
Mendeliome v1.689 LGR4 Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.688 USMG5 Bryony Thompson gene: USMG5 was added
gene: USMG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 29917077; 30240627
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6 MIM#618683
Review for gene: USMG5 was set to AMBER
Added comment: A homozygous splice site mutation in 4 patients from 3 unrelated families of Ashkenazi Jewish descent. Experimental analyses demonstrated that the splice variant leads to loss of protein expression and haplotype analysis suggested a founder effect. In situ cryo-ET analysis of the mitochondria of a homozygous affected case showed profound disturbances of mitochondrial crista ultrastructure.
Sources: Literature
Mendeliome v1.686 SLC35B2 Zornitza Stark reviewed gene: SLC35B2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 NLGN4X Elena Savva reviewed gene: NLGN4X: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36747195; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.684 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 ELOC Achchuthan Shanmugasundram gene: ELOC was added
gene: ELOC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELOC was set to Unknown
Publications for gene: ELOC were set to 35323939
Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343
Review for gene: ELOC was set to RED
Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far.

A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939).

This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.684 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.684 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224 to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.683 TRPM3 Zornitza Stark Publications for gene: TRPM3 were set to 31278393
Mendeliome v1.682 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Added comment: Publications 25090642; 33484482: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant supports association. Amber for this association.; Changed publications: 31278393, 25090642, 33484482; Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224, Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.682 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Mendeliome v1.680 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K; Changed rating: AMBER; Changed publications: 23086801, 36706222
Mendeliome v1.679 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194; 36450800
Mendeliome v1.678 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: 36178483; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.677 EFCAB1 Zornitza Stark reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.676 CST6 Zornitza Stark gene: CST6 was added
gene: CST6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CST6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CST6 were set to 30425301; 36371786
Phenotypes for gene: CST6 were set to Ectodermal dysplasia 15, hypohidrotic/hair type MIM#618535
Review for gene: CST6 was set to GREEN
Added comment: Two families reported and functional data.
Sources: Literature
Mendeliome v1.674 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Mendeliome v1.671 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.670 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mendeliome v1.668 MRPS7 Zornitza Stark edited their review of gene: MRPS7: Added comment: Now second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.; Changed rating: AMBER; Changed publications: 25556185, 36421788
Mendeliome v1.667 STAT6 Zornitza Stark gene: STAT6 was added
gene: STAT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to 36216080; 36758835
Phenotypes for gene: STAT6 were set to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Review for gene: STAT6 was set to GREEN
Added comment: Two families reported with GoF variants and extensive functional data.
Sources: Literature
Mendeliome v1.665 LTV1 Achchuthan Shanmugasundram gene: LTV1 was added
gene: LTV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTV1 were set to 34999892
Phenotypes for gene: LTV1 were set to Inflammatory poikiloderma with hair abnormalities and acral keratoses, OMIM:620199
Review for gene: LTV1 was set to AMBER
Added comment: Comment on classification of gene: This gene should be rated amber as it has been implicated in inflammatory poikiloderma with hair abnormalities and acral keratoses as identified from two unrelated families harbouring the same biallelic variant and supported by functional studies.

PMID:34999892 reported four UK women of South Asian origin (three Pakistani sisters and an unrelated Indian woman) identified with homozygous variant c.503A>G, (p.Asn168Ser) and presented with poikiloderma, hair abnormalities, and acral keratoses, which the authors named as inflammatory poikiloderma with hair abnormalities and acral keratoses (IPHAK).

Both in silico modelling and splicing assays from a patient sample showed that this variant is responsible for splicing defects and defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm in yeast.

This gene has already been associated with relevant phenotype (MIM #620199) in OMIM, but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.665 WNT11 Achchuthan Shanmugasundram gene: WNT11 was added
gene: WNT11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures
Review for gene: WNT11 was set to GREEN
Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.

This gene has not yet been reported with any phenotypes either in OMIM or in G2P.
Sources: Literature
Mendeliome v1.662 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Mendeliome v1.661 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.656 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Mendeliome v1.655 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Mendeliome v1.654 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Mendeliome v1.654 KBTBD13 Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.649 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore gene: RRAGD was added
gene: RRAGD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Mendeliome v1.649 SPTSSA Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data.
Mendeliome v1.648 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to AMBER
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Mendeliome v1.643 C1GALT1C1 Ain Roesley Publications for gene: C1GALT1C1 were set to 18537974; 16251947
Mendeliome v1.642 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Added comment: Red association for aHUS

1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation; Changed publications: 18537974, 16251947, 36599939; Changed phenotypes: Tn polyagglutination syndrome, somatic MIM#300622, atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Mendeliome v1.640 SPRY1 Elena Savva Publications for gene: SPRY1 were set to
Mendeliome v1.635 SPRY1 Elena Savva reviewed gene: SPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36543535; Phenotypes: Craniosynostosis, SPRY1-related, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.635 TPCN2 Paul De Fazio reviewed gene: TPCN2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36641477; Phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.635 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Mendeliome v1.632 PCK2 Ain Roesley reviewed gene: PCK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.632 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mendeliome v1.632 OGDH Zornitza Stark Publications for gene: OGDH were set to 32383294
Mendeliome v1.630 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.628 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.628 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Mendeliome v1.627 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.626 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.625 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Mendeliome v1.624 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.614 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.614 LY96 Zornitza Stark gene: LY96 was added
gene: LY96 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related
Review for gene: LY96 was set to RED
Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Expert Review
Mendeliome v1.612 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986
Mendeliome v1.610 ZNF668 Zornitza Stark reviewed gene: ZNF668: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.607 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.604 SLC26A6 Zornitza Stark reviewed gene: SLC26A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary hyperoxaluria, MONDO:0002474, SLC26A6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.601 RIC1 Paul De Fazio reviewed gene: RIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36493769; Phenotypes: Cleft lip/palate MONDO:0016044, RIC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.600 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Mendeliome v1.598 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Mendeliome v1.597 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.594 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Changed publications: 36458887, 29574422; Changed phenotypes: chromosome instability, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022
- One patient with compound het missense and nonsense variants, both parents are carriers (hets).
- The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical.
- Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes.
- Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.591 UHRF1 Chern Lim reviewed gene: UHRF1: Rating: RED; Mode of pathogenicity: None; Publications: 29574422; Phenotypes: Multi locus imprinting disturbance in offspring; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.590 ARHGAP35 Dean Phelan reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36450800; Phenotypes: Developmental defect of the eye (MONDO:0020145), ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.589 ARHGEF38 Paul De Fazio gene: ARHGEF38 was added
gene: ARHGEF38 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF38 were set to 36493769
Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related
Review for gene: ARHGEF38 was set to AMBER
gene: ARHGEF38 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.588 COBLL1 Paul De Fazio gene: COBLL1 was added
gene: COBLL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COBLL1 were set to 36493769
Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related
gene: COBLL1 was marked as current diagnostic
Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.588 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Mendeliome v1.587 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Mendeliome v1.584 CDK16 Alison Yeung Publications for gene: CDK16 were set to 25644381
Mendeliome v1.583 OXGR1 Sarah Pantaleo gene: OXGR1 was added
gene: OXGR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OXGR1 were set to PMID:35671463
Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related
Penetrance for gene: OXGR1 were set to unknown
Review for gene: OXGR1 was set to AMBER
Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis.

Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised.

A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals.

Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant.

Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function.

Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%).

Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease).
Sources: Literature
Mendeliome v1.583 CDK16 Alison Yeung reviewed gene: CDK16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36323681, 31981491, 25644381; Phenotypes: Neurodevelopmental disorder (MONDO#0700092) CDK16-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.580 CCIN Chern Lim gene: CCIN was added
gene: CCIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCIN were set to 36546111; 36527329
Phenotypes for gene: CCIN were set to Teratozoospermia
Review for gene: CCIN was set to GREEN
gene: CCIN was marked as current diagnostic
Added comment: Two papers with three unrelated patients with teratozoospermia:

PMID: 36546111
- Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia.
- Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility.

PMID: 36527329
- One consanguineous family reported: homozygous missense, with asthenoteratozoospermia.
- Transfected HEK cells showed reduced CCIN protein level.
Sources: Literature
Mendeliome v1.576 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Mendeliome v1.573 TUFT1 Zornitza Stark gene: TUFT1 was added
gene: TUFT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Phenotypes for gene: TUFT1 were set to Ectodermal dysplasia, MONDO:0019287, TUFT1-related
Review for gene: TUFT1 was set to AMBER
Added comment: 9 individuals from three families reported with woolly hair and skin fragility. One of the variants, c.60+1G>A was present in two of the families, founder effect demonstrated by haplotype analysis. Another loss of function variant present in the third family. Some functional data but mostly expression studies.
Sources: Literature
Mendeliome v1.572 ZMYM3 Belinda Chong gene: ZMYM3 was added
gene: ZMYM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ZMYM3 were set to 36586412; 24721225
Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs)
Review for gene: ZMYM3 was set to GREEN
Added comment: PMID: 36586412
Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants.
Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males.
Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T).
ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect.
Sources: Literature
Mendeliome v1.569 GOSR2 Zornitza Stark edited their review of gene: GOSR2: Added comment: PMIDs 29855340; 33639315: at least three families reported with a muscular dystrophy presentation as well as seizures.; Changed publications: 21549339, 24458321, 30363482, 29855340, 33639315; Changed phenotypes: Epilepsy, progressive myoclonic 6 , MIM#614018, Muscular dystrophy, congenital, with or without seizures, MIM# 620166
Mendeliome v1.566 TSPEAR Zornitza Stark Publications for gene: TSPEAR were set to 27736875; 30046887
Mendeliome v1.565 TSPEAR Zornitza Stark edited their review of gene: TSPEAR: Added comment: More than 5 individuals reported with selective tooth agenesis.; Changed rating: GREEN; Changed publications: 30046887, 32112661, 34042254; Changed phenotypes: Selective tooth agenesis-10 (STHAG10), MIM#620173; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.565 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765
Mendeliome v1.563 CDK5 Zornitza Stark edited their review of gene: CDK5: Added comment: Upgraded to Amber following GenCC discrepancy resolution: single family with four affected individuals but extensive supportive experimental evidence including mouse models.; Changed rating: AMBER; Changed publications: 25560765, 32273484, 32097629, 28854363, 7490100
Mendeliome v1.563 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Mendeliome v1.560 CLDN5 Zornitza Stark Publications for gene: CLDN5 were set to 35714222
Mendeliome v1.555 SETD2 Zornitza Stark Publications for gene: SETD2 were set to 29681085
Mendeliome v1.554 SETD2 Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W).

Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine.

Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q).

These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Mendeliome v1.553 RPS15 Zornitza Stark gene: RPS15 was added
gene: RPS15 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RPS15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS15 were set to 19061985
Phenotypes for gene: RPS15 were set to Diamond-Blackfan anaemia
Review for gene: RPS15 was set to RED
Added comment: Single individual reported in 2008, no reports since.
Sources: Expert Review
Mendeliome v1.552 CLDN5 Suliman Khan reviewed gene: CLDN5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 36477332; Phenotypes: seizures, developmental delay, microcephaly, brain calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.552 AMT Xinyu Zhang reviewed gene: AMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 35646099, 25231368, 27362913; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.550 ZFP36L1 Zornitza Stark Publications for gene: ZFP36L1 were set to
Mendeliome v1.548 ZFP36L1 Zornitza Stark reviewed gene: ZFP36L1: Rating: RED; Mode of pathogenicity: None; Publications: 34611029, 22367205; Phenotypes: Oocyte maturation defect 13, MIM# 620154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.545 FZR1 Zornitza Stark reviewed gene: FZR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 109, MIM# 620145; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.541 TNNC2 Zornitza Stark gene: TNNC2 was added
gene: TNNC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNC2 were set to 33755597
Phenotypes for gene: TNNC2 were set to Congenital myopathy, MONDO:0019952, TNNC2-related
Review for gene: TNNC2 was set to GREEN
Added comment: Two families reported: Family 1: 4 individuals, three generations; missense variant p.(Asp34Tyr) Family 2: de novo variant, missense p.(Met79Ile)

Physiological studies in myofibers isolated from patients’ biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC.

Borderline Green: sufficient segregation in Fam 1 plus de novo status in Fam 2, plus functional data.
Sources: Literature
Mendeliome v1.539 CHUK Zornitza Stark Publications for gene: CHUK were set to 25691407; 20961246; 10195895; 10195896; 29523099; 28513979
Mendeliome v1.538 CHUK Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979
Mendeliome v1.538 IRF7 Zornitza Stark Publications for gene: IRF7 were set to 25814066; 15800576
Mendeliome v1.535 IRF7 Zornitza Stark edited their review of gene: IRF7: Added comment: Additional individuals reported PMIDs 35986347, 35670811: total of 7; Changed publications: 25814066, 15800576, 35986347, 35670811
Mendeliome v1.534 NLGN4X Zornitza Stark Publications for gene: NLGN4X were set to 12669065; 18231125; 10071191; 29428674
Mendeliome v1.532 NLGN4X Krithika Murali reviewed gene: NLGN4X: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:26350204, PMID:14963808, PMID:12669065, PMID:23352163, PMID:28263302, PMID:16648374; Phenotypes: Intellectual developmental disorder, X-linked - MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.530 MPC2 Zornitza Stark gene: MPC2 was added
gene: MPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPC2 were set to 36417180
Phenotypes for gene: MPC2 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: MPC2 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.528 ARF3 Zornitza Stark Publications for gene: ARF3 were set to 34346499
Mendeliome v1.526 TIMMDC1 Paul De Fazio reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36349561, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31 MIM#618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.526 LEMD2 Seb Lunke Phenotypes for gene: LEMD2 were changed from Marbach-Rustad progeroid syndrome, OMIM# 619322; progeroid disorder to Marbach-Rustad progeroid syndrome, OMIM# 619322; arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587; Cataract 46, juvenile-onset, OMIM# 212500
Mendeliome v1.525 LEMD2 Seb Lunke Publications for gene: LEMD2 were set to PMID: 30905398
Mendeliome v1.523 LEMD2 Seb Lunke reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31061923, 26788539, 30905398, 36377660; Phenotypes: Marbach-Rustad progeroid syndrome, OMIM# 619322, arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587, Cataract 46, juvenile-onset, OMIM# 212500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.518 DCLRE1B Zornitza Stark Publications for gene: DCLRE1B were set to 20479256; 21647296
Mendeliome v1.515 DCLRE1B Zornitza Stark edited their review of gene: DCLRE1B: Added comment: Three additional families reported.; Changed rating: GREEN; Changed publications: 20479256, 21647296, 35007328
Mendeliome v1.513 NUP54 Hazel Phillimore gene: NUP54 was added
gene: NUP54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to PMID: 36333996
Phenotypes for gene: NUP54 were set to Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mode of pathogenicity for gene: NUP54 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: NUP54 was set to AMBER
Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544.

Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser).

Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu).

Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe)

The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum.

Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina.

Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.
Sources: Literature
Mendeliome v1.512 ARF3 Dean Phelan reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36369169, 34346499; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.511 DCLRE1B Manny Jacobs reviewed gene: DCLRE1B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 10699141, 20479256, 35007328; Phenotypes: Dyskeratosis congenita, autosomal recessive 8; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.511 NPC1 Naomi Baker gene: NPC1 was added
gene: NPC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPC1 were set to 36417180
Phenotypes for gene: NPC1 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: NPC1 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.511 EMILIN1 Zornitza Stark Publications for gene: EMILIN1 were set to PMID: 31978608; 26462740.
Mendeliome v1.507 EMILIN1 Karina Sandoval reviewed gene: EMILIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36351433; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, aortic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.507 GABRA3 Sarah Pantaleo gene: GABRA3 was added
gene: GABRA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRA3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GABRA3 were set to PMID: 29053855
Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features,
Penetrance for gene: GABRA3 were set to Incomplete
Review for gene: GABRA3 was set to GREEN
Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor.
Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus.
The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies.
Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype.
Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype.
Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
Sources: Literature
Mendeliome v1.504 SHROOM4 Alison Yeung reviewed gene: SHROOM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36379543, 35663265; Phenotypes: Congenital anomaly of the kidney and urinary tracy (CAKUT), SHROOM4-related, MONDO:0019719, epilepsy, idiopathic generalised, SHROOM4-related, MONDO:0005579; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.504 UQCRH Chern Lim gene: UQCRH was added
gene: UQCRH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UQCRH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UQCRH were set to 34750991
Phenotypes for gene: UQCRH were set to Mitochondrial complex III deficiency, nuclear type 11, MIM#620137
Review for gene: UQCRH was set to AMBER
gene: UQCRH was marked as current diagnostic
Added comment: PMID: 34750991:
- Two affected cousins, presented with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy.
- Both have a 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH, predicted to culminate in an in-frame deletion exons 2 and 3 of the four-exon UQCRH gene, resulting in a shortened product.
- Mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/-) also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death.
- Patient fibroblasts and Uqcrh-/- mouse tissues showed a CIII defect.
- Expression of wild-type UQCRH in patient fibroblasts ameliorates the CIII defect.
Sources: Literature
Mendeliome v1.504 FEM1C Paul De Fazio gene: FEM1C was added
gene: FEM1C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1C were set to 36336956; 28135719; 33398170; 33398168
Phenotypes for gene: FEM1C were set to Neurodevelopmental disorder, FEM1C-related MONDO:0700092
Review for gene: FEM1C was set to GREEN
gene: FEM1C was marked as current diagnostic
Added comment: PMID:36336956 describes a 9-year-old boy with severe DD, lack of speech, pyramidal signs, and limb ataxia who had a de novo missense variant Asp126His in FEM1C ascertained by WES. The equivalent variant introduced into the nematode C.elegans resulted in disabled locomotion caused by synaptic abnormalities and not muscle dysfunction.

An alternate change Asp126Val was reported in the DDD study de novo in a patient with uncharacterised developmental delay (PMID:28135719).

The Asp126 residue (but not either of the variants above specifically) was shown to be functionally important by in vitro studies (PMID:33398170;33398168). The residue is highly conserved and located in a region of missense constraint.

Borderline green, 2 patients and an animal model. Note all evidence points to the Asp126 residue being of specific importance.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty gene: TCEAL1 was added
gene: TCEAL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCEAL1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TCEAL1 were set to PMID: 36368327
Phenotypes for gene: TCEAL1 were set to hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.
Review for gene: TCEAL1 was set to GREEN
Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.503 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
12 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Mendeliome v1.502 MAN2A2 Zornitza Stark gene: MAN2A2 was added
gene: MAN2A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAN2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2A2 were set to 36357165
Phenotypes for gene: MAN2A2 were set to Congenital disorder of glycosylation, MONDO:0015286, MAN2A2-reated
Review for gene: MAN2A2 was set to RED
Added comment: Single consanguineous family reported with homozygous truncating variant in two brothers with ID. Supportive biochemical data only.
Sources: Literature
Mendeliome v1.499 MLIP Zornitza Stark reviewed gene: MLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.498 UBE3C Zornitza Stark reviewed gene: UBE3C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, UBE3C-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.497 KIF26A Zornitza Stark reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral malformation MONDO:0016054, KIF26-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.495 UBE3C Chirag Patel gene: UBE3C was added
gene: UBE3C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3C were set to PMID: 36401616
Phenotypes for gene: UBE3C were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: UBE3C was set to GREEN
Added comment: 3 patients/2 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in UBE3C. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.493 HECTD4 Chirag Patel gene: HECTD4 was added
gene: HECTD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to PMID: 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: HECTD4 was set to GREEN
Added comment: 7 patients/5 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in HECTD4. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.491 KIF26A Chirag Patel gene: KIF26A was added
gene: KIF26A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to PMID: 36228617
Phenotypes for gene: KIF26A were set to Congenital brain malformations, no OMIM #
Review for gene: KIF26A was set to GREEN
Added comment: 5 unrelated patients with biallelic loss-of-function variants in KIF26A (found through WES), exhibiting a spectrum of congenital brain malformations (schizencephaly, corpus callosum anomalies, polymicrgyria, and ventriculomegaly). Combining mice and human iPSC-derived organoid models, they discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways.
Sources: Literature
Mendeliome v1.489 TAMM41 Zornitza Stark reviewed gene: TAMM41: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency-56 (COXPD56), MIM#620139; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.489 PIGN Zornitza Stark edited their review of gene: PIGN: Added comment: Large cohort study of 21 new and review of 40 previously published cases in PMID 36322149

Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon.; Changed publications: 36322149; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563, Fryns syndrome
Mendeliome v1.488 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to 20493457; 22258530; 32811770; 33578420; 31332438
Mendeliome v1.486 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: PMID 36331550: further 31 individuals reported with mono-allelic variants. Three phenotypes observed:
1. DEE
2. Isolated DD/ID
3. HSP or ataxia; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523, 36331550
Mendeliome v1.485 SEC16B Zornitza Stark gene: SEC16B was added
gene: SEC16B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SEC16B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEC16B were set to 28375157; 28862642; 30652979
Phenotypes for gene: SEC16B were set to Polycystic liver disease (with or without kidney cysts), MONDO:0000447, SEC16B-related
Review for gene: SEC16B was set to AMBER
Added comment: Two unrelated individuals with limited supporting functional data reported. Assessed as LIMITED by ClinGen.
Sources: Expert Review
Mendeliome v1.482 NDUFB7 Zornitza Stark reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency nuclear type 39 (MC1DN39), MIM#620135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.481 ADAMTS9 Chirag Patel reviewed gene: ADAMTS9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.480 MYCN Zornitza Stark reviewed gene: MYCN: Rating: RED; Mode of pathogenicity: None; Publications: 34590686; Phenotypes: cleft lip with or without cleft palate, MONDO:0016034, MYCN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.480 AFDN Zornitza Stark gene: AFDN was added
gene: AFDN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AFDN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AFDN were set to 36384317
Phenotypes for gene: AFDN were set to Cleft lip/palate, MONDO:0016044, AFDN-related
Review for gene: AFDN was set to RED
Added comment: Over-representation of rare AFDN missense variants reported in a cohort of CL/P individuals of African and Brazilian origin. However, almost all of the variants reported have hets in gnomad. The one that is novel has alternative missense at the same aa position.
Sources: Literature
Mendeliome v1.479 FOXA2 Zornitza Stark Publications for gene: FOXA2 were set to 29329447; 28973288; 11445544
Mendeliome v1.478 FOXA2 Zornitza Stark edited their review of gene: FOXA2: Added comment: PMID 33999151: two further individuals reported.; Changed publications: 29329447, 28973288, 11445544, 33999151
Mendeliome v1.478 FOXI1 Zornitza Stark reviewed gene: FOXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.477 CLEC3B Chirag Patel gene: CLEC3B was added
gene: CLEC3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLEC3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLEC3B were set to PMID: 35331648
Phenotypes for gene: CLEC3B were set to Macular dystrophy, retinal, 4, OMIM #619977
Review for gene: CLEC3B was set to GREEN
Added comment: 12 affected individuals from 5 multigenerational Japanese families in a small village in Miyazaki diagnosed with autosomal dominant maculoretinopathy. WES identified a pathogenic variant (p.Ala180Asp) in CLEC3B, which encodes tetranectin, a plasminogen kringle-4 binding protein. Variant cosegregated with the ocular phenotype.

Mice that received subretinal injections with CLEC3B variant displayed multiple subretinal hyperreflective deposits, reduced retinal thickness, and decreased electroretinographic responses. The optokinetic tracking response indicated that spatial frequency was significantly lower (P < .05), implying impaired visual function in the mice.
Sources: Literature
Mendeliome v1.476 PDIA6 Chirag Patel edited their review of gene: PDIA6: Added comment: 2nd patient with large polycystic kidneys, death and end stage renal failure at 18 months, microcephaly, bilateral inguinal hernias, umbilical hernia, developmental delay, bilateral sensorineural hearing loss, visual impairment, steatorrhea, fibrotic changes in liver, and insulin-dependent diabetes. WGS found homozygous stop-gain variant (Tyr368*) in PDIA6. Segregation not performed.; Changed rating: AMBER; Changed publications: PMID: 35856135; Changed phenotypes: Polycystic kidney disease, infancy-onset diabetes, and microcephaly
Mendeliome v1.475 ARPC4 Zornitza Stark reviewed gene: ARPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35047857; Phenotypes: Neurodevelopmental disorder, ARPC4-related MONDO#0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.472 MTSS1 Zornitza Stark gene: MTSS1 was added
gene: MTSS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTSS1 were set to 36067766
Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071)
Review for gene: MTSS1 was set to GREEN
Added comment: Five individuals with the same heterozygous de novo variant in MTSS2 (NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing.

The individuals presented with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms.

Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies.
Sources: Literature
Mendeliome v1.470 TPR Zornitza Stark reviewed gene: TPR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.468 SMC5 Zornitza Stark gene: SMC5 was added
gene: SMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMC5 were set to 36333305
Phenotypes for gene: SMC5 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SMC5 was set to GREEN
Added comment: Four individuals from three families with a chromosome breakage disorder and bi-allelic variants in this gene. However, three of the individuals had the same homozygous missense variant. Evidence for functional impact of the variant was limited. However, zebrafish model recapitulated the phenotype and was not rescued by the introduction of this variant, arguing for functional effect. Borderline Amber/Green
Sources: Literature
Mendeliome v1.466 SLF2 Zornitza Stark gene: SLF2 was added
gene: SLF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLF2 were set to 36333305
Phenotypes for gene: SLF2 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SLF2 was set to GREEN
Added comment: Seven individuals from 6 families with a chromosome breakage disorder and bi-allelic variants in this gene (LoF). Functional data including zebrafish model.
Sources: Literature
Mendeliome v1.465 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to intellectual disability, MONDO:0001071; cerebellar ataxia, MONDO:0000437; microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: This gene should be added to the following diseases: Intellectual disability, microcephaly and ataxia.

Comment on classification of this gene: This gene should be added with a RED rating as the association is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.465 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.465 IRF2BP2 Zornitza Stark Publications for gene: IRF2BP2 were set to 27016798
Mendeliome v1.463 IRF2BP2 Zornitza Stark edited their review of gene: IRF2BP2: Added comment: Reports of additional patients: 4yo with chronic diarrhea, severe eczema, anemia, failure to thrive, fevers, short stature, recurrent infections, cataracts, hypodontia, hypotrichosis alopecia, hypogammaglobulinemia. The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years.; Changed rating: GREEN; Changed publications: 27016798, 32048120, 36193988, 33864888; Changed phenotypes: Immunodeficiency, common variable, 14, MIM# 617765
Mendeliome v1.462 ATP5F1 Zornitza Stark gene: ATP5F1 was added
gene: ATP5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5F1 were set to 36239646
Phenotypes for gene: ATP5F1 were set to Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation-2 (HUMOP2), MIM#620085
Review for gene: ATP5F1 was set to RED
Added comment: Identical twins reported with a de novo missense variant in this gene and hyper metabolism: normal thyroid function, hyperphagia, tachypnea, increased basal temperature, and increased sweating. Biochemical studies demonstrated increased mitochondrial oxygen consumption with inefficient production of ATP in the final steps of oxidative phosphorylation due to an uncoupling defect
Sources: Expert list
Mendeliome v1.459 CACNA1I Zornitza Stark reviewed gene: CACNA1I: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.459 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Mendeliome v1.459 HK1 Zornitza Stark edited their review of gene: HK1: Added comment: PMID 36333503: 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1) identified in individuals with hyperinsulinism.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571, 36333503; Changed phenotypes: Hyperinsulinism MONDO:0002177, HK1-related, Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460
Mendeliome v1.457 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214
Mendeliome v1.455 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: Additional family with 3 individuals in 2 generations reported in PMID 24627108.; Changed rating: GREEN; Changed publications: 32949214, 24627108; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111
Mendeliome v1.455 THAP1 Zornitza Stark Publications for gene: THAP1 were set to 21793105; 22377579
Mendeliome v1.452 WDR5 Bryony Thompson gene: WDR5 was added
gene: WDR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related
Mode of pathogenicity for gene: WDR5 was set to Other
Review for gene: WDR5 was set to GREEN
Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established.
Sources: Literature
Mendeliome v1.451 TOMM7 Bryony Thompson edited their review of gene: TOMM7: Changed publications: 36299998
Mendeliome v1.450 KPNA3 Zornitza Stark reviewed gene: KPNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia-88 (SPG88), MIM#620106; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.448 PI4K2A Zornitza Stark Publications for gene: PI4K2A were set to 32418222
Mendeliome v1.446 DNAJB4 Karina Sandoval gene: DNAJB4 was added
gene: DNAJB4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJB4 were set to PMID: 36264506
Phenotypes for gene: DNAJB4 were set to Myopathy, MONDO:0005336, DNAJB4-related
Review for gene: DNAJB4 was set to GREEN
Added comment: 4 individuals from 3 unrelated families with bi-allelic LoF/missense variants in this gene, and either childhood/adult onset of muscle weakness and respiratory failure. One had HCM.

Functional studies including mouse model.
Sources: Literature
Mendeliome v1.446 ATP11A Zornitza Stark Publications for gene: ATP11A were set to PMID: 34403372; 35278131
Mendeliome v1.445 ATP11A Chern Lim reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36300302; Phenotypes: Deafness, autosomal dominant 84 (MIM#619810); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.444 PI4K2A Seb Lunke reviewed gene: PI4K2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564627, 35880319, 19581584; Phenotypes: complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.442 CAMSAP1 Naomi Baker gene: CAMSAP1 was added
gene: CAMSAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related
Review for gene: CAMSAP1 was set to GREEN
Added comment: Five unrelated families with bi-allelic loss-of-function variants. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe neurodevelopmental delay, cortical visual impairment, and seizures.
Sources: Literature
Mendeliome v1.442 THAP1 Michelle Torres reviewed gene: THAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36205328, 21425335, 20211909; Phenotypes: Dystonia 6, torsion, (MIM#60262); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.442 MYCBP2 Suliman Khan gene: MYCBP2 was added
gene: MYCBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to PMID: 36200388
Phenotypes for gene: MYCBP2 were set to Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; corpus callosum abnormalities
Penetrance for gene: MYCBP2 were set to Complete
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 36200388 reported eight patients with neurodevelopmental disorder including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy, and autistic features. Each patient harbored a de novo LOF variant in MYCBP2 gene. Functional study supported a direct link between MYCBP2 and neurodevelopmental spectrum disorder specifically corpus callosum defects.
Sources: Literature
Mendeliome v1.441 KLHL20 Dean Phelan gene: KLHL20 was added
gene: KLHL20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to PMID: 36214804
Phenotypes for gene: KLHL20 were set to Neurodevelopmental disorder (MONDO:0700092), KLHL20-related
Review for gene: KLHL20 was set to GREEN
Added comment: PMID: 36214804
- 14 patients with de novo missense variants in KLHL20. The patients had mild to severe ID, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity and subtle dysmorphic facial features.
Sources: Literature
Mendeliome v1.440 FICD Alison Yeung gene: FICD was added
gene: FICD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36136088
Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257
Review for gene: FICD was set to GREEN
Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His
One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53

Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy.
Sources: Literature
Mendeliome v1.439 METTL23 Lucy Spencer reviewed gene: METTL23: Rating: AMBER; Mode of pathogenicity: None; Publications: 36099048; Phenotypes: glaucoma MONDO:0005041; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.437 FOXI3 Paul De Fazio gene: FOXI3 was added
gene: FOXI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 36260083
Phenotypes for gene: FOXI3 were set to Dysostosis with predominant craniofacial involvement (MONDO:0800085)
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to GREEN
gene: FOXI3 was marked as current diagnostic
Added comment: Ten affected individuals from 4 families reported with monoallelic variants, 2 with missense variants affecting the nuclear localisation sequence and 2 with frameshift variants.

The missense variants were associated with isolated microtia with aural atresia and affected subcellular localisation of the protein, while the frameshift variants were associated with microtia and mandubular hypoplasia, suggesting dosage sensitivity.

Rated green but CAUTION for incomplete penetrance. 3 of the 4 families had unaffected carriers. Family 1 in particular had 25 genotyped individuals, of which 15 were carriers, of which 5 were affected.
Sources: Literature
Mendeliome v1.437 TOMM7 Zornitza Stark Publications for gene: TOMM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100148
Mendeliome v1.436 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Changed publications: 36299998, 36282599
Mendeliome v1.436 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Added comment: Second family reported in PMID 36282599: single affected individual with homozygous missense variant; clinical presentation with progeroid features but functional data supports underlying mitochondrial aetiology.

Maintain Amber rating as the two patients have quite disparate clinical presentations.; Changed publications: 36282599
Mendeliome v1.435 CBFB Ain Roesley gene: CBFB was added
gene: CBFB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBFB were set to 36241386
Phenotypes for gene: CBFB were set to cleidocranial dysplasia (MONDO#0007340), CBFB-related
Penetrance for gene: CBFB were set to Complete
Review for gene: CBFB was set to GREEN
gene: CBFB was marked as current diagnostic
Added comment: 5 families with 8 individuals, including 2 de novos and 1 intragenic exon 4 deletion

In 1 family, the mother did not report skeletal concerns but had dental abnormalities during childhood
Sources: Literature
Mendeliome v1.433 CEBPE Zornitza Stark Publications for gene: CEBPE were set to 10359588; 11313242; 31256937; 29651288
Mendeliome v1.432 CEBPE Zornitza Stark edited their review of gene: CEBPE: Added comment: Additional family with auto inflammatory phenotype published in 31201888, extensive functional data.; Changed publications: 10359588, 11313242, 31256937, 29651288, 31201888
Mendeliome v1.432 SFTPA1 Zornitza Stark Publications for gene: SFTPA1 were set to 31601679; 30854216; 28869238; 26792177
Mendeliome v1.430 SFTPA1 Zornitza Stark edited their review of gene: SFTPA1: Added comment: Additional 3 families reported with mono-allelic variants.; Changed rating: GREEN; Changed publications: 31601679, 30854216, 28869238, 26792177, 32855221
Mendeliome v1.430 GNPNAT1 Krithika Murali reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36097642, 35427807; Phenotypes: Rhizomelic dysplasia, Ain-Naz type, MIM#619598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.429 SCNM1 Zornitza Stark reviewed gene: SCNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Orofaciodigital syndrome XIX, MIM# 620107; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.427 FGL2 Zornitza Stark gene: FGL2 was added
gene: FGL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGL2 were set to 36243222
Phenotypes for gene: FGL2 were set to Autoinflammatory syndrome, MONDO:0019751, FGL2-related
Review for gene: FGL2 was set to AMBER
Added comment: Child with early onset systemic inflammation, autoantibodies, and vasculitis. Homozygous truncating variant, functional studies include rescue experiments.
Sources: Literature
Mendeliome v1.424 FKBP6 Zornitza Stark reviewed gene: FKBP6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 77, MIM# 620103; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.421 PAX4 Krithika Murali reviewed gene: PAX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Maturity-onset diabetes of the young, type IX - MIM#612225; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.420 PRDM16 Zornitza Stark Publications for gene: PRDM16 were set to 23768516; 29367541; 34915728; 31965688; 29367541
Mendeliome v1.418 PRDM16 Paul De Fazio reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.417 EMILIN1 Zornitza Stark reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.416 TMEM147 Zornitza Stark reviewed gene: TMEM147: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly, MIM# 620075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.415 CCDC34 Zornitza Stark gene: CCDC34 was added
gene: CCDC34 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CCDC34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC34 were set to 34348960
Phenotypes for gene: CCDC34 were set to Spermatogenic failure 76, MIM# 620084
Review for gene: CCDC34 was set to GREEN
Added comment: Two unrelated individuals reported with homozygous frameshift variants. Mouse model recapitulated phenotype.
Sources: Expert list
Mendeliome v1.414 ACTN2 Bryony Thompson reviewed gene: ACTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17097056, 20022194, 25173926, 25224718, 22767232, 27287556, 28436997, 31333075, 31956495, 32973354, 34802252, 33500567, 36078153, 36116040; Phenotypes: intrinsic cardiomyopathy MONDO:0000591; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.413 NFAT5 Zornitza Stark Publications for gene: NFAT5 were set to 25667416
Mendeliome v1.411 NFAT5 Zornitza Stark edited their review of gene: NFAT5: Added comment: Two additional individuals with missense variants reported in PMID 36238298: one with EBV infection with hepatitis and enterocolitis, and one with fatal HLH.; Changed rating: AMBER; Changed publications: 25667416, 36238298; Changed phenotypes: Immune deficiency disease, MONDO:0003778, NFAT5-related, Recurrent infections, Autoimmune enterocolopathy, EBV susceptibility, HLH
Mendeliome v1.406 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.405 IMPA1 Bryony Thompson gene: IMPA1 was added
gene: IMPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IMPA1 were set to 26416544; 24554717; 32839513; 17460611
Phenotypes for gene: IMPA1 were set to intellectual disability, autosomal recessive 59 MONDO:0015020
Review for gene: IMPA1 was set to AMBER
Added comment: A homozygous frameshift variant identified in a large Brazilian consanguineous family with ID, also supporting functional studies and null mouse models.
Sources: Literature
Mendeliome v1.403 ARNT2 Bryony Thompson gene: ARNT2 was added
gene: ARNT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARNT2 were set to 11381139; 24022475
Phenotypes for gene: ARNT2 were set to Webb-Dattani syndrome MONDO:0014404
Review for gene: ARNT2 was set to AMBER
Added comment: A homozygous frameshift (c.1373_1374dupTC) in six affected children from a highly consanguineous family with a syndromic phenotype including microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. In a Arnt2(-/-) mouse model embryos die perinatally and exhibit impaired hypothalamic development.
Sources: Literature
Mendeliome v1.402 HEATR3 Zornitza Stark reviewed gene: HEATR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anaemia 21, MIM# 620072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.401 FRMD5 Zornitza Stark gene: FRMD5 was added
gene: FRMD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Review for gene: FRMD5 was set to GREEN
Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model.
Sources: Literature
Mendeliome v1.400 GIGYF1 Elena Savva Publications for gene: GIGYF1 were set to 33057194; 35917186
Mendeliome v1.400 GIGYF1 Elena Savva Publications for gene: GIGYF1 were set to 33057194
Mendeliome v1.397 GIGYF1 Elena Savva reviewed gene: GIGYF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Intellectual disability, GIGYF1-related (MONDO#0001071); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.396 TOMM7 Zornitza Stark reviewed gene: TOMM7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial disorder MONDO:0004069, TOMM7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.395 TOMM7 Bryony Thompson gene: TOMM7 was added
gene: TOMM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100148
Phenotypes for gene: TOMM7 were set to growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy MONDO:0014911
Review for gene: TOMM7 was set to AMBER
Added comment: A single case identified with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. A mouse model of the missense variant demonstrated a bioenergetic defect and a phenotype of mitochondrial diseases. It also strongly suggested that the variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with a homozygous Tomm7 deletion.
Sources: Literature
Mendeliome v1.393 HECW2 Bryony Thompson reviewed gene: HECW2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35753050, 35487419; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language MONDO:0014995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.392 SEPT4 Bryony Thompson gene: SEPT4 was added
gene: SEPT4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEPT4 were set to 36135717; 15737931; 15737930
Phenotypes for gene: SEPT4 were set to male infertility MONDO:0005372
Review for gene: SEPT4 was set to GREEN
Added comment: Two unrelated cases with primary male infertility (asthenoteratozoospermia) from consanguineous Chinsese families with 2 difference homozygous stopgain variants (Patient 1: c.721A>T, p.R241* and Patient 2: c.205C>T, p.R69*). Multiple supporting mouse models where the male mice are sterile.
Sources: Literature
Mendeliome v1.390 FAM20B Bryony Thompson gene: FAM20B was added
gene: FAM20B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FAM20B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM20B were set to 30847897; 30105814; 22732358; 27405802
Phenotypes for gene: FAM20B were set to Desbuquois dysplasia MONDO:0015426
Review for gene: FAM20B was set to AMBER
Added comment: Two siblings from a single family with neonatal short limb dysplasia resembling Desbuquois dysplasia. One of the siblings underwent genetic testing and compound heterozygous variants were identified in FAM20B ((NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). Multiple mouse models reported with skeletal abnormalities.
Sources: Other
Mendeliome v1.388 EXOC6B Bryony Thompson gene: EXOC6B was added
gene: EXOC6B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC6B were set to 26669664; 30284759; 36150098
Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity MONDO:0019675
Review for gene: EXOC6B was set to GREEN
Added comment: 6 affected individuals from 4 families, and supporting assays in patient cells
PMID: 26669664 - 2 brothers with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones from a consanguineous family, with a homozygous nonsense variant [c.906T>A/p.(Tyr302*)]
PMID: 30284759 - 2 sisters with dislocations of the hips and knees, long slender fingers with distal tapering, significant motor disability but normal (older sister) or low-normal intelligence (younger sister), with a homozygous in-frame deletion of exons 9-20
PMID: 36150098 - 2 unrelated probands from consanguineous families, one with a homozygous frameshift exon 20 deletion and one with a homozygous nonsense variant (c.401T>G p.Leu134Ter). Function assessment of patient fibroblast cell lines indicated abrogation of exocytosis leading to impaired primary ciliogenesis
Sources: Literature
Mendeliome v1.387 VPS33A Bryony Thompson Publications for gene: VPS33A were set to 28013294; 27547915
Mendeliome v1.385 VPS33A Bryony Thompson changed review comment from: PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts; to: Now two missense variants reported with disease in at least 15 probands/families
PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts
Mendeliome v1.384 DPH5 Zornitza Stark gene: DPH5 was added
gene: DPH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, MIM# 620070
Review for gene: DPH5 was set to GREEN
Added comment: 5 individuals from 3 unrelated families reported with severe ID, feeding difficulties, dysmorphic features and congenital anomalies, though there was no consistent pattern to these.
Sources: Literature
Mendeliome v1.383 VPS33A Bryony Thompson reviewed gene: VPS33A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28013294, 27547915, 31936524, 36153662; Phenotypes: Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.381 ADGRL1 Zornitza Stark reviewed gene: ADGRL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.381 GALT Zornitza Stark reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Galactosemia MIM#230400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.378 ALG5 Zornitza Stark reviewed gene: ALG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 7, MIM# 620056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.377 SLC32A1 Zornitza Stark Publications for gene: SLC32A1 were set to 34038384
Mendeliome v1.375 SCNM1 Elena Savva gene: SCNM1 was added
gene: SCNM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to PMID: 36084634
Phenotypes for gene: SCNM1 were set to Ciliopathy, SCNM1-related, MONDO:0005308
Review for gene: SCNM1 was set to GREEN
Added comment: Iturrate (2022): three unrelated families (4 affected) w/ OFD, polydactyly, syndactyly and brachydactyly. All had biallelic variants (fs, missense, AluYc1 sequence insertion) and were consanguinous
- the missense variant was shown to have a splice outcome
Sources: Literature
Mendeliome v1.374 DEPDC5 Dean Phelan reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36067010, 32848577; Phenotypes: Neurodevelopmental disorder, DEPDC5-related, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.374 LETM1 Zornitza Stark reviewed gene: LETM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.372 LETM1 Ee Ming Wong gene: LETM1 was added
gene: LETM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related
gene: LETM1 was marked as current diagnostic
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components
Sources: Literature
Mendeliome v1.371 GABBR1 Zornitza Stark gene: GABBR1 was added
gene: GABBR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to 36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder, GABBR1-related, MONDO:0700092
Review for gene: GABBR1 was set to GREEN
Added comment: Four individuals with de novo variants in this gene and varying severity of DD/ID, seizures and hypotonia.
Sources: Literature
Mendeliome v1.369 DUT Daniel Flanagan gene: DUT was added
gene: DUT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUT were set to 28073829; 35611808
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome (MIM#620044)
Review for gene: DUT was set to GREEN
Added comment: Homozygous missense (p.(Tyr142Cys)) identified in eight affected individuals from four unrelated consanguineous families (French, Egyptian, two Libyan) with diabetes and bone marrow failure. DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway.

