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Mendeliome v0.9431 SFTPA2 Zornitza Stark Gene: sftpa2 has been classified as Green List (High Evidence).
Mendeliome v0.9431 SFTPA2 Zornitza Stark Phenotypes for gene: SFTPA2 were changed from to Pulmonary fibrosis, idiopathic, MIM# 178500
Mendeliome v0.9428 SFTPA2 Zornitza Stark reviewed gene: SFTPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19100526, 32602668; Phenotypes: Pulmonary fibrosis, idiopathic, MIM# 178500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9428 SFTPD Zornitza Stark Gene: sftpd has been classified as Red List (Low Evidence).
Mendeliome v0.9426 SFTPD Zornitza Stark Classified gene: SFTPD as Red List (low evidence)
Mendeliome v0.9426 SFTPD Zornitza Stark Gene: sftpd has been classified as Red List (Low Evidence).
Mendeliome v0.9425 SLC7A7 Zornitza Stark Gene: slc7a7 has been classified as Green List (High Evidence).
Mendeliome v0.9425 SLC7A7 Zornitza Stark Phenotypes for gene: SLC7A7 were changed from to Lysinuric protein intolerance, MIM# 222700
Mendeliome v0.9422 SLC7A7 Zornitza Stark reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10080182, 18716612; Phenotypes: Lysinuric protein intolerance, MIM# 222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9422 JAG2 Zornitza Stark Phenotypes for gene: JAG2 were changed from muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 27, MIM# 619566; muscular dystrophy
Mendeliome v0.9421 JAG2 Zornitza Stark reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 27, MIM# 619566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9421 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
Mendeliome v0.9417 STOX1 Zornitza Stark Gene: stox1 has been classified as Red List (Low Evidence).
Mendeliome v0.9417 STOX1 Zornitza Stark Phenotypes for gene: STOX1 were changed from to Preeclampsia/eclampsia 4 (MIM#609404)
Mendeliome v0.9415 STOX1 Zornitza Stark Classified gene: STOX1 as Red List (low evidence)
Mendeliome v0.9415 STOX1 Zornitza Stark Gene: stox1 has been classified as Red List (Low Evidence).
Mendeliome v0.9414 CHRNA5 Zornitza Stark Gene: chrna5 has been classified as Red List (Low Evidence).
Mendeliome v0.9413 CHRNA5 Zornitza Stark Classified gene: CHRNA5 as Red List (low evidence)
Mendeliome v0.9413 CHRNA5 Zornitza Stark Gene: chrna5 has been classified as Red List (Low Evidence).
Mendeliome v0.9412 TBX4 Zornitza Stark edited their review of gene: TBX4: Changed publications: 31761294, 31965066; Changed phenotypes: Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension MIM#147891, Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360
Mendeliome v0.9412 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Green List (High Evidence).
Mendeliome v0.9409 ADGRG1 Zornitza Stark Gene: adgrg1 has been classified as Green List (High Evidence).
Mendeliome v0.9406 STOX1 Paul De Fazio reviewed gene: STOX1: Rating: RED; Mode of pathogenicity: None; Publications: 15806103, 17290274, 30548667, 33301424; Phenotypes: Preeclampsia/eclampsia 4 (MIM#609404); Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9406 FGF12 Zornitza Stark Gene: fgf12 has been classified as Green List (High Evidence).
Mendeliome v0.9403 KCNAB3 Zornitza Stark Gene: kcnab3 has been classified as Red List (Low Evidence).
Mendeliome v0.9403 KCNAB3 Zornitza Stark Classified gene: KCNAB3 as Red List (low evidence)
Mendeliome v0.9403 KCNAB3 Zornitza Stark Gene: kcnab3 has been classified as Red List (Low Evidence).
Mendeliome v0.9402 TBK1 Zornitza Stark Gene: tbk1 has been classified as Green List (High Evidence).
Mendeliome v0.9402 TBK1 Zornitza Stark Phenotypes for gene: TBK1 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, MIM# 616439
Mendeliome v0.9399 OSTC Zornitza Stark Gene: ostc has been classified as Red List (Low Evidence).
Mendeliome v0.9399 OSTC Zornitza Stark Classified gene: OSTC as Red List (low evidence)
Mendeliome v0.9399 OSTC Zornitza Stark Gene: ostc has been classified as Red List (Low Evidence).
Mendeliome v0.9398 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9397 KCNC2 Zornitza Stark Classified gene: KCNC2 as Amber List (moderate evidence)
Mendeliome v0.9397 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9396 KCTD13 Zornitza Stark Gene: kctd13 has been classified as Red List (Low Evidence).
Mendeliome v0.9393 KCTD13 Zornitza Stark Classified gene: KCTD13 as Red List (low evidence)
Mendeliome v0.9393 KCTD13 Zornitza Stark Gene: kctd13 has been classified as Red List (Low Evidence).
Mendeliome v0.9392 KCTD13 Daniel Flanagan gene: KCTD13 was added
gene: KCTD13 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCTD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCTD13 were set to PMID: 33409479
Review for gene: KCTD13 was set to RED
Added comment: Mouse model and in vitro evidence suggesting the deletion of KCTD13 has a similar metabolic affect as adenylosuccinate lyase deficiency, which has seizures and autistic features.
Sources: Expert list
Mendeliome v0.9392 KCNC2 Daniel Flanagan gene: KCNC2 was added
gene: KCNC2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to PMID:32392612; 31972370
Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonos attacks; intellectual disability; West syndrome
Review for gene: KCNC2 was set to AMBER
Added comment: PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks.

PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable".
Sources: Expert list
Mendeliome v0.9392 OSTC Belinda Chong gene: OSTC was added
gene: OSTC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to PMID: 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Review for gene: OSTC was set to RED
Added comment: A patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
Patient was homozygous for a canonical splice variant (c.431 + 1G > A), mRNA from patient's fibroblast showed mRNA transcript reduced 80-90%/aberrant splicing - predicting NMD.
GnomAD - 10 hets, 0 hom
Sources: Literature
Sources: Literature
Mendeliome v0.9392 TBK1 Lucy Spencer reviewed gene: TBK1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31000212, 25943890; Phenotypes: Frontotemporal dementia, amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9392 KCNAB3 Daniel Flanagan gene: KCNAB3 was added
gene: KCNAB3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNAB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNAB3 were set to PMID: 32990398
Phenotypes for gene: KCNAB3 were set to febrile seizures; afebrile seizure; genetic epilepsy with febrile seizures plus
Review for gene: KCNAB3 was set to RED
Added comment: Missense variant identified in a single Han Chinese family with febrile seizures plus. Three affected carriers and one unaffected carrier. Patch clamp functional studies indicates that the variant accelerates the inactivation of the potassium channels.
Sources: Expert list
Mendeliome v0.9392 DENND5A Zornitza Stark Gene: dennd5a has been classified as Green List (High Evidence).
Mendeliome v0.9389 ZAR1 Zornitza Stark Gene: zar1 has been classified as Red List (Low Evidence).
Mendeliome v0.9389 ZAR1 Zornitza Stark gene: ZAR1 was added
gene: ZAR1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZAR1 were set to 29574422; 31598710; 12539046
Phenotypes for gene: ZAR1 were set to Multi locus imprinting disturbance in offspring
Review for gene: ZAR1 was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) with some features of Beckwith Wiedemann Syndrome. Shown to be a maternal effect gene that functions at the oocyte to embryo transition.
Sources: Expert Review
Mendeliome v0.9388 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Red List (Low Evidence).
Mendeliome v0.9388 UHRF1 Zornitza Stark gene: UHRF1 was added
gene: UHRF1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: UHRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UHRF1 were set to 29574422; 28976982
Phenotypes for gene: UHRF1 were set to Multi locus imprinting disturbance in offspring
Review for gene: UHRF1 was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and Silver Russell Syndrome phenotype. Maenohara et al demonstrate functions of UHRF1 during the global epigenetic reprogramming of oocytes and early embryos.
Sources: Expert Review
Mendeliome v0.9387 MAGEL2 Zornitza Stark Gene: magel2 has been classified as Green List (High Evidence).
Mendeliome v0.9384 L3MBTL1 Zornitza Stark Gene: l3mbtl1 has been classified as Red List (Low Evidence).
Mendeliome v0.9384 L3MBTL1 Zornitza Stark gene: L3MBTL1 was added
gene: L3MBTL1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: L3MBTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: L3MBTL1 were set to 23543057; 15123827; 30794780
Phenotypes for gene: L3MBTL1 were set to Affected tissue: myeloid lineages; Phenotype resulting from under expression: lymphoid malignancy
Review for gene: L3MBTL1 was set to RED
Added comment: Germline variation in this imprinted gene is not currently associated with disease.