p.(Tyr142Cys) has 11 heterozygotes and no homozygotes in gnomAD.
Sources: Expert list
Mendeliome v1.369 DACT1 Paul De Fazio reviewed gene: DACT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36066768; Phenotypes: Townes-Brocks syndrome 2 MONDO:0054582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.369 CENPP Seb Lunke changed review comment from: Sources: Literature; to: Single family with dominant SNHL segregated through 5 family members. Truncating variant in NM_001012267.3(CENPP):c.849T>A (p.Cys283Ter). Note: misannotated as nonsense variant in paper.
Sources: Literature
Mendeliome v1.369 CENPP Seb Lunke gene: CENPP was added
gene: CENPP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CENPP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CENPP were set to 36071244
Phenotypes for gene: CENPP were set to autosomal dominant nonsyndromic hearing loss; MONDO:0019587
Review for gene: CENPP was set to RED
Added comment: Sources: Literature
Mendeliome v1.368 GABRG1 Anna Ritchie gene: GABRG1 was added
gene: GABRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRG1 were set to PMID: 36121006
Phenotypes for gene: GABRG1 were set to Developmental and epileptic encephalopathy MONDO:0100062
Added comment: 2-year-old patient with epileptic encephalopathy, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo missense variant in the GABRG1 gene.
Sources: Literature
Mendeliome v1.368 SLC32A1 Lucy Spencer reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36073542; Phenotypes: developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.366 LAMA5 Belinda Chong reviewed gene: LAMA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29534211, 16790509, 29764427, 30808327, 24130771, 35419533; Phenotypes: Nephrotic syndrome, type 26 620049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.366 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Mendeliome v1.365 ATP6V0C Naomi Baker reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.364 ATP6V0C Alison Yeung reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.364 SLC13A1 Lucy Spencer gene: SLC13A1 was added
gene: SLC13A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 36175384
Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related
Review for gene: SLC13A1 was set to RED
Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad.

Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype.
Sources: Literature
Mendeliome v1.363 LAMA5 Zornitza Stark reviewed gene: LAMA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 35419533; Phenotypes: Nephrotic syndrome, type 26 620049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.361 SARS Ee Ming Wong edited their review of gene: SARS: Added comment: -Two missense variants within the aminoacylation domain identified in 16 affected individuals from 3 distinct CMT families
-Mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation; Changed rating: GREEN; Changed publications: 36088542; Changed phenotypes: Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.359 MTSS1L Elena Savva gene: MTSS1L was added
gene: MTSS1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTSS1L were set to PMID: 36067766
Phenotypes for gene: MTSS1L were set to Intellectual disability, MTSS2-related (MONDO#0001071)
Review for gene: MTSS1L was set to GREEN
Added comment: Alt gene name: MTSS2

Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals.
- Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms.
- Overexpression supports a DN mechanism
Sources: Literature
Mendeliome v1.357 DAW1 Alison Yeung gene: DAW1 was added
gene: DAW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124
Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, MONDO:0016575; Visceral heterotaxy, MONDO:0018677
Review for gene: DAW1 was set to GREEN
Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype
Sources: Literature
Mendeliome v1.355 RABGAP1 Zornitza Stark gene: RABGAP1 was added
gene: RABGAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RABGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RABGAP1 were set to 36083289
Phenotypes for gene: RABGAP1 were set to Neurodevelopmental disorder, RABGAP1-related,MONDO:0700092
Review for gene: RABGAP1 was set to GREEN
Added comment: 5 individuals from three families reported with ID, microcephaly, SNHL and seizures. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v1.354 NAPB Paul De Fazio gene: NAPB was added
gene: NAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 26235277; 28097321; 33189936
Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033
Review for gene: NAPB was set to GREEN
gene: NAPB was marked as current diagnostic
Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD

PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision

PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia.
Sources: Literature
Mendeliome v1.354 FKBP6 Dean Phelan gene: FKBP6 was added
gene: FKBP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FKBP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP6 were set to PMID: 36150389
Phenotypes for gene: FKBP6 were set to Spermatogenic failure (MONDO:0004983), FKBP6-related
Review for gene: FKBP6 was set to GREEN
Added comment: PMID: 36150389 - large cohort study of men with severe spermatogenic failure (SPGF), identified six individuals with rare bi-allelic loss of function variants in FKBP6. RT-qPCR and immunofluorescence confirmed lack of FKBP6 expression. In mice, Fkbp6 has also been shown to be essential for spermatogenesis.
Sources: Literature
Mendeliome v1.353 GCSH Ain Roesley Publications for gene: GCSH were set to 1671321
Mendeliome v1.351 GCSH Ain Roesley reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: glycine encephalopathy MONDO#0011612, GCSH-related, neurodevelopmental disorder MONDO#0700092, GCHS-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.351 NSD2 Zornitza Stark Publications for gene: NSD2 were set to 30345613; 31171569
Mendeliome v1.350 NSD2 Zornitza Stark edited their review of gene: NSD2: Changed publications: 36189577
Mendeliome v1.349 NSD2 Zornitza Stark Publications for gene: NSD2 were set to 30345613; 31171569
Mendeliome v1.348 FOSL2 Krithika Murali gene: FOSL2 was added
gene: FOSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to 36197437
Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related
Review for gene: FOSL2 was set to GREEN
Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies).

In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism.

Clinical features included:
- Cutis aplasia congenital of the scalp (10/11)
- Tooth enamel hypoplasia and discolouration (8/9)
- Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis
- 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset)
- 6/9 IUGR
- 5/9 postnatal growth restriction
- 7/9 developmental delay/ID
- 5/7 ADHD/ASD
- 2/9 seizures
Sources: Literature
Mendeliome v1.348 TRAF3 Zornitza Stark Publications for gene: TRAF3 were set to 20832341
Mendeliome v1.346 TRAF3 Zornitza Stark edited their review of gene: TRAF3: Added comment: PMID 35960817: Nine individuals from five unrelated families with childhood-onset immune diseases and recurrent infections. All patients had suffered recurrent ear and sinopulmonary infections, including pneumonias from encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenza, resulting in early-onset bronchiectasis in several individuals; Changed rating: GREEN; Changed publications: 20832341, 35960817; Changed phenotypes: Autoinflammatory syndrome, TRAF3-related, MONDO:0019751, hypergammaglobulinemia, lymphadenopathy, splenomegaly, Sjögren’s syndrome, {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849
Mendeliome v1.346 KCNK3 Krithika Murali reviewed gene: KCNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36195757; Phenotypes: eurodevelopmental disorder, MONDO:0700092, KCNK3-related, developmental delay with sleep apnoea (DDSA), Pulmonary hypertension, primary, 4-MIM#615344; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.344 DOHH Zornitza Stark reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.343 DPH2 Zornitza Stark reviewed gene: DPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.343 ACAT1 Zornitza Stark Tag treatable tag was added to gene: ACAT1.
Mendeliome v1.342 ACVR1 Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Clinical trial with palovarotene

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.
Mendeliome v1.342 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.339 DPP9 Zornitza Stark gene: DPP9 was added
gene: DPP9 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPP9 were set to 36112693
Phenotypes for gene: DPP9 were set to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Review for gene: DPP9 was set to GREEN
Added comment: Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopenias.
Sources: Expert Review
Mendeliome v1.338 AVPR2 Zornitza Stark reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic 304800, Nephrogenic syndrome of inappropriate antidiuresis 300539; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.338 AVP Zornitza Stark reviewed gene: AVP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, neurohypophyseal MIM#125700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.338 APRT Zornitza Stark reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.337 ANO1 Zornitza Stark reviewed gene: ANO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intestinal dysmotility syndrome, MIM# 620045; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.337 ABCC6 Zornitza Stark Phenotypes for gene: ABCC6 were changed from Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850 to Arterial calcification, generalized, of infancy, 2, MIM# 614473; Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850
Mendeliome v1.336 ABCC6 Zornitza Stark Publications for gene: ABCC6 were set to 11536079; 28102862
Mendeliome v1.335 ABCC6 Zornitza Stark edited their review of gene: ABCC6: Added comment: GACI is a treatable disorder.; Changed rating: GREEN; Changed publications: 33005041, 34355424; Changed phenotypes: Arterial calcification, generalized, of infancy, 2, MIM# 614473; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.333 NDNF Elena Savva reviewed gene: NDNF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883645; Phenotypes: Hypogonadotropic hypogonadism 25 with anosmia MIM#618841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.332 PTPA Zornitza Stark gene: PTPA was added
gene: PTPA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

------

Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Mendeliome v1.330 PKHD1 Zornitza Stark Publications for gene: PKHD1 were set to
Mendeliome v1.328 PKHD1 Zornitza Stark edited their review of gene: PKHD1: Added comment: Notę heterozygous carriers reported to have liver cysts and nephrocalcinosis, gene-disease association considered MODERATE by ClinGen.; Changed publications: 28375157, 21945273; Changed phenotypes: Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200, Nephrocalcinosis, MONDO:0001567, PKHD1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.327 PPP2R5C Zornitza Stark Publications for gene: PPP2R5C were set to
Mendeliome v1.325 PPP2R5C Teresa Zhao reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25972378; Phenotypes: Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.325 MYH8 Ain Roesley reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: 15590965, 17041932, 15282353; Phenotypes: Carney complex variant MIM#60883; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.325 NODAL Zornitza Stark Publications for gene: NODAL were set to 9354794; 19064609
Mendeliome v1.323 NODAL Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.

The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.

A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.

Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987
Mendeliome v1.323 JAG1 Bryony Thompson reviewed gene: JAG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35819173, 30071989, 14993126, 18570795; Phenotypes: thoracic aortic aneurysm MONDO:0005396; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.322 OOEP Bryony Thompson Publications for gene: OOEP were set to 29574422
Mendeliome v1.320 OOEP Bryony Thompson reviewed gene: OOEP: Rating: AMBER; Mode of pathogenicity: None; Publications: 35946397, 18804437; Phenotypes: female infertility due to oocyte meiotic arrest MONDO:0044626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.318 TRAPPC10 Zornitza Stark reviewed gene: TRAPPC10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.317 UBAP2L Zornitza Stark gene: UBAP2L was added
gene: UBAP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature
Mendeliome v1.315 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.314 CHKA Zornitza Stark reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.312 PPFIBP1 Zornitza Stark edited their review of gene: PPFIBP1: Changed publications: 35830857
Mendeliome v1.311 PDZD8 Zornitza Stark gene: PDZD8 was added
gene: PDZD8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Intellectual developmental disorder with autism and dysmorphic facies, MIM# 620021
Review for gene: PDZD8 was set to GREEN
Added comment: Four individuals from two unrelated families, Drosophila and mouse models support gene-disease association.
Sources: Literature
Mendeliome v1.310 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to RED
Added comment: SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Mendeliome v1.309 HNRNPH1 Zornitza Stark Publications for gene: HNRNPH1 were set to 32335897; 29938792
Mendeliome v1.305 NBAS Zornitza Stark Publications for gene: NBAS were set to 31761904
Mendeliome v1.304 NBAS Zornitza Stark edited their review of gene: NBAS: Added comment: PMID 35902954 - Biallelic NBAS variants identifed in three HLH patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-defcient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus.; Changed publications: 31761904, 35902954; Changed phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483, Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541
Mendeliome v1.303 TYMS Zornitza Stark reviewed gene: TYMS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita MONDO:0015780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.302 COX11 Zornitza Stark gene: COX11 was added
gene: COX11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551
Phenotypes for gene: COX11 were set to Mitochondrial disease (MONDO:0044970), COX11-related
Review for gene: COX11 was set to GREEN
Added comment: PMID: 36030551
- Biallelic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated consanguineous families, one with homozygous missense variant, another with homozygous frameshift variant.
- Functional studies supported pathogenicity of the missense variant, and showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10.
- RNA studies suggested the mutant transcript with p.(Val12Glyfs*21) is not degraded by nonsense mediated decay.
Sources: Literature
Mendeliome v1.301 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048
Mendeliome v1.298 SAT1 Zornitza Stark Publications for gene: SAT1 were set to
Mendeliome v1.294 CEP104 Zornitza Stark Publications for gene: CEP104 were set to 26477546
Mendeliome v1.292 GATA1 Zornitza Stark Publications for gene: GATA1 were set to
Mendeliome v1.291 GATA1 Zornitza Stark edited their review of gene: GATA1: Added comment: PMID 36029112: De novo GATA1 initiation codon variant (c.3G>A) identified in a Diamond-Blackfan Anaemia patient. Functional evidence showed that the variant does not affect the GATA1 mRNA but brings about a shorter GATA1 isoform (GATA1s) and reduced full-length functional GATA1 protein (GATA1fl), thereby contributing to an erythropoietic defect. Four other GATA1 variants (c.2T>C, c.220G>C, c.220delG, c.220+2T>C) found in eight families have been described as DBA phenotype.; Changed publications: 36029112; Changed phenotypes: Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367, Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083, Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835, Diamond-Blackfan anemia (MONDO:0015253)
Mendeliome v1.289 LGI3 Zornitza Stark reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.289 TMEM147 Naomi Baker gene: TMEM147 was added
gene: TMEM147 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to PMID: 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related
Review for gene: TMEM147 was set to GREEN
Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction.
Sources: Literature
Mendeliome v1.289 SARS Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder, MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.286 CBLB Alison Yeung gene: CBLB was added
gene: CBLB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBLB were set to 36006710
Phenotypes for gene: CBLB were set to Autoimmune disease, MONDO:0007179
Review for gene: CBLB was set to GREEN
Added comment: Distinct homozygous mutations in CBLB were identified in three unrelated children with early onset autoimmunity. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyper-proliferation in response to antigen receptor cross-linking.
Sources: Literature
Mendeliome v1.285 TYMS Lucy Spencer gene: TYMS was added
gene: TYMS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TYMS was set to Other
Publications for gene: TYMS were set to 35931051
Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780
Review for gene: TYMS was set to RED
Added comment: 8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant.

The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance.

The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children.

Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls.

Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1.
Sources: Literature
Mendeliome v1.285 CEP104 Belinda Chong reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 34196201, 35359234; Phenotypes: CEP104 Neurodevelopmental disorder, MONDO:0014770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.285 HNRNPH1 Hazel Phillimore changed review comment from: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2).
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.; to: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2.
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.
Mendeliome v1.285 HNRNPH1 Hazel Phillimore reviewed gene: HNRNPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35989590; Phenotypes: early onset high myopia, blindness; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.284 MET Zornitza Stark Publications for gene: MET were set to
Mendeliome v1.283 MET Zornitza Stark edited their review of gene: MET: Added comment: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; Changed publications: 30777867
Mendeliome v1.283 TMEM163 Teresa Zhao gene: TMEM163 was added
gene: TMEM163 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM163 were set to PMID: 35953447
Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy
Review for gene: TMEM163 was set to GREEN
Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures and two have ID.
Sources: Literature
Mendeliome v1.283 LGI3 Melanie Marty gene: LGI3 was added
gene: LGI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to PMID: 35948005
Phenotypes for gene: LGI3 were set to Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Review for gene: LGI3 was set to GREEN
Added comment: Sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature
Mendeliome v1.282 NOTCH1 Zornitza Stark Publications for gene: NOTCH1 were set to 25963545; 25132448
Mendeliome v1.279 BUD13 Alison Yeung gene: BUD13 was added
gene: BUD13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BUD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUD13 were set to 35670808
Phenotypes for gene: BUD13 were set to Lipodystrophy, MONDO:0006573
Review for gene: BUD13 was set to AMBER
Added comment: 5 individuals with a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life, 2 are adults with normal intellectual development. All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. Individuals from only two Algerian families.
Sources: Literature
Mendeliome v1.278 GRIN2A Zornitza Stark Publications for gene: GRIN2A were set to 30544257
Mendeliome v1.276 SAT1 Ee Ming Wong reviewed gene: SAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.276 NOTCH1 Chern Lim changed review comment from: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Missense and small inframe insertion variants in the negative regulatory region.; to: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Other clinical features include intellectual disability, spasticity and etc. Childhood onset in most individuals however 15y and 40y reported in two individuals.
- Missense and small inframe insertion variants in the negative regulatory region.
Mendeliome v1.276 ADAMTS15 Naomi Baker gene: ADAMTS15 was added
gene: ADAMTS15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to PMID: 35962790
Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related
Review for gene: ADAMTS15 was set to GREEN
Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Mendeliome v1.276 CAPRIN1 Paul De Fazio gene: CAPRIN1 was added
gene: CAPRIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925
Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092
Review for gene: CAPRIN1 was set to GREEN
gene: CAPRIN1 was marked as current diagnostic
Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals).

All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity.
Sources: Literature
Mendeliome v1.276 LHX8 Alison Yeung gene: LHX8 was added
gene: LHX8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX8 were set to 36029299
Phenotypes for gene: LHX8 were set to Inherited premature ovarian failure, MONDO:0019852, LHX8-related
Review for gene: LHX8 was set to GREEN
Added comment: Heterozygous LOF variants identified in 6 families with premature ovarian failure due to oocyte maturation arrest.
Sources: Literature
Mendeliome v1.275 NOTCH1 Chern Lim reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35947102; Phenotypes: leukoencephalopathy and calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.275 GRIN2A Teresa Zhao reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983985; Phenotypes: Epilepsy, focal, with speech disorder and with or without impaired intellectual development (MIM#245570); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.274 LEF1 Zornitza Stark Publications for gene: LEF1 were set to 32022899
Mendeliome v1.271 LEF1 Zornitza Stark edited their review of gene: LEF1: Added comment: Monoallelic variants in LEF1 reported in 11 affected individuals from 4 unrelated families, and a biallelic variant reported in an affected individual from a consanguineous family. The phenotypic spectrum included various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Haploinsufficiency or loss of DNA binding postulated to be responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants postulated to be associated with a severe phenotype.; Changed rating: GREEN; Changed publications: 32022899, 35583550; Changed phenotypes: Syndromic disease, MONDO:0002254, LEF1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.270 REEP1 Zornitza Stark reviewed gene: REEP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.269 CCDC82 Zornitza Stark Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Mendeliome v1.268 CCDC82 Zornitza Stark reviewed gene: CCDC82: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC82-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.267 NPNT Zornitza Stark Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Mendeliome v1.266 NPNT Zornitza Stark reviewed gene: NPNT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal agenesis, MONDO:0018470, NPNT-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.264 KIF5B Zornitza Stark reviewed gene: KIF5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia, MONDO:0018230; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.262 LNPK Chirag Patel reviewed gene: LNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35599435; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, MIM# 618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.261 CCDC82 Chirag Patel gene: CCDC82 was added
gene: CCDC82 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Phenotypes for gene: CCDC82 were set to Intellectual disability and spastic paraparesis, no OMIM #
Review for gene: CCDC82 was set to GREEN
Added comment: 4 consanguineous families with 9 affected individuals with developmental delay/intellectual disability, and 2 families had spasticity and 1 had epilepsy. WES identified 3 homozgyous truncating variants, segregating with disease and parents as carriers. No functional studies.
Sources: Literature
Mendeliome v1.259 NPNT Chirag Patel gene: NPNT was added
gene: NPNT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM #
Review for gene: NPNT was set to GREEN
Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models.
Sources: Literature
Mendeliome v1.257 KIF5B Chirag Patel gene: KIF5B was added
gene: KIF5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to PMID: 35342932
Phenotypes for gene: KIF5B were set to Kyphomelic dysplasia, no OMIM #
Review for gene: KIF5B was set to GREEN
Added comment: 4 individuals with Kyphomelic dysplasia (severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. WES found de novo heterozygous missense variants in KIF5B encoding kinesin-1 heavy chain. All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. No functional studies of variants. Previously 2 animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte-specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity. Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages.
Sources: Literature
Mendeliome v1.254 MDFIC Zornitza Stark reviewed gene: MDFIC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 12, MIM# 620014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.252 FOCAD Zornitza Stark gene: FOCAD was added
gene: FOCAD was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, MIM# 619991
Review for gene: FOCAD was set to GREEN
Added comment: Moreno Traspas et al 2022 reported 14 children from ten unrelated families with syndromic form of pediatric liver cirrhosis. Genome/exome sequencing analysis reveled biallelic variants in the FOCAD gene. Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein, suggesting that FOCAD may contribute to the stability of RNA helicase (OMIM: 619991).
Sources: Expert Review
Mendeliome v1.250 TAF4 Zornitza Stark Publications for gene: TAF4 were set to 33875846; 28191890
Mendeliome v1.248 TAF4 Zornitza Stark edited their review of gene: TAF4: Changed rating: GREEN; Changed publications: 33875846, 28191890, 35904126; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related
Mendeliome v1.247 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Mendeliome v1.246 TRAC Seb Lunke Added comment: Comment on list classification: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools.
Mendeliome v1.244 PAX5 Zornitza Stark Publications for gene: PAX5 were set to 35094443; 31452935; 28263302; 25418537; 8001127; 27626380
Mendeliome v1.242 PAX5 Zornitza Stark reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PAX5-related, Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.240 SMG9 Zornitza Stark Publications for gene: SMG9 were set to 27018474; 31390136
Mendeliome v1.239 SMG9 Zornitza Stark edited their review of gene: SMG9: Added comment: PMID 35087184: 5 individuals from 3 unrelated Finnish families reported with same homozygous missense variant (founder effect) and predominantly neurological phenotype. Uncertain if this is a distinct disorder or part of a spectrum with the previously reported cases.; Changed publications: 27018474, 31390136, 35087184; Changed phenotypes: Heart and brain malformation syndrome, MIM# 616920, Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Mendeliome v1.238 THUMPD1 Zornitza Stark reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.237 TAF4 Ee Ming Wong reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846, 28191890, 35904126; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TAF4-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.236 SPTBN5 Zornitza Stark Publications for gene: SPTBN5 were set to 32732226; 28007035
Mendeliome v1.233 SPTBN5 Zornitza Stark edited their review of gene: SPTBN5: Added comment: Monoallelic variants:
- Four probands from unrelated families (1x Pakistani and 3x Italian) with de novo heterozygous SPTBN5 variants
- 3x missense variants and 1x LoF variant were reported
- Phenotypes include intellectual disability (mild to severe), aggressive tendencies and variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux; Changed rating: GREEN; Changed publications: 35782384, 32732226, 28007035; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related, Sacral agenesis, congenital anomalies; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.231 CPS1 Zornitza Stark reviewed gene: CPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Pulmonary hypertension, neonatal, susceptibility to} 615371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.230 OTULIN Zornitza Stark Publications for gene: OTULIN were set to 27523608; 27559085
Mendeliome v1.228 OTULIN Zornitza Stark edited their review of gene: OTULIN: Added comment: PMID 35587511: Multiple individuals reported with haploinsufficiency of OTULIN and severe staphylococcal disease, with life-threatening skin or pulmonary necrosis. Functional data.; Changed publications: 27523608, 27559085, 35587511; Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Susceptibility to infection with Staphylococcus aureus, Hereditary predisposition to infections, MONDO:0015979, OTULIN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.228 NOX1 Zornitza Stark gene: NOX1 was added
gene: NOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOX1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NOX1 were set to 29091079; 32064493
Phenotypes for gene: NOX1 were set to Inflammatory bowel disease, MONDO:0005265, NOX1-related
Review for gene: NOX1 was set to AMBER
Added comment: 8 IBD patients with early onset of IBD with progressive and severe colonic disease, refractory to conventional therapy and functional studies suggesting variant-dependent loss of NOX1-mediated superoxide generation. However, high frequency of nonsynonymous mutations in NOX1 suggests that NOX1 is not a highly penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis.

The variant reported in PMID 32064493 is present in 6 hets in gnomad.
Sources: Literature
Mendeliome v1.226 BICD2 Zornitza Stark Publications for gene: BICD2 were set to 23664116; 23664119; 23664120; 27751653; 28635954; 30054298; 29528393
Mendeliome v1.222 SARS Ain Roesley Publications for gene: SARS were set to 28236339; 34570399
Mendeliome v1.220 SARS Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.218 PSMC1 Zornitza Stark reviewed gene: PSMC1: Rating: RED; Mode of pathogenicity: None; Publications: 35861243; Phenotypes: Syndromic disease MONDO:0002254, PSMC1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.218 WARS Seb Lunke Publications for gene: WARS were set to PMID: 28369220; 31321409; 31069783.
Mendeliome v1.214 PPFIBP1 Zornitza Stark Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Mendeliome v1.213 BICD2 Lucy Spencer reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35896821; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), BICD2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.213 KIF15 Krithika Murali reviewed gene: KIF15: Rating: AMBER; Mode of pathogenicity: None; Publications: 28150392; Phenotypes: ?Braddock-Carey syndrome 2 - MIM#619981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.213 WARS Anna Ritchie reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35815345, PMID: 35790048; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), WARS-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.212 PSMC1 Hazel Phillimore gene: PSMC1 was added
gene: PSMC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC1 were set to PMID: 35861243
Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes
Mode of pathogenicity for gene: PSMC1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PSMC1 was set to AMBER
Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr).

Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1.

Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low.
Sources: Literature
Mendeliome v1.212 KIF15 Krithika Murali gene: KIF15 was added
gene: KIF15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF15 were set to 28150392
Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981
Review for gene: KIF15 was set to GREEN
Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly -3SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type.

No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1).
Sources: Literature
Mendeliome v1.211 BMP3 Seb Lunke gene: BMP3 was added
gene: BMP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP3 were set to 35089417
Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Review for gene: BMP3 was set to AMBER
Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive
Sources: Literature
Mendeliome v1.208 ALG5 Chern Lim gene: ALG5 was added
gene: ALG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALG5 were set to 35896117
Phenotypes for gene: ALG5 were set to Cystic renal disease MONDO:0002473, ALG5-related
Review for gene: ALG5 was set to GREEN
gene: ALG5 was marked as current diagnostic
Added comment: PMID:35896117:
- Five unrelated families, including 23 affected individuals with non-enlarged cystic kidneys and few or no liver cysts, 8 of them reached end-stage kidney disease from 62 to 91 years of age. Variant confirmed in all but one individual.
- Various variant types: frameshift, nonsense, two missense, splice.
- Functional studies showed haploinsufficiency is the disease mechanism.
Sources: Literature
Mendeliome v1.208 DOHH Daniel Flanagan gene: DOHH was added
gene: DOHH was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to PMID: 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder, DOHH-related (MONDO#0700092)
Review for gene: DOHH was set to GREEN
Added comment: Bi-allelic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. Clinical features were developmental delay and/or intellectual disability (5/5), microcephaly (5/5), visual impairment (nystagmus (3/5), strabismus (3/5), and cortical visual impairment (1/5)) and congenital heart malformations (3/5 individuals).
Sources: Expert list
Mendeliome v1.208 PPFIBP1 Ee Ming Wong reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35830857; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.208 SLITRK2 Paul De Fazio gene: SLITRK2 was added
gene: SLITRK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLITRK2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SLITRK2 were set to 35840571
Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092
Review for gene: SLITRK2 was set to GREEN
gene: SLITRK2 was marked as current diagnostic
Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients).

The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother.

Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait.
Sources: Literature
Mendeliome v1.208 RFC1 Ain Roesley Publications for gene: RFC1 were set to 30926972
Mendeliome v1.206 C18orf32 Naomi Baker gene: C18orf32 was added
gene: C18orf32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C18orf32 were set to PMID:35107634
Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related
Review for gene: C18orf32 was set to RED
Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples.
Sources: Literature
Mendeliome v1.205 RFC1 Ain Roesley reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.204 ADGRL1 Elena Savva gene: ADGRL1 was added
gene: ADGRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ADGRL1 were set to PMID: 35907405
Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092)
Review for gene: ADGRL1 was set to GREEN
Added comment: PMID: 35907405 - 9 patients w/ ADHD (3/9), autism (4/9), mild-moderate ID (5/9) and epilepsy (2/9) and facial dysmorphism (7/9). Variants include missense (4) and PTCs (5), and were either de novo (7/9) or inherited from parents with learning difficulties/ID (2/9).

Functional studies on both PTCs and missense variants show significant reductions in calcium signalling and surface protein.

Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable.
Sources: Literature
Mendeliome v1.201 DUOX2 Zornitza Stark Publications for gene: DUOX2 were set to
Mendeliome v1.198 DUOX2 Zornitza Stark reviewed gene: DUOX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35429653, 27373512, 26301257, 28683258; Phenotypes: Inflammatory bowel disease, MONDO:0005265, DUOX2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.196 CWH43 Zornitza Stark reviewed gene: CWH43: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrocephalus MONDO:0001150, CWH43-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.196 CWH43 Anna Le Fevre gene: CWH43 was added
gene: CWH43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CWH43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CWH43 were set to PMID: 33459505; 34380733
Phenotypes for gene: CWH43 were set to normal pressure hydrocephalus
Penetrance for gene: CWH43 were set to Incomplete
Review for gene: CWH43 was set to AMBER
Added comment: Sources: Literature
Mendeliome v1.196 ADGRA3 Zornitza Stark gene: ADGRA3 was added
gene: ADGRA3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ADGRA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADGRA3 were set to 23105016
Phenotypes for gene: ADGRA3 were set to Retinitis pigmentosa, MONDO:0019200, ADGRA3-related
Review for gene: ADGRA3 was set to RED
Added comment: Only one report of a missense that is a VUS identified as a candidate through autozygome analysis (PMID: 23105016)
Sources: Expert Review
Mendeliome v1.192 ROBO4 Zornitza Stark Publications for gene: ROBO4 were set to 30455415
Mendeliome v1.189 EIF2B1 Zornitza Stark Publications for gene: EIF2B1 were set to 11835386; 26285592; 15776425; 18263758; 25843247; 25761052; 30014503
Mendeliome v1.187 EIF2B1 Zornitza Stark reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.187 MCM10 Zornitza Stark Publications for gene: MCM10 were set to 32865517; 33712616
Mendeliome v1.185 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: further functional validation.; Changed rating: AMBER; Changed publications: 32865517, 33712616, 33712616
Mendeliome v1.184 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to 21548011; 26981933; 29889099; 31057532; 7923373; 11805317
Mendeliome v1.183 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Added comment: PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.; Changed publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317, 35333544; Changed phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset, Immune dysregulation
Mendeliome v1.182 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454
Mendeliome v1.180 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Added comment: Iranian male with homozygous missense variant with recurrent infection, hypogammaglobulinaemia. Extends inheritance to AR. Supportive functional data.; Changed publications: 34920454, 34826259; Changed phenotypes: Immunodeficiency, MONDO:0021094, IKZF2-related, Immune dysregulation; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.179 TMEM63C Zornitza Stark reviewed gene: TMEM63C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 87, autosomal recessive, MIM# 619966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.179 ROBO4 Elena Savva reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:30455415, 32748548; Phenotypes: Aortic valve disease 8 MIM#618496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.179 EIF2B1 Elena Savva reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31882561; Phenotypes: Leukoencephalopathy with vanishing white matter MIM#603896, permanent neonatal/early onset diabetes and transient liver dysfunction; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.177 INPP5E Zornitza Stark Publications for gene: INPP5E were set to 19668216; 32139166; 29230161; 29052317; 27998989; 27401686; 19668215
Mendeliome v1.176 INPP5E Zornitza Stark edited their review of gene: INPP5E: Added comment: Additional MORM family reported in PMID 34211432, hmz LoF.; Changed publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686, 19668215, 34211432
Mendeliome v1.176 WASL Zornitza Stark gene: WASL was added
gene: WASL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASL were set to 33571872
Phenotypes for gene: WASL were set to Parkinson's disease, MONDO:0005180, WASL-related
Review for gene: WASL was set to RED
Added comment: Single family reported, where bi-allelic variants segregated with PD in three affected individuals.
Sources: Literature
Mendeliome v1.174 PMM2 Zornitza Stark Publications for gene: PMM2 were set to 28108845
Mendeliome v1.173 PMM2 Zornitza Stark edited their review of gene: PMM2: Added comment: Association with HIPKD:
Cabezas et al (2017) reported co-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD in 17 children from 11 unrelated families. Patients presented with hyperinsulinaemic hypoglycaemia in infancy and enlarged kidneys with multiple kidney cysts. Some progressed to ESKD and some had liver cysts. Whole-genome linkage analysis in 5 informative families identified a single significant locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, they found in all patients a promoter mutation (c.-167G>T) in PMM2, either homozygous or in trans with PMM2 coding mutations. They found deglycosylation in cultured pancreatic β cells altered insulin secretion. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. They proposed that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. None of the patients exhibited the typical clinical or diagnostic features of CDG1A. Serum transferrin glycosylation was normal in 11 patients who had assessment.; Changed publications: 28108845, 28373276, 32595772; Changed phenotypes: Congenital disorder of glycosylation, type Ia (MIM#212065), Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related
Mendeliome v1.172 SLCO2A1 Zornitza Stark Publications for gene: SLCO2A1 were set to 23509104; 27134495; 33852188; 22331663; 27134495
Mendeliome v1.171 SLCO2A1 Zornitza Stark edited their review of gene: SLCO2A1: Added comment: PMID 29313109: Over 40 Japanese individuals reported with bi-allelic variants in this gene and multiple small intestinal ulcers of nonspecific histology. Some overlap with the hypertrophic osteoarthropathy also associated with bi-allelic variants in this gene. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO.; Changed publications: 23509104, 27134495, 33852188, 22331663, 27134495, 29313109; Changed phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441, Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related
Mendeliome v1.170 CTR9 Zornitza Stark Publications for gene: CTR9 were set to PMID: 35499524
Mendeliome v1.169 CTR9 Zornitza Stark reviewed gene: CTR9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25099282, 29292210; Phenotypes: Familial Wilms tumour, MONDO:0006058, CTR9-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.169 C20orf24 Zornitza Stark gene: C20orf24 was added
gene: C20orf24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220; 24194475
Phenotypes for gene: C20orf24 were set to Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, MIM# 616994
Review for gene: C20orf24 was set to RED
Added comment: Bi-allelic LoF variant identified in patient originally reported in PMID 24194475.