Somatic deletions of 20q are associated with chronic myeloid malignancies. Aziz et al showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis.
Sources: Expert Review
Mendeliome v0.9383 KCNQ1OT1 Zornitza Stark Gene: kcnq1ot1 has been classified as Red List (Low Evidence).
Mendeliome v0.9383 KCNQ1OT1 Zornitza Stark gene: KCNQ1OT1 was added
gene: KCNQ1OT1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNQ1OT1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: KCNQ1OT1 were set to 22205991; 15372379; 23511928; 30794780; 29377879; 10220444; 32447323; 33177595; 29047350
Phenotypes for gene: KCNQ1OT1 were set to Beckwith-Wiedemann syndrome OMIM:130650; Russell-Silver Syndrome
Review for gene: KCNQ1OT1 was set to AMBER
Added comment: Limited evidence that isolated intragenic variation in KCNQ1OT1 is definitively associated with a phenotype.

KCNQ1OT1 encodes the regulatory antisense non-coding RNA KCNQ1OT1 (KCNQ1 overlapping) and is located within the KCNQ1OT1:TSS DMR (imprinting control region 2; IC2) at 11p15.5. IC2 is located within KCNQ1 intron 10. KCNQ1OT1 is maternally imprinted and paternally expressed. On the paternal chromosome, KCNQ1OT1 is transcribed and represses in cis the flanking imprinted genes, including the growth inhibitor CDKN1C, which is normally transcribed from the maternal allele. In 50% of the BWS patients, loss of methylation (LOM) of IC2 leads to biallelic expression of KCNQ1OT1 and biallelic silencing of CDKN1C (PMID 30635621). Expression is increased in BWS due to IC2 epimutations or paternal UPD.

Single nucleotide variants within KCNQ1OT1 have not been definitively associated with human disease. A heterozygous maternally inherited non-coding variant was identified in an individual with isolated omphalocele. This variant was shown to alter the methylation pattern of the imprinted allele (PMID 29047350).

Eggerman et al (PMID 32447323) described a 132 base pair deletion within KCNQ1OT1 associated with growth retardation in the case of paternal but not maternal transmission. This intragenic deletion did not affect IC2 methylation.

Microdeletions of IC2 involving KCNQ1OT1 on the paternal allele have been identified in a small number of patients with Russell-Silver syndrome. Similarly, microdeletions of IC2 involving KCNQ1OT1 on the maternal allele have been identified in a small number of patients with BWS. These deletions also variably involve KCNQ1 or CDKN1C. LoF in CDKN1C is a known cause of BWS. There is some evidence to suggest that disruption of KCNQ1 prevents maternal methylation at IC2 (PMID 30778172).
Sources: Expert Review
Mendeliome v0.9382 H19 Zornitza Stark Gene: h19 has been classified as Red List (Low Evidence).
Mendeliome v0.9382 H19 Zornitza Stark gene: H19 was added
gene: H19 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: H19 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: H19 were set to 20007505; 15743916; 23118352; 21863054; 21571108; 18245780; 24916376; 25943194
Phenotypes for gene: H19 were set to Phenotypes resulting from gene over expression: Silver-Russell Syndrome (proven effects of dosage alteration rather than gene muation); Affected tissue: all; Phenotype resulting from under expression: Beckwith-Wiedemann Syndrome
Review for gene: H19 was set to RED
Added comment: Methylation changes rather than sequence variation are associated with BWS/RSS.
Sources: Expert Review
Mendeliome v0.9379 OOEP Zornitza Stark Gene: ooep has been classified as Red List (Low Evidence).
Mendeliome v0.9379 OOEP Zornitza Stark gene: OOEP was added
gene: OOEP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OOEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OOEP were set to 29574422
Phenotypes for gene: OOEP were set to Multi locus imprinting disturbance in offspring
Review for gene: OOEP was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and a transient neonatal diabetes mellitus phenotype.

This gene encodes part of the subcortical maternal complex (SCMC). Other genes in this group act as 'maternal effect' genes and are associated with early embryonic arrest, recurrent hydatiform mole and MLID in offspring.

As is the case for other genes encoding components of the SCMC, the pathogenicity of variants can be difficult to establish as reproductive outcomes are not recorded in genomic databases and variants may be listed in population databases as they are not classed as pathogenic in males or women with no reproductive history.

Functional studies of genes encoding components of the SCMC are limited as their expression is restricted to the oocyte and early embryo.
Sources: Literature
Mendeliome v0.9378 ZNF445 Zornitza Stark Gene: znf445 has been classified as Red List (Low Evidence).
Mendeliome v0.9378 ZNF445 Zornitza Stark gene: ZNF445 was added
gene: ZNF445 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF445 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF445 were set to 34039421; 30602440; 30846001
Phenotypes for gene: ZNF445 were set to Temple syndrome; Multi locus imprinting disturbance (MLID)
Review for gene: ZNF445 was set to RED
Added comment: Single report (Kagami 2021) of a child with Temple syndrome and MLID found to have a novel homozygous truncating variant in ZNF445.