HGNC approved name is RAB5IF.
Sources: Literature
Mendeliome v1.167 IL23R Zornitza Stark Publications for gene: IL23R were set to 30578351
Mendeliome v1.165 IL23R Zornitza Stark edited their review of gene: IL23R: Added comment: PMID 35829840: 48yo male with disseminated NTM homozygous (p.R381X) with supportive functional data.; Changed rating: AMBER; Changed publications: 30578351, 35829840
Mendeliome v1.164 HYOU1 Zornitza Stark edited their review of gene: HYOU1: Added comment: Second individual reported in PMID: 35822684 with severe neutropenia.; Changed rating: AMBER; Changed publications: 27913302, 35822684; Changed phenotypes: Immunodeficiency 59 and hypoglycemia, MIM# 233600
Mendeliome v1.162 CHD5 Elena Savva reviewed gene: CHD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33944996; Phenotypes: Parenti-Mignot neurodevelopmental syndrome MIM#619873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.162 PPP1R13L Krithika Murali reviewed gene: PPP1R13L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.161 GINS3 Zornitza Stark gene: GINS3 was added
gene: GINS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related
Review for gene: GINS3 was set to GREEN
Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model.
Sources: Literature
Mendeliome v1.159 UBA2 Zornitza Stark reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ACCES syndrome, MIM# 619959; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.158 C9orf84 Zornitza Stark gene: C9orf84 was added
gene: C9orf84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C9orf84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C9orf84 were set to 32741963; 32900840; 35485979
Phenotypes for gene: C9orf84 were set to Spermatogenic failure 75, MIM# 619949
Review for gene: C9orf84 was set to GREEN
Added comment: 8 families reported with bi-allelic variants in this gene and spermatogenic failure.
Sources: Literature
Mendeliome v1.156 HIST1H4E Zornitza Stark reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.156 KMT2B Zornitza Stark Publications for gene: KMT2B were set to 27839873; 27992417
Mendeliome v1.155 KMT2B Zornitza Stark edited their review of gene: KMT2B: Added comment: Nine individuals reported in PMID 33150406 with heterozygous variants in this gene and intellectual disability, speech delay, microcephaly, growth delay, feeding problems, and dysmorphic features, including epicanthic folds, posteriorly rotated ears, syndactyly/clinodactyly of toes, and fifth finger clinodactyly, normal MRIs and NO dystonia.; Changed publications: 27839873, 27992417, 33150406; Changed phenotypes: Dystonia 28, childhood-onset 617284, MONDO:0015004, Intellectual developmental disorder, autosomal dominant 68, MIM# 619934
Mendeliome v1.152 CDH2 Zornitza Stark edited their review of gene: CDH2: Added comment: PMID 34702855: three sibs with homozygous missense and strikingly severe ADHD. Mouse model of same variant recapitulated the phenotype. AMBER for bi-allelic association (segregation and functional data).; Changed publications: 31585109, 34702855; Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929:Attention deficit-hyperactivity disorder 8 , MIM# 619957; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.150 KITLG Zornitza Stark Publications for gene: KITLG were set to 26522471
Mendeliome v1.147 CLDN5 Zornitza Stark gene: CLDN5 was added
gene: CLDN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 35714222
Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related
Mode of pathogenicity for gene: CLDN5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CLDN5 was set to AMBER
Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg).

One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis.

CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype.
Sources: Literature
Mendeliome v1.146 PSMB9 Zornitza Stark Publications for gene: PSMB9 were set to 26524591
Mendeliome v1.143 PSMB9 Zornitza Stark edited their review of gene: PSMB9: Added comment: Two additional individuals with neonatal onset autoinflammatory syndrome and a mouse model. De novo recurrent missense G156D.; Changed rating: GREEN; Changed publications: 26524591, 34819510; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.142 HCK Zornitza Stark gene: HCK was added
gene: HCK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammatory syndrome, MONDO:0019751, HCK-related
Mode of pathogenicity for gene: HCK was set to Other
Review for gene: HCK was set to AMBER
Added comment: Single patient with supportive functional data.
Sources: Literature
Mendeliome v1.140 TTC25 Zornitza Stark Publications for gene: TTC25 were set to 27486780
Mendeliome v1.138 KITLG Dean Phelan reviewed gene: KITLG: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 35543077, 28504826, 19375057, 21368769; Phenotypes: deafness, heterochromia iridis, hypopigmentation of the skin, hyperpigmentation of the skin, Waardenburg syndrome,MONDO:0018094, KITLG-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.137 NFATC2 Paul De Fazio gene: NFATC2 was added
gene: NFATC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC2 were set to 35789258
Phenotypes for gene: NFATC2 were set to Skeletal system disorder MONDO:0005172
Review for gene: NFATC2 was set to RED
gene: NFATC2 was marked as current diagnostic
Added comment: Patient born to consanguineous parents homozygous for a frameshift variant. No other (unaffected) members of the family were homozygous. Family history of recurrent childhood deaths.

After a healthy birth the patient developed painless decreased range of motion at 1.5yrs leading to difficulty with ambulation at 3yrs. Formal orthopedic assessment at age 15 years
demonstrated a neurodevelopmentally normal young man with marked bilateral fixed flexion contractures of knees, hips, and ankles. The main musculoskeletal findings were painless contractures of the large and small joints of the upper and lower limbs, osteochondromas, and osteopenia. Patient was diagnosed with B-cell lymphoma at age 18.

Patient CD8+ T-cells show impaired polyfunctionality, and the patient had an accumulation of non-functional memory CD4+ T-cells. TFH cell function was also impaired.
Sources: Literature
Mendeliome v1.134 PIK3C2B Krithika Murali gene: PIK3C2B was added
gene: PIK3C2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIK3C2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C2B were set to PMID:35786744
Phenotypes for gene: PIK3C2B were set to familial partial epilepsy - MONDO#0017704
Review for gene: PIK3C2B was set to AMBER
Added comment: No OMIM gene disease association.

Gozzelino et al.(2022) Brain - report enrichment of ultra-rare PIK3C2B variants in focal epilepsy cohorts, including one variant shown to be de novo (G1294Q). Segregation data not provided for all cases. The p.G1345S variant was inherited from an affected father. The p.K584* variant was inherited from an unaffected father suggesting incomplete penetrance. Functional studies supported a LoF mechanism and mouse model studies suggestive of mTORC1 pathway hyperactivation.
Sources: Literature
Mendeliome v1.134 CCDC155 Melanie Marty gene: CCDC155 was added
gene: CCDC155 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC155 were set to 35674372; 35708642; 29790874; 35587281
Phenotypes for gene: CCDC155 were set to Non-obstructive azoospermia; Premature ovarian insufficiency
Review for gene: CCDC155 was set to GREEN
Added comment: Current HGNC name is KASH5

Summary: 4 families reported with non-obstructive azoospermia or premature ovarian insufficiency. Functional studies have been performed and mouse models recapitulate the phenotype.

PMID: 35674372 CNV and frameshift variants in KASH5 were identified in a non-obstructive azoospermia affected patient and in his infertile sister by whole-exome sequencing and CNV array. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis.

PMID: 35708642 Hom splice identified in KASH5 in 2 sisters with premature ovarian insufficiency. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes.

PMID: 29790874 2 brothers with non-obstructive azoospermia with hom missense in CCDC155

35587281 2 siblings with hom missense in CCDC155 non-obstructive azoospermia and premature ovarian insufficiency.
Sources: Literature
Mendeliome v1.132 ASPH Zornitza Stark Publications for gene: ASPH were set to 24768550; 30194805; 34018898
Mendeliome v1.130 SLC30A7 Naomi Baker gene: SLC30A7 was added
gene: SLC30A7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC30A7 were set to PMID: 35751429
Phenotypes for gene: SLC30A7 were set to Joubert syndrome (MONDO:0018772), SLC30A7-related
Review for gene: SLC30A7 was set to AMBER
Added comment: PMID: 35751429: Two individuals reported with de novo variants, one missense and one delins resulting in missense. The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. No functional studies reported.
Sources: Literature
Mendeliome v1.130 ASPH Paul De Fazio reviewed gene: ASPH: Rating: AMBER; Mode of pathogenicity: None; Publications: 35697689; Phenotypes: Exertional heat illness, malignant hyperthermia susceptibility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.128 PABPC1 Elena Savva gene: PABPC1 was added
gene: PABPC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to PMID: 35511136
Phenotypes for gene: PABPC1 were set to Neurodevelopmental disorder, PABPC1-related (MONDO#0700092)
Review for gene: PABPC1 was set to GREEN
Added comment: PMID: 35511136 - 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1.
Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not.
Sources: Literature
Mendeliome v1.127 WNK3 Zornitza Stark reviewed gene: WNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.126 CHMP3 Chern Lim gene: CHMP3 was added
gene: CHMP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to PMID: 35710109
Phenotypes for gene: CHMP3 were set to Hereditary spastic paraplegia (MONDO:0019064), CHMP3-related
Review for gene: CHMP3 was set to AMBER
gene: CHMP3 was marked as current diagnostic
Added comment: PMID: 35710109
- Single large family with consanguinity, homozygous missense variant in 5 affected individuals with intellectual and progressive motor disabilities, seizures and spastic quadriplegia.
- Functional studies showed reduced CHMP3 protein in patient's fibroblasts, lenti-rescue study showed improved cellular phenotypes associated with impaired autophagy.
Sources: Literature
Mendeliome v1.126 WNK3 Lucy Spencer gene: WNK3 was added
gene: WNK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 35678782
Phenotypes for gene: WNK3 were set to Neurodevelopmental disorder, WNK3-related (MONDO#0700092)
Added comment: 6 maternally inherited hemizygous variants, 3 missense, 2 canonical splice, and a nonsense. Seen in 14 individuals from 6 families, all 14 are male who inherited hemizygous variants from their unaffected heterozygous mothers. The variants cosegregated with disease in 3 families with multiple affected individuals. All 14 patients have ID, 11 have speech delay, 10 have facial abnormalities, 5 have seizures, 6 with microcephaly and 7 with anomalies in brain imaging.
Sources: Literature
Mendeliome v1.125 WNT7B Zornitza Stark gene: WNT7B was added
gene: WNT7B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT7B were set to 35790350
Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome; Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related
Review for gene: WNT7B was set to GREEN
Added comment: Three families reported with fetuses with multiple congenital anomalies and bi-allelic LoF variants. Two of the families had at the same variant. Supportive zebrafish model.
Sources: Literature
Mendeliome v1.123 TMEM63C Elena Savva gene: TMEM63C was added
gene: TMEM63C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to PMID: 35718349
Phenotypes for gene: TMEM63C were set to Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related
Review for gene: TMEM63C was set to GREEN
Added comment: PMID: 35718349 - Four NMD PTCs observed in at least 3 unrelated patients. Two segregated strongly in highly consanguineous families.
Common clinical details include mild ID, spastic paraplegia, hypereflexia, spasticity, delayed motor development. Single patient was microcephalic
Sources: Literature
Mendeliome v1.121 MAL Zornitza Stark gene: MAL was added
gene: MAL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to Leukodystrophy MONDO:0019046, MAL-related
Review for gene: MAL was set to AMBER
Added comment: Single family with two affected siblings reported, with homozygous missense variant, some functional data.
Sources: Literature
Mendeliome v1.120 RELN Zornitza Stark Publications for gene: RELN were set to 32001840
Mendeliome v1.119 RELN Zornitza Stark edited their review of gene: RELN: Added comment: PMID 35769015: 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants had moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Additional 7 individuals from 4 families with bi-allelic variants.; Changed publications: 35769015
Mendeliome v1.118 TAF8 Zornitza Stark gene: TAF8 was added
gene: TAF8 was added to Mendeliome. Sources: Literature
founder tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder, MONDO:0700092, TAF8-related
Review for gene: TAF8 was set to GREEN
Added comment: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants.
Sources: Literature
Mendeliome v1.116 PNPT1 Zornitza Stark Publications for gene: PNPT1 were set to 31752325; 30244537; 28594066; 28645153; 33199448
Mendeliome v1.114 PNPT1 Zornitza Stark edited their review of gene: PNPT1: Added comment: Three families reported with heterozygous variants and SCA25. Incomplete penetrance in one of the families. In the third family, the variant was inherited from an asymptomatic 80+ year old. Note bi-allelic variants in this gene cause a mitochondrial disorder. Exact mechanism through which mono-allelic variants cause SCA25 not elucidated: authors speculate abnormal accumulation of mitochondrial RNA with subsequent leakage into the cytosol that may trigger a type 1 interferon response leading to neuroinflammation with neuronal dysfunction or neuronal loss.; Changed rating: AMBER; Changed publications: 35411967; Changed phenotypes: Spinocerebellar ataxia 25, MIM# 608703; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.114 TTC25 Arina Puzriakova reviewed gene: TTC25: Rating: GREEN; Mode of pathogenicity: None; Publications: 27486780, 31765523, 33715250, 33746037, 34215651; Phenotypes: Ciliary dyskinesia, primary, 35, OMIM:617092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.113 CXCR2 Zornitza Stark edited their review of gene: CXCR2: Added comment: 4 unrelated patients with neutropaenia reported.; Changed rating: GREEN; Changed publications: 24777453, 34854278; Changed phenotypes: WHIM syndrome 2, MIM#619407
Mendeliome v1.112 RHOG Zornitza Stark gene: RHOG was added
gene: RHOG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RHOG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHOG were set to 33513601
Phenotypes for gene: RHOG were set to Genetic HLH, MONDO:0015541, RHOG-related
Review for gene: RHOG was set to AMBER
Added comment: Single individual reported, extensive functional data supports gene-disease association.
Sources: Literature
Mendeliome v1.111 TNFSF13 Zornitza Stark gene: TNFSF13 was added
gene: TNFSF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF13 were set to 32298700
Phenotypes for gene: TNFSF13 were set to Hypogammaglobulinaemia, MONDO:0015977, TNSF13-related
Review for gene: TNFSF13 was set to RED
Added comment: Single individual, consanguineous parents.
Sources: Literature
Mendeliome v1.110 POU2AF1 Zornitza Stark gene: POU2AF1 was added
gene: POU2AF1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: POU2AF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POU2AF1 were set to 33571536
Phenotypes for gene: POU2AF1 were set to Agammaglobulinaemia, MONDO:0015977, POU2AF1-related
Review for gene: POU2AF1 was set to RED
Added comment: Single individual from consanguineous parents lacking immunoglobulins despite normal total B-cell numbers.
Sources: Expert Review
Mendeliome v1.108 CD28 Zornitza Stark gene: CD28 was added
gene: CD28 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CD28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD28 were set to 34214472
Phenotypes for gene: CD28 were set to Hereditary predisposition to infections, MONDO:0015979, CD28-related; isolated susceptibility to cutaneous α- and γ-HPVs
Review for gene: CD28 was set to RED
Added comment: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data.
Sources: Expert Review
Mendeliome v1.106 IKZF3 Zornitza Stark edited their review of gene: IKZF3: Added comment: Additional multigenerational family where novel missense variant segregated with disease in 4 individuals.; Changed rating: GREEN; Changed publications: 34155405, 34694366
Mendeliome v1.105 COPG1 Zornitza Stark gene: COPG1 was added
gene: COPG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: COPG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPG1 were set to 33529166
Phenotypes for gene: COPG1 were set to Combined immunodeficiency MONDO:0015131, COPG1-related
Review for gene: COPG1 was set to RED
Added comment: Five Omani siblings, born to consanguineous parents, homozygous missense.

Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice.
Sources: Expert Review
Mendeliome v1.104 TSPAN7 Zornitza Stark edited their review of gene: TSPAN7: Added comment: Two families reported with LoF variants and ID: Abidi FE et al. 2002 Jun (PMID:12070254); Zemni R et al. 2000 Feb (PMID:10655063)

Assessed as MODERATE by ClinGen.; Changed rating: AMBER; Changed publications: 12070254, 10655063
Mendeliome v1.104 IFNAR2 Zornitza Stark Publications for gene: IFNAR2 were set to 26424569
Mendeliome v1.102 IFNAR2 Zornitza Stark edited their review of gene: IFNAR2: Added comment: Five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination; Changed rating: GREEN; Changed publications: 26424569, 35442417
Mendeliome v1.101 IFNAR1 Zornitza Stark Publications for gene: IFNAR1 were set to 31270247
Mendeliome v1.99 IFNAR1 Zornitza Stark edited their review of gene: IFNAR1: Added comment: Seven children from five unrelated kindreds; Changed publications: 31270247, 35442418; Changed phenotypes: Immunodeficiency 106, susceptibility to viral infections, MIM# 619935, Severe disease caused by Yellow Fever vaccine and Measles vaccine
Mendeliome v1.93 DRD2 Zornitza Stark reviewed gene: DRD2: Rating: RED; Mode of pathogenicity: Other; Publications: 33200438; Phenotypes: Combined dystonia, MONDO:0020065, DRD2-related, dystonia, chorea, anxiety, ataxia, orofacial dyskinesia, tremor, memory problems; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.92 THSD1 Zornitza Stark Publications for gene: THSD1 were set to 27895300
Mendeliome v1.89 SLC26A1 Krithika Murali reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Nephrolithiasis, calcium oxalate - MIM#167030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.88 TNNT1 Bryony Thompson Publications for gene: TNNT1 were set to
Mendeliome v1.85 TNNT1 Bryony Thompson reviewed gene: TNNT1: Rating: AMBER; Mode of pathogenicity: Other; Publications: 29178646, 35510366; Phenotypes: nemaline myopathy MONDO:0018958; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.85 EPHA2 Elena Savva reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34638995, 19005574, 19649315, 19306328, 33671840; Phenotypes: Early-Onset Cataract, cataract 6 multiple types MONDO:0007288; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.84 GRIA1 Zornitza Stark Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178
Mendeliome v1.82 GRIA1 Zornitza Stark edited their review of gene: GRIA1: Added comment: Single individual reported with bi-allelic LoF variant. RED/AMBER for bi-allelic variants.; Changed publications: 28628100, 23033978, 26350204, 24896178, 35675825; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.80 MSH5 Zornitza Stark reviewed gene: MSH5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 74, MIM# 619937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.79 THSD1 Elena Savva reviewed gene: THSD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33569873, 27895300; Phenotypes: Aneurysm, intracranial berry, 12 MIM# 618734, nonimmune hydrops fetalis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.78 GCH1 Zornitza Stark Publications for gene: GCH1 were set to 7874165; 11113234; 15753436; 9667588; 10987649; 32170445; 32278297; 32746945; 30314816
Mendeliome v1.77 GCH1 Zornitza Stark reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21935284, 24509643, 33713342; Phenotypes: Hereditary spastic paraplegia MONDO:0019064, GCH1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.73 KCNA5 Chern Lim reviewed gene: KCNA5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.72 KCNC2 Zornitza Stark Publications for gene: KCNC2 were set to 32392612; 31972370
Mendeliome v1.70 KCNC2 Zornitza Stark reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314505; Phenotypes: Developmental and epileptic encephalopathy 103, MIM# 619913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.70 KCNJ1 Zornitza Stark Publications for gene: KCNJ1 were set to 28630040
Mendeliome v1.69 KCNJ1 Zornitza Stark reviewed gene: KCNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841184, 19096086, 7635463, 12086641, 9580661, 12122007; Phenotypes: Bartter syndrome, type 2, MIM#241200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.68 ATP2B1 Zornitza Stark reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, MIM# 619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.67 PRDM13 Zornitza Stark Publications for gene: PRDM13 were set to 30710461; 34730112; 35390279
Mendeliome v1.66 PRDM13 Zornitza Stark edited their review of gene: PRDM13: Added comment: Note only single family reported with Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976 -- this likely lies on the same spectrum as Pontocerebellar hypoplasia, type 17, MIM# 619909 rather than being a distinct disorder.; Changed publications: 30710461, 34730112; Changed phenotypes: Retinal dystrophy, Chorioretinal atrophy, progressive bifocal, MIM# 600790, Pontocerebellar hypoplasia, type 17, MIM# 619909, Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.64 CSNK2B Bryony Thompson Publications for gene: CSNK2B were set to 28585349; 28762608
Mendeliome v1.63 CSNK2B Bryony Thompson reviewed gene: CSNK2B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35571680; Phenotypes: Craniodigital syndrome-intellectual disability syndrome MONDO:0015463; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.62 SLC5A6 Zornitza Stark Publications for gene: SLC5A6 were set to 31754459; 27904971
Mendeliome v1.61 SLC5A6 Zornitza Stark edited their review of gene: SLC5A6: Added comment: PMID 35013551: 5 individuals from 3 unrelated families reported with predominantly neuropathy phenotype.; Changed publications: 31754459, 27904971, 35013551; Changed phenotypes: Peripheral motor neuropathy, childhood-onset, biotin-responsive, MIM# 619903, Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Mendeliome v1.59 BUB1 Zornitza Stark reviewed gene: BUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, BUB1-related MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.58 IREB2 Zornitza Stark Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
Mendeliome v1.56 GIMAP6 Zornitza Stark reviewed gene: GIMAP6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome MONDO:0019751, GIMAP6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.54 PAN2 Zornitza Stark reviewed gene: PAN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease MONDO:0002254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.52 RRM1 Seb Lunke Added comment: Comment on list classification: 3 families but only 2 Hom variants, not convinced they are definitely unrelated. 4th probed inconclusive.
Mendeliome v1.49 RRM1 Daniel Flanagan gene: RRM1 was added
gene: RRM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRM1 were set to 35617047
Phenotypes for gene: RRM1 were set to Multiple mitochondrial DNA deletion syndrome (MONDO:0016797)
Review for gene: RRM1 was set to GREEN
Added comment: Homozygous missense were identified in 4 four probands (p.Arg381Cys or p.Arg381His) from three families, who presented with ptosis and ophthalmoplegia, plus other manifestations and multiple mtDNA deletions in muscle. Heterozygous carriers were unaffected. An additional proband was heterozygous for a different RRM1 missense (p.Asn427Lys), another variant not identified.
Sources: Expert list
Mendeliome v1.47 PAN2 Naomi Baker gene: PAN2 was added
gene: PAN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to PMID:35304602; 29620724
Phenotypes for gene: PAN2 were set to Neurodevelopmental disorder, MONDO:0700092, PAN2-related
Review for gene: PAN2 was set to GREEN
Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck.

PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system.
Sources: Literature
Mendeliome v1.47 PRPF8 Krithika Murali reviewed gene: PRPF8: Rating: GREEN; Mode of pathogenicity: None; Publications: 35543142; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.45 PTPN13 Ain Roesley gene: PTPN13 was added
gene: PTPN13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN13 were set to 35643866
Phenotypes for gene: PTPN13 were set to bone marrow failure syndrome MONDO#0000159, PTPN13-related
Review for gene: PTPN13 was set to AMBER
gene: PTPN13 was marked as current diagnostic
Added comment: 2 families

Family A: 3 affecteds only 2 sequenced. Hom for a missense
3/3 Anaemia, 1x thrombocytopaenia, 1x severe neutropaenia, bone marrow with pure red cell aplasia
noted that the sibling who wasn't sequenced had normal bone marrow morphology

Family B: Chet for a missense and inframe del of 1 amino acid
Persistent hypogammaglobulinemia after transplant (at least 14 months after) with normal blood counts and Pre-B ALL with MLL rearrangement

In vitro studies of individual variants were LoF, including defective erythroid and megakaryocytic differentiation, consistent with anaemia and thrombocytopaenia reported in family A
Sources: Literature
Mendeliome v1.44 ATOH1 Chloe Stutterd gene: ATOH1 was added
gene: ATOH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATOH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATOH1 were set to 35518571
Phenotypes for gene: ATOH1 were set to Pontocerebellar hypoplasia; developmental delay; hearing loss
Penetrance for gene: ATOH1 were set to unknown
Review for gene: ATOH1 was set to AMBER
Added comment: Single report of novel homozygous missense variant in functional domain segregating with disease in two affected siblings with pontocerebellar hypoplasia, developmental delay and hearing loss. Similar phenotype previously reported in animal model with biallelic missense variant affecting same functional domain. Homology modelling predicts this missense variant affects binding capability of the bHLH domain to the DNA. Gene encodes a core transcription factor in developing cerebellum, brainstem, dorsal spinal cord and ear.
Sources: Literature
Mendeliome v1.44 BUB1 Paul De Fazio gene: BUB1 was added
gene: BUB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816; 19772675; 19117986; 23209306
Phenotypes for gene: BUB1 were set to Intellectual disability and microcephaly
Review for gene: BUB1 was set to GREEN
gene: BUB1 was marked as current diagnostic
Added comment: 2 unrelated patients with ID, microcephaly, short stature, dysmorphic features reported with biallelic variants:

P1 (3yo male): homozygous start-loss variant (2 hets and 0 hom in gnomAD). Functional testing showed a small amount of full-length protein was translated, and BUB1 recruitment to kinetochores was nearly undetectable.
P2 (16yo female): compound heterozygous for a canonical splice variant (1 het and no hom in gnomAD) and an NMD-predicted frameshift variant (absent from gnomAD). The splice variant was shown to result in an in-frame deletion of 54 amino acids in the kinase domain. P2 cells have reduced protein levels but essentially no kinase activity.

BUB1 patient cells have impaired mitotic fidelity.

Homozygous Bub1 disruption in mice is embryonic lethal (PMID:19772675). A hypomorphic mouse is viable with increased tumourigenesis with ageing and aneuploidy (PMID:19117986). A kinase-dead mouse does not show increased tumourigenesis but does have a high frequency of aneuploid cells (PMID:23209306)
Sources: Literature
Mendeliome v1.44 LMOD2 Melanie Marty gene: LMOD2 was added
gene: LMOD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMOD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMOD2 were set to PMID: 31517052; PMID: 34888509; PMID: 35082396; PMID: 35188328; PMID: 26487682
Phenotypes for gene: LMOD2 were set to Dilated cardiomyopathy
Review for gene: LMOD2 was set to GREEN
Added comment: 4 unrelated families with early onset dilated cardiomyopathy, autosomal recessive inheritance, functional studies showing loss of protein and a mouse model reported.

PMID: 31517052 1 x neonate with DCM, homozygous nonsense variant identified.

PMID: 34888509 2 x neonatal deaths (from 1 family) related to dilated cardiomyopathy (DCM), compound heterozygous loss-of-function variants identified.

PMID:35082396 2 x siblings with DCM who died shortly after birth due to heart failure, homozygous canonical splice variant identified. Functional studies show loss of donor site and loss of protein.

PMID: 35188328 1 x child (9 months) with DCM, with homozygous frameshift variant. Functional studies showed absence of LMOD2 protein (western blot).

PMID: 26487682 Lmod2 null (knockout) mice present with short cardiac thin filaments and die at ~3 weeks due to dysfunctional, dilated hearts
Sources: Literature
Mendeliome v1.42 SEMA6B Zornitza Stark Publications for gene: SEMA6B were set to 32169168
Mendeliome v1.40 SEMA6B Dean Phelan reviewed gene: SEMA6B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35604360; Phenotypes: Intellectual disability, MONDO:0001071, SEMA6B related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.37 IREB2 Lucy Spencer reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35602653; Phenotypes: Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.36 SRRM2 Michelle Torres reviewed gene: SRRM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35567594; Phenotypes: neurodevelopmental disorder MONDO:0700092 SRRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.35 GIMAP6 Elena Savva gene: GIMAP6 was added
gene: GIMAP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GIMAP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP6 were set to PMID: 35551368; 33328581
Phenotypes for gene: GIMAP6 were set to Autophagy, immune competence and inflammation
Review for gene: GIMAP6 was set to AMBER
Added comment: PMID: 35551368, PMID: 33328581
- K/O mice show autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids and die prematurely from microangiopathic glomerulosclerosis with immunodeficiency.
- 2 unrelated families (3 patients) w/ a homozygous missense (p.Gly153Val) and nonsense (p.Trp86*). All unaffected siblings were heterozygous.
Patient 1 (missense) presented with Coombs-positive hemolytic anemia, hepatosplenomegaly, Cranial MRI showed bilateral effusions, sulcal hyperintensity, and lateral parietal subcortical acute focal ischemic lesions.
Patient 2 (nonsense) presented with recurrent purulent otitis media and a chronic wet cough, persistent jaundice, recurrent chest and ear infections, lingular consolidation, mild bronchiectasis, bibasilar bronchial wall thickening, right peribronchial consolidation, right lower lobe bronchiectasis, bilateral axillary lymphadenopathy, and splenomegaly.
Patient 3 (nonsense) presented with suffered headaches, abdomen pain, mouth ulcers, and recurrent infections

- Functional studies show patient 1 (missense) with reduced protein expression on western blot, and patient 2/3 (nonsense) with no protein expression. T cells of Pt 1 were similar to mouse K/O model (elevated basal LC3-II, reduced autophagic flux).

gnomAD: 0 homozygous PTCs, but a very common canonical splice which is present in the non-canonical transcript
Sources: Literature
Mendeliome v1.34 HEATR3 Chern Lim gene: HEATR3 was added
gene: HEATR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to PMID: 35213692
Phenotypes for gene: HEATR3 were set to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability
Review for gene: HEATR3 was set to GREEN
gene: HEATR3 was marked as current diagnostic
Added comment: PMID: 35213692:
- 4 unrelated individuals with biallelic HEATR3 variants (missense and splice site variants), exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability.
- Functional analysis showed HEATR3 variants destabilised the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis.
Sources: Literature
Mendeliome v1.34 TRIM47 Zornitza Stark gene: TRIM47 was added
gene: TRIM47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM47 were set to 35511193
Phenotypes for gene: TRIM47 were set to Genetic cerebral small vessel disease MONDO:0018787
Review for gene: TRIM47 was set to RED
Added comment: GWAS data: Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. Observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology.
Sources: Literature
Mendeliome v1.28 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: Leveille et al (2019) - 2 patients with HSP with biallelic missense SPTAN1 variants Previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. Xie et al (2022) - 1 patient with complicated HSP and homozygous SPTAN1 mutation. Healthy parents and sister all carried the heterozygous mutation. Van de Vondel et al (2022) - 22 patients from 14 families with five novel heterozygous SPTAN1 variants. Presentations ranged from cerebellar ataxia, intellectual disability, epilepsy, and spastic paraplegia. A recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia. Through protein modeling they showed that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523; Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.26 MSX1 Zornitza Stark Publications for gene: MSX1 were set to 33419968, 33708320, 32192766
Mendeliome v1.25 LRP2 Zornitza Stark Publications for gene: LRP2 were set to
Mendeliome v1.23 AURKC Zornitza Stark Publications for gene: AURKC were set to
Mendeliome v1.21 AURKC Zornitza Stark reviewed gene: AURKC: Rating: GREEN; Mode of pathogenicity: None; Publications: 21733974, 19147683; Phenotypes: Spermatogenic failure 5 , OMIM #243060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.20 GJA5 Zornitza Stark reviewed gene: GJA5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.19 ATG16L1 Zornitza Stark reviewed gene: ATG16L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.18 PLCH1 Zornitza Stark reviewed gene: PLCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Holoprosencephaly 14, MIM# 619895; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.17 TULP3 Zornitza Stark reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hepatorenocardiac degenerative fibrosis, MIM# 619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.17 IKBKG Zornitza Stark edited their review of gene: IKBKG: Changed publications: 31874111, 35289316
Mendeliome v1.17 IKBKG Zornitza Stark Publications for gene: IKBKG were set to
Mendeliome v1.13 SLC38A3 Zornitza Stark reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, MIM# 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.13 FAT2 Elena Savva Publications for gene: FAT2 were set to 29053796
Mendeliome v1.12 FAT2 Elena Savva reviewed gene: FAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33884300, 29053796; Phenotypes: Spinocerebellar ataxia 45, MIM#617769; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.7 PROSER1 Zornitza Stark gene: PROSER1 was added
gene: PROSER1 was added to Mendeliome. Sources: Expert Review
founder tags were added to gene: PROSER1.
Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PROSER1 were set to 35229282
Phenotypes for gene: PROSER1 were set to Syndromic disease MONDO:0002254, PROSER1-related
Review for gene: PROSER1 was set to RED
Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families, likely founder effect.
Sources: Expert Review
Mendeliome v1.5 SPATA22 Zornitza Stark gene: SPATA22 was added
gene: SPATA22 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SPATA22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA22 were set to 35285020
Phenotypes for gene: SPATA22 were set to Premature ovarian insufficiency and nonobstructive azoospermia; Genetic infertility MONDO:0017143
Review for gene: SPATA22 was set to AMBER
Added comment: 1 consanguineous family with two premature ovarian insufficiency (POI) and two nonobstructive azoospermia (NOA) patients. WES identified a homozygous variant in SPATA22 (c.400C>T:p.R134X). Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. 2nd patient found with idiopathic POI and compound heterozygous variants in SPATA22 (c.900+1G>A and c.31C>T:p.R11X).
Sources: Expert Review
Mendeliome v1.3 RDH11 Zornitza Stark edited their review of gene: RDH11: Added comment: 2nd case reported: 1 Chinese patient with retinitis pigmentosa, juvenile cataracts, intellectual disability, and myopathy. Trio-based WES and whole genomic CNV detection found compound heterozygous variants in RDH11 (p.Leu313Pro and c.75-3C>A) with biparental inheritance. Variant c.75-3C>A was confirmed to be a splice-site mutation by cDNA sequencing. It caused exon 2 skipping, resulting in a frameshift mutation and premature translation termination (p.Lys26Serfs*38). They found mislocalization of RDH11 protein in muscle cells of the patient by using immunofluorescence staining. Retinol dehydrogenase 11 (RDH11) is an 11-cis-retinol dehydrogenase that has a well-characterized, albeit auxiliary role in the retinoid cycle. Diseases caused by mutations in the RDH11 gene are very rare, and only one affected family with eye and intelligence involvement has been reported.; Changed rating: AMBER; Changed publications: 24916380, 15634683, 30731079, 18326732, 34988992
Mendeliome v1.2 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Mendeliome v0.14798 GLRX3 Zornitza Stark Publications for gene: GLRX3 were set to
Mendeliome v0.14794 DNASE1L3 Zornitza Stark Publications for gene: DNASE1L3 were set to
Mendeliome v0.14789 DNAJC6 Zornitza Stark Publications for gene: DNAJC6 were set to
Mendeliome v0.14785 DNAJC5 Zornitza Stark Publications for gene: DNAJC5 were set to
Mendeliome v0.14783 DNAJC3 Zornitza Stark Publications for gene: DNAJC3 were set to
Mendeliome v0.14780 DNAJC21 Zornitza Stark Publications for gene: DNAJC21 were set to
Mendeliome v0.14778 DNM2 Zornitza Stark Publications for gene: DNM2 were set to
Mendeliome v0.14771 AVP Zornitza Stark Publications for gene: AVP were set to
Mendeliome v0.14770 DRAM2 Zornitza Stark Publications for gene: DRAM2 were set to
Mendeliome v0.14766 ATP6V1E1 Zornitza Stark Publications for gene: ATP6V1E1 were set to
Mendeliome v0.14759 ATP2A1 Zornitza Stark Publications for gene: ATP2A1 were set to
Mendeliome v0.14756 DSC3 Zornitza Stark Publications for gene: DSC3 were set to
Mendeliome v0.14752 DSCAM Zornitza Stark Publications for gene: DSCAM were set to
Mendeliome v0.14747 DSE Zornitza Stark Publications for gene: DSE were set to
Mendeliome v0.14744 DSG4 Zornitza Stark Publications for gene: DSG4 were set to
Mendeliome v0.14735 EPS8 Zornitza Stark Publications for gene: EPS8 were set to
Mendeliome v0.14730 EYS Zornitza Stark Publications for gene: EYS were set to
Mendeliome v0.14728 ETV2 Ain Roesley gene: ETV2 was added
gene: ETV2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ETV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ETV2 were set to 33359164
Phenotypes for gene: ETV2 were set to multiple fetal anomalies; congenital heart disease MONDO:000545, ETV2-related; vertebral malformations
Review for gene: ETV2 was set to RED
gene: ETV2 was marked as current diagnostic
Added comment: 1 family with 4 fetus-es, cHet for a fs (NMD-predicted) and a missense

3/4 vertebral malformations
2/4 Tetralogy of Fallot
1/4 arterial septal defect
1/4 ventricular septal defect, aortic dilatation
1/4 pre-axial polydactyly
Sources: Literature
Mendeliome v0.14727 GABRB2 Zornitza Stark Publications for gene: GABRB2 were set to
Mendeliome v0.14724 GALNT3 Zornitza Stark Publications for gene: GALNT3 were set to
Mendeliome v0.14721 GALT Zornitza Stark Publications for gene: GALT were set to
Mendeliome v0.14718 GAMT Zornitza Stark Publications for gene: GAMT were set to
Mendeliome v0.14715 GAN Zornitza Stark Publications for gene: GAN were set to
Mendeliome v0.14712 GBA2 Zornitza Stark Publications for gene: GBA2 were set to
Mendeliome v0.14709 GCDH Zornitza Stark Publications for gene: GCDH were set to
Mendeliome v0.14706 GCH1 Zornitza Stark Publications for gene: GCH1 were set to
Mendeliome v0.14703 GCK Zornitza Stark Publications for gene: GCK were set to
Mendeliome v0.14700 GCNT2 Zornitza Stark Phenotypes for gene: GCNT2 were changed from to Cataract 13 with adult i phenotype, OMIM # 116700
Mendeliome v0.14700 GDNF Elena Savva Publications for gene: GDNF were set to
Mendeliome v0.14699 GCNT2 Zornitza Stark Publications for gene: GCNT2 were set to
Mendeliome v0.14694 GATAD1 Elena Savva Publications for gene: GATAD1 were set to
Mendeliome v0.14691 GDAP1 Zornitza Stark Publications for gene: GDAP1 were set to
Mendeliome v0.14688 GDF2 Zornitza Stark Publications for gene: GDF2 were set to
Mendeliome v0.14685 GDF9 Zornitza Stark Publications for gene: GDF9 were set to
Mendeliome v0.14683 GEMIN4 Zornitza Stark Phenotypes for gene: GEMIN4 were changed from to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913
Mendeliome v0.14682 GEMIN4 Zornitza Stark Publications for gene: GEMIN4 were set to
Mendeliome v0.14679 GFM2 Zornitza Stark Publications for gene: GFM2 were set to
Mendeliome v0.14676 GIF Zornitza Stark Publications for gene: GIF were set to
Mendeliome v0.14674 KATNB1 Elena Savva reviewed gene: KATNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25521378, 25521379, 26640080; Phenotypes: Lissencephaly 6, with microcephaly MIM#616212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14673 TIA1 Elena Savva Publications for gene: TIA1 were set to
Mendeliome v0.14670 GINS1 Zornitza Stark Publications for gene: GINS1 were set to
Mendeliome v0.14669 PRKAG3 Elena Savva Publications for gene: PRKAG3 were set to
Mendeliome v0.14663 DMGDH Elena Savva Publications for gene: DMGDH were set to
Mendeliome v0.14662 LYZ Abhijit Kulkarni reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 1808634 8464497 15745733; Phenotypes: Amyloidosis, renal (MIM: 105200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14662 LRP5 Krithika Murali reviewed gene: LRP5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Exudative vitreoretinopathy 4 - MIM#601813 (AD, AR), Hyperostosis, endosteal - MIM#144750 (AD), Osteopetrosis, autosomal dominant 1 - MIM#607634(AD), Osteoporosis-pseudoglioma syndrome - MIM#259770 (AR), Osteosclerosis - #144750 (AD), Polycystic liver disease 4 with or without kidney cysts - MIM#617875 (AD), van Buchem disease, type 2 - MIM#607636; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14661 MSX1 Elena Savva Publications for gene: MSX1 were set to 33419968, 33708320, 32192766
Mendeliome v0.14660 LRP6 Krithika Murali reviewed gene: LRP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387593; Phenotypes: Tooth agenesis, selective, 7 - MIM#616724; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14660 LYRM7 Krithika Murali reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8 - MIM#615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14660 LYST Krithika Murali reviewed gene: LYST: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chediak-Higashi syndrome - MIM#214500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14659 MSX1 Elena Savva Publications for gene: MSX1 were set to
Mendeliome v0.14658 LYZ Krithika Murali reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 1808634, 8464497, 15745733,; Phenotypes: Amyloidosis, renal - MIM#105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14656 GJA1 Zornitza Stark Publications for gene: GJA1 were set to
Mendeliome v0.14653 GJA5 Zornitza Stark Publications for gene: GJA5 were set to
Mendeliome v0.14651 LRP2 Chirag Patel reviewed gene: LRP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17632512; Phenotypes: Donnai-Barrow syndrome, MIM#222448; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14651 LINS1 Chirag Patel reviewed gene: LINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32802957, 34450347, 32499722, 31922598; Phenotypes: Intellectual developmental disorder, autosomal recessive 27, MIM# 614340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14651 ATPAF2 Krithika Murali reviewed gene: ATPAF2: Rating: RED; Mode of pathogenicity: None; Publications: 14757859; Phenotypes: ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 - MIM#604273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14650 ADD1 Chirag Patel gene: ADD1 was added
gene: ADD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ADD1 were set to PMID: 34906466
Phenotypes for gene: ADD1 were set to Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM #
Review for gene: ADD1 was set to GREEN
Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown
Sources: Literature
Mendeliome v0.14649 AVP Chirag Patel reviewed gene: AVP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 6526016, 1840604, 8554046; Phenotypes: Diabetes insipidus, neurohypophyseal MIM#125700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14648 AURKC Chirag Patel reviewed gene: AURKC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 5 , OMIM #243060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 ATPAF2 Chirag Patel reviewed gene: ATPAF2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14757859; Phenotypes: ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, OMIM# 604273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 ATP6V1E1 Chirag Patel reviewed gene: ATP6V1E1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28065471, 27023906; Phenotypes: Cutis laxa, autosomal recessive, type IIC MIM#617402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 ATP2A1 Chirag Patel reviewed gene: ATP2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32040565; Phenotypes: Brody myopathy, OMIM # 601003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 GJA5 Chirag Patel commented on gene: GJA5: Gollob et al. (2006) presented evidence that tissue-specific mutations in the GJA5 gene may predispose the atria to fibrillation. They identified a heterozygous missense mutation in blood and cardiac tissue in patient with AF. They also found 3 heterozygous missense mutations in cardiac tissue only in 3 other patients, indicating a somatic source of the genetic defects

Yang et al. (2010) identified a heterozygous nonsense mutationin a 64-year-old female patient who was diagnosed with paroxysmal AF at 32 years of age. The mutation was detected in 6 additional affected family members, but was not found in 6 unaffected family members or in 200 ethnically matched controls.

Yang et al. (2010) identified 3 heterozygous missense mutations in 3 probands with AF. The mutations segregated with disease in all 3 families and were not found in 200 ethnically matched controls.

Sun et al. (2013) identified a heterozygous missense mutation in a 42-year-old woman who had been diagnosed with AF at age 40 years. The mutation was also detected in her father, who had been diagnosed with lone AF at 41 years of age, but it was not found in unaffected family members, in 200 controls, or in the dbSNP database. Functional analysis demonstrated that the I75F mutant is unable to form functional gap junction channels and also impairs coupling when expressed with wildtype CX40 or CX43.
Mendeliome v0.14647 GJA5 Chirag Patel reviewed gene: GJA5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16790700, 20818502, 20650941, 23348765; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14647 GEMIN4 Chirag Patel reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25558065, 30237576, 27878435; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14646 GJB2 Zornitza Stark Publications for gene: GJB2 were set to
Mendeliome v0.14643 GJB3 Zornitza Stark Publications for gene: GJB3 were set to
Mendeliome v0.14642 GJB2 Chirag Patel reviewed gene: GJB2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 11179004, 9529365, 14985372, 19941053, 11354642; Phenotypes: Bart-Pumphrey syndrome, MIM#149200, Deafness, autosomal dominant 3A, MIM#601544, Deafness, autosomal recessive 1A, MIM#220290, Hystrix-like ichthyosis with deafness, MIM#602540, Keratitis-ichthyosis-deafness syndrome, MIM#148210, Keratoderma, palmoplantar, with deafness, MIM#148350, Vohwinkel syndrome, MIM# 124500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14640 GJB3 Zornitza Stark reviewed gene: GJB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843209, 10594760, 10798362, 12019212; Phenotypes: Erythrokeratodermia variabilis et progressiva 1, MIM# 133200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14640 GJB3 Chirag Patel reviewed gene: GJB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 9843209, 10798362, 10594760, 17446259, 9843210; Phenotypes: Erythrokeratodermia variabilis et progressiva 1, OMIM #133200, Deafness, autosomal dominant 2B, OMIM # 612644; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14640 GNB5 Chirag Patel reviewed gene: GNB5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27523599, 27677260, 28697420, 29368331; Phenotypes: Intellectual developmental disorder with cardiac arrhythmia, OMIM #617173, Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM # 617182, Early infantile epileptic encephalopathy (EIEE); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14639 GJB4 Zornitza Stark Publications for gene: GJB4 were set to
Mendeliome v0.14637 GJB4 Zornitza Stark reviewed gene: GJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11017804, 12648223, 19291775; Phenotypes: Erythrokeratodermia variabilis et progressiva 2, MIM# 617524; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14636 GJB6 Zornitza Stark Publications for gene: GJB6 were set to
Mendeliome v0.14634 GJB6 Zornitza Stark reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11017065, 23219093, 11874494, 18717672, 27137747, 25808784, 19416251, 26620415, 17227867; Phenotypes: Deafness, autosomal dominant 3B, MIM# 612643, Deafness, autosomal recessive 1B, MIM# 612645, Ectodermal dysplasia 2, Clouston type, MIM# 129500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14633 GK Zornitza Stark Publications for gene: GK were set to
Mendeliome v0.14628 GLCCI1 Zornitza Stark reviewed gene: GLCCI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Glucocorticoid therapy, response to} 614400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14627 GLE1 Zornitza Stark Publications for gene: GLE1 were set to
Mendeliome v0.14624 GLIS3 Zornitza Stark Publications for gene: GLIS3 were set to
Mendeliome v0.14622 GLIS3 Zornitza Stark reviewed gene: GLIS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21139041, 35410112, 35394098, 34093443; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism, MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14621 GLUL Zornitza Stark Publications for gene: GLUL were set to
Mendeliome v0.14618 GLYCTK Zornitza Stark Publications for gene: GLYCTK were set to
Mendeliome v0.14615 GMPPA Zornitza Stark Publications for gene: GMPPA were set to
Mendeliome v0.14613 GMPPA Zornitza Stark reviewed gene: GMPPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24035193, 28574218; Phenotypes: Alacrima, achalasia, and mental retardation syndrome, MIM# 615510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14611 GMPPB Zornitza Stark reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14609 GNAS Zornitza Stark reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osseous heteroplasia, progressive (166350) AD, Pituitary adenoma 3, multiple types, somatic (617686), Pseudohypoparathyroidism Ia (103580) AD, Pseudohypoparathyroidism Ib (603233) AD, Pseudohypoparathyroidism Ic (612462) AD, Pseudopseudohypoparathyroidism (612463); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14608 GNAT1 Zornitza Stark Publications for gene: GNAT1 were set to
Mendeliome v0.14606 GNAT1 Zornitza Stark reviewed gene: GNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8673138, 17584859, 22190596, 26472407, 11095744, 11095744, 30051303; Phenotypes: Night blindness, congenital stationary, autosomal dominant 3, MIM# 610444, Night blindness, congenital stationary, type 1G, MIM# 616389; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14605 GNB3 Zornitza Stark Publications for gene: GNB3 were set to
Mendeliome v0.14603 GNB3 Zornitza Stark reviewed gene: GNB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27063057, 17065478; Phenotypes: Night blindness, congenital stationary, type 1H, MIM# 617024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14602 GNMT Zornitza Stark Publications for gene: GNMT were set to
Mendeliome v0.14599 GOSR2 Zornitza Stark Publications for gene: GOSR2 were set to
Mendeliome v0.14597 GOSR2 Zornitza Stark reviewed gene: GOSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21549339, 24458321, 30363482; Phenotypes: Epilepsy, progressive myoclonic 6 , MIM#614018; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14595 GOT1 Zornitza Stark reviewed gene: GOT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aspartate aminotransferase, serum level of, QTL1, MIM# 614419; Mode of inheritance: None
Mendeliome v0.14594 GPC4 Zornitza Stark Publications for gene: GPC4 were set to
Mendeliome v0.14592 GPNMB Krithika Murali reviewed gene: GPNMB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31226264, 29336782, 31260093, 34551863, 33687658; Phenotypes: Amyloidosis, primary localized cutaneous, 3 - MIM#617920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14592 GLE1 Chirag Patel reviewed gene: GLE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18204449, 22357925; Phenotypes: Lethal congenital contracture syndrome 1, MIM# 253310; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14592 GDF2 Chirag Patel reviewed gene: GDF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23972370, 27081547, 32573726, 32992168, 34611981, 33834622, 32669404, 26056270, 23972370; Phenotypes: Telangiectasia, hereditary hemorrhagic, type 5 OMIM # 615506, pulmonary arteriovenous malformations; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14592 GCNT2 Chirag Patel reviewed gene: GCNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15161861, 27936067, 12424189, 28224043; Phenotypes: Cataract 13 with adult i phenotype, OMIM # 116700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14592 GJA1 Chirag Patel reviewed gene: GJA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19338053; Phenotypes: Oculodentodigital dysplasia, autosomal recessive, MIM# 257850, Oculodentodigital dysplasia, MIM# 164200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14592 GCK Chirag Patel reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19790256; Phenotypes: Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853), Diabetes mellitus, permanent neonatal 1, AR (MIM#606176), Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485), MODY, type II, AD (MIM#125851); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14592 GINS1 Chirag Patel reviewed gene: GINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28414293; Phenotypes: Immunodeficiency 55, OMIM #617827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14591 GDNF Chirag Patel reviewed gene: GDNF: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 8896568, 8968758; Phenotypes: {Hirschsprung disease, susceptibility to, 3}, OMIM # 613711; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14591 GFM2 Chirag Patel reviewed gene: GFM2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22700954, 26016410, 29075935; Phenotypes: Combined oxidative phosphorylation deficiency 39, OMIM #618397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14591 GDF9 Chirag Patel reviewed gene: GDF9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29044499, 8849725, 33036707; Phenotypes: Premature ovarian failure 14, OMIM# 618014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14591 GIGYF2 Chirag Patel Publications for gene: GIGYF2 were set to
Mendeliome v0.14589 GIGYF2 Chirag Patel reviewed gene: GIGYF2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 18358451; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14588 GCH1 Chirag Patel reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 7874165, 11113234, 15753436, 9667588, 10987649, 32170445, 32278297, 32746945, 30314816; Phenotypes: Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910, Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14584 MYF6 Zornitza Stark Publications for gene: MYF6 were set to
Mendeliome v0.14580 GBA2 Chirag Patel reviewed gene: GBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23332916, 23332917, 29524657; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM# 614409, MONDO:0013737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14579 GATAD1 Chirag Patel reviewed gene: GATAD1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 21965549; Phenotypes: ?Cardiomyopathy, dilated, 2B, OMIM # 614672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14579 GAN Chirag Patel reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 11062483; Phenotypes: Giant axonal neuropathy-1, MIM# 256850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14579 GALNT3 Chirag Patel reviewed gene: GALNT3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15133511, 20358599, 32125652; Phenotypes: Tumoral calcinosis, hyperphosphatemic, familial, 1, MIM# 211900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14578 GPD1 Zornitza Stark Publications for gene: GPD1 were set to
Mendeliome v0.14576 GPD1 Zornitza Stark reviewed gene: GPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22226083, 24549054, 35365473, 34484308, 33447932; Phenotypes: Hypertriglyceridaemia, transient infantile, MIM# 614480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14576 GPHN Zornitza Stark Publications for gene: GPHN were set to 22040219; 11095995; 26613940; 24561070; 23393157
Mendeliome v0.14574 GPNMB Zornitza Stark Publications for gene: GPNMB were set to
Mendeliome v0.14572 GPNMB Zornitza Stark reviewed gene: GPNMB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29336782; Phenotypes: Amyloidosis, primary localized cutaneous, 3, MIM# 617920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14571 GREM1 Zornitza Stark Publications for gene: GREM1 were set to
Mendeliome v0.14567 MRAP Zornitza Stark Publications for gene: MRAP were set to
Mendeliome v0.14565 MRAP Zornitza Stark reviewed gene: MRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 15654338; Phenotypes: Glucocorticoid deficiency 2, MIM# 607398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14564 MPZL2 Zornitza Stark Publications for gene: MPZL2 were set to
Mendeliome v0.14562 MPZL2 Zornitza Stark reviewed gene: MPZL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29982980, 29961571; Phenotypes: Deafness, autosomal recessive 111, MIM#618145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14561 MPZ Zornitza Stark Publications for gene: MPZ were set to
Mendeliome v0.14558 MPV17 Zornitza Stark Publications for gene: MPV17 were set to
Mendeliome v0.14553 MPO Zornitza Stark reviewed gene: MPO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Myeloperoxidase deficiency, MIM# 254600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14552 MPC1 Zornitza Stark Publications for gene: MPC1 were set to
Mendeliome v0.14550 MPC1 Zornitza Stark reviewed gene: MPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22628558, 34873722; Phenotypes: Mitochondrial pyruvate carrier deficiency, MIM# 614741; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14549 MOG Zornitza Stark Publications for gene: MOG were set to
Mendeliome v0.14546 MOG Zornitza Stark reviewed gene: MOG: Rating: RED; Mode of pathogenicity: None; Publications: 21907016; Phenotypes: Narcolepsy 7 , MIM# 614250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14545 MOCS3 Zornitza Stark Publications for gene: MOCS3 were set to
Mendeliome v0.14542 MOCS3 Zornitza Stark reviewed gene: MOCS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 33897766, 28544736; Phenotypes: Molybdenum cofactor deficiency MONDO:0020480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14542 MOCS1 Zornitza Stark Publications for gene: MOCS1 were set to 21031595; 9921896; 12754701
Mendeliome v0.14540 MNX1 Zornitza Stark Publications for gene: MNX1 were set to
Mendeliome v0.14537 MMP2 Zornitza Stark Publications for gene: MMP2 were set to
Mendeliome v0.14535 MMP2 Zornitza Stark reviewed gene: MMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11431697, 15691365, 17059372, 17400654; Phenotypes: Multicentric osteolysis, nodulosis, and arthropathy, MIM# 259600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14535 ATP6V1A Elena Savva Publications for gene: ATP6V1A were set to 29668857; 28065471; 33320377
Mendeliome v0.14533 ATP6V1A Elena Savva Publications for gene: ATP6V1A were set to
Mendeliome v0.14532 ATP6V1A Elena Savva reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29668857, 28065471, 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID MIM#617403, Developmental and epileptic encephalopathy 93 MIM#618012; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14531 ATP6AP2 Elena Savva Publications for gene: ATP6AP2 were set to
Mendeliome v0.14530 ATP6AP2 Elena Savva reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23595882; Phenotypes: ?Parkinsonism with spasticity, X-linked MIM#300911, Congenital disorder of glycosylation, type IIr MIM#301045, Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14529 MMADHC Zornitza Stark Publications for gene: MMADHC were set to
Mendeliome v0.14526 MMACHC Zornitza Stark Publications for gene: MMACHC were set to
Mendeliome v0.14522 MMAB Zornitza Stark reviewed gene: MMAB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, vitamin B12-responsive, cblB type, MIM# 251110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14520 MMAA Zornitza Stark reviewed gene: MMAA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, vitamin B12-responsive, cblA type, MIM# 251100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14519 MLPH Zornitza Stark Publications for gene: MLPH were set to
Mendeliome v0.14517 MLPH Zornitza Stark reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 32864751, 31721180; Phenotypes: Griscelli syndrome, type 3, MIM# 609227; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14516 MITF Zornitza Stark Publications for gene: MITF were set to
Mendeliome v0.14514 MITF Zornitza Stark reviewed gene: MITF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27889061, 32541011; Phenotypes: COMMAD syndrome, MIM# 617306, Tietz albinism-deafness syndrome, MIM# 103500, Waardenburg syndrome, type 2A, MIM# 193510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14513 MIR936 Zornitza Stark reviewed gene: MIR936: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14512 MIR184 Zornitza Stark Publications for gene: MIR184 were set to
Mendeliome v0.14510 MIR184 Zornitza Stark reviewed gene: MIR184: Rating: GREEN; Mode of pathogenicity: None; Publications: 21996275, 22131394, 25373792, 24138095; Phenotypes: EDICT syndrome, MIM# 614303; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14509 MIR183 Zornitza Stark reviewed gene: MIR183: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14508 CPSF3 Zornitza Stark reviewed gene: CPSF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and seizures (NEDMHS), MIM#619876; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14508 ATP2C1 Elena Savva Publications for gene: ATP2C1 were set to 28551824
Mendeliome v0.14506 ATP2C1 Elena Savva Publications for gene: ATP2C1 were set to
Mendeliome v0.14504 MIR182 Zornitza Stark reviewed gene: MIR182: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14504 MIP Zornitza Stark Phenotypes for gene: MIP were changed from to Cataract 15, multiple types, MIM# 615274
Mendeliome v0.14503 MIP Zornitza Stark Publications for gene: MIP were set to
Mendeliome v0.14501 MIP Zornitza Stark reviewed gene: MIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802646, 16564824, 33530927, 30214549; Phenotypes: Cataract 15, multiple types, MIM# 615274; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14498 MIF Zornitza Stark reviewed gene: MIF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Rheumatoid arthritis, systemic juvenile, susceptibility to}, MIM# 604302; Mode of inheritance: None
Mendeliome v0.14497 MGME1 Zornitza Stark Publications for gene: MGME1 were set to
Mendeliome v0.14495 MGME1 Zornitza Stark reviewed gene: MGME1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23313956, 29572490, 28711739; Phenotypes: Mitochondrial DNA depletion syndrome 11, MIM# 615084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14495 MFN2 Zornitza Stark Publications for gene: MFN2 were set to
Mendeliome v0.14493 MFF Zornitza Stark Publications for gene: MFF were set to
Mendeliome v0.14491 MFF Zornitza Stark reviewed gene: MFF: Rating: GREEN; Mode of pathogenicity: None; Publications: 22499341, 26783368, 32181496]; Phenotypes: Encephalopathy due to defective mitochondrial and peroxisomal fission 2, MIM# 617086; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14490 METTL23 Zornitza Stark Publications for gene: METTL23 were set to
Mendeliome v0.14488 METTL23 Zornitza Stark reviewed gene: METTL23: Rating: GREEN; Mode of pathogenicity: None; Publications: 24501276, 24626631; Phenotypes: Intellectual developmental disorder, autosomal recessive 44, MIM# 615942; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14486 MET Zornitza Stark reviewed gene: MET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Papillary renal cell carcinoma MONDO:0017884; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14485 MERTK Zornitza Stark Publications for gene: MERTK were set to
Mendeliome v0.14483 MERTK Zornitza Stark reviewed gene: MERTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 11062461, 17301963, 20300561, 22180149; Phenotypes: Retinitis pigmentosa 38, MIM# 613862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14482 MEIS1 Zornitza Stark reviewed gene: MEIS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14480 ATG16L1 Elena Savva Publications for gene: ATG16L1 were set to
Mendeliome v0.14477 ATP2A2 Elena Savva Publications for gene: ATP2A2 were set to
Mendeliome v0.14475 ATG16L1 Elena Savva reviewed gene: ATG16L1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 20602997; Phenotypes: {Inflammatory bowel disease (Crohn disease) 10} MIM#611081; Mode of inheritance: None
Mendeliome v0.14474 ATP2A2 Elena Savva reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24336169; Phenotypes: Acrokeratosis verruciformis MIM#101900, Darier disease MIM#124200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14474 ATP1A1 Elena Savva Publications for gene: ATP1A1 were set to
Mendeliome v0.14473 ATL3 Elena Savva Publications for gene: ATL3 were set to
Mendeliome v0.14470 MEGF8 Zornitza Stark Publications for gene: MEGF8 were set to
Mendeliome v0.14468 MEGF8 Zornitza Stark reviewed gene: MEGF8: Rating: GREEN; Mode of pathogenicity: None; Publications: 23063620; Phenotypes: Carpenter syndrome, MIM#614976; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14468 ASPN Elena Savva Publications for gene: ASPN were set to
Mendeliome v0.14465 MEFV Zornitza Stark reviewed gene: MEFV: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Familial Mediterranean fever MIM# 249100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14464 MED23 Zornitza Stark Publications for gene: MED23 were set to
Mendeliome v0.14462 MED23 Zornitza Stark reviewed gene: MED23: Rating: GREEN; Mode of pathogenicity: None; Publications: 21868677, 25845469, 27311965, 30847200, 31164858; Phenotypes: Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy, MIM# 614249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14461 MED13 Zornitza Stark Publications for gene: MED13 were set to
Mendeliome v0.14459 MED13 Zornitza Stark reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: 29740699; Phenotypes: Intellectual developmental disorder, autosomal dominant 61, MIM# 618009; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14458 MECP2 Zornitza Stark Publications for gene: MECP2 were set to
Mendeliome v0.14456 MECP2 Zornitza Stark reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rett syndrome, MIM# 312750, Intellectual developmental disorder, X-linked, syndromic 13, MIM# 300055, Encephalopathy, neonatal severe, MIM# 300673; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.14455 MCM9 Zornitza Stark Publications for gene: MCM9 were set to
Mendeliome v0.14453 MCM9 Zornitza Stark reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25480036, 26771056, 33538981, 33095795; Phenotypes: Ovarian dysgenesis 4, MIM# 616185; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14449 ARV1 Elena Savva Publications for gene: ARV1 were set to
Mendeliome v0.14447 MCM8 Zornitza Stark Publications for gene: MCM8 were set to
Mendeliome v0.14445 MCM8 Zornitza Stark reviewed gene: MCM8: Rating: GREEN; Mode of pathogenicity: None; Publications: 25437880, 25873734; Phenotypes: Premature ovarian failure 10, MIM# 612885; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14442 MCM6 Zornitza Stark reviewed gene: MCM6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lactase persistence/nonpersistence 223100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14440 MCEE Zornitza Stark Publications for gene: MCEE were set to
Mendeliome v0.14437 MCCC2 Zornitza Stark Publications for gene: MCCC2 were set to
Mendeliome v0.14435 MCCC2 Zornitza Stark reviewed gene: MCCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14434 MCCC1 Zornitza Stark Publications for gene: MCCC1 were set to
Mendeliome v0.14432 MCCC1 Zornitza Stark reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14429 MC3R Zornitza Stark reviewed gene: MC3R: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Obesity, severe, susceptibility to, BMIQ9} 602025; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14428 MC2R Zornitza Stark Publications for gene: MC2R were set to
Mendeliome v0.14426 MC2R Zornitza Stark reviewed gene: MC2R: Rating: GREEN; Mode of pathogenicity: None; Publications: 8094489, 8227361; Phenotypes: Glucocorticoid deficiency, due to ACTH unresponsiveness, MIM# 202200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14422 MBL2 Zornitza Stark reviewed gene: MBL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Chronic infections, due to MBL deficiency} 614372; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14421 MATR3 Zornitza Stark Publications for gene: MATR3 were set to
Mendeliome v0.14419 MATR3 Zornitza Stark reviewed gene: MATR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344878, 24686783, 35205163, 34659085, 34173818, 26493020; Phenotypes: Amyotrophic lateral sclerosis 21, MIM# 606070, Distal myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14418 MAP3K1 Zornitza Stark Publications for gene: MAP3K1 were set to
Mendeliome v0.14416 MAP3K1 Zornitza Stark reviewed gene: MAP3K1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129722, 32986312; Phenotypes: 46XY sex reversal 6 (MIM#613762); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14415 MAK Zornitza Stark Publications for gene: MAK were set to
Mendeliome v0.14413 MAK Zornitza Stark reviewed gene: MAK: Rating: GREEN; Mode of pathogenicity: None; Publications: 21825139, 21835304; Phenotypes: Retinitis pigmentosa 62, MIM# 614181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14412 MAGT1 Zornitza Stark Publications for gene: MAGT1 were set to
Mendeliome v0.14410 MAGT1 Zornitza Stark reviewed gene: MAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31036665, 31714901; Phenotypes: Congenital disorder of glycosylation, type Icc (MIM# 301031), Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14410 GREM1 Krithika Murali reviewed gene: GREM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 22561515, 26493165, 21128281, 29804199; Phenotypes: hereditary mixed polyposis syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14410 MNX1 Abhijit Kulkarni reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571425, 33836786 , 11528505; Phenotypes: Currarino syndrome, MIM# 176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14410 MSX1 Abhijit Kulkarni reviewed gene: MSX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33419968, 33708320, 32192766; Phenotypes: Witkop syndrome (Ectodermal Dysplasia) (MIM: 189500),Cleft Lip+/- Cleft Palate (Rofacial Cleft- MIM :608874), Oligodontia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14409 MAGI2 Zornitza Stark Publications for gene: MAGI2 were set to
Mendeliome v0.14407 MAGI2 Zornitza Stark reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27932480, 25108225, 25271328, 31171376, 31010479; Phenotypes: Nephrotic syndrome, type 15, MIM# 617609; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14406 OPHN1 Zornitza Stark Publications for gene: OPHN1 were set to
Mendeliome v0.14404 OPHN1 Zornitza Stark edited their review of gene: OPHN1: Changed publications: 20528889, 9582072, 12807966, 16221952
Mendeliome v0.14403 PAH Zornitza Stark Publications for gene: PAH were set to
Mendeliome v0.14400 PCDH12 Zornitza Stark Publications for gene: PCDH12 were set to
Mendeliome v0.14398 PCDH12 Zornitza Stark reviewed gene: PCDH12: Rating: GREEN; Mode of pathogenicity: None; Publications: 27164683, 30178464; Phenotypes: Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14397 PEPD Zornitza Stark Publications for gene: PEPD were set to
Mendeliome v0.14394 PEX10 Zornitza Stark Publications for gene: PEX10 were set to
Mendeliome v0.14391 PCK1 Zornitza Stark Publications for gene: PCK1 were set to
Mendeliome v0.14388 REEP1 Zornitza Stark Publications for gene: REEP1 were set to
Mendeliome v0.14385 RLBP1 Zornitza Stark Publications for gene: RLBP1 were set to
Mendeliome v0.14380 RNASEH1 Zornitza Stark Publications for gene: RNASEH1 were set to
Mendeliome v0.14379 RBFOX2 Chern Lim edited their review of gene: RBFOX2: Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.; Changed publications: PMID: 26785492, 27670201, 27485310, 25205790, 35137168, 26785492
Mendeliome v0.14377 RNASEH2A Zornitza Stark Publications for gene: RNASEH2A were set to
Mendeliome v0.14374 RNF139 Zornitza Stark Publications for gene: RNF139 were set to
Mendeliome v0.14370 RP1 Zornitza Stark Publications for gene: RP1 were set to
Mendeliome v0.14367 RP2 Zornitza Stark Publications for gene: RP2 were set to
Mendeliome v0.14364 RP9 Zornitza Stark Publications for gene: RP9 were set to
Mendeliome v0.14359 RYR1 Zornitza Stark Publications for gene: RYR1 were set to
Mendeliome v0.14357 RYR1 Zornitza Stark reviewed gene: RYR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Central core disease, MIM# 117000, King-Denborough syndrome , MIM#619542, Minicore myopathy with external ophthalmoplegia , MIM#255320, Neuromuscular disease, congenital, with uniform type 1 fiber, MIM# 117000; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14354 SCN11A Zornitza Stark Publications for gene: SCN11A were set to
Mendeliome v0.14351 TMC8 Zornitza Stark Publications for gene: TMC8 were set to
Mendeliome v0.14349 TMC8 Zornitza Stark reviewed gene: TMC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 12426567, 28646613; Phenotypes: Epidermodysplasia verruciformis 2, MIM# 618231; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14347 ATP6V0A1 Bryony Thompson Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Mendeliome v0.14345 RLBP1 Belinda Chong reviewed gene: RLBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326942, 11453974, 11868161, 21447491, 25429852, 14718298; Phenotypes: Fundus albipunctatus MIM#136880, Bothnia retinal dystrophy MIM#607475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14345 RBFOX2 Chern Lim gene: RBFOX2 was added
gene: RBFOX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to PMID: 26785492; 27670201; 27485310; 25205790; 35137168
Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS)
Review for gene: RBFOX2 was set to AMBER
gene: RBFOX2 was marked as current diagnostic
Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS).
No further patient-specific clinical or variant info were available.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Sources: Literature
Mendeliome v0.14345 ATF1 Abhijit Kulkarni reviewed gene: ATF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14345 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to
Mendeliome v0.14344 GRIA4 Ain Roesley reviewed gene: GRIA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35518358, 29220673; Phenotypes: Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.14344 GRID2 Ain Roesley Publications for gene: GRID2 were set to
Mendeliome v0.14343 GRID2 Ain Roesley reviewed gene: GRID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622959, 32170608; Phenotypes: Spinocerebellar ataxia, autosomal recessive 18 MIM#616204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14342 GRIN2D Ain Roesley Publications for gene: GRIN2D were set to
Mendeliome v0.14341 GRIN2D Ain Roesley reviewed gene: GRIN2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616483, 30280376; Phenotypes: Developmental and epileptic encephalopathy 46 617162; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.14341 ASPN Abhijit Kulkarni reviewed gene: ASPN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 25689697; Mode of inheritance: None
Mendeliome v0.14341 TMC8 Abhijit Kulkarni reviewed gene: TMC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34459021, 28646613; Phenotypes: Epidermodysplasia verruciformis 2 (MIM: 61831); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14341 BICC1 Abhijit Kulkarni reviewed gene: BICC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: renal dysplasia, cystic, susceptibility to; Mode of inheritance: None
Mendeliome v0.14341 ARV1 Abhijit Kulkarni reviewed gene: ARV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35227294, 27270415, 25558065; Phenotypes: DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 38 ( MIM:61720) Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14341 RMND1 Belinda Chong reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 11 MIM#614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14338 UNG Zornitza Stark Publications for gene: UNG were set to
Mendeliome v0.14336 UQCC2 Zornitza Stark Publications for gene: UQCC2 were set to
Mendeliome v0.14333 UQCRB Zornitza Stark Publications for gene: UQCRB were set to
Mendeliome v0.14330 UROD Zornitza Stark Publications for gene: UROD were set to
Mendeliome v0.14327 MAGED2 Zornitza Stark Publications for gene: MAGED2 were set to
Mendeliome v0.14325 MAGED2 Zornitza Stark reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27120771; Phenotypes: Bartter syndrome, type 5, antenatal, transient, MIM# 300971; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14324 MRPS2 Zornitza Stark Publications for gene: MRPS2 were set to
Mendeliome v0.14322 MRPS2 Zornitza Stark reviewed gene: MRPS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576219, 34991560; Phenotypes: Combined oxidative phosphorylation deficiency 36, MIM# 617950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14321 MSH3 Zornitza Stark Publications for gene: MSH3 were set to
Mendeliome v0.14319 MSH3 Zornitza Stark reviewed gene: MSH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476653, 10706084, 34843512; Phenotypes: Familial adenomatous polyposis 4 , MIM#617100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14318 MSRB3 Zornitza Stark Publications for gene: MSRB3 were set to
Mendeliome v0.14316 MSRB3 Zornitza Stark reviewed gene: MSRB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19650862, 24191262, 21185009; Phenotypes: Deafness, autosomal recessive 74, MIM# 613718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14315 MTAP Zornitza Stark Publications for gene: MTAP were set to
Mendeliome v0.14312 MTAP Zornitza Stark reviewed gene: MTAP: Rating: AMBER; Mode of pathogenicity: None; Publications: 22464254; Phenotypes: Diaphyseal medullary stenosis with malignant fibrous histiocytoma, MIM# 112250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14311 MTFMT Zornitza Stark Publications for gene: MTFMT were set to
Mendeliome v0.14309 MTFMT Zornitza Stark reviewed gene: MTFMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907147, 23499752, 24461907, 22499348; Phenotypes: Combined oxidative phosphorylation deficiency 15, MIM# 614947, Mitochondrial complex I deficiency, nuclear type 27, MIM# 618248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14309 MTHFD1 Zornitza Stark Publications for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780
Mendeliome v0.14307 MTHFD1 Zornitza Stark Publications for gene: MTHFD1 were set to
Mendeliome v0.14304 MTHFR Zornitza Stark Publications for gene: MTHFR were set to
Mendeliome v0.14301 MTM1 Zornitza Stark Publications for gene: MTM1 were set to
Mendeliome v0.14299 MTM1 Zornitza Stark reviewed gene: MTM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10790201; Phenotypes: Myopathy, centronuclear, X-linked, MIM# 310400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14298 MTO1 Zornitza Stark Publications for gene: MTO1 were set to
Mendeliome v0.14296 MTO1 Zornitza Stark reviewed gene: MTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26061759, 29331171, 23929671; Phenotypes: Combined oxidative phosphorylation deficiency 10, OMIM #614702; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14294 MTOR Zornitza Stark Publications for gene: MTOR were set to
Mendeliome v0.14292 MTOR Zornitza Stark reviewed gene: MTOR: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28892148, 25878179, 26018084; Phenotypes: Smith-Kingsmore syndrome, MIM# 616638, Focal cortical dysplasia, type II, somatic, MIM# 607341, Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, MONDO:0100283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14291 DNASE1 Krithika Murali reviewed gene: DNASE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Systemic lupus erythematosus, susceptibility to} - MIM#152700; Mode of inheritance: None
Mendeliome v0.14291 DNAJC6 Krithika Murali reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22563501, 23211418, 26528954; Phenotypes: Parkinson disease 19a, juvenile-onset - MIM#615528, Parkinson disease 19b, early-onset - MIM#615528; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DNAJC5 Krithika Murali reviewed gene: DNAJC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22978711, 21820099, 22235333, 31919451, 26659577; Phenotypes: Ceroid lipofuscinosis, neuronal, 4 (Kufs type), autosomal dominant - MIM#162350, ceroid lipofuscinosis, neuronal, 4 (Kufs type) - MONDO:0008083; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14291 DNAJC3 Krithika Murali reviewed gene: DNAJC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33486469, 34630333, 34654017, 32738013; Phenotypes: ?Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus - MIM#616192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DNAJC21 Krithika Murali reviewed gene: DNAJC21: Rating: GREEN; Mode of pathogenicity: None; Publications: 29700810, 28062395, 27346687; Phenotypes: Bone marrow failure syndrome 3 - MIM#617052; Mode of inheritance: None
Mendeliome v0.14291 DNASE1L3 Krithika Murali reviewed gene: DNASE1L3: Rating: ; Mode of pathogenicity: None; Publications: 30008451, 22019780, 27821515; Phenotypes: Systemic lupus erythematosus 16 - MIM#614420; Mode of inheritance: None
Mendeliome v0.14291 DNM1L Krithika Murali reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR), Optic atrophy 5 - MIM#610708 (AD); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14291 DPY19L2 Krithika Murali reviewed gene: DPY19L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 9 - MIM#613958; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DRAM2 Krithika Murali reviewed gene: DRAM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25983245, 29555955, 31394102; Phenotypes: Cone-rod dystrophy 21 - MIM#616502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DRD2 Krithika Murali reviewed gene: DRD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14291 DRD3 Krithika Murali reviewed gene: DRD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Essential tremor, hereditary, 1} - MIM#190300, {Schizophrenia, susceptibility to} - MIM#181500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14291 DSCAM Krithika Murali edited their review of gene: DSCAM: Added comment: No OMIM gene disease association. Variants predominantly identified from large cohort studies with limited phenotypic information. Associations with ID, ASD, Hirschsprung disease reported. One homozygous splice site variant reported with no parental phenotypes provided.

PMID 34253863 Lim et al 2021 - 12 yo proband with severe autism spectrum disorder diagnosed age 3, de novo heterozygous c.2051 del p.(L684X) variant identified (absent from gnomAD). Skin fibroblast human iPSC cells generated from proband and healthy controls. Forebrain-like induced neuronal cells showed reduced mRNA expression for NMDA-R subunits.

PMID 28600779 Monies et al 2017 - Homozygous splice site variant identified in proband from consanguineous Saudi family. Proband had growth restriction, microcephaly, developmental delay. Parental phenotype not provided.

PMID 30095639 and PMID 23671607 - report association between DSCAM polymorphisms and Hirschsprung disease in Chinese and European populations.

PMID 27824329 Wang et al 2016 - 2 denovo mutations in mixed ID/ASD cohort of 1,045; including comparison of previously published cases 6 LOF out of 4,998 cases.