ZNF445 has been shown to play a critical role in the maintenance of postfertilisation methylation imprints (Takahashi 2019). Mechanism and parent of origin effects remain uncertain.
Sources: Literature
Mendeliome v0.9377 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Mendeliome v0.9377 NSRP1 Zornitza Stark Classified gene: NSRP1 as Green List (high evidence)
Mendeliome v0.9377 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Mendeliome v0.9374 ERGIC1 Zornitza Stark Classified gene: ERGIC1 as Green List (high evidence)
Mendeliome v0.9374 ERGIC1 Zornitza Stark Gene: ergic1 has been classified as Green List (High Evidence).
Mendeliome v0.9373 ERGIC1 Zornitza Stark edited their review of gene: ERGIC1: Added comment: Pehlivan et al. 2019 (PMID:31230720) identified the third case of arthrogryposis in a child who harboured a previously unreported homozygous variant (c.782G>A; p.Gly261Asp) in this gene. Parents were heterozygous carriers. Functional studies were not performed.; Changed rating: GREEN; Changed publications: 28317099, 34037256, 31230720
Mendeliome v0.9371 GABRD Zornitza Stark Classified gene: GABRD as Green List (high evidence)
Mendeliome v0.9371 GABRD Zornitza Stark Gene: gabrd has been classified as Green List (High Evidence).
Mendeliome v0.9370 GABRD Zornitza Stark changed review comment from: Limited reports. The variant originally reported in PMID 15115768 in association with epilepsy is present in >4,000 hets in gnomad and 55 homs which is not consistent with a Mendelian disorder.; to: Susceptibility to epilepsy, MIM#613060: Limited reports. The variant originally reported in PMID 15115768 in association with epilepsy is present in >4,000 hets in gnomad and 55 homs which is not consistent with a Mendelian disorder.
Mendeliome v0.9370 GABRD Zornitza Stark edited their review of gene: GABRD: Added comment: 10 individuals with 7 unique variants reported in individuals with neurodevelopmental disorders and epilepsy. Six of the variants were demonstrated to be GoF, and those individuals with neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. In contrast, the one individual carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms.; Changed rating: GREEN; Changed publications: 15115768, 34633442; Changed phenotypes: Intellectual disability, Epilepsy, Susceptibility to epilepsy, MIM#613060
Mendeliome v0.9367 NLRP5 Zornitza Stark Classified gene: NLRP5 as Green List (high evidence)
Mendeliome v0.9367 NLRP5 Zornitza Stark Gene: nlrp5 has been classified as Green List (High Evidence).
Mendeliome v0.9364 KCTD3 Zornitza Stark Gene: kctd3 has been classified as Green List (High Evidence).
Mendeliome v0.9361 GYPC Zornitza Stark Gene: gypc has been classified as Red List (Low Evidence).
Mendeliome v0.9358 GYPC Zornitza Stark Classified gene: GYPC as Red List (low evidence)
Mendeliome v0.9358 GYPC Zornitza Stark Gene: gypc has been classified as Red List (Low Evidence).
Mendeliome v0.9356 TARS2 Zornitza Stark Classified gene: TARS2 as Green List (high evidence)
Mendeliome v0.9356 TARS2 Zornitza Stark Gene: tars2 has been classified as Green List (High Evidence).
Mendeliome v0.9355 SLC4A3 Daniel Flanagan gene: SLC4A3 was added
gene: SLC4A3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC4A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC4A3 were set to PMID: 29167417; 34557911
Phenotypes for gene: SLC4A3 were set to Short QT syndrome
Review for gene: SLC4A3 was set to AMBER
Added comment: Moderate evidence for autosomal dominant short QT syndrome 1 by ClinGen /gene curation expert panel (PMID: 34557911). A single missense variant (absent gnomAD) identified in two SQTS families. In family 1, it segregated with SQTS (QTc<370ms) in 23 carriers, and 19 non-carriers had a QTc>370ms. In family 2, it segregated in 4 individuals. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration.
ClinGen expert panel was divided between strong (4 votes) and moderate (5 votes).
Sources: Expert Review
Mendeliome v0.9355 USP48 Zornitza Stark Added comment: Comment when marking as ready: Borderline Green: one of the variants is present at a high frequency in the normal population. However, even if just two families are considered, supportive functional data including zebrafish model.
Mendeliome v0.9355 USP48 Zornitza Stark Gene: usp48 has been classified as Green List (High Evidence).
Mendeliome v0.9355 USP48 Zornitza Stark Classified gene: USP48 as Green List (high evidence)
Mendeliome v0.9355 USP48 Zornitza Stark Gene: usp48 has been classified as Green List (High Evidence).
Mendeliome v0.9354 MARS Zornitza Stark Gene: mars has been classified as Green List (High Evidence).
Mendeliome v0.9354 MARS Zornitza Stark Gene: mars has been classified as Green List (High Evidence).
Mendeliome v0.9351 MARS Zornitza Stark changed review comment from: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT and mono-allelic variants: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.
Mendeliome v0.9351 MARS Zornitza Stark changed review comment from: Association with interstitial lung and liver disease: More than 5 unrelated families reported. Founder variants in Reunion Island, p.Ser567Leu and p.Ala393Thr, in cis.

Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis.; to: Association with interstitial lung and liver disease and bi-allelic variants: More than 5 unrelated families reported. Founder variants in Reunion Island, p.Ser567Leu and p.Ala393Thr, in cis.

Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis.
Mendeliome v0.9351 MARS Zornitza Stark changed review comment from: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.
Mendeliome v0.9351 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Association with interstitial lung and liver disease: More than 5 unrelated families reported. Founder variants in Reunion Island, p.Ser567Leu and p.Ala393Thr, in cis.

Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis.; Changed rating: GREEN; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9347 USP48 Eleanor Williams gene: USP48 was added
gene: USP48 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: USP48 were set to 34059922
Phenotypes for gene: USP48 were set to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497
Penetrance for gene: USP48 were set to Incomplete
Review for gene: USP48 was set to GREEN
Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance.
In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis.
In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein.
In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens.
In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths.
Sources: Literature
Mendeliome v0.9347 AARS Eleanor Williams changed review comment from: PMID: 33909043 - Botta et al 2021 - using WES or WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified 2 unrelated cases carrying 4 potentially pathogenic variants in the AARS1 gene (previously known as AARSB. Both patients had very rare compound heterozygous missense variants. In one family there was an older affected sibling but segregation data was not available for either family.; to: PMID: 33909043 - Botta et al 2021 - using WES or WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified 2 unrelated cases carrying 4 potentially pathogenic variants in the AARS1 gene (previously known as AARSB. Both patients had very rare compound heterozygous missense variants. In one family there was an older affected sibling but segregation data was not available for either family. Functional studies suggest that the variants affects gene product stability.
Mendeliome v0.9347 AIP Zornitza Stark Gene: aip has been classified as Green List (High Evidence).
Mendeliome v0.9347 AIP Zornitza Stark Phenotypes for gene: AIP were changed from to Pituitary adenoma predisposition MIM#102200
Mendeliome v0.9343 AP1G1 Zornitza Stark Phenotypes for gene: AP1G1 were changed from Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy to Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467; Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548; Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Mendeliome v0.9342 AP1G1 Zornitza Stark edited their review of gene: AP1G1: Changed rating: GREEN; Changed phenotypes: Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467, Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9341 CERKL Zornitza Stark Gene: cerkl has been classified as Green List (High Evidence).
Mendeliome v0.9338 AIP Paul De Fazio changed review comment from: Germline variants in AIP cause predisposition to pituitary adenomas which may result in acromegaly.

A 2015 cohort study of 143 patients with pituitary gigantism who consented to genetic testing found 29% had variants in AIP. Age at first symptoms was 9-13 years, age at diagnosis 14-20 years.; to: Germline variants in AIP cause predisposition to pituitary adenomas which may result in acromegaly.

A 2015 cohort study of 143 patients with pituitary gigantism who consented to genetic testing found 29% had variants in AIP. Age at first symptoms was 9-13 years, age at diagnosis 14-20 years.

Many patients have no family history, suggesting low penetrance.
Mendeliome v0.9338 AIP Paul De Fazio reviewed gene: AIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16728643, 17360484, 26187128; Phenotypes: Pituitary adenoma predisposition MIM#102200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.9338 SHANK1 Zornitza Stark Gene: shank1 has been classified as Green List (High Evidence).
Mendeliome v0.9335 GDF11 Zornitza Stark Classified gene: GDF11 as Green List (high evidence)
Mendeliome v0.9335 GDF11 Zornitza Stark Gene: gdf11 has been classified as Green List (High Evidence).
Mendeliome v0.9334 GDF11 Zornitza Stark edited their review of gene: GDF11: Added comment: Ravenscroft et al. (2021) report additional 6 probands who presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). They found de novo and inherited variants in GDF11. gdf11 mutant zebrafish showed craniofacial abnormalities and body segmentation defects that matched some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants are partial LOF variants.; Changed rating: GREEN; Changed publications: 31215115, 34113007
Mendeliome v0.9334 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Mendeliome v0.9334 PLXNA1 Zornitza Stark Classified gene: PLXNA1 as Green List (high evidence)
Mendeliome v0.9334 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Mendeliome v0.9333 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Mendeliome v0.9330 HNRNPD Zornitza Stark Classified gene: HNRNPD as Green List (high evidence)
Mendeliome v0.9330 HNRNPD Zornitza Stark Gene: hnrnpd has been classified as Green List (High Evidence).
Mendeliome v0.9328 UNC13B Zornitza Stark Gene: unc13b has been classified as Red List (Low Evidence).
Mendeliome v0.9328 UNC13B Zornitza Stark gene: UNC13B was added
gene: UNC13B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: UNC13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UNC13B were set to 33876820
Phenotypes for gene: UNC13B were set to Epilepsy
Review for gene: UNC13B was set to RED
Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex).

Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Conflicting data esp regarding MOI, and evidence for pathogenicity of several of the variants is limited.

Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified:
x1 de novo nonsense variant, absent in gnomad, damaging in silicos
x1 de novo splice site, absent in gnomad, damaging in silicos
x1 splice site variant present in unaffected mother (low frequency in gnomad)
x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad)
x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad
x1 missense variant - highly conserved residue, not in gnomad
x2 other missense variant - highly conserved residue, low frequency in gnomad
Latter 4 missense variants cosegregated with affected individuals in the families

In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila

De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder
Sources: Expert Review
Mendeliome v0.9327 VARS2 Zornitza Stark Gene: vars2 has been classified as Green List (High Evidence).
Mendeliome v0.9324 CHD4 Zornitza Stark Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, MIM 617159 to Sifrim-Hitz-Weiss syndrome, MIM 617159; Childhood idiopathic epilepsy and sinus arrhythmia
Mendeliome v0.9322 CHD4 Zornitza Stark reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34109749; Phenotypes: Childhood idiopathic epilepsy and sinus arrhythmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9322 BCL11A Zornitza Stark Gene: bcl11a has been classified as Green List (High Evidence).
Mendeliome v0.9319 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Red List (Low Evidence).
Mendeliome v0.9319 CFAP221 Zornitza Stark gene: CFAP221 was added
gene: CFAP221 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325
Phenotypes for gene: CFAP221 were set to Primary ciliary dyskinesia
Review for gene: CFAP221 was set to RED
Added comment: WES in 1 family with 3 siblings with clinical symptoms of PCD identified compound heterozygous loss-of-function variants in CFAP221, which segregated with disease. No functional studies. Nasal epithelial cells from 1 of the subjects demonstrated slightly reduced beat frequency, however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. A candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.
Sources: Literature
Mendeliome v0.9313 DAB1 Zornitza Stark Classified gene: DAB1 as Red List (low evidence)
Mendeliome v0.9313 DAB1 Zornitza Stark Gene: dab1 has been classified as Red List (Low Evidence).
Mendeliome v0.9312 ERBB4 Zornitza Stark Gene: erbb4 has been classified as Green List (High Evidence).
Mendeliome v0.9312 ERBB4 Zornitza Stark Phenotypes for gene: ERBB4 were changed from to Amyotrophic lateral sclerosis 19, MIM# MIM#615515; Intellectual disability
Mendeliome v0.9309 ERBB4 Zornitza Stark reviewed gene: ERBB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24119685, 28889094, 33603162; Phenotypes: Amyotrophic lateral sclerosis 19, MIM# MIM#615515, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9306 PANX1 Zornitza Stark Classified gene: PANX1 as Green List (high evidence)
Mendeliome v0.9306 PANX1 Zornitza Stark Gene: panx1 has been classified as Green List (High Evidence).
Mendeliome v0.9303 ZDHHC15 Krithika Murali changed review comment from: Lewis et al Neurology Genetics 2021

Functional analysis of 4 ZDHHC15 variants - x2 Jin et al, others identified through GeneMatcher

Yeast cells expressing ZDHHC15 p.L13P (Jin et al, maternally inherited), p.K115R (maternally inherited) and p.S330p were indistinguishable from cells harboring the reference ZDHHC15 allele, however those expressing p.H158R (also reported in Jin et al, maternally inherited) disrupted normal protein function.; to: Lewis et al Neurology Genetics 2021

Functional analysis of 4 ZDHHC15 variants - x2 Jin et al Nat Genet 2020 PMID 32989326, others identified through GeneMatcher

Yeast cells expressing ZDHHC15 p.L13P (Jin et al, maternally inherited), p.K115R (maternally inherited) and p.S330p were indistinguishable from cells harboring the reference ZDHHC15 allele, however those expressing p.H158R (also reported in Jin et al, maternally inherited) disrupted normal protein function.
Mendeliome v0.9303 ABHD16A Seb Lunke Classified gene: ABHD16A as Green List (high evidence)
Mendeliome v0.9303 ABHD16A Seb Lunke Gene: abhd16a has been classified as Green List (High Evidence).
Mendeliome v0.9302 WIPI2 Zornitza Stark Gene: wipi2 has been classified as Green List (High Evidence).
Mendeliome v0.9301 WIPI2 Zornitza Stark Classified gene: WIPI2 as Green List (high evidence)
Mendeliome v0.9301 WIPI2 Zornitza Stark Gene: wipi2 has been classified as Green List (High Evidence).
Mendeliome v0.9299 ATP11A Zornitza Stark Gene: atp11a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9299 ATP11A Zornitza Stark Classified gene: ATP11A as Amber List (moderate evidence)
Mendeliome v0.9299 ATP11A Zornitza Stark Gene: atp11a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9298 WIPI2 Dean Phelan reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30968111, 34557665; Phenotypes: global developmental delay, intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, dyskinesia, speech and visual impairment, autistic features, ataxic gait; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9298 WLS Zornitza Stark Gene: wls has been classified as Green List (High Evidence).
Mendeliome v0.9298 WLS Zornitza Stark Classified gene: WLS as Green List (high evidence)
Mendeliome v0.9298 WLS Zornitza Stark Gene: wls has been classified as Green List (High Evidence).
Mendeliome v0.9297 ABHD16A Lucy Spencer gene: ABHD16A was added
gene: ABHD16A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to PMID: 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia
Review for gene: ABHD16A was set to GREEN
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature
Mendeliome v0.9297 ATP11A Elena Savva gene: ATP11A was added
gene: ATP11A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP11A were set to PMID: 34403372
Phenotypes for gene: ATP11A were set to Neurological disorder
Mode of pathogenicity for gene: ATP11A was set to Other
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Mendeliome v0.9297 WLS Teresa Zhao changed review comment from: - We identified homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature; to: - Homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Mendeliome v0.9297 WLS Teresa Zhao gene: WLS was added
gene: WLS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to PMID: 34587386
Phenotypes for gene: WLS were set to Syndromic structural birth defects
Review for gene: WLS was set to GREEN
Added comment: - We identified homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Mendeliome v0.9297 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9297 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9297 SHQ1 Zornitza Stark Classified gene: SHQ1 as Amber List (moderate evidence)
Mendeliome v0.9297 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9295 SARS Bryony Thompson Classified gene: SARS as Amber List (moderate evidence)
Mendeliome v0.9295 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9294 SARS Bryony Thompson gene: SARS was added
gene: SARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.
PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Mendeliome v0.9293 NDN Zornitza Stark Gene: ndn has been classified as Red List (Low Evidence).
Mendeliome v0.9291 NDN Zornitza Stark Classified gene: NDN as Red List (low evidence)
Mendeliome v0.9291 NDN Zornitza Stark Gene: ndn has been classified as Red List (Low Evidence).
Mendeliome v0.9290 NFIB Zornitza Stark Gene: nfib has been classified as Green List (High Evidence).
Mendeliome v0.9287 ZNF407 Zornitza Stark Phenotypes for gene: ZNF407 were changed from Global developmental delay; Intellectual disability to SIMHA syndrome, MIM# 619557; Global developmental delay; Intellectual disability
Mendeliome v0.9286 ZNF407 Zornitza Stark edited their review of gene: ZNF407: Changed phenotypes: SIMHA syndrome, MIM# 619557, Global developmental delay, Intellectual disability
Mendeliome v0.9285 EIF3F Zornitza Stark edited their review of gene: EIF3F: Added comment: Hüffmeier et al (2021) reported 21 patients who were homozygous/compound heterozygous for Phe232Val variant in EIF3F. All affected individuals had developmental delay and speech delay. About half had behavioural problems, altered muscular tone, hearing loss, and short stature. The study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum.; Changed publications: 30409806, 33736665; Changed phenotypes: Mental retardation, autosomal recessive 67, MIM# 618295
Mendeliome v0.9285 PTPRC Zornitza Stark Gene: ptprc has been classified as Green List (High Evidence).
Mendeliome v0.9285 PTPRC Zornitza Stark Phenotypes for gene: PTPRC were changed from to Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971; Hepatitis C virus, susceptibility to MIM# 609532
Mendeliome v0.9282 PTPRC Zornitza Stark reviewed gene: PTPRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11145714, 12073144, 22689986, 10700239; Phenotypes: Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971, Hepatitis C virus, susceptibility to MIM# 609532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9282 CORO1A Zornitza Stark Gene: coro1a has been classified as Green List (High Evidence).
Mendeliome v0.9279 POU6F2 Zornitza Stark Gene: pou6f2 has been classified as Red List (Low Evidence).
Mendeliome v0.9279 POU6F2 Zornitza Stark Classified gene: POU6F2 as Red List (low evidence)
Mendeliome v0.9279 POU6F2 Zornitza Stark Gene: pou6f2 has been classified as Red List (Low Evidence).
Mendeliome v0.9278 CDH15 Zornitza Stark Gene: cdh15 has been classified as Red List (Low Evidence).
Mendeliome v0.9275 CDH15 Zornitza Stark Classified gene: CDH15 as Red List (low evidence)
Mendeliome v0.9275 CDH15 Zornitza Stark Gene: cdh15 has been classified as Red List (Low Evidence).
Mendeliome v0.9274 CDH15 Zornitza Stark commented on gene: CDH15: PMID: 19012874 - 4 unrelated patients with missense variants and mild-severe ID. Only two genes checked. All variants are common in gnomAD (>20 hets each) and classified as VUS or likely benign in ClinVar (paper is from 2008, pre-dates gnomAD). Functional studies were performed showing a LOF effect, where cell adhesion was reduced.
However NMD PTCs are present in gnomAD (many >=6 hets each)