PMID 28191889 2 denovo LOF in 13,407 mixed ID/ASD cases plus 4 previosly published cases our ot 6158; conclude denovo LOF enriched in cases vs controls

PMID 21904980; mouse model – het LOF mice show hydrocephalus, decreased motor function and impaired motor learning ability,

Evidence for missense lacking currently; Changed publications: 34253863, 32807774, 28600779, 21904980, 28191889, 27824329, 30095639, 23671607
Mendeliome v0.14291 DSCAM Krithika Murali reviewed gene: DSCAM: Rating: AMBER; Mode of pathogenicity: None; Publications: 34253863, 32807774, 28600779; Phenotypes: Autism, ID; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14290 MTTP Zornitza Stark Publications for gene: MTTP were set to
Mendeliome v0.14288 MTTP Zornitza Stark reviewed gene: MTTP: Rating: GREEN; Mode of pathogenicity: None; Publications: 17275380, 34078172, 34052173, 33258201; Phenotypes: Abetalipoproteinaemia, MIM# 200100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14287 MUT Zornitza Stark Publications for gene: MUT were set to
Mendeliome v0.14285 MUT Zornitza Stark reviewed gene: MUT: Rating: GREEN; Mode of pathogenicity: None; Publications: 1977311, 11528502, 12948746; Phenotypes: Methylmalonic aciduria, mut(0) type, MIM# 251000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14284 MVK Zornitza Stark Publications for gene: MVK were set to
Mendeliome v0.14282 MVK Zornitza Stark reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mevalonic aciduria MIM#610377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14281 MXI1 Zornitza Stark reviewed gene: MXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14280 MYD88 Zornitza Stark Publications for gene: MYD88 were set to
Mendeliome v0.14278 MYD88 Zornitza Stark reviewed gene: MYD88: Rating: GREEN; Mode of pathogenicity: None; Publications: 18669862, 20538326, 31301515; Phenotypes: Immunodeficiency 68, MIM# 612260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14277 MYH14 Zornitza Stark Publications for gene: MYH14 were set to
Mendeliome v0.14275 MYH14 Zornitza Stark reviewed gene: MYH14: Rating: GREEN; Mode of pathogenicity: None; Publications: 15015131, 25719458, 31045651, 28221712, 34681017, 21480433, 31653586, 31631044, 31231018; Phenotypes: Deafness, autosomal dominant 4A, MIM# 600652, Peripheral neuropathy, myopathy, hoarseness, and hearing loss 614369; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14274 MYH3 Zornitza Stark Publications for gene: MYH3 were set to
Mendeliome v0.14272 MYH3 Zornitza Stark reviewed gene: MYH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25957469, 26544689, 21531865, 18695058; Phenotypes: Arthrogryposis, distal, type 2A (Freeman-Sheldon) 193700, Arthrogryposis, distal, type 2B3 (Sheldon-Hall) 618436, Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A 178110, Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B 618469; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14271 MYO1E Zornitza Stark Publications for gene: MYO1E were set to
Mendeliome v0.14269 MYO1E Zornitza Stark reviewed gene: MYO1E: Rating: GREEN; Mode of pathogenicity: None; Publications: 21756023, 31520189, 25739341, 23977349; Phenotypes: Glomerulosclerosis, focal segmental, 6, MIM# 614131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14268 WNT1 Zornitza Stark Publications for gene: WNT1 were set to
Mendeliome v0.14266 WNT1 Zornitza Stark reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23499309, 23499310, 23656646, 26671912; Phenotypes: Osteogenesis imperfecta, type XV, MIM# 615220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14265 WNK4 Zornitza Stark Publications for gene: WNK4 were set to
Mendeliome v0.14263 WNK4 Zornitza Stark reviewed gene: WNK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22266938, 31044551; Phenotypes: Pseudohypoaldosteronism, type IIB, MIM# 614491; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14262 WNK1 Zornitza Stark Publications for gene: WNK1 were set to
Mendeliome v0.14259 WDR4 Zornitza Stark Publications for gene: WDR4 were set to
Mendeliome v0.14257 WDR4 Zornitza Stark reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26416026, 30079490, 29597095, 28617965; Phenotypes: Galloway-Mowat syndrome 6, OMIM #618347, Microcephaly, growth deficiency, seizures, and brain malformations, OMIM #618346; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14256 WDR36 Zornitza Stark edited their review of gene: WDR36: Changed publications: 15677485, 18172102, 20813748, 34681019, 29540704
Mendeliome v0.14255 WDR36 Zornitza Stark Publications for gene: WDR36 were set to
Mendeliome v0.14253 WDR36 Zornitza Stark reviewed gene: WDR36: Rating: GREEN; Mode of pathogenicity: None; Publications: 15677485, 18172102, 20813748; Phenotypes: Glaucoma 1, open angle, G, MIM# 609887; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14252 WASHC5 Zornitza Stark Publications for gene: WASHC5 were set to
Mendeliome v0.14250 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17160902, 23455931, 30778698, 24065355, 33456446; Phenotypes: Ritscher-Schinzel syndrome 1, MIM# 220210, Spastic paraplegia 8, autosomal dominant, MIM# 603563; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14249 WASF1 Zornitza Stark Publications for gene: WASF1 were set to
Mendeliome v0.14247 WASF1 Zornitza Stark reviewed gene: WASF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961568, 34845217, 34478686, 34356165; Phenotypes: Neurodevelopmental disorder with absent language and variable seizures , MIM#618707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14246 WAC Zornitza Stark Publications for gene: WAC were set to
Mendeliome v0.14244 WAC Zornitza Stark reviewed gene: WAC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26264232, 25356899, 35266333; Phenotypes: Desanto-Shinawi syndrome, MIM# 616708; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14244 RNASEH1 Belinda Chong reviewed gene: RNASEH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26094573, 31258551; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 MIM#616479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14243 FXYD2 Bryony Thompson Publications for gene: FXYD2 were set to
Mendeliome v0.14239 FXYD2 Bryony Thompson reviewed gene: FXYD2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 17980699, 12763862, 18448590, 11062458, 25765846, 27014088; Phenotypes: Renal hypomagnesemia 2 MONDO:0007937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14238 RIPPLY2 Zornitza Stark Publications for gene: RIPPLY2 were set to
Mendeliome v0.14236 RIPPLY2 Zornitza Stark reviewed gene: RIPPLY2: Rating: ; Mode of pathogenicity: None; Publications: 25343988, 33410135, 32212228, 29761784; Phenotypes: Spondylocostal dysostosis 6, MIM# 616566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14235 MYOC Zornitza Stark Publications for gene: MYOC were set to
Mendeliome v0.14233 MYOC Zornitza Stark reviewed gene: MYOC: Rating: GREEN; Mode of pathogenicity: None; Publications: 9005853, 9535666, 15108121; Phenotypes: Glaucoma 1A, primary open angle, MIM# 137750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14231 MYOCD Zornitza Stark Publications for gene: MYOCD were set to
Mendeliome v0.14229 MYOCD Zornitza Stark reviewed gene: MYOCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31513549, 35005812; Phenotypes: Megabladder, congenital, MIM3 618719; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14228 MYOT Zornitza Stark Publications for gene: MYOT were set to
Mendeliome v0.14226 MYOT Zornitza Stark reviewed gene: MYOT: Rating: GREEN; Mode of pathogenicity: None; Publications: 10958653, 15111675, 16380616, 33250842, 32509353, 29924655; Phenotypes: Myopathy, myofibrillar, 3, MIM# 609200, Myopathy, spheroid body, MIM# 182920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14225 FXN Bryony Thompson Publications for gene: FXN were set to
Mendeliome v0.14223 FXN Bryony Thompson edited their review of gene: FXN: Added comment: Well-established gene-disease association. 96% of cases are caused by biallelic intronic GAA triplet repeat expansion and 4% are attributable to biallelic single nucleotide variants and small indels. Loss of function is the mechanism of disease.; Changed rating: GREEN; Changed publications: 20301458, 26704351; Changed phenotypes: Friedreich ataxia MONDO:0100339; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Mendeliome v0.14223 RNF139 Belinda Chong reviewed gene: RNF139: Rating: RED; Mode of pathogenicity: None; Publications: 9689122; Phenotypes: Renal cell carcinoma MIM#144700; Mode of inheritance: Other
Mendeliome v0.14222 FUT8 Bryony Thompson Publications for gene: FUT8 were set to
Mendeliome v0.14220 FUT8 Bryony Thompson reviewed gene: FUT8: Rating: GREEN; Mode of pathogenicity: None; Publications: 29304374, 34389986, 32049367, 16236725; Phenotypes: Congenital disorder of glycosylation with defective fucosylation 1 MONDO:0020775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14219 FUT1 Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants produce the Bombay blood group, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene.
Mendeliome v0.14218 FUT1 Bryony Thompson Publications for gene: FUT1 were set to
Mendeliome v0.14217 FUT1 Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants cause Bombay phenotype, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene.
Mendeliome v0.14215 FTO Bryony Thompson Publications for gene: FTO were set to
Mendeliome v0.14212 FTO Bryony Thompson reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234441, 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14211 RIMS1 Zornitza Stark Publications for gene: RIMS1 were set to
Mendeliome v0.14209 RIMS1 Zornitza Stark reviewed gene: RIMS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12659814, 25284784, 25961944; Phenotypes: Cone-rod dystrophy 7 , MIM#603649, Autism MONDO:0005260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14207 RHEB Zornitza Stark Publications for gene: RHEB were set to
Mendeliome v0.14205 RHEB Zornitza Stark reviewed gene: RHEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31337748, 29051493; Phenotypes: Neurodevelopmental disorder MONDO:0700092, RHEB-related, Intellectual disability, Macrocephaly, Focal cortical dysplasia; Mode of inheritance: Other
Mendeliome v0.14205 FSHR Bryony Thompson Publications for gene: FSHR were set to
Mendeliome v0.14203 FSHR Bryony Thompson reviewed gene: FSHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 16630814, 7553856, 9020851, 9769327, 20087398, 9854118, 12930928, 12930927, 17721928, 26911863; Phenotypes: Ovarian dysgenesis 1 MONDO:0024463, Ovarian hyperstimulation syndrome MONDO:0011972; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14202 RHCE Zornitza Stark Publications for gene: RHCE were set to
Mendeliome v0.14200 RHCE Zornitza Stark reviewed gene: RHCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 9657766, 16271106, 25413218; Phenotypes: Rh-null disease, amorph type, MIM# 617970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14199 RGS9BP Zornitza Stark Publications for gene: RGS9BP were set to
Mendeliome v0.14197 RGS9BP Zornitza Stark reviewed gene: RGS9BP: Rating: GREEN; Mode of pathogenicity: None; Publications: 14702087, 19818506; Phenotypes: Bradyopsia, MIM# 608415; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14196 RGS9 Zornitza Stark Publications for gene: RGS9 were set to
Mendeliome v0.14194 RGS9 Zornitza Stark reviewed gene: RGS9: Rating: GREEN; Mode of pathogenicity: None; Publications: 14702087, 10676965, 19818506; Phenotypes: Bradyopsia, MIM# 608415; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14194 RFX6 Zornitza Stark reviewed gene: RFX6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitchell-Riley syndrome, MIM# 615710; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14193 RFX6 Zornitza Stark Publications for gene: RFX6 were set to
Mendeliome v0.14190 FXYD6 Bryony Thompson Publications for gene: FXYD6 were set to
Mendeliome v0.14188 FXYD6 Bryony Thompson reviewed gene: FXYD6: Rating: RED; Mode of pathogenicity: None; Publications: 17357072, 26193471, 29895895; Phenotypes: Schizophrenia MONDO:0005090; Mode of inheritance: None
Mendeliome v0.14187 FZD2 Bryony Thompson Publications for gene: FZD2 were set to
Mendeliome v0.14185 FBP2 Zornitza Stark gene: FBP2 was added
gene: FBP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBP2 were set to 33977262
Phenotypes for gene: FBP2 were set to Leukodystrophy, childhood-onset, remitting, MIM# 619864
Review for gene: FBP2 was set to AMBER
Added comment: 8 individuals from 3 generations in a single family reported with a variant in this gene. The children presented with episode of regression and leukodystrophy in early childhood, from which they made a slow recovery. The adults had a broad range of neurobehavioural phenotypes but also had leukodystrophy on imaging. Some functional data presented (in vitro).
Sources: Expert list
Mendeliome v0.14183 TLR7 Zornitza Stark Publications for gene: TLR7 were set to 32706371
Mendeliome v0.14181 TLR7 Zornitza Stark edited their review of gene: TLR7: Added comment: SLE
XLD: only affected females reported; 4 individuals from three unrelated families. Mouse model.; Changed publications: 32706371, 35477763; Changed phenotypes: Immunodeficiency 74, COVID19-related, X-linked, MIM# 301051, Systemic lupus erythematosus 17, MIM# 301080; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.14180 MOV10L1 Zornitza Stark gene: MOV10L1 was added
gene: MOV10L1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MOV10L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOV10L1 were set to 35476666; 20534472
Phenotypes for gene: MOV10L1 were set to Spermatogenic failure 73, MIM#619878
Review for gene: MOV10L1 was set to AMBER
Added comment: Two unrelated individuals and a mouse model.
Sources: Expert list
Mendeliome v0.14177 RFC2 Zornitza Stark reviewed gene: RFC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.14176 REST Zornitza Stark Publications for gene: REST were set to
Mendeliome v0.14174 REST Zornitza Stark reviewed gene: REST: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961578, 34828371, 26551668, 28686854; Phenotypes: Deafness, autosomal dominant 27, MIM# 612431, {Wilms tumor 6, susceptibility to}, MIM# 616806, Fibromatosis, gingival, 5, MIM# 617626; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14173 REEP6 Zornitza Stark Publications for gene: REEP6 were set to
Mendeliome v0.14172 RP1 Belinda Chong reviewed gene: RP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10391211, 10465120, 10465120, 10484783, 29425069, 31213501; Phenotypes: Retinitis pigmentosa 1 MIM#180100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14171 REEP6 Zornitza Stark reviewed gene: REEP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 27889058, 33917198, 31538292, 29120066, 28475715; Phenotypes: Retinitis pigmentosa 77, MIM# 617304; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14170 RCBTB1 Zornitza Stark Publications for gene: RCBTB1 were set to
Mendeliome v0.14168 RCBTB1 Zornitza Stark reviewed gene: RCBTB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27486781, 35057699, 33624564, 33104391; Phenotypes: Retinal dystrophy with or without extraocular anomalies, MIM# 617175; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14167 FZD2 Bryony Thompson reviewed gene: FZD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25759469, 30455931, 29383834, 29230162; Phenotypes: Autosomal dominant omodysplasia MONDO:0008123; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14166 FSHB Bryony Thompson Publications for gene: FSHB were set to
Mendeliome v0.14164 FSHB Bryony Thompson reviewed gene: FSHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8220432, 9280841, 9624193, 9806482, 9271483, 16630814; Phenotypes: Hypogonadotropic hypogonadism 24 without anosmia MONDO:0009239; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14162 FRZB Bryony Thompson Publications for gene: FRZB were set to
Mendeliome v0.14160 FRRS1L Bryony Thompson Publications for gene: FRRS1L were set to
Mendeliome v0.14158 FRZB Bryony Thompson reviewed gene: FRZB: Rating: RED; Mode of pathogenicity: None; Publications: 15210948; Phenotypes: {Osteoarthritis susceptibility 1} MIM#165720; Mode of inheritance: Unknown
Mendeliome v0.14158 FRRS1L Bryony Thompson reviewed gene: FRRS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27236917, 27239025, 30692144; Phenotypes: Developmental and epileptic encephalopathy, 37 MONDO:0014859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14156 RBPJ Zornitza Stark Publications for gene: RBPJ were set to
Mendeliome v0.14154 RBPJ Zornitza Stark reviewed gene: RBPJ: Rating: GREEN; Mode of pathogenicity: None; Publications: 22883147, 29924900; Phenotypes: Adams-Oliver syndrome 3, MIM# 614814; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14154 FOXN1 Bryony Thompson Publications for gene: FOXN1 were set to
Mendeliome v0.14152 FOXN1 Bryony Thompson reviewed gene: FOXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10206641, 20978268, 20978268, 28636882, 31566583, 31447097; Phenotypes: T-cell immunodeficiency, congenital alopecia, and nail dystrophy MONDO:0011132; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14151 FOXI1 Bryony Thompson Publications for gene: FOXI1 were set to
Mendeliome v0.14149 FOXI1 Bryony Thompson reviewed gene: FOXI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843211, 12642503, 29242249, 17503324, 30268946, 27997596, 22285650, 23965030, 24860705, 32447495, 19204907; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14148 FOXD3 Bryony Thompson Publications for gene: FOXD3 were set to
Mendeliome v0.14146 FOXD3 Bryony Thompson reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: 16098053; Phenotypes: Autoimmune disease, susceptibility to, 1 MONDO:0011919; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14144 RBP3 Zornitza Stark Publications for gene: RBP3 were set to
Mendeliome v0.14142 RBP3 Zornitza Stark reviewed gene: RBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19074801, 29571629, 26066594, 25766589; Phenotypes: Retinitis pigmentosa 66, MIM# 615233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14141 RBM28 Zornitza Stark Publications for gene: RBM28 were set to
Mendeliome v0.14137 RASGRP2 Zornitza Stark Publications for gene: RASGRP2 were set to
Mendeliome v0.14135 RBM28 Crystle Lee reviewed gene: RBM28: Rating: AMBER; Mode of pathogenicity: None; Publications: 18439547, 33941690, 27077951; Phenotypes: Alopecia, neurologic defects, and endocrinopathy syndrome (MIM#612079); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14135 RASGRP2 Crystle Lee reviewed gene: RASGRP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28762304, 27663674, 28637664, 27235135; Phenotypes: Bleeding disorder, platelet-type, 18 (MIM#615888); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14135 SCN2A Zornitza Stark Publications for gene: SCN2A were set to
Mendeliome v0.14134 SCN2A Zornitza Stark edited their review of gene: SCN2A: Changed publications: 19786696, 23662938, 15028761, 30185235, 20956790, 24650168, 23935176, 22495306
Mendeliome v0.14128 SLC22A5 Zornitza Stark Publications for gene: SLC22A5 were set to
Mendeliome v0.14125 SLC22A12 Zornitza Stark Publications for gene: SLC22A12 were set to
Mendeliome v0.14122 SLC1A2 Zornitza Stark Publications for gene: SLC1A2 were set to
Mendeliome v0.14119 SLC1A2 Zornitza Stark reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27476654, 28777935, 30937933, 23934111; Phenotypes: Developmental and epileptic encephalopathy 41, MIM# 617105; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14118 SLC1A1 Zornitza Stark Publications for gene: SLC1A1 were set to
Mendeliome v0.14115 SLC1A1 Zornitza Stark reviewed gene: SLC1A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21123949; Phenotypes: Dicarboxylic aminoaciduria, MIM# 222730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14114 SLC19A3 Zornitza Stark Publications for gene: SLC19A3 were set to
Mendeliome v0.14112 SLC19A3 Zornitza Stark reviewed gene: SLC19A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15871139, 20065143, 23482991, 24878502, 23589815, 24166474, 26975589, 27896110; Phenotypes: Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), MIM# 607483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14111 SLC17A8 Zornitza Stark Publications for gene: SLC17A8 were set to
Mendeliome v0.14109 SLC17A8 Zornitza Stark reviewed gene: SLC17A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 18674745, 26797701, 28647561; Phenotypes: Deafness, autosomal dominant 25, MIM# 605583; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14108 SLC17A3 Zornitza Stark Publications for gene: SLC17A3 were set to
Mendeliome v0.14104 SLC16A1 Zornitza Stark Publications for gene: SLC16A1 were set to
Mendeliome v0.14102 SLC16A1 Zornitza Stark reviewed gene: SLC16A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25390740, 32170320; Phenotypes: Erythrocyte lactate transporter defect, MIM# 245340, Hyperinsulinemic hypoglycaemia, familial, 7, MIM# 610021, Monocarboxylate transporter 1 deficiency, MIM# 616095; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14101 SLC11A2 Zornitza Stark Publications for gene: SLC11A2 were set to
Mendeliome v0.14098 SH2D1A Zornitza Stark Publications for gene: SH2D1A were set to
Mendeliome v0.14096 SH2D1A Zornitza Stark reviewed gene: SH2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphoproliferative syndrome, X-linked, 1, MIM# 308240; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14095 SGCG Zornitza Stark Publications for gene: SGCG were set to
Mendeliome v0.14093 FMR1 Bryony Thompson Publications for gene: FMR1 were set to
Mendeliome v0.14090 FMR1 Bryony Thompson reviewed gene: FMR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8156595, 28176767, 29178241; Phenotypes: Fragile X syndrome MONDO:0010383; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.14090 FLVCR1 Bryony Thompson Publications for gene: FLVCR1 were set to
Mendeliome v0.14087 FLVCR1 Bryony Thompson edited their review of gene: FLVCR1: Added comment: At least 5 unrelated families reported with visual impairment and ataxia. Onset is usually in childhood.; Changed publications: 21070897, 22279524, 21267618; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; Set current diagnostic: yes
Mendeliome v0.14087 FLNC Bryony Thompson Publications for gene: FLNC were set to
Mendeliome v0.14085 FLNC Bryony Thompson reviewed gene: FLNC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15929027, 32112656; Phenotypes: Myofibrillar myopathy MONDO:0018943, Dilated cardiomyopathy MONDO:0005021, distal myopathy with posterior leg and anterior hand involvement MONDO:0013550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.14083 FLNB Bryony Thompson Publications for gene: FLNB were set to
Mendeliome v0.14081 FLNB Bryony Thompson reviewed gene: FLNB: Rating: GREEN; Mode of pathogenicity: None; Publications: 14991055, 17360453, 20301736, 29566257, 16801345, 22190451; Phenotypes: spondylocarpotarsal synostosis syndrome MONDO:0010094, osteochondrodysplasia MONDO:0005516; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14080 FLI1 Bryony Thompson Publications for gene: FLI1 were set to
Mendeliome v0.14078 FLI1 Bryony Thompson reviewed gene: FLI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10891501, 10981960, 24100448, 28255014, 26316623; Phenotypes: Bleeding disorder, platelet-type, 21 MONDO:0054577; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14077 FLG Bryony Thompson Publications for gene: FLG were set to
Mendeliome v0.14074 ASS1 Elena Savva Publications for gene: ASS1 were set to
Mendeliome v0.14072 FLG Bryony Thompson reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16444271, 19349982, 34608691; Phenotypes: Ichthyosis vulgaris MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14072 ASTN1 Elena Savva Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Mendeliome v0.14072 ASTN1 Elena Savva Publications for gene: ASTN1 were set to
Mendeliome v0.14069 FKTN Bryony Thompson Publications for gene: FKTN were set to
Mendeliome v0.14067 FKTN Bryony Thompson reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 9690476, 19017726, 20301385, 28680109; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14066 GSN Zornitza Stark Publications for gene: GSN were set to
Mendeliome v0.14064 GSN Zornitza Stark edited their review of gene: GSN: Changed publications: 2176164, 28139293
Mendeliome v0.14064 GSN Zornitza Stark reviewed gene: GSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 2176164; Phenotypes: Amyloidosis, Finnish type, MIM# 105120; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.14063 GSS Zornitza Stark Publications for gene: GSS were set to
Mendeliome v0.14061 GSS Zornitza Stark reviewed gene: GSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9215686; Phenotypes: Glutathione synthetase deficiency, MIM# 266130, Haemolytic anemia due to glutathione synthetase deficiency 231900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14060 GTF3C3 Zornitza Stark Publications for gene: GTF3C3 were set to
Mendeliome v0.14058 GTF3C3 Zornitza Stark reviewed gene: GTF3C3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 28097321, 30552426; Phenotypes: Neurodevelopmental disorder MONDO:0700092, GTF3C3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14057 GUCA1A Zornitza Stark Publications for gene: GUCA1A were set to
Mendeliome v0.14055 GUCA1A Zornitza Stark reviewed gene: GUCA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9425234, 15953638, 11146732, 28125083; Phenotypes: Cone dystrophy-3, MIM# 602093, Cone-rod dystrophy 14, MIM# 602093; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14055 ASB10 Elena Savva Publications for gene: ASB10 were set to PMID: 26713451; 22156576
Mendeliome v0.14054 ASB10 Elena Savva Publications for gene: ASB10 were set to
Mendeliome v0.14053 ASB10 Elena Savva reviewed gene: ASB10: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 26713451, 22156576; Phenotypes: Glaucoma 1, open angle, F MIM#603383; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14052 FKRP Bryony Thompson Publications for gene: FKRP were set to
Mendeliome v0.14049 FKRP Bryony Thompson reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 11592034, 11741828, 14647208, 19299310, 19155270; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14048 ART4 Elena Savva Publications for gene: ART4 were set to
Mendeliome v0.14047 ART4 Elena Savva reviewed gene: ART4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33675039, 33206405; Phenotypes: {Macular degeneration, age-related, 8} MIM#613778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14045 ASPA Elena Savva Publications for gene: ASPA were set to
Mendeliome v0.14044 ASPA Elena Savva reviewed gene: ASPA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Canavan disease MIM#271900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14043 FHL1 Bryony Thompson Publications for gene: FHL1 were set to
Mendeliome v0.14041 ASH1L Elena Savva Publications for gene: ASH1L were set to 23033978; 25961944; 28394464; 28191889; 27824329
Mendeliome v0.14039 FHL1 Bryony Thompson reviewed gene: FHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19716112, 20186852, 20301609, 18179901, 25274776, 34366191, 18274675, 19181672; Phenotypes: Reducing body myopathy MONDO:0019948, X-linked Emery-Dreifuss muscular dystrophy MONDO:0010680; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.14038 ASH1L Elena Savva Publications for gene: ASH1L were set to
Mendeliome v0.14037 ARMS2 Elena Savva reviewed gene: ARMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Macular degeneration, age-related, 8} MIM#613778; Mode of inheritance: Unknown
Mendeliome v0.14037 ARL2BP Elena Savva Publications for gene: ARL2BP were set to PMID: 23849777; 27790702; 29718757
Mendeliome v0.14036 ARL2BP Elena Savva Publications for gene: ARL2BP were set to
Mendeliome v0.14034 ARL2BP Elena Savva reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa with or without situs inversus MIM#615434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14033 FH Bryony Thompson Publications for gene: FH were set to
Mendeliome v0.14031 FH Bryony Thompson changed review comment from: Well established gene-disease associations. Loss of function is the mechanism of disease. Monoallelic variants associated with decreased fumarate hydratase enzyme activity cause FH tumour predisposition syndrome (also known as HLRCC; PMID: 11865300, 28300276). FH deficiency (also known as fumarase deficiency or fumaric aciduria) caused by biallelic variants results in severe neonatal and early infantile encephalopathy (PMID: 8200987, 20549362, 31746132). FH encodes for both mitochondrial and cytosolic FH enzyme isoforms, which catalyze hydration of fumarate to malate.; to: Well established gene-disease associations. Loss of function is the mechanism of disease. Monoallelic variants associated with decreased fumarate hydratase enzyme activity cause FH tumour predisposition syndrome (also known as HLRCC; PMID: 11865300, 28300276, 20301430). FH deficiency (also known as fumarase deficiency or fumaric aciduria) caused by biallelic variants results in severe neonatal and early infantile encephalopathy (PMID: 8200987, 20549362, 31746132, 20301679). FH encodes for both mitochondrial and cytosolic FH enzyme isoforms, which catalyze hydration of fumarate to malate.
Mendeliome v0.14031 FH Bryony Thompson edited their review of gene: FH: Changed publications: 11865300, 28300276, 20301430, 8200987, 20549362, 31746132, 20301679
Mendeliome v0.14031 FH Bryony Thompson reviewed gene: FH: Rating: GREEN; Mode of pathogenicity: None; Publications: 11865300, 28300276, 8200987, 20549362, 31746132; Phenotypes: hereditary leiomyomatosis and renal cell cancer MONDO:0007888, fumaric aciduria MONDO:0011730; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14029 ARID1B Elena Savva reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome 1 MIM#135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14028 FGG Bryony Thompson Publications for gene: FGG were set to
Mendeliome v0.14026 ARHGDIA Elena Savva Publications for gene: ARHGDIA were set to PMID: 23867502; 35060086
Mendeliome v0.14024 FGG Bryony Thompson reviewed gene: FGG: Rating: GREEN; Mode of pathogenicity: None; Publications: 2713997, 11001902, 11001903, 9746756, 23560673, 28992465, 10980108, 15304068; Phenotypes: congenital fibrinogen deficiency MONDO:0018060; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.14023 FGFR3 Bryony Thompson Publications for gene: FGFR3 were set to 26740388; 20301331; 20301540; 20301650; 20301628; 24864036; 17033969
Mendeliome v0.14020 FGFR3 Bryony Thompson changed review comment from: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome where bialellic loss-of-function is the expected mechanism of disease. Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.; to: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome (CATSHL syndrome, see separate curation below). Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.
Moderate evidence for CATSHL syndrome, AD & AR: PMID: 8630492, 17033969, 27139183, 24864036, 32641982 - 2 apparently unrelated families segregating the same missense, p.Arg621His. One consanguineous family with 2 affected brothers with homozygous p.Thr546Lys. Heterozygous individuals in the family were unaffected. No functional assays were conducted for either missense to demonstrate loss of function. Null mouse and zebrafish models are similar to the human CATSHL syndrome phenotype.
Mendeliome v0.14019 GUCA1B Zornitza Stark Publications for gene: GUCA1B were set to
Mendeliome v0.14016 FGFR3 Bryony Thompson edited their review of gene: FGFR3: Changed mode of pathogenicity: Other; Changed publications: 8630492, 32641982, 27139183, 24864036, 17033969, 20301331, 20301540, 20301650, 20301628; Changed phenotypes: achondroplasia MONDO:0007037, Thanatophoric dysplasia type 1 MONDO:0008546, Thanatophoric dysplasia type 2 MONDO:0008547, hypochondroplasia MONDO:0007793, Muenke syndrome MONDO:0011274, FGFR3-related chondrodysplasia MONDO:0019685, severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658, Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833, camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14016 GUCA1B Zornitza Stark reviewed gene: GUCA1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 15452722, 26161267; Phenotypes: Retinitis pigmentosa 48, MIM# 613827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14015 GUCY1A3 Zornitza Stark Publications for gene: GUCY1A3 were set to
Mendeliome v0.14013 GUCY1A3 Zornitza Stark reviewed gene: GUCY1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24581742, 26777256, 34381413, 33109895; Phenotypes: Moyamoya 6 with achalasia, MIM# 615750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14012 GYG1 Zornitza Stark Publications for gene: GYG1 were set to
Mendeliome v0.14010 GYG1 Zornitza Stark reviewed gene: GYG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32905144, 31791869, 29422440, 25272951, 20357282; Phenotypes: Polyglucosan body myopathy 2, MIM# 616199, Glycogen storage disease XV , MIM# 613507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14009 GUCY2D Zornitza Stark Publications for gene: GUCY2D were set to
Mendeliome v0.14007 GUCY2D Zornitza Stark reviewed gene: GUCY2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314386, 35205358; Phenotypes: Cone-rod dystrophy 6, MIM# 601777, Leber congenital amaurosis 1, MIM# 204000, Night blindness, congenital stationary, type 1I, MIM# 618555; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14005 ARHGEF18 Elena Savva Publications for gene: ARHGEF18 were set to
Mendeliome v0.14004 ARHGEF18 Elena Savva reviewed gene: ARHGEF18: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28132693; Phenotypes: Retinitis pigmentosa 78 MIM#617433; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14004 ARHGDIA Elena Savva Publications for gene: ARHGDIA were set to
Mendeliome v0.14003 ARHGDIA Elena Savva reviewed gene: ARHGDIA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23867502, 35060086; Phenotypes: Nephrotic syndrome, type 8 MIM#615244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14002 ARHGAP31 Elena Savva Publications for gene: ARHGAP31 were set to
Mendeliome v0.14000 ARHGAP31 Elena Savva reviewed gene: ARHGAP31: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33655927, 29924900; Phenotypes: Adams-Oliver syndrome 1, MIM#100300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13999 ANXA5 Elena Savva Publications for gene: ANXA5 were set to
Mendeliome v0.13994 GYPA Zornitza Stark reviewed gene: GYPA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Blood group, MNSs system] 111300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13991 GYPB Zornitza Stark reviewed gene: GYPB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Blood group, Ss] 111740; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13991 HAAO Zornitza Stark reviewed gene: HAAO: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942433; Phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 DSE Krithika Murali reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 23704329, 25703627, 32130795; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 2 - MIM#615539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 DSG4 Krithika Murali reviewed gene: DSG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12705872, 16439973, 16543896, 16575393, 17392831; Phenotypes: Hypotrichosis 6 - MIM#607903; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 DSPP Krithika Murali reviewed gene: DSPP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal dominant 39, with dentinogenesis - MIM#605594, Dentin dysplasia, type II - MIM#125420, Dentinogenesis imperfecta, Shields type II - MIM#125490, Dentinogenesis imperfecta, Shields type III - MIM#125500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13991 DUOX2 Krithika Murali reviewed gene: DUOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thyroid dyshormonogenesis 6 - MIM#607200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 DUOXA2 Krithika Murali reviewed gene: DUOXA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thyroid dyshormonogenesis 5 - MIM#274900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 RP2 Belinda Chong reviewed gene: RP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9697692, 10053026, 10942419, 11462235, 12417528, 8225316, 26143542; Phenotypes: Retinitis pigmentosa 2 MIM#312600; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.13991 RP9 Belinda Chong reviewed gene: RP9: Rating: RED; Mode of pathogenicity: None; Publications: 16799052, 16671097; Phenotypes: ?Retinitis pigmentosa 9 MIM#180104; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13989 LZTS1 Alison Yeung reviewed gene: LZTS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Esophageal squamous cell carcinoma, somatic, MIM# 133239; Mode of inheritance: Unknown
Mendeliome v0.13988 LYZ Alison Yeung Publications for gene: LYZ were set to
Mendeliome v0.13978 LTC4S Alison Yeung reviewed gene: LTC4S: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukotriene C4 synthase deficiency, MIM# 614037; Mode of inheritance: Other
Mendeliome v0.13975 LTA Alison Yeung reviewed gene: LTA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myocardial infarction, susceptibility to, MIM# 608446; Mode of inheritance: Other
Mendeliome v0.13969 LRIG2 Alison Yeung Publications for gene: LRIG2 were set to 23313374; 27855655; 30885509
Mendeliome v0.13969 LRIG2 Alison Yeung Publications for gene: LRIG2 were set to
Mendeliome v0.13967 LRIG2 Alison Yeung reviewed gene: LRIG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23313374, 27855655, 30885509; Phenotypes: Urofacial syndrome 2, MIM# 615112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13966 FGFR3 Bryony Thompson Publications for gene: FGFR3 were set to
Mendeliome v0.13964 FGFR3 Bryony Thompson reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26740388, 20301331, 20301540, 20301650, 20301628, 24864036, 17033969; Phenotypes: achondroplasia MONDO:0007037, Thanatophoric dysplasia type 1 MONDO:0008546, Thanatophoric dysplasia type 2 MONDO:0008547, hypochondroplasia MONDO:0007793, Muenke syndrome MONDO:0011274, FGFR3-related chondrodysplasia MONDO:0019685, severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658, camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504, Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13963 DNAJB6 Ain Roesley Publications for gene: DNAJB6 were set to
Mendeliome v0.13962 DNAJB6 Ain Roesley reviewed gene: DNAJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26847086, 26338452, 24170373; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 1 MIM#603511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13960 DNAH1 Ain Roesley Publications for gene: DNAH1 were set to
Mendeliome v0.13958 DNAH1 Ain Roesley reviewed gene: DNAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31507630, 31765523, 25927852, 24360805, 33577779; Phenotypes: primary ciliary dyskinesia,37 MIM#617577, Spermatogenic failure 18 MIM#617576; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13957 DNA2 Ain Roesley Publications for gene: DNA2 were set to
Mendeliome v0.13956 DNA2 Ain Roesley reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 31045292, 23352259, 25635128, 28554558; Phenotypes: Seckel syndrome 8, MIM#615807, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 MIM#615156; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13956 DMP1 Ain Roesley Publications for gene: DMP1 were set to
Mendeliome v0.13955 DMP1 Ain Roesley reviewed gene: DMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32920683, 17033625, 17033621; Phenotypes: Hypophosphatemic rickets MIM#241520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13953 DMD Ain Roesley Publications for gene: DMD were set to
Mendeliome v0.13952 DMD Ain Roesley reviewed gene: DMD: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301298; Phenotypes: Becker muscular dystrophy MIM@300376 XLR, Cardiomyopathy, dilated, 3B MIM#302045 XL, Duchenne muscular dystrophy MIM#310200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.13952 DLX3 Ain Roesley Publications for gene: DLX3 were set to
Mendeliome v0.13951 DLX3 Ain Roesley reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467018, 15666299, 18203197; Phenotypes: Amelogenesis imperfecta, type IV, MIM# 104510, Trichodontoosseous syndrome, MIM# 190320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13951 DLAT Ain Roesley Publications for gene: DLAT were set to
Mendeliome v0.13949 DLAT Ain Roesley reviewed gene: DLAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 34138529; Phenotypes: Pyruvate dehydrogenase E2 deficiency MIM#245348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13949 SLC22A12 Manny Jacobs reviewed gene: SLC22A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 14655203, 34412930, 34756726, 34829836, 26821810; Phenotypes: Hypouricemia, renal, MIM# 220150, MONDO:0020728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13949 DISC1 Ain Roesley Publications for gene: DISC1 were set to
Mendeliome v0.13948 DISC1 Ain Roesley reviewed gene: DISC1: Rating: RED; Mode of pathogenicity: None; Publications: 18945897; Phenotypes: {Schizophrenia 9, susceptibility to} MIM#604906; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13946 LPL Alison Yeung reviewed gene: LPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined hyperlipidemia, familial, MIM# 144250, Lipoprotein lipase deficiency, MIM# 238600; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13946 DHTKD1 Ain Roesley Publications for gene: DHTKD1 were set to
Mendeliome v0.13941 LPAR6 Alison Yeung reviewed gene: LPAR6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Woolly hair, autosomal recessive 1, with or without hypotrichosis, MIM# 609239; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13937 LOXL1 Alison Yeung reviewed gene: LOXL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Exfoliation syndrome, susceptibility to, MIM#177650; Mode of inheritance: Other
Mendeliome v0.13935 LMF1 Alison Yeung reviewed gene: LMF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipase deficiency, combined, MIM# 246650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13934 LMBRD1 Alison Yeung Publications for gene: LMBRD1 were set to
Mendeliome v0.13930 LMBR1 Alison Yeung reviewed gene: LMBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Laurin-Sandrow syndrome, MIM# 135750, Polydactyly, preaxial type II 174500, Triphalangeal thumb, type I, MIM# 174500, Syndactyly, type IV, MIM# 186200, Acheiropody, MIM# 200500, Triphalangeal thumb-polysyndactyly syndrome, MIM# 174500, Hypoplastic or aplastic tibia with polydactyly, MIM# 188740; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13930 SLC17A3 Samantha Ayres reviewed gene: SLC17A3: Rating: RED; Mode of pathogenicity: None; Publications: 34290818, 20810651; Phenotypes: [Uric acid concentration, serum, QTL4], MIM# 612671, {Gout susceptibility 4}, MIM#612671; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13930 SLC22A5 Manny Jacobs reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916797, 10072434, 10051646, 10425211, 10480371, 10679939, 9837751, 23379544, 31399326; Phenotypes: Carnitine deficiency, systemic primary, MIM# 212140, MONDO:0008919; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13929 CYP27B1 Ain Roesley Publications for gene: CYP27B1 were set to
Mendeliome v0.13928 CYP27B1 Ain Roesley reviewed gene: CYP27B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9486994, 9415400, 12050193, 27473561, 34492747, 33823104; Phenotypes: Vitamin D-dependent rickets, type I MIM#264700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13928 CYP51A1 Ain Roesley Phenotypes for gene: CYP51A1 were changed from to congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome MONDO#0033853
Mendeliome v0.13927 CYP51A1 Ain Roesley Publications for gene: CYP51A1 were set to
Mendeliome v0.13925 CYP4V2 Ain Roesley Publications for gene: CYP4V2 were set to
Mendeliome v0.13924 CYP4V2 Ain Roesley reviewed gene: CYP4V2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15042513, 22497028; Phenotypes: Bietti crystalline corneoretinal dystrophy, MIM# 210370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13924 CYP2R1 Ain Roesley Publications for gene: CYP2R1 were set to 15128933; 28548312
Mendeliome v0.13923 CYP2R1 Ain Roesley Publications for gene: CYP2R1 were set to
Mendeliome v0.13922 CYP2R1 Ain Roesley reviewed gene: CYP2R1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15128933, 28548312; Phenotypes: Rickets due to defect in vitamin D 25-hydroxylation deficiency MIM#600081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13921 CYP2D6 Ain Roesley Publications for gene: CYP2D6 were set to
Mendeliome v0.13920 CYP2D6 Ain Roesley reviewed gene: CYP2D6: Rating: RED; Mode of pathogenicity: None; Publications: 18406467, 24458010; Phenotypes: {Codeine sensitivity} MIM#608902, {Debrisoquine sensitivity} MIM#608902; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13918 DGUOK Zornitza Stark Publications for gene: DGUOK were set to
Mendeliome v0.13916 DGUOK Zornitza Stark reviewed gene: DGUOK: Rating: GREEN; Mode of pathogenicity: None; Publications: 11687800, 12874104, 15887277, 23043144, 26874653; Phenotypes: Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880, Portal hypertension, noncirrhotic, 1, MIM# 617068, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13915 DGKE Zornitza Stark Publications for gene: DGKE were set to
Mendeliome v0.13913 DGKE Zornitza Stark reviewed gene: DGKE: Rating: GREEN; Mode of pathogenicity: None; Publications: 23274426, 23542698; Phenotypes: Nephrotic syndrome, type 7, MIM# 615008; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13912 DES Zornitza Stark Publications for gene: DES were set to
Mendeliome v0.13911 DES Zornitza Stark reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: None; Publications: 20718792, 19879535, 20423733, 24200904, 22395865, 29212896, 23168288, 20829228, 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 33947203; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765, Myopathy, myofibrillar, 1 , MIM#601419, Arrhythmogenic right ventricular cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13910 DEPDC5 Zornitza Stark Publications for gene: DEPDC5 were set to
Mendeliome v0.13908 DEPDC5 Zornitza Stark reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444548, 23542697, 23542701; Phenotypes: Epilepsy, familial focal, with variable foci 1 MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13907 DECR1 Zornitza Stark reviewed gene: DECR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13906 DDIT3 Zornitza Stark reviewed gene: DDIT3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13905 DDHD2 Zornitza Stark Publications for gene: DDHD2 were set to
Mendeliome v0.13903 DDHD2 Zornitza Stark reviewed gene: DDHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23486545, 24482476, 23176823, 31302745; Phenotypes: Spastic paraplegia 54, autosomal recessive, MIM# 615033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13902 DDC Zornitza Stark Publications for gene: DDC were set to
Mendeliome v0.13900 DDC Zornitza Stark reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 20505134, 30952622; Phenotypes: Aromatic L-amino acid decarboxylase deficiency, MIM# 608643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13899 DDB2 Zornitza Stark Publications for gene: DDB2 were set to
Mendeliome v0.13898 AQP3 Elena Savva Publications for gene: AQP3 were set to
Mendeliome v0.13896 AQP3 Elena Savva reviewed gene: AQP3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 10737773, 12239222; Phenotypes: [Blood group GIL] MIM#607457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13895 DDB2 Zornitza Stark reviewed gene: DDB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33276309, 32530099, 32239545, 32228487; Phenotypes: Xeroderma pigmentosum, group E, DDB-negative subtype, MIM# 278740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13894 DCTN1 Zornitza Stark Publications for gene: DCTN1 were set to
Mendeliome v0.13892 AQP5 Elena Savva Publications for gene: AQP5 were set to PMID: 35014096; 23830519
Mendeliome v0.13891 AQP5 Elena Savva Publications for gene: AQP5 were set to
Mendeliome v0.13890 AQP5 Elena Savva reviewed gene: AQP5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35014096, 23830519; Phenotypes: Palmoplantar keratoderma, Bothnian type MIM#600231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13890 AR Elena Savva Publications for gene: AR were set to
Mendeliome v0.13888 AR Elena Savva reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22334387; Phenotypes: Hypospadias 1, X-linked MIM#30063, Androgen insensitivity MIM#300068, Androgen insensitivity, partial, with or without breast cancer MIM#312300, Spinal and bulbar muscular atrophy of Kennedy MIM#313200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13887 DCLRE1C Zornitza Stark Publications for gene: DCLRE1C were set to
Mendeliome v0.13885 DCLRE1C Zornitza Stark reviewed gene: DCLRE1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19953608, 15699179, 12055248, 34220820; Phenotypes: Severe combined immunodeficiency, Athabascan type MIM# 602450, Omenn syndrome, MIM# 603554; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13883 DCHS1 Zornitza Stark Publications for gene: DCHS1 were set to
Mendeliome v0.13881 DCHS1 Zornitza Stark reviewed gene: DCHS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27262615, 22473091, 24056717, 29046692; Phenotypes: Van Maldergem syndrome 1, MIM# 601390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13880 APPL1 Elena Savva Publications for gene: APPL1 were set to
Mendeliome v0.13879 AQP1 Elena Savva Publications for gene: AQP1 were set to PMID:22683574; 29650961
Mendeliome v0.13877 AQP1 Elena Savva Publications for gene: AQP1 were set to
Mendeliome v0.13875 AQP1 Elena Savva reviewed gene: AQP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:22683574, 29650961; Phenotypes: Pulmonary arterial hypertension; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13875 APRT Elena Savva Publications for gene: APRT were set to
Mendeliome v0.13873 APOC4-APOC2 Elena Savva Publications for gene: APOC4-APOC2 were set to
Mendeliome v0.13872 APRT Elena Savva reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 3680503, 2227934, 7915931, 1353080; Phenotypes: Adenine phosphoribosyltransferase deficiency MIM#614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13871 APOC4-APOC2 Elena Savva reviewed gene: APOC4-APOC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 31034468; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13870 APOC3 Elena Savva Publications for gene: APOC3 were set to PMID: 19074352
Mendeliome v0.13869 APOC2 Elena Savva Publications for gene: APOC2 were set to
Mendeliome v0.13868 APOC2 Elena Savva reviewed gene: APOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32562799, 26044956, 32292609, 32280258; Phenotypes: Hyperlipoproteinemia, type Ib MIM#207750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13868 APOC3 Elena Savva Publications for gene: APOC3 were set to
Mendeliome v0.13865 APOC3 Elena Savva reviewed gene: APOC3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 19074352; Phenotypes: Apolipoprotein C-III deficiency MIM#614028; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13865 ANXA5 Elena Savva reviewed gene: ANXA5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 17339269, 12665588, 34878150; Phenotypes: {Pregnancy loss, recurrent, susceptibility to, 3} MIM#614391; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13864 CCDC50 Zornitza Stark Publications for gene: CCDC50 were set to 17503326; 27911912
Mendeliome v0.13862 CCDC50 Zornitza Stark reviewed gene: CCDC50: Rating: AMBER; Mode of pathogenicity: None; Publications: 17503326, 27911912, 24875298; Phenotypes: Deafness, autosomal dominant 44 MIM#607453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13861 KCNJ2 Ain Roesley Publications for gene: KCNJ2 were set to
Mendeliome v0.13860 KCNJ2 Ain Roesley edited their review of gene: KCNJ2: Changed publications: 24383070
Mendeliome v0.13859 DCAF17 Zornitza Stark Publications for gene: DCAF17 were set to
Mendeliome v0.13857 DCAF17 Zornitza Stark reviewed gene: DCAF17: Rating: GREEN; Mode of pathogenicity: None; Publications: 19026396, 20507343, 35002959, 34877714, 34732557, 34590781; Phenotypes: Woodhouse-Sakati syndrome, MIM# 241080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13857 CYP2C19 Ain Roesley Publications for gene: CYP2C19 were set to
Mendeliome v0.13856 CYP2C19 Ain Roesley reviewed gene: CYP2C19: Rating: GREEN; Mode of pathogenicity: None; Publications: 27981572, 26616742, 31549386, 31549389; Phenotypes: Voriconazole; Mode of inheritance: Other; Current diagnostic: yes
Mendeliome v0.13854 CYP2B6 Ain Roesley reviewed gene: CYP2B6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Efavirenz, poor metabolism of MIM#614546; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13853 DAZ4 Zornitza Stark reviewed gene: DAZ4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13852 DAZ3 Zornitza Stark reviewed gene: DAZ3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13851 CYP2A6 Ain Roesley reviewed gene: CYP2A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coumarin resistance MIM#122700; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13850 DAZ2 Zornitza Stark reviewed gene: DAZ2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13849 DAZ1 Zornitza Stark reviewed gene: DAZ1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13847 CYP27A1 Ain Roesley Publications for gene: CYP27A1 were set to
Mendeliome v0.13845 DARS2 Zornitza Stark Publications for gene: DARS2 were set to
Mendeliome v0.13843 CYP26C1 Ain Roesley Publications for gene: CYP26C1 were set to
Mendeliome v0.13842 CYP26C1 Ain Roesley reviewed gene: CYP26C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29263414, 23161670, 16530710; Phenotypes: Focal facial dermal dysplasia 4 MIM#614974; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13842 DARS2 Zornitza Stark reviewed gene: DARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17384640, 15002045, 16788019; Phenotypes: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13841 D2HGDH Zornitza Stark Publications for gene: D2HGDH were set to
Mendeliome v0.13839 D2HGDH Zornitza Stark reviewed gene: D2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 25778941, 31349060, 15609246, 20020533; Phenotypes: D-2-hydroxyglutaric aciduria MIM#600721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13838 CYP7B1 Zornitza Stark Publications for gene: CYP7B1 were set to
Mendeliome v0.13835 CYP1A2 Ain Roesley reviewed gene: CYP1A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13833 CYP19A1 Ain Roesley Publications for gene: CYP19A1 were set to
Mendeliome v0.13832 CYP19A1 Ain Roesley reviewed gene: CYP19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13831 CYCS Ain Roesley Publications for gene: CYCS were set to
Mendeliome v0.13830 CYCS Ain Roesley reviewed gene: CYCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24326104, 18345000, 30051457; Phenotypes: Thrombocytopenia 4, MIM# 612004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13827 CYC1 Ain Roesley Publications for gene: CYC1 were set to
Mendeliome v0.13826 CYC1 Ain Roesley reviewed gene: CYC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910460, 34252606; Phenotypes: Mitochondrial complex III deficiency, nuclear type 6 MIM#615453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13822 DTYMK Zornitza Stark Publications for gene: DTYMK were set to 31271740
Mendeliome v0.13819 CREB1 Zornitza Stark reviewed gene: CREB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Agenesis of corpus callosum, MONDO:0009022; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13819 SLC16A12 Zornitza Stark Phenotypes for gene: SLC16A12 were changed from to Cataract 47, juvenile, with microcornea, MIM# 612018
Mendeliome v0.13818 SLC16A12 Zornitza Stark Publications for gene: SLC16A12 were set to
Mendeliome v0.13815 SLC14A1 Zornitza Stark Publications for gene: SLC14A1 were set to
Mendeliome v0.13811 SLC12A5 Zornitza Stark Publications for gene: SLC12A5 were set to
Mendeliome v0.13808 DUSP6 Zornitza Stark Publications for gene: DUSP6 were set to
Mendeliome v0.13804 DYRK1B Zornitza Stark Publications for gene: DYRK1B were set to
Mendeliome v0.13801 COL27A1 Zornitza Stark reviewed gene: COL27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Steel syndrome MIM #615155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13799 DTYMK Daniel Flanagan reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: 34918187, 31271740; Phenotypes: Neurodegeneration, childhood-onset, with progressive microcephaly (MIM# 619847); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13799 NRG1 Alison Yeung Added comment: Comment on list classification: Red for peripheral neuropathy (single family reported)
Amber for Hirschsprung disease
Mendeliome v0.13798 KLF4 Elena Savva gene: KLF4 was added
gene: KLF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KLF4 were set to PMID: 35168889; 10431239
Phenotypes for gene: KLF4 were set to Hereditary palmoplantar keratoderma MONDO:0019272, KFL4-related
Review for gene: KLF4 was set to GREEN
Added comment: PMID: 35168889 - 3 patients from 2 unrelated families with palmoplantar keratoderma. Two variants found, fs and a missense.
Functional studies on patient skin biopsy shows "slightly but significantly decreased" protein expression in both children.
Gene was shown to bind the DSG1 promoter and regulate expression. Transfected cells showed reduced DSG1 expression.

PMID: 10431239 - mouse K/O died shortly after birth due to loss of skin barrier function

gnomAD: single het fs in the population
Sources: Literature
Mendeliome v0.13798 P3H2 Zornitza Stark Publications for gene: P3H2 were set to 21885030; 24172257; 25469533
Mendeliome v0.13797 HNRNPA2B1 Naomi Baker reviewed gene: HNRNPA2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:35484142; Phenotypes: oculopharyngeal muscular dystrophy, MONDO:0008116; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13796 P3H2 Daniel Flanagan reviewed gene: P3H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35499085; Phenotypes: Myopia, high, with cataract and vitreoretinal degeneration (MIM# 614292); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13796 CDH4 Ain Roesley gene: CDH4 was added
gene: CDH4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDH4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH4 were set to 35034853
Phenotypes for gene: CDH4 were set to coloboma MONDO#0001476, CDH4-related
Review for gene: CDH4 was set to RED
gene: CDH4 was marked as current diagnostic
Added comment: 1x family with AD coloboma

Also presented with ID and post natal microcephaly

zebrafish KO model
Sources: Literature
Mendeliome v0.13795 NRG1 Lucy Spencer reviewed gene: NRG1: Rating: RED; Mode of pathogenicity: None; Publications: 35485770; Phenotypes: Peripheral neuropathy MONDO:0005244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13794 PDGFRA Ain Roesley Publications for gene: PDGFRA were set to 14699510; 17087943; 25975287; 29486293; 33449152; 34107389; 17566086; 18670346
Mendeliome v0.13793 PDGFRA Ain Roesley reviewed gene: PDGFRA: Rating: RED; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, PDGFRA-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13792 CD164 Alison Yeung gene: CD164 was added
gene: CD164 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CD164 were set to 26197441; 35254497; 26197441
Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66, MIM# 616969
Review for gene: CD164 was set to GREEN
Added comment: p.(Arg192Ter), a truncating variant that results in loss of 6 amino acids, was detected in two families (one Polish and one Korean) with hearing loss. Four affected (heterozygous) and two unaffected (neg) were tested, however 14 members had been diagnosed with HL in a large multi generational family (gene panel 237 genes). The second family (WES) had two affected heterozygous and no unaffected were tested. This same variant had previously been reported in a Danish family (12 affected heterozygous and 13 unaffected negative, but one younger member unaffected are heterozygous) with hearing loss (PMID: 26197441), for which functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments. The YHTL motif, deleted by the c.574C>T nonsense mutation, is a canonical sorting motif
known to be recognized by specific adaptor proteins in the cytosol, leading to subcellular trafficking of the transmembrane protein to endosomes and lysosomes.
Sources: Literature
Mendeliome v0.13791 CTR9 Dean Phelan gene: CTR9 was added
gene: CTR9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTR9 were set to PMID: 35499524
Phenotypes for gene: CTR9 were set to Neurodevelopmental disorder (MONDO:0700092), CTR9 related; Intellectual disability (MONDO:0001071); hypotonia (HP:0001252); joint hyperlaxity (HP:0001388); speech delay; coordination problems; tremor (HP:0001337); autism spectrum disorder (MONDO:0005258)
Review for gene: CTR9 was set to GREEN
Added comment: PMID: 35499524 - Thirteen individuals with variables degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. Eleven of the variants were shown to be de novo.
Sources: Literature
Mendeliome v0.13790 BMPR1B Ain Roesley Publications for gene: BMPR1B were set to 15805157; 24129431; 26105076; 25758993; 14523231; 14523231
Mendeliome v0.13789 BMPR1B Ain Roesley reviewed gene: BMPR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, BMPR1B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13789 DNAH14 Chern Lim gene: DNAH14 was added
gene: DNAH14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to PMID: 35438214
Phenotypes for gene: DNAH14 were set to Neurodevelopmental disorder, DNAH14-related (MONDO#0700092)
Review for gene: DNAH14 was set to GREEN
gene: DNAH14 was marked as current diagnostic
Added comment: PMID: 35438214:
- Three previously unreported patients with compound heterozygous DNAH14 variants, including one nonsense, one frameshift, and four missense variants. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia.
Sources: Literature
Mendeliome v0.13788 ANK3 Ain Roesley Publications for gene: ANK3 were set to 23390136; 28687526; 34218362
Mendeliome v0.13787 TULP3 Anna Ritchie gene: TULP3 was added
gene: TULP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP3 were set to PMID: 35397207
Phenotypes for gene: TULP3 were set to progressive degenerative liver fibrosis with variable fibrocystic kidney disease; hypertrophic cardiomyopathy MONDO:0005045
Review for gene: TULP3 was set to GREEN
Added comment: 15 individuals from eight unrelated families with bi-allelic variants in TULP3 were detected. The affected individuals reported are mostly adults, in the 3rd through 7th decades of life, and presented with progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy.

The human phenotype was ecapitulated in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals
Sources: Literature
Mendeliome v0.13787 ANK3 Ain Roesley reviewed gene: ANK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 35034853; Phenotypes: coloboma MONDO#0001476, ANK3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13787 PRDM13 Zornitza Stark Publications for gene: PRDM13 were set to 30710461; 34730112
Mendeliome v0.13784 EFEMP1 Alison Yeung reviewed gene: EFEMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34923728; Phenotypes: Juvenile-onset open angle glaucoma, MONDO:0020367, EFEMP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13784 PRDM13 Dean Phelan reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35390279; Phenotypes: Pontocerebellar hypoplasia (MONDO:0020135), PRDM13 related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13784 DROSHA Lucy Spencer gene: DROSHA was added
gene: DROSHA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Neurodevelopmental disorder (MONDO#0700092), DROSHA-related
Review for gene: DROSHA was set to AMBER
Added comment: 2 individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. Both variants are missense, absent from gnomad. Both individuals noted to have Rett-like features.

Functional studies in patient fibroblasts showed one of the missense altered the expression of mature miRNA. Fruit fly models with homozygous LOF variants die during larval stages. introduction of the missense seen in the patients was able to partially rescue this phenotype suggesting LOF is not the mechanism.
Sources: Literature
Mendeliome v0.13784 KCNH5 Elena Savva gene: KCNH5 was added
gene: KCNH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNH5 were set to https://www.medrxiv.org/content/10.1101/2022.04.26.22274147v1
Phenotypes for gene: KCNH5 were set to Neurodevelopmental disorders
Mode of pathogenicity for gene: KCNH5 was set to Other
Review for gene: KCNH5 was set to GREEN
Added comment: Happ (2022), preprint: Screen of 893 patients with DEE found 17 patients with missense variants (16/17 de novo, 1/17 inherited). GOF mechanism suggested.
Patient phenotypes included focal/generalized seizures, Cognitive outcome for the ten individuals >5 years ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID)

p.Arg327His (7 probands), p.Arg333His (4 probands) were recurring
Sources: Literature
Mendeliome v0.13781 PPFIBP1 Zornitza Stark gene: PPFIBP1 was added
gene: PPFIBP1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: PPFIBP1 was set to GREEN
Added comment: 16 individuals from 10 unrelated families reported with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Drosophila model.
Sources: Expert Review
Mendeliome v0.13776 HYDIN Zornitza Stark Publications for gene: HYDIN were set to
Mendeliome v0.13774 HYDIN Zornitza Stark reviewed gene: HYDIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 23022101, 23849777, 28441829, 31116566; Phenotypes: Ciliary dyskinesia, primary, 5 (MIM#608647); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13773 HTRA2 Zornitza Stark Publications for gene: HTRA2 were set to
Mendeliome v0.13771 HTRA2 Zornitza Stark reviewed gene: HTRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27208207, 27696117; Phenotypes: 3-methylglutaconic aciduria, type VIII, MIM# 617248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13770 HTR1A Zornitza Stark Publications for gene: HTR1A were set to
Mendeliome v0.13767 HTR1A Zornitza Stark reviewed gene: HTR1A: Rating: RED; Mode of pathogenicity: None; Publications: 21990073; Phenotypes: Periodic fever, menstrual cycle dependent, MIM# 614674; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13766 HSPD1 Zornitza Stark Publications for gene: HSPD1 were set to
Mendeliome v0.13764 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18571143, 27405012, 32532876, 28377887, 27405012, 11898127, 17420924; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233, Spastic paraplegia 13, autosomal dominant, MIM# 605280; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13763 HSD3B7 Zornitza Stark Publications for gene: HSD3B7 were set to
Mendeliome v0.13760 HSD3B2 Zornitza Stark Publications for gene: HSD3B2 were set to
Mendeliome v0.13758 HSD3B2 Zornitza Stark reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1363812, 18252794; Phenotypes: Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, MIM# 201810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13757 CUBN Ain Roesley Publications for gene: CUBN were set to
Mendeliome v0.13755 CUBN Ain Roesley reviewed gene: CUBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31613795, 21903995, 31497480; Phenotypes: Imerslund-Grasbeck syndrome 1 MIM#261100 AR, [Proteinuria, chronic benign] MIM#618884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13755 CTSF Ain Roesley Publications for gene: CTSF were set to
Mendeliome v0.13753 CTSF Ain Roesley reviewed gene: CTSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28749476, 27668283, 27524508; Phenotypes: Ceroid lipofuscinosis, neuronal, 13, Kufs type, MIM# 615362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13752 CTSC Ain Roesley reviewed gene: CTSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11106356, 32601924, 10581027, 14974080, 10662808; Phenotypes: Haim-Munk syndrome MIM#245010, Papillon-Lefevre syndrome MIM#245000, Periodontitis 1, juvenile MIM#170650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13752 CTSC Ain Roesley Publications for gene: CTSC were set to
Mendeliome v0.13749 CTNS Ain Roesley Publications for gene: CTNS were set to
Mendeliome v0.13747 CTNS Ain Roesley reviewed gene: CTNS: Rating: ; Mode of pathogenicity: None; Publications: 20301574, 9537412, 31068690; Phenotypes: Cystinosis, atypical nephropathic MIM#219800, Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900, Cystinosis, nephropathic MIM#219800, Cystinosis, ocular nonnephropathic MIM#219750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13746 CTNNA1 Ain Roesley Publications for gene: CTNNA1 were set to
Mendeliome v0.13745 CTNNA1 Ain Roesley reviewed gene: CTNNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26691986, 33497368; Phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970, Familial exudative vitreoretinopathy MONDO#0019516, CTNNA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13745 CTHRC1 Ain Roesley Publications for gene: CTHRC1 were set to
Mendeliome v0.13743 CTHRC1 Ain Roesley reviewed gene: CTHRC1: Rating: RED; Mode of pathogenicity: None; Publications: 21791690; Phenotypes: Barrett esophagus/esophageal adenocarcinoma MIM#614266; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13742 CSRP3 Ain Roesley Publications for gene: CSRP3 were set to
Mendeliome v0.13741 CSRP3 Ain Roesley reviewed gene: CSRP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18505755, 30681346, 12507422, 14567970, 19412328; Phenotypes: hypertrophic cardiomyopathy12 MIM#612124, dilated cardiomyopathy 1M MIM#607482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13741 CRYGS Ain Roesley Phenotypes for gene: CRYGS were changed from to Cataract 20, multiple types MIM#116100
Mendeliome v0.13740 CRYGS Ain Roesley Publications for gene: CRYGS were set to
Mendeliome v0.13739 CRYGS Ain Roesley reviewed gene: CRYGS: Rating: GREEN; Mode of pathogenicity: None; Publications: 34014271, 16141006, 18587492, 19262743; Phenotypes: Cataract 20, multiple types MIM#116100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13739 CRYGB Ain Roesley Phenotypes for gene: CRYGB were changed from to Cataract 39, multiple types, autosomal dominant MIM#615188
Mendeliome v0.13739 CRYGB Ain Roesley Publications for gene: CRYGB were set to
Mendeliome v0.13737 CRYGB Ain Roesley reviewed gene: CRYGB: Rating: RED; Mode of pathogenicity: None; Publications: 23288985; Phenotypes: Cataract 39, multiple types, autosomal dominant MIM#615188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13737 CRYAB Ain Roesley Phenotypes for gene: CRYAB were changed from to Cataract 16, multiple types MIM#613763 AD, AR; Myopathy, myofibrillar, 2 MIM#608810 AD; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related MIM#613869 AR
Mendeliome v0.13736 CRYAB Ain Roesley Publications for gene: CRYAB were set to
Mendeliome v0.13735 CRYAB Ain Roesley reviewed gene: CRYAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31215171, 21337604, 21130652, 32420686, 33272090; Phenotypes: Cataract 16, multiple types MIM#613763 AD, AR, Myopathy, myofibrillar, 2 MIM#608810 AD, Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related MIM#613869 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13734 CRX Ain Roesley Publications for gene: CRX were set to
Mendeliome v0.13733 CRX Ain Roesley reviewed gene: CRX: Rating: GREEN; Mode of pathogenicity: None; Publications: 12208271, 9931337, 9537410, 29568065, 27427859, 25270190, 32927963, 33910785; Phenotypes: Leber congenital amaurosis 7, MIM# 613829, Cone-rod retinal dystrophy-2 MIM#120970; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13731 CREB1 Ain Roesley Publications for gene: CREB1 were set to
Mendeliome v0.13729 CREB1 Ain Roesley reviewed gene: CREB1: Rating: RED; Mode of pathogenicity: None; Publications: 22267179; Phenotypes: corpus callosum agenesis, thyroid follicular hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13729 SLC16A12 Samantha Ayres reviewed gene: SLC16A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 20181839, 21778275, 18304496, 29088427, 34126080; Phenotypes: Cataract 47, juvenile, with microcornea, MIM# 612018; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13729 CRBN Ain Roesley Publications for gene: CRBN were set to
Mendeliome v0.13727 CRBN Ain Roesley reviewed gene: CRBN: Rating: AMBER; Mode of pathogenicity: None; Publications: 15557513, 28143899; Phenotypes: Intellectual developmental disorder, autosomal recessive 2 MIM#607417; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13726 CRB1 Ain Roesley Publications for gene: CRB1 were set to
Mendeliome v0.13725 CRB1 Ain Roesley reviewed gene: CRB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30285347, 32922261, 31884620, 15459956; Phenotypes: Leber congenital amaurosis 8 MIM#613835, Pigmented paravenous chorioretinal atrophy MIM#172870, Retinitis pigmentosa-12 MIM#600105; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13724 CPT1A Ain Roesley Publications for gene: CPT1A were set to
Mendeliome v0.13723 CPT1A Ain Roesley reviewed gene: CPT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 12189492, 25778941, 23430932; Phenotypes: CPT deficiency, hepatic, type IA, MIM# 255120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13723 CPS1 Ain Roesley Publications for gene: CPS1 were set to
Mendeliome v0.13722 CPS1 Ain Roesley reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950, 31268178; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13722 CPOX Ain Roesley Publications for gene: CPOX were set to
Mendeliome v0.13720 CPOX Ain Roesley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 30828546, 28349448, 23582006, 24156084; Phenotypes: Coproporphyria, MIM#121300, Harderoporphyria, MIM#121300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13719 CPN1 Ain Roesley Publications for gene: CPN1 were set to
Mendeliome v0.13717 CPN1 Ain Roesley reviewed gene: CPN1: Rating: RED; Mode of pathogenicity: None; Publications: 12560874, 7437116; Phenotypes: Carboxypeptidase N deficiency MIM#212070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13716 HSD11B1 Zornitza Stark Publications for gene: HSD11B1 were set to
Mendeliome v0.13713 HSD11B1 Zornitza Stark reviewed gene: HSD11B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21325058; Phenotypes: Cortisone reductase deficiency 2, MIM# 614662; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13713 SLC14A1 Samantha Ayres reviewed gene: SLC14A1: Rating: RED; Mode of pathogenicity: None; Publications: 28065763, 27834480; Phenotypes: [Blood group, Kidd], MIM#111000; Mode of inheritance: Unknown
Mendeliome v0.13713 SLC12A5 Samantha Ayres reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 26333769, 27436767, 24928908, 30763027, 24668262; Phenotypes: Developmental and epileptic encephalopathy 34, MIM# 616645, {Epilepsy, idiopathic generalized, susceptibility to, 14}, MIM# 616685; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13712 HRG Zornitza Stark Publications for gene: HRG were set to
Mendeliome v0.13710 HRG Zornitza Stark reviewed gene: HRG: Rating: GREEN; Mode of pathogenicity: None; Publications: 8236132, 11057869, 11057869, 29108964; Phenotypes: Thrombophilia 11 due to HRG deficiency, MIM# 613116; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13708 HP Zornitza Stark reviewed gene: HP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Anhaptoglobinemia] 614081, [Hypohaptoglobinemia] 614081; Mode of inheritance: None
Mendeliome v0.13707 HOXD13 Zornitza Stark Publications for gene: HOXD13 were set to
Mendeliome v0.13705 HOXD13 Zornitza Stark reviewed gene: HOXD13: Rating: GREEN; Mode of pathogenicity: None; Publications: 34777468, 32509852; Phenotypes: Brachydactyly, type E 113300 Brachydactyly, type D, MIM# 113200, Syndactyly, type V, MIM# 186300, Synpolydactyly 1, MIM# 186000, Brachydactyly-syndactyly syndrome, MIM# 610713; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13704 HOXA13 Zornitza Stark Publications for gene: HOXA13 were set to
Mendeliome v0.13702 HOXA13 Zornitza Stark reviewed gene: HOXA13: Rating: GREEN; Mode of pathogenicity: None; Publications: 10839976, 9020844; Phenotypes: Hand-foot-uterus syndrome, MIM# 140000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13701 HOXA1 Zornitza Stark Publications for gene: HOXA1 were set to
Mendeliome v0.13699 HOXA1 Zornitza Stark reviewed gene: HOXA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16155570, 18412118, 32864817; Phenotypes: Athabaskan brainstem dysgenesis syndrome MIM#601536, Bosley-Salih-Alorainy syndrome MIM#601536; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13698 HNRNPA1 Zornitza Stark Publications for gene: HNRNPA1 were set to
Mendeliome v0.13696 HNRNPA1 Zornitza Stark reviewed gene: HNRNPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23455423, 34291734; Phenotypes: Amyotrophic lateral sclerosis 20 MIM#615426; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13695 HNF4A Zornitza Stark Publications for gene: HNF4A were set to
Mendeliome v0.13693 HNF4A Zornitza Stark reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31875549, 24285859, 22802087, 30005691, 28458902; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026, MODY, type I, OMIM # 125850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13692 HNF1A Zornitza Stark Publications for gene: HNF1A were set to
Mendeliome v0.13690 HNF1A Zornitza Stark reviewed gene: HNF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9097962, 9112026; Phenotypes: Diabetes mellitus, insulin-dependent, 20, MIM# 612520, MODY, type III , MIM#600496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13689 HMX1 Zornitza Stark Publications for gene: HMX1 were set to
Mendeliome v0.13687 HMX1 Zornitza Stark changed review comment from: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage.

At least two families and two animal models. Also evidence that duplication of long-range enhancer causes microbial.; to: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage.

At least two families and two animal models. Also evidence that duplication of long-range enhancer causes microtia.
Mendeliome v0.13687 HMX1 Zornitza Stark reviewed gene: HMX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18423520, 25574057, 33465110, 32552830, 31691317; Phenotypes: Oculoauricular syndrome, MIM#612109; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13686 COL9A1 Ain Roesley Publications for gene: COL9A1 were set to
Mendeliome v0.13685 COL9A1 Ain Roesley reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16909383, 21421862, 31090205; Phenotypes: Stickler syndrome, type IV, MIM# 614134; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13685 CORIN Ain Roesley Publications for gene: CORIN were set to
Mendeliome v0.13684 CORIN Ain Roesley Added comment: Comment on list classification: pre-eclampsia is typically not monogenic
Mendeliome v0.13683 CORIN Ain Roesley reviewed gene: CORIN: Rating: AMBER; Mode of pathogenicity: None; Publications: 22437503; Phenotypes: Preeclampsia/eclampsia 5 MIM#614595; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13682 DUSP6 Krithika Murali reviewed gene: DUSP6: Rating: RED; Mode of pathogenicity: None; Publications: 23643382; Phenotypes: Hypogonadotropic hypogonadism 19 with or without anosmia - MIM#615269; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13682 COQ9 Ain Roesley Publications for gene: COQ9 were set to
Mendeliome v0.13681 COQ9 Ain Roesley reviewed gene: COQ9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19375058, 26081641, 23255162, 31821167; Phenotypes: Coenzyme Q10 deficiency, primary, 5, MIM#614654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13681 COQ8B Ain Roesley Publications for gene: COQ8B were set to
Mendeliome v0.13680 COQ8B Ain Roesley reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 24270420; Phenotypes: Nephrotic syndrome, type 9 MIM#615573; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13680 COQ8A Ain Roesley Publications for gene: COQ8A were set to
Mendeliome v0.13679 COQ8A Ain Roesley reviewed gene: COQ8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32337771; Phenotypes: Coenzyme Q10 deficiency, primary, 4 MIM#612016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13679 COQ7 Ain Roesley Publications for gene: COQ7 were set to
Mendeliome v0.13678 COQ7 Ain Roesley reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26084283, 31240163, 33215859, 28409910; Phenotypes: Coenzyme Q10 deficiency, primary, 8 MIM#616733; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13678 COQ6 Ain Roesley Publications for gene: COQ6 were set to
Mendeliome v0.13677 COQ6 Ain Roesley reviewed gene: COQ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28125198; Phenotypes: Coenzyme Q10 deficiency, primary, 6 MIM#614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13677 COMP Ain Roesley Publications for gene: COMP were set to
Mendeliome v0.13675 COMP Ain Roesley reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301302, 20301660; Phenotypes: Epiphyseal dysplasia, multiple, 1 MIM#132400, Pseudoachondroplasia MIM#177170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13675 COL9A2 Ain Roesley Publications for gene: COL9A2 were set to
Mendeliome v0.13674 COL9A2 Ain Roesley reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205, 33356723, 10364514, 15633184, 20358595, 8528240; Phenotypes: Stickler syndrome, type V MIM#614284' Epiphyseal dysplasia, multiple, 2 MIM#600204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13674 DYRK1B Krithika Murali reviewed gene: DYRK1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 34193236, 34786696, 24827035, 28743892; Phenotypes: Abdominal obesity-metabolic syndrome 3 - MIM#615812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13674 COL6A3 Ain Roesley Publications for gene: COL6A3 were set to
Mendeliome v0.13673 COL6A3 Ain Roesley edited their review of gene: COL6A3: Changed publications: 20301676, 26004199, 32037012, 26872670, 32037012
Mendeliome v0.13673 COL6A2 Ain Roesley edited their review of gene: COL6A2: Changed publications: 20301676
Mendeliome v0.13673 COL6A2 Ain Roesley edited their review of gene: COL6A2: Changed publications: 20301676, 26004199, 32037012, 26872670, 32037012
Mendeliome v0.13673 COL6A3 Ain Roesley reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Dystonia 27 MIM#616411, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13673 COL6A2 Ain Roesley changed review comment from: GeneReviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL621 accounts for 44-46% of Collagen VI-Related Dystrophies cases; to: GeneReviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL6A2 accounts for 44-46% of Collagen VI-Related Dystrophies cases
Mendeliome v0.13672 COL6A2 Ain Roesley Publications for gene: COL6A2 were set to
Mendeliome v0.13671 COL6A2 Ain Roesley reviewed gene: COL6A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13671 COL6A1 Ain Roesley changed review comment from: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly; to: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL6A1 accounts for 35-38% of Collagen VI-Related Dystrophies cases
Mendeliome v0.13671 COL6A1 Ain Roesley Publications for gene: COL6A1 were set to
Mendeliome v0.13670 COL6A1 Ain Roesley edited their review of gene: COL6A1: Changed publications: 20301676, 25535305, 15955946, 23738969, 29277723, 24443028; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13669 COL6A1 Ain Roesley changed review comment from: Well established association

Both loss-of-function and dominant negative mechanism has been reported for this gene. Mutations result in a spectrum of disease, ranging from the milder Bethlem myopathy (monoallelic) to the more severe Ullrich congenital muscular dystrophy (biallelic) (PMID: 29277723; 24443028).
Sources: Literature; to: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly
Mendeliome v0.13669 COL6A1 Ain Roesley reviewed gene: COL6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25535305, 15955946, 23738969, 29277723, 24443028; Phenotypes: Bethlem myopathy MIM#158810, Ullrich congenital muscular dystrophy MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13669 COL5A2 Ain Roesley Publications for gene: COL5A2 were set to
Mendeliome v0.13668 COL5A2 Ain Roesley reviewed gene: COL5A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301422; Phenotypes: Ehlers-Danlos syndrome, classic type, 2 MIM#130010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13667 COL4A4 Ain Roesley Publications for gene: COL4A4 were set to
Mendeliome v0.13666 COL4A4 Ain Roesley reviewed gene: COL4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301386; Phenotypes: Alport syndrome 2, autosomal recessive MIM#203780, Hematuria, familial benign MIM#141200; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13665 COL4A3 Ain Roesley reviewed gene: COL4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alport syndrome 2, autosomal recessive, MIM# 203780, Alport syndrome 3, autosomal dominant, MIM# 104200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13665 COL4A2 Ain Roesley Publications for gene: COL4A2 were set to
Mendeliome v0.13664 COL4A2 Ain Roesley reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 33912663, 22209246, 30315939, 22333902; Phenotypes: Cerebral Palsy MONDO#0006497, COL4A2-related, Brain small vessel disease 2 MIM# 614483; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13663 COL4A1 Ain Roesley Publications for gene: COL4A1 were set to
Mendeliome v0.13662 COL4A1 Ain Roesley reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24628545, 25719457, 21625620, 23225343, 23065703, 20818663, 20301768; Phenotypes: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773, Brain small vessel disease with or without ocular anomalies MIM#175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13661 HMOX1 Zornitza Stark Publications for gene: HMOX1 were set to
Mendeliome v0.13657 COL27A1 Ain Roesley Publications for gene: COL27A1 were set to
Mendeliome v0.13656 COL27A1 Ain Roesley reviewed gene: COL27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24986830, 28276056, 28322503, 32360765, 33963180; Phenotypes: Steel syndrome, OMIM #615155; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13655 COL1A2 Ain Roesley Publications for gene: COL1A2 were set to
Mendeliome v0.13653 COL1A2 Ain Roesley reviewed gene: COL1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 32091183, 2993307, 30821104; Phenotypes: Ehlers-Danlos syndrome, arthrochalasia type, 2 MIM#617821, Ehlers-Danlos syndrome, cardiac valvular type MIM#225320; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13653 COL1A1 Ain Roesley Publications for gene: COL1A1 were set to
Mendeliome v0.13652 COL1A1 Ain Roesley reviewed gene: COL1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301422, 20301667, 30071989, 28981071, 12362985, 28956891; Phenotypes: Caffey disease MIM#114000, Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 MIM#619115, Ehlers-Danlos syndrome, arthrochalasia type, 1 MIM#130060, Osteogenesis imperfecta, type I MIM#166200, Osteogenesis imperfecta, type II MIM#166210, Osteogenesis imperfecta, type III MIM#259420, Osteogenesis imperfecta, type IV MIM#166220; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13651 COL18A1 Ain Roesley Publications for gene: COL18A1 were set to
Mendeliome v0.13650 COL18A1 Ain Roesley reviewed gene: COL18A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27259167, 25456301; Phenotypes: Knobloch syndrome, type 1, MIM# 267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13650 COL17A1 Ain Roesley Publications for gene: COL17A1 were set to
Mendeliome v0.13649 COL17A1 Ain Roesley reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27309958, 29708937, 25676728, 20301304; Phenotypes: Epidermolysis bullosa, junctional 4, intermediate MIM#619787, Epithelial recurrent erosion dystrophy MIM#122400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13649 COL12A1 Ain Roesley Publications for gene: COL12A1 were set to 28306229; 31273343; 24334604
Mendeliome v0.13648 COL12A1 Ain Roesley Publications for gene: COL12A1 were set to
Mendeliome v0.13647 COL12A1 Ain Roesley reviewed gene: COL12A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 31273343, 24334604; Phenotypes: Myopathic EDS, Bethlem myopathy 2 MIM#616471, Ullrich congenital muscular dystrophy 2 MIM#616470; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13646 COL11A2 Ain Roesley Publications for gene: COL11A2 were set to
Mendeliome v0.13645 COL11A2 Ain Roesley reviewed gene: COL11A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10581026, 25633957, 16033917, 25240749, 22796475, 20112039; Phenotypes: Stickler syndrome type 3, Deafness, autosomal dominant 13 MIM#601868, Deafness, autosomal recessive 53 MIM#609706, Fibrochondrogenesis 2 MIM#614524, Otospondylomegaepiphyseal dysplasia, autosomal dominant MIM#184840, Otospondylomegaepiphyseal dysplasia, autosomal recessive MIM#215150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13644 COG7 Ain Roesley Publications for gene: COG7 were set to
Mendeliome v0.13643 COG7 Ain Roesley reviewed gene: COG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 15107842, 17356545, 28883096; Phenotypes: Congenital disorder of glycosylation, type IIe , MIM#608779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13643 COASY Ain Roesley Publications for gene: COASY were set to
Mendeliome v0.13642 COASY Ain Roesley reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334, 24360804, 35499143; Phenotypes: Neurodegeneration with brain iron accumulation 6 MIM#615643, Pontocerebellar hypoplasia, type 12 MIM#v618266; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13640 HMBS Zornitza Stark reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, acute intermittent, MIM#176000, Porphyria, acute intermittent, non-erythroid variant, MIM#176000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13639 HK1 Zornitza Stark Publications for gene: HK1 were set to
Mendeliome v0.13637 HK1 Zornitza Stark edited their review of gene: HK1: Added comment: Mono-allelic variants and ID: PMID30778173, 7 patients from 6 unrelated families with denovo missense variants in the N-terminal half of HK1

Mono-allelic variants and RP: Seven families reported with the same heterozygous missense variant, p.Glu847Lys and RP from different ethnicities. Some supportive evidence. Variant is present in 3 hets in gnomad.