PMID: 12052883 - null mouse model were viable, showed no gross developmental defects. In particular, the skeletal musculature appeared essentially normal. In the cerebellum of M-cadherin-lacking mutants, typical contactus adherens junctions were present and similar in size and numbers to the equivalent junctions in wild-type animals. However, the adhesion plaques in the cerebellum of these mutants appeared to contain elevated levels of N-cadherin compared to wild-type animals.

PMID: 28422132 - reviewed microdeletions spanning multiple genes including CDH15, suggests it may contribute to a more severe neurological phenotype, with particular regard to brain malformations.

PMID: 26506440 - speculates low penetrance for PTCs in this gene. Acknowledges variants in ExAC, describes them as benign

Note no P/LP variants in ClinVar
Mendeliome v0.9274 JAK3 Danielle Ariti reviewed gene: JAK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 14615376, 11668610; Phenotypes: SCID, autosomal recessive, T-negative/B-positive type MIM# 600802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9274 FGF8 Zornitza Stark Phenotypes for gene: FGF8 were changed from Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Femoral hypoplasia to Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Hypoplastic femurs and pelvis, MIM#619545
Mendeliome v0.9273 ARL6IP6 Zornitza Stark Gene: arl6ip6 has been classified as Red List (Low Evidence).
Mendeliome v0.9273 ARL6IP6 Zornitza Stark gene: ARL6IP6 was added
gene: ARL6IP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARL6IP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP6 were set to 31142202
Phenotypes for gene: ARL6IP6 were set to Cutis marmorata telangiectatica congenita
Review for gene: ARL6IP6 was set to RED
Added comment: A single case reported from a consanguineous family with a homozygous nonsense variant (p.Trp64Ter).
Sources: Literature
Mendeliome v0.9271 CPE Zornitza Stark Classified gene: CPE as Green List (high evidence)
Mendeliome v0.9271 CPE Zornitza Stark Gene: cpe has been classified as Green List (High Evidence).
Mendeliome v0.9270 CSTB Zornitza Stark Gene: cstb has been classified as Green List (High Evidence).
Mendeliome v0.9270 CSTB Zornitza Stark Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800; Keratolytic winter erythema (MIM#148370)
Mendeliome v0.9267 CSTB Zornitza Stark reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 32920378, 18028412, 9012407, 9054946; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9267 CD3E Zornitza Stark Gene: cd3e has been classified as Green List (High Evidence).
Mendeliome v0.9264 CD3D Zornitza Stark Gene: cd3d has been classified as Green List (High Evidence).
Mendeliome v0.9261 ARHGAP26 Zornitza Stark Gene: arhgap26 has been classified as Red List (Low Evidence).
Mendeliome v0.9261 ARHGAP26 Zornitza Stark Classified gene: ARHGAP26 as Red List (low evidence)
Mendeliome v0.9261 ARHGAP26 Zornitza Stark Gene: arhgap26 has been classified as Red List (Low Evidence).
Mendeliome v0.9260 LEFTY2 Zornitza Stark Added comment: Comment when marking as ready: No reports since 1999.
Mendeliome v0.9260 LEFTY2 Zornitza Stark Gene: lefty2 has been classified as Red List (Low Evidence).
Mendeliome v0.9257 LEFTY2 Zornitza Stark Classified gene: LEFTY2 as Red List (low evidence)
Mendeliome v0.9257 LEFTY2 Zornitza Stark Gene: lefty2 has been classified as Red List (Low Evidence).
Mendeliome v0.9256 MPL Zornitza Stark Phenotypes for gene: MPL were changed from Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR to Myelofibrosis with myeloid metaplasia, somatic, MIM#254450; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR
Mendeliome v0.9255 EPAS1 Zornitza Stark Phenotypes for gene: EPAS1 were changed from Familial erythrocytosis (MIM#4611783), AD to Familial erythrocytosis (MIM#611783), AD
Mendeliome v0.9252 MAOB Zornitza Stark Gene: maob has been classified as Red List (Low Evidence).
Mendeliome v0.9251 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9251 ATP6V0C Zornitza Stark Classified gene: ATP6V0C as Amber List (moderate evidence)
Mendeliome v0.9251 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9250 ATP6V0C Zornitza Stark gene: ATP6V0C was added
gene: ATP6V0C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Review for gene: ATP6V0C was set to AMBER
Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures.
Sources: Literature
Mendeliome v0.9249 KDM7A Zornitza Stark Gene: kdm7a has been classified as Red List (Low Evidence).
Mendeliome v0.9248 ROBO1 Zornitza Stark Gene: robo1 has been classified as Green List (High Evidence).
Mendeliome v0.9245 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Mendeliome v0.9245 ARFGEF1 Zornitza Stark Classified gene: ARFGEF1 as Green List (high evidence)
Mendeliome v0.9245 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Mendeliome v0.9243 NPR3 Zornitza Stark Gene: npr3 has been classified as Green List (High Evidence).
Mendeliome v0.9239 KCNC3 Zornitza Stark Gene: kcnc3 has been classified as Green List (High Evidence).
Mendeliome v0.9236 MINPP1 Zornitza Stark Phenotypes for gene: MINPP1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia, type 16, MIM# 619527
Mendeliome v0.9235 MINPP1 Zornitza Stark edited their review of gene: MINPP1: Changed phenotypes: Pontocerebellar hypoplasia, type 16, MIM# 619527
Mendeliome v0.9235 ZC4H2 Zornitza Stark Gene: zc4h2 has been classified as Green List (High Evidence).
Mendeliome v0.9232 ALG10 Zornitza Stark Gene: alg10 has been classified as Red List (Low Evidence).
Mendeliome v0.9232 ALG10 Zornitza Stark gene: ALG10 was added
gene: ALG10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Review for gene: ALG10 was set to RED
Added comment: Single individual with homozygous variant identified in a progressive myoclonus epilepsy cohort.
Sources: Literature
Mendeliome v0.9231 LRRK1 Zornitza Stark Gene: lrrk1 has been classified as Green List (High Evidence).
Mendeliome v0.9231 LRRK1 Zornitza Stark Classified gene: LRRK1 as Green List (high evidence)
Mendeliome v0.9231 LRRK1 Zornitza Stark Gene: lrrk1 has been classified as Green List (High Evidence).
Mendeliome v0.9230 LRRK1 Zornitza Stark gene: LRRK1 was added
gene: LRRK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750
Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198)
Review for gene: LRRK1 was set to GREEN
Added comment: At least 4 unrelated families reported.
Sources: Expert Review
Mendeliome v0.9228 KIF4A Zornitza Stark Classified gene: KIF4A as Green List (high evidence)
Mendeliome v0.9228 KIF4A Zornitza Stark Gene: kif4a has been classified as Green List (High Evidence).
Mendeliome v0.9227 HNRNPH1 Zornitza Stark Gene: hnrnph1 has been classified as Green List (High Evidence).
Mendeliome v0.9227 HNRNPH1 Zornitza Stark Classified gene: HNRNPH1 as Green List (high evidence)
Mendeliome v0.9227 HNRNPH1 Zornitza Stark Gene: hnrnph1 has been classified as Green List (High Evidence).
Mendeliome v0.9226 IRGM Zornitza Stark Gene: irgm has been classified as Red List (Low Evidence).
Mendeliome v0.9224 IRGM Zornitza Stark Classified gene: IRGM as Red List (low evidence)
Mendeliome v0.9224 IRGM Zornitza Stark Gene: irgm has been classified as Red List (Low Evidence).
Mendeliome v0.9223 UTP4 Zornitza Stark Gene: utp4 has been classified as Red List (Low Evidence).
Mendeliome v0.9223 UTP4 Zornitza Stark Phenotypes for gene: UTP4 were changed from to North American Indian childhood cirrhosis
Mendeliome v0.9220 UTP4 Zornitza Stark Classified gene: UTP4 as Red List (low evidence)
Mendeliome v0.9220 UTP4 Zornitza Stark Gene: utp4 has been classified as Red List (Low Evidence).
Mendeliome v0.9219 UTP4 Zornitza Stark reviewed gene: UTP4: Rating: RED; Mode of pathogenicity: None; Publications: 12417987, 27535533; Phenotypes: North American Indian childhood cirrhosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9219 FMN1 Bryony Thompson Gene: fmn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9219 FMN1 Bryony Thompson Classified gene: FMN1 as Amber List (moderate evidence)