Bi-allelic variants and haemolytic anaemia: more than 10 families reported.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571; Changed phenotypes: Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13635 RPE65 Zornitza Stark Publications for gene: RPE65 were set to
Mendeliome v0.13632 SLC24A1 Zornitza Stark Publications for gene: SLC24A1 were set to
Mendeliome v0.13629 SLC25A1 Zornitza Stark Publications for gene: SLC25A1 were set to
Mendeliome v0.13626 RRAS Zornitza Stark Publications for gene: RRAS were set to
Mendeliome v0.13623 RRAS Zornitza Stark reviewed gene: RRAS: Rating: AMBER; Mode of pathogenicity: None; Publications: 24705357; Phenotypes: Noonan syndrome, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13621 SLC11A1 Zornitza Stark Publications for gene: SLC11A1 were set to
Mendeliome v0.13619 LIPT2 Zornitza Stark edited their review of gene: LIPT2: Changed publications: 28757203
Mendeliome v0.13619 LIPT2 Zornitza Stark reviewed gene: LIPT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, MIM# 617668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13618 SIL1 Zornitza Stark Publications for gene: SIL1 were set to
Mendeliome v0.13616 LIPC Zornitza Stark edited their review of gene: LIPC: Changed publications: 1671786, 12777476, 1883393, 23219720, 26423094, 22464213, 22798447
Mendeliome v0.13616 LIPC Zornitza Stark reviewed gene: LIPC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hepatic lipase deficiency, MIM# 614025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13616 RPE65 Belinda Chong reviewed gene: RPE65: Rating: GREEN; Mode of pathogenicity: None; Publications: 14962443, 12960219, 11786058, 21654732, 27307694, 9501220, 16754667, 15557452; Phenotypes: Leber congenital amaurosis 2 MIM#204100, Retinitis pigmentosa 20 MIM#613794, Retinitis pigmentosa 87 with choroidal involvement MIM#618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13616 SLC24A1 Manny Jacobs reviewed gene: SLC24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35486108, 35446361, 20850105, 26822852; Phenotypes: Night blindness, congenital stationary (complete), 1D, autosomal recessive, MIM#613830, MONDO:0013450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13615 SIK1 Zornitza Stark Publications for gene: SIK1 were set to
Mendeliome v0.13613 SLC25A1 Manny Jacobs reviewed gene: SLC25A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26870663, 31527857, 31808147, 23561848, 23393310; Phenotypes: Combined D-2- and L-2-hydroxyglutaric aciduria MIM#: 615182, MONDO:0014072, Myasthenic syndrome, congenital, 23, presynaptic, MIM#618197, MONDO:0032596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13613 RRAS Belinda Chong changed review comment from: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents.

Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).; to: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents.

Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).
Mendeliome v0.13613 RRAS Belinda Chong reviewed gene: RRAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24705357, 32815881; Phenotypes: Noonan syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13612 HIBCH Zornitza Stark Publications for gene: HIBCH were set to
Mendeliome v0.13610 HIBCH Zornitza Stark reviewed gene: HIBCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 26026795, 25251209, 24299452, 32677093; Phenotypes: 3-hydroxyisobutryl-CoA hydrolase deficiency, MIM# 250620; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13609 HGF Zornitza Stark Publications for gene: HGF were set to
Mendeliome v0.13607 HGF Zornitza Stark reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 19576567; Phenotypes: Deafness, autosomal recessive 39, MIM# 608265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13606 HGD Zornitza Stark Publications for gene: HGD were set to
Mendeliome v0.13602 HFE Zornitza Stark reviewed gene: HFE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Haemochromatosis, MIM# 235200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13600 HESX1 Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Growth hormone deficiency with pituitary anomalies, MIM#182230, Pituitary hormone deficiency, combined, 5, MIM#182230, Septooptic dysplasia, MIM#182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13599 SLC11A1 Samantha Ayres reviewed gene: SLC11A1: Rating: RED; Mode of pathogenicity: None; Publications: 35140349; Phenotypes: {Buruli ulcer, susceptibility to}, MIM#610446, {Mycobacterium tuberculosis, susceptibility to infection by} , MIM#607948; Mode of inheritance: Unknown
Mendeliome v0.13598 HERC1 Zornitza Stark Publications for gene: HERC1 were set to
Mendeliome v0.13596 HERC1 Zornitza Stark reviewed gene: HERC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28323226, 27108999, 26153217, 26138117, 20041218; Phenotypes: Macrocephaly, dysmorphic facies, and psychomotor retardation, MIM# 617011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13595 HEPACAM Zornitza Stark Publications for gene: HEPACAM were set to
Mendeliome v0.13593 HEPACAM Zornitza Stark reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 21419380, 21419380; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts 2A, MIM# 613925, Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, MIM# 613926; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13592 SIL1 Samantha Ayres reviewed gene: SIL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24176978, 16282977, 20301371; Phenotypes: Marinesco-Sjogren syndrome, MIM#248800, MONDO#0009567; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13591 LIPT2 Alison Yeung Publications for gene: LIPT2 were set to
Mendeliome v0.13588 LIPH Alison Yeung reviewed gene: LIPH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Woolly hair, autosomal recessive 2 with or without hypotrichosis, MIM# 604379, Hypotrichosis 7, MIM# 604379; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13586 LIPC Alison Yeung Publications for gene: LIPC were set to
Mendeliome v0.13582 LINS1 Alison Yeung Publications for gene: LINS1 were set to
Mendeliome v0.13580 HCRT Zornitza Stark Publications for gene: HCRT were set to
Mendeliome v0.13577 HCRT Zornitza Stark reviewed gene: HCRT: Rating: RED; Mode of pathogenicity: None; Publications: 10973318, 11148249, 11723284; Phenotypes: Narcolepsy 1 , MIM# 161400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13577 LIM2 Alison Yeung Phenotypes for gene: LIM2 were changed from to Cataract 19, multiple types, MIM# 615277
Mendeliome v0.13576 LIM2 Alison Yeung Publications for gene: LIM2 were set to
Mendeliome v0.13574 LIM2 Alison Yeung reviewed gene: LIM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27814360, 11917274, 18596884, 33708862, 32202185, 21617753; Phenotypes: Cataract 19, multiple types, MIM# 615277; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13573 HCN1 Zornitza Stark Publications for gene: HCN1 were set to
Mendeliome v0.13571 HCN1 Zornitza Stark reviewed gene: HCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747641, 30351409, 30351409; Phenotypes: Developmental and epileptic encephalopathy 24, MIM# 615871, Generalized epilepsy with febrile seizures plus, type 10, MIM# 618482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13570 HCCS Zornitza Stark Publications for gene: HCCS were set to
Mendeliome v0.13568 HCCS Zornitza Stark reviewed gene: HCCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033964, 30068298, 24735900; Phenotypes: Linear skin defects with multiple congenital anomalies 1, MIM# 309801; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.13566 HBA2 Zornitza Stark reviewed gene: HBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Erythrocytosis 7, MIM# 617981, Heinz body anaemia, MIM# 140700, Haemoglobin H disease, deletional and nondeletional, MIM# 613978, Thalassaemia, alpha-, MIM# 604131; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13563 HBA1 Zornitza Stark reviewed gene: HBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Erythrocytosis 7, MIM# 617981, Heinz body anemias, alpha-, MIM# 140700, Methemoglobinemia, alpha type , MIM#617973, Thalassemias, alpha-, MIM# 604131, Hemoglobin H disease, nondeletional, MIM# 613978; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13562 HAO1 Zornitza Stark reviewed gene: HAO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13561 HAMP Zornitza Stark Publications for gene: HAMP were set to
Mendeliome v0.13559 HAMP Zornitza Stark reviewed gene: HAMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12469120, 34828384, 15198949; Phenotypes: Haemochromatosis, type 2B, MIM# 613313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13558 HADHB Zornitza Stark Publications for gene: HADHB were set to
Mendeliome v0.13556 HADHB Zornitza Stark reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30682426, 28515471; Phenotypes: Trifunctional protein deficiency, MIM# 609015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13554 HADHA Zornitza Stark reviewed gene: HADHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: LCHAD deficiency, MIM# 609016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13552 HADH Zornitza Stark reviewed gene: HADH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-hydroxyacyl-CoA dehydrogenase deficiency, MIM# 231530, Hyperinsulinemic hypoglycemia, familial, 4, MIM# 609975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13551 HACD1 Zornitza Stark Publications for gene: HACD1 were set to
Mendeliome v0.13549 HACD1 Zornitza Stark reviewed gene: HACD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15829503, 23933735, 32426512; Phenotypes: Congenital myopathy, MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13548 HAAO Zornitza Stark Publications for gene: HAAO were set to
Mendeliome v0.13545 H6PD Zornitza Stark Publications for gene: H6PD were set to
Mendeliome v0.13543 H6PD Zornitza Stark reviewed gene: H6PD: Rating: GREEN; Mode of pathogenicity: None; Publications: 18628520; Phenotypes: Cortisone reductase deficiency 1, MIM# 604931; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13543 SIK1 Samantha Ayres reviewed gene: SIK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25839329, 27966542, 35267137; Phenotypes: Developmental and epileptic encephalopathy 30, MIM#616341, developmental and epileptic encephalopathy, MONDO#0100062; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13542 BUD23 Zornitza Stark reviewed gene: BUD23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13539 BTNL2 Zornitza Stark reviewed gene: BTNL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Sarcoidosis, susceptibility to, 2} 612387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13538 BTK Zornitza Stark Publications for gene: BTK were set to
Mendeliome v0.13536 BTK Zornitza Stark reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697; Phenotypes: Agammaglobulinaemia, X-linked 1, MIM# 300755, Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13535 BRIP1 Zornitza Stark Publications for gene: BRIP1 were set to
Mendeliome v0.13533 BRIP1 Zornitza Stark reviewed gene: BRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27107905; Phenotypes: Fanconi anaemia, complementation group J, MIM# 609054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13532 BRAF Zornitza Stark Publications for gene: BRAF were set to
Mendeliome v0.13529 BRAF Zornitza Stark reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 19206169, 18042262; Phenotypes: Noonan syndrome 7, MIM# 613706, Cardiofaciocutaneous syndrome, MIM# 115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13528 BPGM Zornitza Stark Publications for gene: BPGM were set to
Mendeliome v0.13525 BPGM Zornitza Stark reviewed gene: BPGM: Rating: AMBER; Mode of pathogenicity: None; Publications: 1421379, 27651169, 25015942; Phenotypes: Erythrocytosis, familial, 8, MIM# 222800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13524 BMPR1A Zornitza Stark Publications for gene: BMPR1A were set to
Mendeliome v0.13522 BMPR1A Zornitza Stark reviewed gene: BMPR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11381269; Phenotypes: Polyposis, juvenile intestinal, MIM# 174900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13521 BLVRA Zornitza Stark Publications for gene: BLVRA were set to
Mendeliome v0.13518 BLVRA Zornitza Stark reviewed gene: BLVRA: Rating: AMBER; Mode of pathogenicity: None; Publications: 19580635, 21278388; Phenotypes: Hyperbiliverdinaemia , MIM#614156; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13517 BLK Zornitza Stark Publications for gene: BLK were set to
Mendeliome v0.13514 BLK Zornitza Stark reviewed gene: BLK: Rating: AMBER; Mode of pathogenicity: None; Publications: 25926555; Phenotypes: Common variable immunodeficiency, MONDO:0015517; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13511 BHLHE41 Zornitza Stark reviewed gene: BHLHE41: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Short sleep, familial natural, 1] 612975; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13511 BFSP1 Zornitza Stark Phenotypes for gene: BFSP1 were changed from to Cataract 33, multiple types, MIM# 611391
Mendeliome v0.13510 BFSP1 Zornitza Stark Publications for gene: BFSP1 were set to
Mendeliome v0.13508 BFSP1 Zornitza Stark reviewed gene: BFSP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17225135, 26694549, 24379646, 28450710, 31842807, 26694549; Phenotypes: Cataract 33, multiple types, MIM# 611391; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13507 BCL2 Zornitza Stark reviewed gene: BCL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13506 BCKDK Zornitza Stark Publications for gene: BCKDK were set to
Mendeliome v0.13503 BCL10 Zornitza Stark Publications for gene: BCL10 were set to
Mendeliome v0.13499 BCHE Zornitza Stark reviewed gene: BCHE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Butyrylcholinesterase deficiency, MIM# 617936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13498 BBS2 Zornitza Stark Publications for gene: BBS2 were set to
Mendeliome v0.13495 BBS12 Zornitza Stark Publications for gene: BBS12 were set to
Mendeliome v0.13492 BBS10 Zornitza Stark Publications for gene: BBS10 were set to
Mendeliome v0.13489 BBS1 Zornitza Stark Publications for gene: BBS1 were set to
Mendeliome v0.13486 BAG3 Zornitza Stark Publications for gene: BAG3 were set to
Mendeliome v0.13484 BAG3 Zornitza Stark reviewed gene: BAG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21353195, 25008357, 25448463, 24623017, 27391596, 28211974, 30442290, 31983221, 28737513, 29323723, 33947203, 25208129, 32453099, 22734908; Phenotypes: Cardiomyopathy, dilated, 1HH, MIM# 613881, Myopathy, myofibrillar, 6, MIM# 612954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13483 BACH2 Zornitza Stark Publications for gene: BACH2 were set to
Mendeliome v0.13481 BACH2 Zornitza Stark reviewed gene: BACH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28530713; Phenotypes: Immunodeficiency 60 and autoimmunity, MIM# 618394; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13480 B4GALT1 Zornitza Stark Publications for gene: B4GALT1 were set to
Mendeliome v0.13477 B4GALNT1 Zornitza Stark Publications for gene: B4GALNT1 were set to 23746551 24103911
Mendeliome v0.13476 B4GALNT1 Zornitza Stark Publications for gene: B4GALNT1 were set to
Mendeliome v0.13474 B4GALNT1 Zornitza Stark reviewed gene: B4GALNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23746551 24103911; Phenotypes: Spastic paraplegia 26, autosomal recessive (MIM #609195); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13473 B3GLCT Zornitza Stark Publications for gene: B3GLCT were set to
Mendeliome v0.13471 B3GLCT Zornitza Stark reviewed gene: B3GLCT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18798333, 19796186, 32533185, 32204707, 31795264; Phenotypes: Peters-plus syndrome, MIM#261540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13470 AP1S2 Zornitza Stark Publications for gene: AP1S2 were set to
Mendeliome v0.13469 AP1S2 Zornitza Stark reviewed gene: AP1S2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186471, 17617514, 19377476, 30714330, 23756445; Phenotypes: Pettigrew syndrome, MIM# 304340; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13468 APCDD1 Zornitza Stark Publications for gene: APCDD1 were set to
Mendeliome v0.13466 APCDD1 Zornitza Stark reviewed gene: APCDD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypotrichosis 1, MIM#605389; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13465 ANO10 Zornitza Stark Publications for gene: ANO10 were set to
Mendeliome v0.13464 ANO10 Zornitza Stark reviewed gene: ANO10: Rating: GREEN; Mode of pathogenicity: None; Publications: 21092923, 25182700; Phenotypes: Spinocerebellar ataxia, autosomal recessive 10, MIM#613728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13463 PHOX2B Zornitza Stark Publications for gene: PHOX2B were set to
Mendeliome v0.13460 PEX26 Zornitza Stark Publications for gene: PEX26 were set to
Mendeliome v0.13457 PEX2 Zornitza Stark Publications for gene: PEX2 were set to
Mendeliome v0.13453 PEX16 Zornitza Stark Publications for gene: PEX16 were set to
Mendeliome v0.13450 PEX14 Zornitza Stark Publications for gene: PEX14 were set to
Mendeliome v0.13444 ENTPD1 Zornitza Stark Publications for gene: ENTPD1 were set to 24482476; 30652007
Mendeliome v0.13443 ENTPD1 Zornitza Stark edited their review of gene: ENTPD1: Changed publications: 24482476, 30652007, 35471564
Mendeliome v0.13442 RSPH1 Zornitza Stark Publications for gene: RSPH1 were set to
Mendeliome v0.13438 APOA5 Elena Savva Publications for gene: APOA5 were set to PMID: 19447388; 16200213; 11588264
Mendeliome v0.13438 APOA5 Elena Savva Publications for gene: APOA5 were set to
Mendeliome v0.13437 APOA5 Elena Savva reviewed gene: APOA5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19447388, 16200213, 11588264; Phenotypes: Hyperchylomicronemia, late-onset MIM#144650, {Hypertriglyceridemia, susceptibility to} MIM#145750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13437 APOA2 Elena Savva Publications for gene: APOA2 were set to
Mendeliome v0.13435 APOA2 Elena Savva reviewed gene: APOA2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 12522687, 2107739, 25904114; Phenotypes: Apolipoprotein A-II deficiency, {Hypercholesterolemia, familial, modifier of} MIM#143890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13434 APOA1 Elena Savva reviewed gene: APOA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyloidosis, 3 or more types MIM#105200, Hypoalphalipoproteinemia, primary, 2 MIM#618463, Hypoalphalipoproteinemia, primary, 2, intermediate MIM#619836; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13432 APCDD1 Elena Savva reviewed gene: APCDD1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 22512811; Phenotypes: Hypotrichosis 1 MIM#605389; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13429 PHOX2B Krithika Murali reviewed gene: PHOX2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444792; Phenotypes: Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease - MIM#209880, Neuroblastoma with Hirschsprung disease - MIM#613013; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13429 PEX26 Krithika Murali reviewed gene: PEX26: Rating: GREEN; Mode of pathogenicity: None; Publications: 12717447, 15858711, 17336976; Phenotypes: Peroxisome biogenesis disorder 7A (Zellweger) - MIM#614872, Peroxisome biogenesis disorder 7B - MIM#614873; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13429 PEX2 Krithika Murali reviewed gene: PEX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 14630978, 10528859, 23430938, 1546315; Phenotypes: Peroxisome biogenesis disorder 5A (Zellweger) - MIM#614866, Peroxisome biogenesis disorder 5B - MIM#614867; Mode of inheritance: None
Mendeliome v0.13429 PEX19 Krithika Murali reviewed gene: PEX19: Rating: GREEN; Mode of pathogenicity: None; Publications: 10051604, 20683989, 11883941, 28391327; Phenotypes: Peroxisome biogenesis disorder 12A (Zellweger) - MIM#614886; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13429 PEX16 Krithika Murali reviewed gene: PEX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 20647552, 12223482, 9837814, 11890679; Phenotypes: Peroxisome biogenesis disorder 8A (Zellweger) - MIM#614876, Peroxisome biogenesis disorder 8B - MIM#614877; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13429 PEX14 Krithika Murali reviewed gene: PEX14: Rating: GREEN; Mode of pathogenicity: None; Publications: 18285423, 26627464, 21686775, 15146459; Phenotypes: Peroxisome biogenesis disorder 13A (Zellweger) - MIM#614887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13429 PEX13 Krithika Murali reviewed gene: PEX13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 11A (Zellweger) - MIM#614883, Peroxisome biogenesis disorder 11B - MIM#614885; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13429 PEX12 Krithika Murali reviewed gene: PEX12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 3A (Zellweger) - MIM#614859, Peroxisome biogenesis disorder 3B - MIM#266510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13426 DIO1 Zornitza Stark reviewed gene: DIO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Thyroid hormone metabolism, abnormal, 2, MIM# 619855; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13425 TUBA8 Zornitza Stark Publications for gene: TUBA8 were set to 19896110; 31481326; 28388629
Mendeliome v0.13422 TUBA8 Zornitza Stark edited their review of gene: TUBA8: Added comment: Mono-allelic variants and macrothrombocytopaenia: 6 unrelated individuals with missense variants found in a large cohort of blood donors, some functional data. Individuals were generally asymptomatic.; Changed rating: AMBER; Changed publications: 34704371; Changed phenotypes: Macrothrombocytopaenia, isolated, 2, autosomal dominant, MIM# 619840; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13421 NRCAM Zornitza Stark reviewed gene: NRCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13419 PEX3 Zornitza Stark Publications for gene: PEX3 were set to
Mendeliome v0.13417 PEX3 Zornitza Stark reviewed gene: PEX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10942428, 10958759, 10968777, 27557811, 33101983; Phenotypes: Peroxisome biogenesis disorder 10A (Zellweger), MIM# 614882, Peroxisome biogenesis disorder 10B , MIM# 617370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13416 PEX5 Zornitza Stark Publications for gene: PEX5 were set to
Mendeliome v0.13414 PEX5 Zornitza Stark reviewed gene: PEX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 7719337, 26220973, 20301621; Phenotypes: Peroxisome biogenesis disorder 2A (Zellweger), MIM# 214110, Peroxisome biogenesis disorder 2B, MIM# 202370, Rhizomelic chondrodysplasia punctata, type 5, MIM# 616716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13413 PEX7 Zornitza Stark Publications for gene: PEX7 were set to
Mendeliome v0.13411 PEX7 Zornitza Stark edited their review of gene: PEX7: Added comment: Well established gene-disease associations.; Changed publications: 11781871, 12522768, 12325024; Changed phenotypes: Peroxisome biogenesis disorder 9B, MIM# 614879, Rhizomelic chondrodysplasia punctata, type 1, MIM# 215100
Mendeliome v0.13410 PFKM Zornitza Stark Publications for gene: PFKM were set to
Mendeliome v0.13408 PFKM Zornitza Stark reviewed gene: PFKM: Rating: GREEN; Mode of pathogenicity: None; Publications: 2140573, 8444874, 7513946, 7550225; Phenotypes: Glycogen storage disease VII, MIM# 232800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13407 PGAM2 Zornitza Stark Publications for gene: PGAM2 were set to
Mendeliome v0.13405 PGAM2 Zornitza Stark reviewed gene: PGAM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8447317, 34237446, 30310767; Phenotypes: Glycogen storage disease X, MIM# 261670; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13404 PHF11 Zornitza Stark reviewed gene: PHF11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13403 PHIP Zornitza Stark Publications for gene: PHIP were set to
Mendeliome v0.13401 PHIP Zornitza Stark reviewed gene: PHIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23033978, 27900362, 29209020]; Phenotypes: Chung-Jansen syndrome, MIM# 617991; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13400 PHKA2 Zornitza Stark Publications for gene: PHKA2 were set to
Mendeliome v0.13398 PHKA2 Zornitza Stark reviewed gene: PHKA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7711737, 7847371, 8733134; Phenotypes: Glycogen storage disease, type IXa1 and a2, MIM# 306000; Mode of inheritance: None
Mendeliome v0.13396 PIK3CA Zornitza Stark reviewed gene: PIK3CA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Megalencephaly-capillary malformation (MCAP) syndrome , MIM#602501, CLAPO syndrome, somatic, MIM# 613089, CLOVE syndrome, somatic, MIM# 612918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13396 PISD Zornitza Stark Phenotypes for gene: PISD were changed from to Liberfarb syndrome, MIM# 618889; Intellectual disability; cataracts; retinal degeneration; microcephaly; deafness; short stature; white matter abnormalities
Mendeliome v0.13395 PISD Zornitza Stark Publications for gene: PISD were set to
Mendeliome v0.13393 PISD Zornitza Stark edited their review of gene: PISD: Changed phenotypes: Liberfarb syndrome, MIM# 618889, Intellectual disability, cataracts, retinal degeneration, microcephaly, deafness, short stature, white matter abnormalities
Mendeliome v0.13392 PHYH Zornitza Stark Publications for gene: PHYH were set to
Mendeliome v0.13390 PHYH Zornitza Stark edited their review of gene: PHYH: Added comment: Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells.

Well established gene-disease association.; Changed publications: 9326939, 9326940
Mendeliome v0.13389 PIEZO2 Zornitza Stark Publications for gene: PIEZO2 were set to
Mendeliome v0.13387 PIEZO2 Zornitza Stark edited their review of gene: PIEZO2: Changed publications: 27653382, 27607563, 27843126, 27974811, 24726473
Mendeliome v0.13387 RSPH1 Belinda Chong reviewed gene: RSPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23993197; Phenotypes: Ciliary dyskinesia, primary, 24 MIM#615481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13387 PIEZO2 Zornitza Stark reviewed gene: PIEZO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27653382, 27607563, 27843126, 27974811; Phenotypes: Marden-Walker syndrome (MIM#248700), Arthrogryposis, distal, type 3 (MIM#114300), Arthrogryposis, distal, type 5 (MIM#108145); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13386 BSCL2 Zornitza Stark Publications for gene: BSCL2 were set to
Mendeliome v0.13384 BSCL2 Zornitza Stark edited their review of gene: BSCL2: Added comment: Multiple families reported with bi-allelic variants and isolated or syndromic lipodystrophy.

Mono-allelic variants and DEE: Two families reported with de novo variants in PMIDs 31369919 and 35290466. We are aware of further three individuals identified as a result of clinical testing, so a total of 4 with a change at position p.Pro149; Changed publications: 14981520, 15732094, 11479539, 15181077, 15126564, 23564749, 31369919, 35290466
Mendeliome v0.13383 CNNM2 Ain Roesley Publications for gene: CNNM2 were set to
Mendeliome v0.13382 CNNM2 Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13381 PIGC Zornitza Stark Publications for gene: PIGC were set to
Mendeliome v0.13379 PIGC Zornitza Stark reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694521, 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, MIM# 617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13378 CNGB1 Ain Roesley Publications for gene: CNGB1 were set to
Mendeliome v0.13377 CNGB1 Ain Roesley reviewed gene: CNGB1: Rating: ; Mode of pathogenicity: None; Publications: 11379879, 15557452, 23661369, 33847019; Phenotypes: Retinitis pigmentosa 45 MIM#613767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13376 CNGA1 Ain Roesley Publications for gene: CNGA1 were set to
Mendeliome v0.13375 CNGA1 Ain Roesley edited their review of gene: CNGA1: Changed publications: 33633220, 32705276, 30652268, 20301590, 7479749
Mendeliome v0.13375 CNGA1 Ain Roesley reviewed gene: CNGA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633220, 32705276, 30652268, 20301590, 7479749]; Phenotypes: Retinitis pigmentosa 49 MIM#613756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13375 CLN8 Ain Roesley Publications for gene: CLN8 were set to
Mendeliome v0.13374 CLN8 Ain Roesley reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: None; Publications: 10508524, 15024724, 16570191; Phenotypes: Ceroid lipofuscinosis, neuronal, 8, MIM# 600143, Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant, MIM# 610003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13373 CLN6 Ain Roesley Publications for gene: CLN6 were set to
Mendeliome v0.13372 CLN6 Ain Roesley reviewed gene: CLN6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11791207, 11727201, 21549341, 30561534; Phenotypes: Ceroid lipofuscinosis, neuronal, 6, MIM# 601780, Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, MIM# 204300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13371 CLEC7A Ain Roesley Publications for gene: CLEC7A were set to
Mendeliome v0.13370 CLEC7A Ain Roesley edited their review of gene: CLEC7A: Changed publications: 19864674, 20807886; Changed phenotypes: {Aspergillosis, susceptibility to} MIM#614079, candidiasis, familial, 4, autosomal recessive MIM#613108; Set current diagnostic: yes
Mendeliome v0.13370 CLEC7A Ain Roesley reviewed gene: CLEC7A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13369 PIGW Zornitza Stark Publications for gene: PIGW were set to
Mendeliome v0.13367 PIGW Zornitza Stark reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 24367057, 27626616, 30813920, 32198969; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13366 PIK3R2 Zornitza Stark Publications for gene: PIK3R2 were set to
Mendeliome v0.13364 PIK3R2 Zornitza Stark reviewed gene: PIK3R2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22729224, 23745724, 33604570; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, MIM# 603387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13363 PITX2 Zornitza Stark Publications for gene: PITX2 were set to
Mendeliome v0.13361 PITX2 Zornitza Stark reviewed gene: PITX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32499604, 32400113, 31341655, 31185933, 30457409; Phenotypes: Anterior segment dysgenesis 4, MIM# 137600, Axenfeld-Rieger syndrome, type 1, MIM# 180500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13361 PITX3 Zornitza Stark Phenotypes for gene: PITX3 were changed from Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia to Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia MONDO:0021129
Mendeliome v0.13360 PITX3 Zornitza Stark Phenotypes for gene: PITX3 were changed from to Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia
Mendeliome v0.13359 PITX3 Zornitza Stark Publications for gene: PITX3 were set to
Mendeliome v0.13357 PITX3 Zornitza Stark reviewed gene: PITX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29405783; Phenotypes: Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250, Cataract 11, multiple types, MIM# 610623, Microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13355 PEX11B Zornitza Stark Publications for gene: PEX11B were set to
Mendeliome v0.13352 PER2 Zornitza Stark Publications for gene: PER2 were set to
Mendeliome v0.13348 PDZD7 Zornitza Stark Publications for gene: PDZD7 were set to
Mendeliome v0.13345 PDYN Zornitza Stark Publications for gene: PDYN were set to
Mendeliome v0.13342 PDGFRA Zornitza Stark Publications for gene: PDGFRA were set to
Mendeliome v0.13339 RSPH3 Zornitza Stark Publications for gene: RSPH3 were set to
Mendeliome v0.13336 RSPH4A Zornitza Stark Publications for gene: RSPH4A were set to
Mendeliome v0.13333 RSPH9 Zornitza Stark Publications for gene: RSPH9 were set to
Mendeliome v0.13329 BVES Zornitza Stark Publications for gene: BVES were set to
Mendeliome v0.13327 BVES Zornitza Stark reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642364, 32528171, 31119192; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 25, MIM# 616812; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13326 CLDN19 Ain Roesley edited their review of gene: CLDN19: Changed publications: 17033971, 22422540, 27530400
Mendeliome v0.13325 CLDN19 Ain Roesley Publications for gene: CLDN19 were set to
Mendeliome v0.13324 CLDN19 Ain Roesley reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033971, 22422540, 27530400]; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM#248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13324 CLDN16 Ain Roesley Publications for gene: CLDN16 were set to
Mendeliome v0.13323 CLDN16 Ain Roesley reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 16501001, 10878661, 32869508; Phenotypes: Hypomagnesemia 3, renal MIM#248250, amelogenesis imperfecta MONDO#0019507, CLDN16-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13323 CLDN1 Ain Roesley Publications for gene: CLDN1 were set to
Mendeliome v0.13322 CLDN1 Ain Roesley reviewed gene: CLDN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12164927, 11889141, 29146216; Phenotypes: Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis MIM#607626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13322 CLCNKB Ain Roesley Publications for gene: CLCNKB were set to
Mendeliome v0.13320 CLCNKB Ain Roesley reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326936, 15044642, 18310267; Phenotypes: Bartter syndrome, type 3, MIM# 607364, Bartter syndrome, type 4b, digenic, MIM# 613090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13319 CLCF1 Ain Roesley Publications for gene: CLCF1 were set to
Mendeliome v0.13318 CLCF1 Ain Roesley reviewed gene: CLCF1: Rating: ; Mode of pathogenicity: None; Publications: 16782820, 20400119, 21370513; Phenotypes: Cold-induced sweating syndrome 2 MIM#610313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13318 PEX11B Krithika Murali reviewed gene: PEX11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301621, 22581968; Phenotypes: Peroxisome biogenesis disorder 14B - MIM#614920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13318 PER2 Krithika Murali reviewed gene: PER2: Rating: RED; Mode of pathogenicity: None; Publications: 33474825, 31527662, 11232563, 10408444, 11395012, 11232563; Phenotypes: ?Advanced sleep phase syndrome, familial, 1 - MIM#604348; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13318 CIT Ain Roesley Publications for gene: CIT were set to 27453578; 27503289; 27453579
Mendeliome v0.13316 CIT Ain Roesley Publications for gene: CIT were set to
Mendeliome v0.13315 CIT Ain Roesley reviewed gene: CIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453578, 27503289, 27453579; Phenotypes: Microcephaly 17, primary, autosomal recessive (MIM#617090); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13314 CISH Ain Roesley reviewed gene: CISH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13314 PDZD7 Krithika Murali reviewed gene: PDZD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 20440071, 19028668, 26416264, 26849169, 27068579, 26445815, 28173822l, 24334608; Phenotypes: Deafness, autosomal recessive 57, MIM# 618003, Usher syndrome, type IIC, GPR98/PDZD7 digenic, MIM# 605472; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13314 CISD2 Ain Roesley Publications for gene: CISD2 were set to
Mendeliome v0.13313 CISD2 Ain Roesley reviewed gene: CISD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29237418, 28335035, 27459537, 26230298, 17846994; Phenotypes: Wolfram syndrome 2 MIM#604928; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13312 CILP Ain Roesley reviewed gene: CILP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13312 PDYN Krithika Murali reviewed gene: PDYN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301317, 23471613, 23108490, 22243190, 22287014; Phenotypes: Spinocerebellar ataxia 23 - MIM#610245; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13311 CIC Ain Roesley Publications for gene: CIC were set to
Mendeliome v0.13310 CIC Ain Roesley reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28288114, 21076407; Phenotypes: Intellectual developmental disorder, autosomal dominant 45 MIM#617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13309 CHST14 Ain Roesley Publications for gene: CHST14 were set to
Mendeliome v0.13308 CHST14 Ain Roesley reviewed gene: CHST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 25703627, 26373698; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1 MIM# 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13307 CHRNA2 Ain Roesley Publications for gene: CHRNA2 were set to
Mendeliome v0.13306 CHRNA2 Ain Roesley reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826524, 25770198, 30809122, 25847220; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4 MIM#610353; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13305 CHRM2 Ain Roesley Publications for gene: CHRM2 were set to
Mendeliome v0.13304 CHRM2 Ain Roesley reviewed gene: CHRM2: Rating: RED; Mode of pathogenicity: None; Publications: 23743182, 18451336; Phenotypes: Familial Dilated Cardiomyopathy MONDO#0016333, CHRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13304 CHN1 Ain Roesley Publications for gene: CHN1 were set to 20301369
Mendeliome v0.13303 CHN1 Ain Roesley Publications for gene: CHN1 were set to
Mendeliome v0.13301 CHN1 Ain Roesley reviewed gene: CHN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301369; Phenotypes: Duane retraction syndrome 2,MIM#604356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13301 CHMP4B Ain Roesley Phenotypes for gene: CHMP4B were changed from to Cataract 31, multiple types MIM#605387
Mendeliome v0.13300 CHMP4B Ain Roesley Publications for gene: CHMP4B were set to
Mendeliome v0.13299 CHMP4B Ain Roesley reviewed gene: CHMP4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 34722561, 17701905, 10682967, 30078984; Phenotypes: Cataract 31, multiple types MIM#605387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13299 CHM Ain Roesley Publications for gene: CHM were set to
Mendeliome v0.13298 CHM Ain Roesley reviewed gene: CHM: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301511; Phenotypes: Choroideremia MIM#303100; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.13298 CHIT1 Ain Roesley Publications for gene: CHIT1 were set to
Mendeliome v0.13296 CHIT1 Ain Roesley reviewed gene: CHIT1: Rating: RED; Mode of pathogenicity: None; Publications: 23430794; Phenotypes: [Chitotriosidase deficiency] MIM#614122; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13296 CHD1 Ain Roesley Publications for gene: CHD1 were set to
Mendeliome v0.13294 CHD1 Ain Roesley reviewed gene: CHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: Pilarowski-Bjornsson syndrome, MIM#617682; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13293 CFP Ain Roesley Publications for gene: CFP were set to
Mendeliome v0.13292 CFP Ain Roesley reviewed gene: CFP: Rating: GREEN; Mode of pathogenicity: None; Publications: 8871668, 10909851, 22229731, 9476131, 10698340, 10540191, 16511390, 19328743; Phenotypes: Properdin deficiency, X-linked MIM#312060; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v0.13292 PDGFRA Krithika Murali reviewed gene: PDGFRA: Rating: GREEN; Mode of pathogenicity: None; Publications: 14699510, 17087943, 25975287, 29486293, 33449152, 34107389, 17566086, 18670346; Phenotypes: Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial - MIM#175510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13291 CFI Ain Roesley Publications for gene: CFI were set to
Mendeliome v0.13289 CFI Ain Roesley reviewed gene: CFI: Rating: GREEN; Mode of pathogenicity: None; Publications: 29292855, 28942469, 27091480, 20301541; Phenotypes: Complement factor I deficiency MIM#610984, {Hemolytic uremic syndrome, atypical, susceptibility to, 3} MIM#612923; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13289 RSPH3 Belinda Chong reviewed gene: RSPH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26073779; Phenotypes: Ciliary dyskinesia, primary, 32 MIM#616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13287 PKD1 Zornitza Stark reviewed gene: PKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 1, MIM# 173900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13285 PKD2 Zornitza Stark reviewed gene: PKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 2, MIM# 613095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13284 PKLR Zornitza Stark Publications for gene: PKLR were set to
Mendeliome v0.13282 PKLR Zornitza Stark reviewed gene: PKLR: Rating: GREEN; Mode of pathogenicity: None; Publications: 1896471, 9160692, 9057665, 16704447, 9090535; Phenotypes: Pyruvate kinase deficiency, MIM# 266200, Adenosine triphosphate, elevated, of erythrocytes, MIM# 102900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13281 PKP1 Zornitza Stark Publications for gene: PKP1 were set to
Mendeliome v0.13279 PKP1 Zornitza Stark reviewed gene: PKP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24073657, 16781314, 11994137, 10951270, 32346906; Phenotypes: Ectodermal dysplasia/skin fragility syndrome, MIM# 604536; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13278 PLA2G5 Zornitza Stark Publications for gene: PLA2G5 were set to
Mendeliome v0.13276 PLA2G5 Zornitza Stark reviewed gene: PLA2G5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22137173; Phenotypes: [Fleck retina, familial benign], MIM# 228980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13275 PLCE1 Zornitza Stark Publications for gene: PLCE1 were set to
Mendeliome v0.13273 PLCE1 Zornitza Stark reviewed gene: PLCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17086182, 18065803, 20591883; Phenotypes: Nephrotic syndrome, type 3, MIM# 610725; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13272 PLCG2 Zornitza Stark Publications for gene: PLCG2 were set to
Mendeliome v0.13268 PLEKHM1 Zornitza Stark Publications for gene: PLEKHM1 were set to 27291868; 21054159; 17997709; 17404618
Mendeliome v0.13266 PLEKHM1 Zornitza Stark edited their review of gene: PLEKHM1: Changed publications: 27291868, 21054159, 17997709, 17404618, 28290981; Changed phenotypes: Osteopetrosis, autosomal dominant 3, MIM# 618107, Osteopetrosis, autosomal recessive 6 , MIM# 611497; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13265 PLEKHM1 Zornitza Stark Publications for gene: PLEKHM1 were set to
Mendeliome v0.13263 PLEKHM1 Zornitza Stark reviewed gene: PLEKHM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27291868, 21054159, 17997709, 17404618; Phenotypes: Osteopetrosis, autosomal dominant 3, MIM# 618107; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13263 RSPH4A Belinda Chong edited their review of gene: RSPH4A: Changed publications: 23798057, 23798057, 23798057, 25789548, 22448264
Mendeliome v0.13263 RSPH4A Belinda Chong reviewed gene: RSPH4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23798057, 23798057, 23798057; Phenotypes: Ciliary dyskinesia, primary, 11 OMIM#612649; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13263 RSPH9 Belinda Chong reviewed gene: RSPH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25789548, 22384920, 23993197, 19200523, 27626380; Phenotypes: Ciliary dyskinesia, primary, 12 MIM#612650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13262 PLN Zornitza Stark Publications for gene: PLN were set to
Mendeliome v0.13260 PLN Zornitza Stark reviewed gene: PLN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33947203; Phenotypes: Cardiomyopathy, dilated, 1P, MIM# 609909, Cardiomyopathy, hypertrophic, 18 (MIM #613874); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13259 PLOD1 Zornitza Stark Publications for gene: PLOD1 were set to
Mendeliome v0.13257 PLOD1 Zornitza Stark reviewed gene: PLOD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306225; Phenotypes: Ehlers-Danlos syndrome, kyphoscoliotic type, 1.<O<# 225400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13256 PLOD2 Zornitza Stark Publications for gene: PLOD2 were set to
Mendeliome v0.13254 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22689593, 12881513, 33664768, 33778323, 29178448; Phenotypes: Bruck syndrome 2, MIM# 609220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13253 PMFBP1 Zornitza Stark Publications for gene: PMFBP1 were set to
Mendeliome v0.13251 PMFBP1 Zornitza Stark reviewed gene: PMFBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33484382, 33452591, 32285443; Phenotypes: Male infertility with teratozoospermia due to single gene mutation, MONDO:0018394; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13250 PMPCA Zornitza Stark Publications for gene: PMPCA were set to
Mendeliome v0.13248 PMPCA Zornitza Stark reviewed gene: PMPCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25808372, 26657514, 33272776, 30617178; Phenotypes: Spinocerebellar ataxia, autosomal recessive 2, MIM# 213200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13247 PMPCB Zornitza Stark Publications for gene: PMPCB were set to
Mendeliome v0.13244 PNPO Zornitza Stark Publications for gene: PNPO were set to
Mendeliome v0.13242 PNPO Zornitza Stark reviewed gene: PNPO: Rating: GREEN; Mode of pathogenicity: None; Publications: 34769443, 33981986, 33748042, 32888189; Phenotypes: Pyridoxamine 5'-phosphate oxidase deficiency, MIM# 610090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13241 PODXL Zornitza Stark Publications for gene: PODXL were set to
Mendeliome v0.13239 PODXL Zornitza Stark reviewed gene: PODXL: Rating: GREEN; Mode of pathogenicity: None; Publications: 30523047, 29244787, 28117080, 24048372; Phenotypes: Nephrotic syndrome, MONDO:0005377, PODXL-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13238 POFUT1 Zornitza Stark Publications for gene: POFUT1 were set to
Mendeliome v0.13235 POLG Zornitza Stark Publications for gene: POLG were set to
Mendeliome v0.13234 POLG Zornitza Stark edited their review of gene: POLG: Changed publications: 30451971
Mendeliome v0.13233 POLG Zornitza Stark reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Progressive external ophthalmoplegia, autosomal dominant 1, MIM# 157640; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13232 POMGNT1 Zornitza Stark Publications for gene: POMGNT1 were set to
Mendeliome v0.13230 POMGNT1 Zornitza Stark reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27391550, 26908613, 30961548, 30937090; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 MIM#614830, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135, Retinitis pigmentosa 76 617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13229 POMGNT2 Zornitza Stark Publications for gene: POMGNT2 were set to
Mendeliome v0.13227 POMGNT2 Zornitza Stark reviewed gene: POMGNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34301702, 27066570, 26060116, 22958903; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13226 POMK Zornitza Stark Publications for gene: POMK were set to
Mendeliome v0.13224 POMK Zornitza Stark reviewed gene: POMK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32907597, 31833209, 29910097, 28109637, 24925318, 24556084; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12, MIM# 615249, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 12, MIM# 616094; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13223 RAX2 Zornitza Stark Publications for gene: RAX2 were set to
Mendeliome v0.13221 RAX2 Zornitza Stark reviewed gene: RAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15028672, 25789692, 30607024; Phenotypes: Cone-rod dystrophy 11, MIM# 610381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13221 DNAJB11 Zornitza Stark Publications for gene: DNAJB11 were set to 29706351; 29777155; 33129895
Mendeliome v0.13219 PDX1 Zornitza Stark Publications for gene: PDX1 were set to
Mendeliome v0.13216 PDP1 Zornitza Stark Publications for gene: PDP1 were set to 15855260
Mendeliome v0.13215 PDP1 Zornitza Stark reviewed gene: PDP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31392110, 19184109, 15855260; Phenotypes: Pyruvate dehydrogenase phosphatase deficiency - MIM#608782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13214 PDP1 Zornitza Stark Publications for gene: PDP1 were set to
Mendeliome v0.13209 RSPO1 Zornitza Stark Publications for gene: RSPO1 were set to
Mendeliome v0.13205 FAT1 Zornitza Stark reviewed gene: FAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease MONDO:0002254, FAT1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13202 PDHA1 Zornitza Stark Publications for gene: PDHA1 were set to
Mendeliome v0.13200 FAS Zornitza Stark reviewed gene: FAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13199 PDE6H Zornitza Stark Publications for gene: PDE6H were set to
Mendeliome v0.13196 PDE6G Zornitza Stark Publications for gene: PDE6G were set to
Mendeliome v0.13192 PDE6C Zornitza Stark Publications for gene: PDE6C were set to
Mendeliome v0.13190 PDE6C Zornitza Stark reviewed gene: PDE6C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19615668, 30080950; Phenotypes: Cone dystrophy 4, MIM# 613093, Achromatopsia-5; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13189 PDE6B Zornitza Stark Publications for gene: PDE6B were set to
Mendeliome v0.13186 PDE6A Zornitza Stark Publications for gene: PDE6A were set to
Mendeliome v0.13184 PDE6A Zornitza Stark reviewed gene: PDE6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 35033039, 34926197, 18849587; Phenotypes: Retinitis pigmentosa 43 - MIM#613810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13183 PDE4D Zornitza Stark Publications for gene: PDE4D were set to
Mendeliome v0.13181 PDE4D Zornitza Stark reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: 22464250, 22464252, 23033274, 24203977; Phenotypes: Acrodysostosis 2, with or without hormone resistance, MIM# 614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13178 PDE11A Zornitza Stark Publications for gene: PDE11A were set to
Mendeliome v0.13174 SHH Zornitza Stark Publications for gene: SHH were set to
Mendeliome v0.13172 FAM111B Zornitza Stark reviewed gene: FAM111B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13172 SH3BP2 Zornitza Stark commented on gene: SH3BP2: Cherubism is characterized by a loss of bone, restricted to the jaws, and by the replacement of this bone with fibrous tissues, leading to facial swelling. Involvement of the infraorbital rim and the orbital floor leads to the upward tilting of the eyeballs and consequent exposure of the inferior part of the sclerae, giving a 'cherubic' appearance. Submandibular lymph node enlargement is often reported. Functional impairment includes mastication and speech problems, tooth alterations, and loss of normal vision. Onset of the disease is usually between 14 months and 4 years of age. The disease progresses through puberty, then stabilizes, and in some cases regresses without treatment.
Mendeliome v0.13171 SH3BP2 Zornitza Stark Publications for gene: SH3BP2 were set to
Mendeliome v0.13168 SH3BP2 Zornitza Stark reviewed gene: SH3BP2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: Cherubism, MIM#118400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13167 ATP11A Zornitza Stark reviewed gene: ATP11A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 24 , MIM# 619851; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13165 CEBPA Zornitza Stark Publications for gene: CEBPA were set to
Mendeliome v0.13162 CEBPA Zornitza Stark reviewed gene: CEBPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 15575056, 32430494, 31309983; Phenotypes: Leukaemia, acute myeloid , MIM# 601626; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13159 CDKN2A Zornitza Stark reviewed gene: CDKN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Melanoma, cutaneous malignant, 2} MIM#155601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13158 DNAJB11 Elena Savva reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34177435, 29706351, 29777155, 33129895; Phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome, Prenatal Polycystic Kidney Disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13156 SLC12A3 Zornitza Stark Publications for gene: SLC12A3 were set to
Mendeliome v0.13154 SLC12A3 Zornitza Stark reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 8528245, 11102542; Phenotypes: Gitelman syndrome, MIM# 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13154 CC2D2A Zornitza Stark Publications for gene: CC2D2A were set to 18387594; 18950740; 18513680; 18950740; 19574260; 21725307; 33486889
Mendeliome v0.13153 CC2D2A Zornitza Stark edited their review of gene: CC2D2A: Changed publications: 18387594, 18950740, 18513680, 18950740, 19574260, 21725307, 33486889, 30267408
Mendeliome v0.13151 SLC12A1 Zornitza Stark Publications for gene: SLC12A1 were set to
Mendeliome v0.13149 SLC12A1 Zornitza Stark reviewed gene: SLC12A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8640224, 9355073, 28095294; Phenotypes: Bartter syndrome, type 1, MIM# 601678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13148 FGF23 Bryony Thompson Publications for gene: FGF23 were set to
Mendeliome v0.13147 PDX1 Krithika Murali reviewed gene: PDX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326926, 10545531, 10720084, 12970316, 20009086, 19496967; Phenotypes: Pancreatic agenesis 1 - MIM#260370 (AR), MODY, type IV - MIM#606392(AD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13143 FGF23 Bryony Thompson reviewed gene: FGF23: Rating: GREEN; Mode of pathogenicity: Other; Publications: 11062477, 14966565, 15590700, 16151858, 16030159, 25378588, 34444516; Phenotypes: autosomal dominant hypophosphatemic rickets MONDO:0008660, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome MONDO:0100251; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13143 PDP1 Krithika Murali reviewed gene: PDP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15855260; Phenotypes: Pyruvate dehydrogenase phosphatase deficiency - MIM#608782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13143 PDHB Krithika Murali reviewed gene: PDHB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pyruvate dehydrogenase E1-beta deficiency - MIM#614111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13143 FGF14 Bryony Thompson Publications for gene: FGF14 were set to
Mendeliome v0.13141 FGF14 Bryony Thompson edited their review of gene: FGF14: Added comment: 4 families with spinocerebellar ataxia and 7 families with episodic ataxia. Supporting animal models for both SCA and EA.; Changed publications: 12123606, 12489043, 15470364, 29253853, 30017992, 32112487, 32162847; Changed phenotypes: spinocerebellar ataxia type 27 MONDO:0012247, hereditary episodic ataxia MONDO:0016227; Set current diagnostic: yes
Mendeliome v0.13140 FGF10 Bryony Thompson Publications for gene: FGF10 were set to
Mendeliome v0.13138 FGF10 Bryony Thompson reviewed gene: FGF10: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916808, 15654336, 16501574, 16630169, 17213838, 33967277, 30639323; Phenotypes: congenital alveolar dysplasia due to FGF10 MONDO:0100090, acinar dysplasia caused by mutation in FGF10 MONDO:0600017; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13137 FFAR4 Bryony Thompson Publications for gene: FFAR4 were set to
Mendeliome v0.13136 FDXR Bryony Thompson reviewed gene: FDXR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.13135 FFAR4 Bryony Thompson reviewed gene: FFAR4: Rating: RED; Mode of pathogenicity: None; Publications: 22343897, 34043793; Phenotypes: {Obesity, susceptibility to} MIM#607514; Mode of inheritance: Unknown
Mendeliome v0.13134 FDX2 Bryony Thompson Publications for gene: FDX2 were set to
Mendeliome v0.13132 FDX2 Bryony Thompson reviewed gene: FDX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24281368, 28803783, 30010796, 35079622, 34905296; Phenotypes: inborn mitochondrial myopathy MONDO:0009637; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13131 FDFT1 Bryony Thompson Publications for gene: FDFT1 were set to
Mendeliome v0.13129 FDFT1 Bryony Thompson reviewed gene: FDFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909962; Phenotypes: squalene synthase deficiency MONDO:0032566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13128 FBXO7 Bryony Thompson Publications for gene: FBXO7 were set to
Mendeliome v0.13125 FBXO7 Bryony Thompson reviewed gene: FBXO7: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513678, 19038853, 34781237; Phenotypes: parkinsonian-pyramidal syndrome MONDO:0009830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13125 RSPO1 Belinda Chong reviewed gene: RSPO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17041600, 18085567, 18250098, 18250097; Phenotypes: Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644, Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13123 FBP1 Bryony Thompson Publications for gene: FBP1 were set to
Mendeliome v0.13121 FBP1 Bryony Thompson reviewed gene: FBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9382095, 12126934, 27101822, 30858132; Phenotypes: fructose-1,6-bisphosphatase deficiency MONDO:0009251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13121 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.13120 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.13119 GLRA2 Zornitza Stark gene: GLRA2 was added
gene: GLRA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GLRA2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GLRA2 were set to 26370147; 20479760; 35294868
Phenotypes for gene: GLRA2 were set to Intellectual developmental disorder, X-linked, syndromic, Pilorge type, MIM# 301076
Review for gene: GLRA2 was set to GREEN
Added comment: More than 10 unrelated families reported. Both males and females affected, though some mothers are asymptomatic or mild. Zebrafish model.
Sources: Expert list
Mendeliome v0.13116 FASTKD2 Bryony Thompson Publications for gene: FASTKD2 were set to
Mendeliome v0.13115 FASTKD2 Bryony Thompson reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 34234304; Phenotypes: FASTKD2-related infantile mitochondrial encephalomyopathy MONDO:0015632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13114 FASLG Bryony Thompson Publications for gene: FASLG were set to
Mendeliome v0.13112 FASLG Bryony Thompson reviewed gene: FASLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16627752, 17605793, 19794494, 8787672, 22857792, 33356695, 26334989, 25451160; Phenotypes: autoimmune lymphoproliferative syndrome MONDO:0017979; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13112 PDHA1 Krithika Murali reviewed gene: PDHA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8504309; Phenotypes: Pyruvate dehydrogenase E1-alpha deficiency - MIM#312170; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.13111 FAS Bryony Thompson Publications for gene: FAS were set to
Mendeliome v0.13109 FAS Bryony Thompson reviewed gene: FAS: Rating: ; Mode of pathogenicity: None; Publications: 7540117, 7539157, 15459302, 33995372, 34171534; Phenotypes: autoimmune lymphoproliferative syndrome MONDO:0017979; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13109 FARSB Bryony Thompson Phenotypes for gene: FARSB were changed from to Rajab interstitial lung disease with brain calcifications 1 MONDO:0100215
Mendeliome v0.13108 FARSB Bryony Thompson Publications for gene: FARSB were set to
Mendeliome v0.13106 FARSB Bryony Thompson reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573043, 30014610, 29979980; Phenotypes: Rajab interstitial lung disease with brain calcifications 1 MONDO:0100215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13105 FARS2 Bryony Thompson Publications for gene: FARS2 were set to
Mendeliome v0.13103 PDE6H Krithika Murali reviewed gene: PDE6H: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901948; Phenotypes: Achromatopsia 6 - MIM#610024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13103 FARS2 Bryony Thompson reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250868, 30177229, 29126765, 28043061; Phenotypes: combined oxidative phosphorylation defect type 14 MONDO:0013986, hereditary spastic paraplegia 77 MONDO:0014882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13102 FAM58A Bryony Thompson Publications for gene: FAM58A were set to
Mendeliome v0.13101 PDE6G Krithika Murali reviewed gene: PDE6G: Rating: AMBER; Mode of pathogenicity: None; Publications: 20655036; Phenotypes: Retinitis pigmentosa 57 - MIM#613582; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13101 PDE6C Krithika Murali reviewed gene: PDE6C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone dystrophy 4 - MIM#613093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13100 PDE6B Krithika Murali reviewed gene: PDE6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8394174, 8075643, 17044014, 7599633, 18854872; Phenotypes: Night blindness, congenital stationary, autosomal dominant 2 - MIM#163500, Retinitis pigmentosa-40 - MIM#613801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13100 PDE6A Krithika Murali reviewed gene: PDE6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21039428, 17110911, 7493036; Phenotypes: Retinitis pigmentosa 43 - MIM#613810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13100 FAM58A Bryony Thompson reviewed gene: FAM58A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18297069, 8818947, 28322501, 8818947; Phenotypes: syndactyly-telecanthus-anogenital and renal malformations syndrome MONDO:0010408; Mode of inheritance: Other; Current diagnostic: yes
Mendeliome v0.13100 PDE4D Krithika Murali reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: 24203977, 22464250; Phenotypes: Acrodysostosis 2, with or without hormone resistance-MIM#614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13100 PDE3A Krithika Murali reviewed gene: PDE3A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertension and brachydactyly syndrome - MIM#112410; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13100 PDE11A Krithika Murali reviewed gene: PDE11A: Rating: RED; Mode of pathogenicity: None; Publications: 16767104, 18559625, 21047926, 17178847; Phenotypes: Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13099 FAM161A Bryony Thompson Publications for gene: FAM161A were set to
Mendeliome v0.13097 FAM161A Bryony Thompson reviewed gene: FAM161A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20705278, 20705279, 31236346, 24833722; Phenotypes: retinitis pigmentosa 28 MONDO:0011630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13097 FAM126A Bryony Thompson Publications for gene: FAM126A were set to
Mendeliome v0.13096 SHH Samantha Ayres reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 21976454, 12503095, 22791840, 19057928, 19533790; Phenotypes: Holoprosencephaly 3, MIM#142945, Microphthalmia with coloboma 5, MIM#611638, Schizencephaly, MIM#269160, Single median maxillary central incisor, MIM#147250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13095 FAM126A Bryony Thompson reviewed gene: FAM126A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16951682, 21911699, 23998934, 22749724; Phenotypes: hypomyelinating leukodystrophy 5 MONDO:0012514; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13093 FAM111B Bryony Thompson Publications for gene: FAM111B were set to
Mendeliome v0.13090 FAM111B Bryony Thompson reviewed gene: FAM111B: Rating: ; Mode of pathogenicity: Other; Publications: 24268661, 26471370, 26495788, 27406236; Phenotypes: hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13089 FAM111A Bryony Thompson Publications for gene: FAM111A were set to
Mendeliome v0.13086 FAM111A Bryony Thompson reviewed gene: FAM111A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23684011, 32996714, 32765931, 33010201; Phenotypes: autosomal dominant Kenny-Caffey syndrome MONDO:0007478; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13085 FADD Bryony Thompson Publications for gene: FADD were set to
Mendeliome v0.13083 FAH Bryony Thompson Publications for gene: FAH were set to
Mendeliome v0.13081 FAH Bryony Thompson reviewed gene: FAH: Rating: GREEN; Mode of pathogenicity: None; Publications: 8253378, 1401056, 8364576, 8318997, 25681080; Phenotypes: Tyrosinemia type I MONDO:0010161; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13080 FADD Bryony Thompson reviewed gene: FADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 21109225, 25794656, 32350755, 32971525; Phenotypes: FADD-related immunodeficiency MONDO:0013408; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13080 SH3BP2 Samantha Ayres reviewed gene: SH3BP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11381256, 22640988, 20301316, 22153076; Phenotypes: Cherubism, MIM#118400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13079 F12 Bryony Thompson Publications for gene: F12 were set to
Mendeliome v0.13077 POMP Zornitza Stark Publications for gene: POMP were set to
Mendeliome v0.13075 POMP Zornitza Stark reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20226437, 27503413, 29805043; Phenotypes: Keratosis linearis with ichthyosis congenita and sclerosing keratoderma MIM#601952, Proteasome-associated autoinflammatory syndrome 2, MIM# 618048; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13073 POMT1 Zornitza Stark reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 613155, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13071 POMT2 Zornitza Stark reviewed gene: POMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150 Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2 613156 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 613158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13068 PPARA Zornitza Stark reviewed gene: PPARA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hyperapobetalipoproteinemia, susceptibility to}; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13067 PPM1K Zornitza Stark Publications for gene: PPM1K were set to
Mendeliome v0.13064 PPM1K Zornitza Stark reviewed gene: PPM1K: Rating: RED; Mode of pathogenicity: None; Publications: 23086801; Phenotypes: Maple syrup urine disease, mild variant, MIM#615135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13063 PPOX Zornitza Stark Publications for gene: PPOX were set to
Mendeliome v0.13061 PPOX Zornitza Stark reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 12357337, 32247286, 23324528, 27982422; Phenotypes: Porphyria variegata , MIM#176200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13061 SH2D1A Samantha Ayres reviewed gene: SH2D1A: Rating: ; Mode of pathogenicity: None; Publications: 6306053, 9771704, 11049992, 20301580; Phenotypes: Lymphoproliferative syndrome, X-linked, 1, MIM# 308240; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13061 SGCG Samantha Ayres reviewed gene: SGCG: Rating: GREEN; Mode of pathogenicity: None; Publications: 18285821, 8923014, 7481775, 8968757, 27708273; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 5 MIM#253700, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13060 CFHR5 Ain Roesley Publications for gene: CFHR5 were set to
Mendeliome v0.13059 CFHR5 Ain Roesley reviewed gene: CFHR5: Rating: GREEN; Mode of pathogenicity: None; Publications: 30844074, 30197990, 24067434, 21566112, 20800271, 27490940, 24334459; Phenotypes: Nephropathy due to CFHR5 deficiency, MIM#614809; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13059 CFH Ain Roesley Publications for gene: CFH were set to
Mendeliome v0.13058 CFH Ain Roesley reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: 27572114, 25814826, 20301541, 9312129, 10803850, 29888403, 30905644; Phenotypes: Basal laminar drusen MIM#126700, Complement factor H deficiency MIM#609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1} MIMI#235400; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13057 PPP1R15B Zornitza Stark Publications for gene: PPP1R15B were set to
Mendeliome v0.13054 PPP1R15B Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 26159176, 26307080, 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13053 PPP1R3A Zornitza Stark Publications for gene: PPP1R3A were set to
Mendeliome v0.13050 PPP1R3A Zornitza Stark reviewed gene: PPP1R3A: Rating: RED; Mode of pathogenicity: None; Publications: 29948331, 12118251, 18232732; Phenotypes: Insulin resistance, severe, digenic 125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13049 PRCD Zornitza Stark Publications for gene: PRCD were set to
Mendeliome v0.13047 PRCD Zornitza Stark reviewed gene: PRCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 16938425, 20507925, 33087780, 31640229, 31189593, 26497376; Phenotypes: Retinitis pigmentosa 36, MIM# 610599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13046 PRDM16 Zornitza Stark Publications for gene: PRDM16 were set to
Mendeliome v0.13043 PRDM16 Zornitza Stark reviewed gene: PRDM16: Rating: AMBER; Mode of pathogenicity: None; Publications: 23768516, 29367541, 34915728, 31965688, 29367541; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13042 CFD Ain Roesley Publications for gene: CFD were set to
Mendeliome v0.13040 CFD Ain Roesley reviewed gene: CFD: Rating: GREEN; Mode of pathogenicity: None; Publications: 11457876, 16527897, 31440263; Phenotypes: Complement factor D deficiency MIM#613912; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13039 CEP78 Ain Roesley Publications for gene: CEP78 were set to
Mendeliome v0.13038 CEP78 Ain Roesley reviewed gene: CEP78: Rating: GREEN; Mode of pathogenicity: None; Publications: 28005958, 27588451, 27588452, 27627988; Phenotypes: Cone-rod dystrophy and hearing loss MIM#617236; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13037 CEBPA Ain Roesley reviewed gene: CEBPA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukemia, acute myeloid, somatic MIM#601626; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13037 CEACAM16 Ain Roesley Publications for gene: CEACAM16 were set to
Mendeliome v0.13036 CEACAM16 Ain Roesley reviewed gene: CEACAM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 21368133, 22544735, 29703829, 25589040, 31249509, 30514912; Phenotypes: Deafness, autosomal dominant 4B, MIM# 614614, Deafness, autosomal recessive 113, MIM# 618410; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13035 CDKN2A Ain Roesley reviewed gene: CDKN2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Melanoma and neural system tumor syndrome} MIM#155755, {Melanoma, cutaneous malignant, 2} MIM#155601, {Melanoma-pancreatic cancer syndrome} MIM#606719; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13034 CDKN1B Ain Roesley Publications for gene: CDKN1B were set to
Mendeliome v0.13033 CDKN1B Ain Roesley reviewed gene: CDKN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 24819502, 17030811, 23555276; Phenotypes: Multiple endocrine neoplasia type 4, MEN4, OMIM #610755; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13031 CDK4 Ain Roesley reviewed gene: CDK4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Melanoma, cutaneous malignant, 3} MIM#609048; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13031 CDK10 Ain Roesley Publications for gene: CDK10 were set to
Mendeliome v0.13030 CDK10 Ain Roesley reviewed gene: CDK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 28886341, 34974531; Phenotypes: Al Kaissi syndrome MIM#617694; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13029 CDHR1 Ain Roesley Publications for gene: CDHR1 were set to
Mendeliome v0.13028 CDHR1 Ain Roesley reviewed gene: CDHR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20805371, 20087419, 34926197, 32277948, 32783370, 31387115, 32681094; Phenotypes: Cone-rod dystrophy 15 MIM#613660, Retinitis pigmentosa 65 MIM#613660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13028 CDC73 Ain Roesley Publications for gene: CDC73 were set to
Mendeliome v0.13027 CDC73 Ain Roesley reviewed gene: CDC73: Rating: GREEN; Mode of pathogenicity: None; Publications: 12434154; Phenotypes: Hyperparathyroidism-jaw tumour syndrome, MIM# 145001, Hyperparathyroidism, familial primary, MIM# 145000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13026 CDC42 Ain Roesley Publications for gene: CDC42 were set to 29394990; 31601675; 32303876; 32231661
Mendeliome v0.13025 CDC42 Ain Roesley Publications for gene: CDC42 were set to
Mendeliome v0.13024 CDC42 Ain Roesley reviewed gene: CDC42: Rating: GREEN; Mode of pathogenicity: None; Publications: 29394990, 31601675, 32303876, 32231661; Phenotypes: Takenouchi-Kosaki syndrome, MIM#616737; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13023 CDC14A Ain Roesley Publications for gene: CDC14A were set to
Mendeliome v0.13022 CDC14A Ain Roesley reviewed gene: CDC14A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29293958, 2725905; Phenotypes: Deafness, autosomal recessive 32, with or without immotile sperm, MIM# 608653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13022 CD79B Ain Roesley Publications for gene: CD79B were set to
Mendeliome v0.13020 CD79B Ain Roesley reviewed gene: CD79B: Rating: GREEN; Mode of pathogenicity: None; Publications: 17709424, 17675462, 33733381, 24722855; Phenotypes: Agammaglobulinemia 6 MIM#612692; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13019 PRDM5 Zornitza Stark Publications for gene: PRDM5 were set to
Mendeliome v0.13017 PRDM5 Zornitza Stark reviewed gene: PRDM5: Rating: GREEN; Mode of pathogenicity: None; Publications: 21664999, 22122778, 21664999, 33739556, 27032025; Phenotypes: Brittle cornea syndrome 2, MIM# 614170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13016 PREPL Zornitza Stark Publications for gene: PREPL were set to
Mendeliome v0.13013 PRG4 Zornitza Stark Publications for gene: PRG4 were set to
Mendeliome v0.13011 PRG4 Zornitza Stark reviewed gene: PRG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545950, 29397575; Phenotypes: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome, MIM# 208250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13009 PRICKLE1 Zornitza Stark Publications for gene: PRICKLE1 were set to
Mendeliome v0.13007 PRICKLE1 Zornitza Stark reviewed gene: PRICKLE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34597683, 30564977, 30345727, 29790814, 26727662, 31035234; Phenotypes: Epilepsy, progressive myoclonic 1B, MIM# 612437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13006 PRKAR1A Zornitza Stark Publications for gene: PRKAR1A were set to
Mendeliome v0.13004 PRKAR1A Zornitza Stark reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973256, 11115848, 12424709, 21651393; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800, Carney complex, type 1, MIM# 160980, Myxoma, intracardiac, MIM# 255960, Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13003 PRKCG Zornitza Stark Publications for gene: PRKCG were set to
Mendeliome v0.13001 PRKCG Zornitza Stark reviewed gene: PRKCG: Rating: GREEN; Mode of pathogenicity: None; Publications: 12644968, 14676051, 14694043, 16193476, 33739604, 34292398; Phenotypes: Spinocerebellar ataxia 14, MIM# 605361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13000 PRKG1 Zornitza Stark Publications for gene: PRKG1 were set to
Mendeliome v0.12998 PRKG1 Zornitza Stark reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 23910461, 30577811; Phenotypes: Aortic aneurysm, familial thoracic 8, MIM# 615436; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12997 PRMT7 Zornitza Stark Publications for gene: PRMT7 were set to
Mendeliome v0.12995 PRMT7 Zornitza Stark reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26437029, 27718516, 30513135; Phenotypes: Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12994 PRODH Zornitza Stark Publications for gene: PRODH were set to
Mendeliome v0.12991 PROK2 Zornitza Stark Publications for gene: PROK2 were set to
Mendeliome v0.12989 PROK2 Zornitza Stark reviewed gene: PROK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18559922, 17054399, 17959774, 18285834; Phenotypes: Hypogonadotropic hypogonadism 4 with or without anosmia, MIM# 610628; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12988 PROM1 Zornitza Stark Publications for gene: PROM1 were set to
Mendeliome v0.12986 PROM1 Zornitza Stark reviewed gene: PROM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10587575, 17605048, 18654668, 29416601, 31576780, 34664634, 32820593; Phenotypes: Inherited retinal dystrophy, MONDO:0019118, Cone-rod dystrophy 12, MIM# 612657, Macular dystrophy, retinal, 2, MI# 608051, Retinitis pigmentosa 41, MIM# 612095, Stargardt disease 4, MIM# 603786; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12985 PROS1 Zornitza Stark Publications for gene: PROS1 were set to
Mendeliome v0.12983 PROS1 Zornitza Stark reviewed gene: PROS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7545463, 19466456, 10063989, 20484936, 19729839; Phenotypes: Thrombophilia 5 due to protein S deficiency, autosomal dominant, MIM# 612336, Thrombophilia 5 due to protein S deficiency, autosomal recessive, MIM# 614514; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12982 PRPF3 Zornitza Stark Publications for gene: PRPF3 were set to
Mendeliome v0.12980 PRPF3 Zornitza Stark reviewed gene: PRPF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11773002, 27886254; Phenotypes: Retinitis pigmentosa 18, MIM# 601414; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12979 PRPF4 Zornitza Stark Publications for gene: PRPF4 were set to
Mendeliome v0.12977 PRPF4 Zornitza Stark reviewed gene: PRPF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24419317, 25383878; Phenotypes: Retinitis pigmentosa 70, MIM# 615922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12976 PRPF6 Zornitza Stark Publications for gene: PRPF6 were set to
Mendeliome v0.12973 PRPF6 Zornitza Stark reviewed gene: PRPF6: Rating: AMBER; Mode of pathogenicity: None; Publications: 21549338, 32335390; Phenotypes: Retinitis pigmentosa 60, MIM# 613983; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12972 PRPH Zornitza Stark Publications for gene: PRPH were set to
Mendeliome v0.12969 PRPH Zornitza Stark reviewed gene: PRPH: Rating: AMBER; Mode of pathogenicity: None; Publications: 20363051, 15322088, 15446584; Phenotypes: {Amyotrophic lateral sclerosis, susceptibility to}, 105400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12968 PRSS1 Zornitza Stark Publications for gene: PRSS1 were set to
Mendeliome v0.12966 PRSS1 Zornitza Stark reviewed gene: PRSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841182, 10204851, 10529393, 11097832, 11702203, 15776435, 16791840, 18461367, 17072318; Phenotypes: Pancreatitis, hereditary, MIM# 167800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12965 PRSS12 Zornitza Stark Publications for gene: PRSS12 were set to
Mendeliome v0.12962 PRSS12 Zornitza Stark reviewed gene: PRSS12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12961 PSMC2 Zornitza Stark reviewed gene: PSMC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.12960 PSMC3IP Zornitza Stark Publications for gene: PSMC3IP were set to
Mendeliome v0.12958 PSMC3IP Zornitza Stark reviewed gene: PSMC3IP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963259, 35352317, 34878148, 30406445, 29240891; Phenotypes: Ovarian dysgenesis 3, MIM# 614324; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12957 PSMD12 Zornitza Stark Publications for gene: PSMD12 were set to
Mendeliome v0.12955 PSMD12 Zornitza Stark reviewed gene: PSMD12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132691, 34906456; Phenotypes: Stankiewicz-Isidor syndrome, MIM# 617516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12954 PSPH Zornitza Stark Publications for gene: PSPH were set to
Mendeliome v0.12951 PSTPIP1 Zornitza Stark Publications for gene: PSTPIP1 were set to
Mendeliome v0.12949 PSTPIP1 Zornitza Stark reviewed gene: PSTPIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11971877, 34938582, 34778321, 34745107, 34492165, 34047005; Phenotypes: Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12946 PTGDR Zornitza Stark reviewed gene: PTGDR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Asthma, susceptibility to, 1} 607277; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12945 PTH Zornitza Stark Publications for gene: PTH were set to
Mendeliome v0.12943 PTH Zornitza Stark reviewed gene: PTH: Rating: GREEN; Mode of pathogenicity: None; Publications: 2212001, 1302009, 10523031, 35165722, 32421798; Phenotypes: Hypoparathyroidism, familial isolated 1, MIM# 146200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12942 PTH1R Zornitza Stark Publications for gene: PTH1R were set to
Mendeliome v0.12941 PTH1R Zornitza Stark edited their review of gene: PTH1R: Changed publications: 7701349, 8855805, 17164305, 15525660, 19061984
Mendeliome v0.12940 PTH1R Zornitza Stark reviewed gene: PTH1R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Failure of tooth eruption, primary MIM#125350, Eiken syndrome MIM#600002, Metaphyseal chondrodysplasia, Murk Jansen type MIM#156400, Chondrodysplasia, Blomstrand type MIM#215045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12939 PTHLH Zornitza Stark Publications for gene: PTHLH were set to
Mendeliome v0.12937 PTHLH Zornitza Stark reviewed gene: PTHLH: Rating: GREEN; Mode of pathogenicity: None; Publications: 20015959, 34897794, 29947179, 28211986; Phenotypes: Brachydactyly, type E2, MIM# 613382; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12936 PTPN14 Zornitza Stark Publications for gene: PTPN14 were set to
Mendeliome v0.12934 PTPN14 Zornitza Stark reviewed gene: PTPN14: Rating: GREEN; Mode of pathogenicity: None; Publications: 20826270; Phenotypes: Choanal atresia and lymphoedema, MIM# 613611; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12934 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.12933 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.12932 GCNA Zornitza Stark reviewed gene: GCNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure, X-linked, 4, MIM# 301077; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.12928 PTPN22 Zornitza Stark reviewed gene: PTPN22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12927 PTPRO Zornitza Stark Publications for gene: PTPRO were set to
Mendeliome v0.12925 PTPRO Zornitza Stark reviewed gene: PTPRO: Rating: GREEN; Mode of pathogenicity: None; Publications: 21722858, 34546508, 30065916; Phenotypes: Nephrotic syndrome, type 6, MIM# 614196; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12924 PTRH2 Zornitza Stark Publications for gene: PTRH2 were set to
Mendeliome v0.12920 PTS Zornitza Stark reviewed gene: PTS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, A, MIM# 261640; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12919 PUM1 Zornitza Stark Publications for gene: PUM1 were set to
Mendeliome v0.12917 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905, 30903679, 31859446; Phenotypes: Spinocerebellar ataxia 47, MIM# 617931, Neurodevelopmental disorder, MONDO:0700092, PUM1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12916 PYCR2 Zornitza Stark Publications for gene: PYCR2 were set to
Mendeliome v0.12914 PYCR2 Zornitza Stark reviewed gene: PYCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25865492, 27130255; Phenotypes: Leukodystrophy, hypomyelinating, 10, MIM# 616420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12912 PYROXD1 Zornitza Stark Publications for gene: PYROXD1 were set to
Mendeliome v0.12910 F12 Bryony Thompson commented on gene: F12: Also associated with FXII deficiency - PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584, 30700128 - Biallalelic loss-of-function variants are a well-established cause of FXII deficiency. FXII deficiency is not associated with bleeding risk unlike other coagulation factors, it is either asymptomatic or characterized by a prolonged activated partial thromboplastin time. DEFINITIVE gene-disease validity classification by the ClinGen Hemostasis Thrombosis VCEP, Classification - 01/22/2020
Mendeliome v0.12910 PYROXD1 Zornitza Stark reviewed gene: PYROXD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27745833; Phenotypes: Myopathy, myofibrillar, 8 , MIM#617258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12910 F12 Bryony Thompson reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26193639, 16638441, 17381464, 21849258, 17186468, 19178938, 30463937, 23994767; Phenotypes: Hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12909 SGCD Zornitza Stark Publications for gene: SGCD were set to
Mendeliome v0.12907 SGCD Zornitza Stark reviewed gene: SGCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841194, 19259135, 20623375, 10838250, 10735275, 9832045, 30733730; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 6, MIM# 601287, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12906 SGCB Zornitza Stark Publications for gene: SGCB were set to
Mendeliome v0.12903 SGCA Zornitza Stark Publications for gene: SGCA were set to
Mendeliome v0.12900 SFXN4 Zornitza Stark Publications for gene: SFXN4 were set to
Mendeliome v0.12897 SFRP4 Zornitza Stark Publications for gene: SFRP4 were set to
Mendeliome v0.12895 SFRP4 Zornitza Stark reviewed gene: SFRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pyle disease, MIM#265900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12894 RASGRP1 Zornitza Stark Publications for gene: RASGRP1 were set to
Mendeliome v0.12890 PDCD1 Zornitza Stark Publications for gene: PDCD1 were set to
Mendeliome v0.12882 PCCB Zornitza Stark Publications for gene: PCCB were set to