Mendeliome v0.9219 FMN1 Bryony Thompson Gene: fmn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9218 FMN1 Bryony Thompson gene: FMN1 was added
gene: FMN1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: FMN1.
Mode of inheritance for gene: FMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Phenotypes for gene: FMN1 were set to oligosyndactyly; radioulnar synostosis; hearing loss; renal defects
Review for gene: FMN1 was set to AMBER
Added comment: A 263 Kb homozygous deletion of FMN1 has been identified in a single case with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects. Also, a supporting null mouse model with oligosyndactyly. Also, a large duplication including GREM1 reported in association with Cenani–Lenz syndrome.
Sources: Literature
Mendeliome v0.9217 LBX1 Zornitza Stark Gene: lbx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9217 LBX1 Zornitza Stark Classified gene: LBX1 as Amber List (moderate evidence)
Mendeliome v0.9217 LBX1 Zornitza Stark Gene: lbx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9216 LBX1 Zornitza Stark gene: LBX1 was added
gene: LBX1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to 30487221
Phenotypes for gene: LBX1 were set to Central hypoventilation syndrome, congenital, 3, MIM#619483
Review for gene: LBX1 was set to AMBER
Added comment: Two siblings reported with homozygous LoF variant in this gene, supportive mouse model.
Sources: Expert Review
Mendeliome v0.9212 FBXW4 Bryony Thompson Classified gene: FBXW4 as Red List (low evidence)
Mendeliome v0.9212 FBXW4 Bryony Thompson Gene: fbxw4 has been classified as Red List (Low Evidence).
Mendeliome v0.9211 RAF1 Zornitza Stark Gene: raf1 has been classified as Green List (High Evidence).
Mendeliome v0.9207 CDKN1C Zornitza Stark Gene: cdkn1c has been classified as Green List (High Evidence).
Mendeliome v0.9207 CDKN1C Zornitza Stark Phenotypes for gene: CDKN1C were changed from to Beckwith-Wiedemann syndrome, MIM# 130650; IMAGe syndrome, MIM# 614732; Silver-Russell syndrome
Mendeliome v0.9204 CDKN1C Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 10424811, 8841187, 22205991, 20503313, 19843502, 15372379, 23511928, 30794780, 33076988, 31976094, 31497289; Phenotypes: Beckwith-Wiedemann syndrome, MIM# 130650, IMAGe syndrome, MIM# 614732, Silver-Russell syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.9204 B9D1 Bryony Thompson Classified gene: B9D1 as Green List (high evidence)
Mendeliome v0.9204 B9D1 Bryony Thompson Gene: b9d1 has been classified as Green List (High Evidence).
Mendeliome v0.9203 B9D1 Bryony Thompson changed review comment from: hNow N
PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort)
PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction.; to: 3 unrelated cases with a syndromic phenotype and a supporting null mouse model
PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort)
PMID: 24886560 - 2 Joubert syndrome cases
PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction.
Mendeliome v0.9203 CARMIL2 Zornitza Stark Gene: carmil2 has been classified as Green List (High Evidence).
Mendeliome v0.9200 PNLDC1 Zornitza Stark Gene: pnldc1 has been classified as Green List (High Evidence).
Mendeliome v0.9200 PNLDC1 Zornitza Stark Classified gene: PNLDC1 as Green List (high evidence)
Mendeliome v0.9200 PNLDC1 Zornitza Stark Gene: pnldc1 has been classified as Green List (High Evidence).
Mendeliome v0.9198 FOXP1 Zornitza Stark Gene: foxp1 has been classified as Green List (High Evidence).
Mendeliome v0.9196 HSCB Zornitza Stark Gene: hscb has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9196 HSCB Zornitza Stark Classified gene: HSCB as Amber List (moderate evidence)
Mendeliome v0.9196 HSCB Zornitza Stark Gene: hscb has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9195 HSCB Zornitza Stark gene: HSCB was added
gene: HSCB was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSCB were set to 32634119
Phenotypes for gene: HSCB were set to Anaemia, sideroblastic, 5, MIM# 619523
Review for gene: HSCB was set to AMBER
Added comment: Single individual reported with compound heterozygous variants in this gene. Good functional data including animal model.
Sources: Expert list
Mendeliome v0.9192 BCAP31 Zornitza Stark Gene: bcap31 has been classified as Green List (High Evidence).
Mendeliome v0.9189 AMPD2 Zornitza Stark Gene: ampd2 has been classified as Green List (High Evidence).
Mendeliome v0.9189 AMPD2 Zornitza Stark Phenotypes for gene: AMPD2 were changed from to Pontocerebellar hypoplasia, type 9, MIM#615809
Mendeliome v0.9186 AMPD2 Zornitza Stark edited their review of gene: AMPD2: Added comment: Well established gene-disease association. Clinical features include severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination.; Changed rating: GREEN; Changed publications: 23911318, 27066553
Mendeliome v0.9186 ALS2 Zornitza Stark Gene: als2 has been classified as Green List (High Evidence).
Mendeliome v0.9186 ALS2 Zornitza Stark Classified gene: ALS2 as Green List (high evidence)
Mendeliome v0.9186 ALS2 Zornitza Stark Gene: als2 has been classified as Green List (High Evidence).
Mendeliome v0.9185 HBG2 Zornitza Stark Gene: hbg2 has been classified as Green List (High Evidence).
Mendeliome v0.9185 HBG2 Zornitza Stark Phenotypes for gene: HBG2 were changed from to Fetal hemoglobin quantitative trait locus 1, MIM# 141749; Cyanosis, transient neonatal, MIM# 613977
Mendeliome v0.9182 HBG2 Zornitza Stark reviewed gene: HBG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26500940; Phenotypes: Fetal hemoglobin quantitative trait locus 1, MIM# 141749, Cyanosis, transient neonatal, MIM# 613977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9182 HBG1 Zornitza Stark Gene: hbg1 has been classified as Green List (High Evidence).
Mendeliome v0.9182 HBG1 Zornitza Stark Classified gene: HBG1 as Green List (high evidence)
Mendeliome v0.9182 HBG1 Zornitza Stark Gene: hbg1 has been classified as Green List (High Evidence).
Mendeliome v0.9181 HBG1 Zornitza Stark gene: HBG1 was added
gene: HBG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HBG1 were set to 26500940
Phenotypes for gene: HBG1 were set to Fetal haemoglobin quantitative trait locus 1, 141749
Review for gene: HBG1 was set to GREEN
Added comment: Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or haematologic manifestations.
Sources: Expert Review
Mendeliome v0.9180 WNT9B Zornitza Stark Gene: wnt9b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9180 WNT9B Zornitza Stark Phenotypes for gene: WNT9B were changed from to Renal agenesis/hypoplasia/dysplasia
Mendeliome v0.9177 WNT9B Zornitza Stark Classified gene: WNT9B as Amber List (moderate evidence)
Mendeliome v0.9177 WNT9B Zornitza Stark Gene: wnt9b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9176 WNT9B Zornitza Stark reviewed gene: WNT9B: Rating: AMBER; Mode of pathogenicity: None; Publications: 34145744; Phenotypes: Renal agenesis/hypoplasia/dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9176 DDX23 Zornitza Stark Gene: ddx23 has been classified as Green List (High Evidence).
Mendeliome v0.9174 DDX23 Zornitza Stark Classified gene: DDX23 as Green List (high evidence)
Mendeliome v0.9174 DDX23 Zornitza Stark Gene: ddx23 has been classified as Green List (High Evidence).
Mendeliome v0.9172 TAF2 Zornitza Stark Classified gene: TAF2 as Green List (high evidence)
Mendeliome v0.9172 TAF2 Zornitza Stark Gene: taf2 has been classified as Green List (High Evidence).
Mendeliome v0.9171 ERGIC1 Zornitza Stark Gene: ergic1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9171 ERGIC1 Zornitza Stark Classified gene: ERGIC1 as Amber List (moderate evidence)
Mendeliome v0.9171 ERGIC1 Zornitza Stark Gene: ergic1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9170 ERGIC1 Zornitza Stark gene: ERGIC1 was added
gene: ERGIC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC1 were set to 28317099; 34037256
Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100
Review for gene: ERGIC1 was set to AMBER
Added comment: Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi.

Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents.
Sources: Literature
Mendeliome v0.9167 HMGB1 Chirag Patel Classified gene: HMGB1 as Green List (high evidence)
Mendeliome v0.9167 HMGB1 Chirag Patel Gene: hmgb1 has been classified as Green List (High Evidence).
Mendeliome v0.9166 FCGR2B Zornitza Stark Gene: fcgr2b has been classified as Red List (Low Evidence).
Mendeliome v0.9163 FCGR2B Zornitza Stark Classified gene: FCGR2B as Red List (low evidence)
Mendeliome v0.9163 FCGR2B Zornitza Stark Gene: fcgr2b has been classified as Red List (Low Evidence).
Mendeliome v0.9162 GPX1 Zornitza Stark Gene: gpx1 has been classified as Red List (Low Evidence).
Mendeliome v0.9160 CYB5A Zornitza Stark Gene: cyb5a has been classified as Green List (High Evidence).
Mendeliome v0.9157 COL14A1 Zornitza Stark Gene: col14a1 has been classified as Red List (Low Evidence).
Mendeliome v0.9157 COL14A1 Zornitza Stark gene: COL14A1 was added
gene: COL14A1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: COL14A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL14A1 were set to 22972947
Phenotypes for gene: COL14A1 were set to Punctate palmoplantar keratoderma type 1B
Review for gene: COL14A1 was set to RED
Added comment: 4 affected individuals and 2 unaffected controls from one Chinese PPPK family where disease locus was mapped at 8q24.13-8q24.21 by previous linkage analysis. Exome sequencing analysis identified a heterozygous variant in COL14A1 gene (c.4505C>T (p.Pro1502Leu)). The variant was shared by 4 affected individuals, but not 2 controls of the family. Sanger sequencing confirmed this variant in another four cases from this family. Variant was absent in the normal controls of this family as well as 676 unrelated normal controls and 781 patients with other disease. The missense substitution occurs at a highly conserved amino acid residue across multiple species.
Sources: Expert Review
Mendeliome v0.9156 EGLN1 Zornitza Stark Gene: egln1 has been classified as Green List (High Evidence).
Mendeliome v0.9156 EGLN1 Zornitza Stark Phenotypes for gene: EGLN1 were changed from to Erythrocytosis, familial, 3, MIM# 609820
Mendeliome v0.9153 EGLN1 Zornitza Stark reviewed gene: EGLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19092153, 16407130, 17579185; Phenotypes: Erythrocytosis, familial, 3, MIM# 609820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9153 FGFR2 Zornitza Stark Gene: fgfr2 has been classified as Green List (High Evidence).
Mendeliome v0.9153 FGFR2 Zornitza Stark Phenotypes for gene: FGFR2 were changed from to Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis,MIM# 207410; Apert syndrome, MIM# 101200; Beare-Stevenson cutis gyrata syndrome, MIM# 123790; Bent bone dysplasia syndrome, MIM# 614592; Craniofacial-skeletal-dermatologic dysplasia, MIM# 101600; Craniosynostosis, nonspecific; Crouzon syndrome , MIM#123500; Jackson-Weiss syndrome,MIM# 123150; LADD syndrome, MIM# 149730; Pfeiffer syndrome,MIM# 101600; Saethre-Chotzen syndrome 101400
Mendeliome v0.9150 SLC4A1 Zornitza Stark Gene: slc4a1 has been classified as Green List (High Evidence).
Mendeliome v0.9150 SLC4A1 Zornitza Stark Phenotypes for gene: SLC4A1 were changed from to Cryohydrocytosis MIM# 185020; Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590; Ovalocytosis, SA type MIM# 166900; Spherocytosis, type 4 MIM# 612653; Distal renal tubular acidosis 1 MIM# 179800
Mendeliome v0.9147 SLC4A1 Danielle Ariti reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16227998, 15211439, 7949112, 8640229, 16227998, 8640229, 16227998, 33881640, 32632909; Phenotypes: Cryohydrocytosis MIM# 185020, Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590, Ovalocytosis, SA type MIM# 166900, Spherocytosis, type 4 MIM# 612653, Distal renal tubular acidosis 1 MIM# 179800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9145 STEAP3 Zornitza Stark Classified gene: STEAP3 as Red List (low evidence)
Mendeliome v0.9145 STEAP3 Zornitza Stark Gene: steap3 has been classified as Red List (Low Evidence).
Mendeliome v0.9144 STEAP3 Zornitza Stark changed review comment from: Single family reported. Three affected sibs, variant inherited from unaffected father. Some supportive functional evidence.; to: Single family reported. Three affected sibs, variant inherited from unaffected father. Some supportive functional evidence.

Conflicting evidence (PMID 26675350): Large Chinese study (of normal and α-thalassemia subjects) investigated the prevalence of STEAP3 mutations in humans and their physiologic consequences. Discovered a relatively high prevalence of potentially harmful recessive alleles. However, whilst the identified STEAP3 mutations exhibited impaired ferrireductase activity in vitro, they had little or no effect on erythrocyte phenotypes
Mendeliome v0.9144 NT5C3A Zornitza Stark Gene: nt5c3a has been classified as Green List (High Evidence).
Mendeliome v0.9140 ABCC11 Zornitza Stark Gene: abcc11 has been classified as Red List (Low Evidence).
Mendeliome v0.9139 ABCC11 Zornitza Stark Classified gene: ABCC11 as Red List (low evidence)
Mendeliome v0.9139 ABCC11 Zornitza Stark Gene: abcc11 has been classified as Red List (Low Evidence).
Mendeliome v0.9137 KCNN4 Zornitza Stark edited their review of gene: KCNN4: Changed publications: 26148990, 26198474, 26178367, 33519508, 31091145, 28619848; Changed phenotypes: Dehydrated hereditary stomatocytosis 2, MIM# 616689
Mendeliome v0.9137 MTRR Zornitza Stark Gene: mtrr has been classified as Green List (High Evidence).
Mendeliome v0.9134 MTR Zornitza Stark Gene: mtr has been classified as Green List (High Evidence).
Mendeliome v0.9131 LPIN2 Zornitza Stark Gene: lpin2 has been classified as Green List (High Evidence).
Mendeliome v0.9128 FOXE3 Zornitza Stark Gene: foxe3 has been classified as Green List (High Evidence).
Mendeliome v0.9128 FOXE3 Zornitza Stark Phenotypes for gene: FOXE3 were changed from to Anterior segment dysgenesis 2, multiple subtypes, MIM#610256; Cataract 34, multiple types, MIM#612968; Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349
Mendeliome v0.9125 FOXE3 Eleanor Williams reviewed gene: FOXE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26854927, 27218149, 16826526, 19708017, 20140963, 20664696, 20361012, 24019743, 27669367, 29878917, 32436650, 34046667, 11159941, 19708017, 20806047, 21150893, 11980846, 34046667; Phenotypes: Anterior segment dysgenesis 2, multiple subtypes, MIM#610256, Cataract 34, multiple types, MIM#612968, Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9125 SLC26A1 Zornitza Stark Phenotypes for gene: SLC26A1 were changed from to Nephrolithiasis, calcium oxalate, MIM#167030
Mendeliome v0.9122 SLC26A1 Zornitza Stark Classified gene: SLC26A1 as Amber List (moderate evidence)
Mendeliome v0.9122 SLC26A1 Zornitza Stark Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9121 SLC26A1 Zornitza Stark reviewed gene: SLC26A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27210743, 20160351, 30383413, 27125215; Phenotypes: Nephrolithiasis, calcium oxalate, MIM#167030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9121 RHAG Zornitza Stark Gene: rhag has been classified as Green List (High Evidence).
Mendeliome v0.9121 RHAG Zornitza Stark Phenotypes for gene: RHAG were changed from to Anaemia, haemolytic, Rh-null, regulator type MIM# 268150; Overhydrated hereditary stomatocytosis MIM#185000
Mendeliome v0.9118 SPTA1 Zornitza Stark Gene: spta1 has been classified as Green List (High Evidence).
Mendeliome v0.9118 SPTA1 Zornitza Stark Phenotypes for gene: SPTA1 were changed from to Elliptocytosis-2 MIM# 130600; Pyropoikilocytosis MIM# 266140; Spherocytosis, type 3 MIM# 270970
Mendeliome v0.9115 SPTA1 Danielle Ariti reviewed gene: SPTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9075575, 8018926, 29484404, 27667160, 31333484, 8941647, 3785322; Phenotypes: Elliptocytosis-2 MIM# 130600, Pyropoikilocytosis MIM# 266140, Spherocytosis, type 3 MIM# 270970; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9115 SPTB Zornitza Stark Gene: sptb has been classified as Green List (High Evidence).
Mendeliome v0.9115 SPTB Zornitza Stark Phenotypes for gene: SPTB were changed from to Spherocytosis, type 2 MIM# 616649; Elliptocytosis-3 MIM# 617948; Anaemia, neonatal haemolytic, fatal or near-fatal MIM# 617948
Mendeliome v0.9112 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
Mendeliome v0.9112 TF Zornitza Stark Phenotypes for gene: TF were changed from to Atransferrinaemia MIM# 209300; iron overload; hypochromic anaemia; low serum transferrin; Hemosiderosis of the heart and/or liver; Congestive heart failure
Mendeliome v0.9109 RHAG Danielle Ariti reviewed gene: RHAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30990901, 28470789, 4962358, 18931342, 21849667, 23406318; Phenotypes: Anaemia, haemolytic, Rh-null, regulator type MIM# 268150, Overhydrated hereditary stomatocytosis MIM#185000; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9109 SPTB Danielle Ariti reviewed gene: SPTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 19538529, 8102379, 9075575, 7883966, 9005995, 32256302; Phenotypes: Spherocytosis, type 2 MIM# 616649, Elliptocytosis-3 MIM# 617948, Anaemia, neonatal haemolytic, fatal or near-fatal MIM# 617948; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9109 TF Danielle Ariti reviewed gene: TF: Rating: GREEN; Mode of pathogenicity: None; Publications: 11110675, 3472216; Phenotypes: Atransferrinaemia MIM# 209300, iron overload, hypochromic anaemia, low serum transferrin, Hemosiderosis of the heart and/or liver, Congestive heart failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9108 GSR Zornitza Stark Gene: gsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9105 GSR Zornitza Stark Classified gene: GSR as Amber List (moderate evidence)
Mendeliome v0.9105 GSR Zornitza Stark Gene: gsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9104 MAGEL2 Anna Le Fevre reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33820833, 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, Chitayat-Hall Syndrome, Arthrogryposis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.9104 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Mendeliome v0.9101 UMPS Zornitza Stark edited their review of gene: UMPS: Added comment: 20 unrelated patients have been reported with biallelic missense variants; one mouse model

Orotic aciduria is characterised by megaloblastic anaemia and orotic acid crystalluria, frequently associated with a degree of physical and intellectual disability. Other features include, congenital malformations (Atrial/ Ventricular septal defect) and immunodeficiencies (T-cell dysfunction, failure to thrive, recurrent infections).

Haematology features
- Megaloblastic anaemia
- Low to normal reticulocyte count
- Anisocytosis
- Poikilocytosis
- Hypochromia; Changed publications: 9042911, 33489760; Changed phenotypes: Orotic aciduria, MIM# 258900
Mendeliome v0.9101 TMPRSS6 Zornitza Stark Gene: tmprss6 has been classified as Green List (High Evidence).
Mendeliome v0.9098 TPI1 Zornitza Stark changed review comment from: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital hemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.; to: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital haemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.
Mendeliome v0.9098 TPI1 Zornitza Stark edited their review of gene: TPI1: Added comment: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital hemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.; Changed publications: 9338582, 32873690, 8503454; Changed phenotypes: Haemolytic anaemia due to triosephosphate isomerase deficiency, MIM# 615512
Mendeliome v0.9098 YARS2 Zornitza Stark Gene: yars2 has been classified as Green List (High Evidence).
Mendeliome v0.9098 YARS2 Zornitza Stark Phenotypes for gene: YARS2 were changed from to Myopathy, lactic acidosis, and sideroblastic anaemia 2 MIM# 613561; sideroblastic anaemia; muscle atrophy; myopathy; lactic acidosis; Hypertrophic cardiomyopathy; Hepatomegaly; Decreased cytochrome C oxidase activity
Mendeliome v0.9095 YARS2 Zornitza Stark reviewed gene: YARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24430573, 24344687; Phenotypes: Myopathy, lactic acidosis, and sideroblastic anaemia 2 MIM# 613561, sideroblastic anaemia, muscle atrophy, myopathy, lactic acidosis, Hypertrophic cardiomyopathy, Hepatomegaly, Decreased cytochrome C oxidase activity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9095 GCLC Zornitza Stark Gene: gclc has been classified as Green List (High Evidence).
Mendeliome v0.9092 PDGFRL Zornitza Stark Gene: pdgfrl has been classified as Red List (Low Evidence).
Mendeliome v0.9092 PDGFRL Zornitza Stark Classified gene: PDGFRL as Red List (low evidence)
Mendeliome v0.9092 PDGFRL Zornitza Stark Gene: pdgfrl has been classified as Red List (Low Evidence).
Mendeliome v0.9091 IFIH1 Zornitza Stark Gene: ifih1 has been classified as Green List (High Evidence).
Mendeliome v0.9088 IFIH1 Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified.
Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant.
Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
Mendeliome v0.9088 IFIH1 Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight patients with Very Early Onset Inflammatory Bowel Disease (VEOIBD) with VEOIBD from a combined cohort of 42 children. One homozygous truncating variant in a neonate from a consanguineous family, seven carriers of LoF variants (three of whom also have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.
Mendeliome v0.9088 PRICKLE2 Hazel Phillimore changed review comment from: Six subjects from four unrelated families with heterozygous variants (two de novo missense (c.122 C>T; p.(Pro41Leu) and c.680C>G; p.(Thr227Arg)), one de novo nonsense variant (c.214 C>T; p.(Arg72*) and one frameshift variant (c.1286_1287delGT; p.(Ser429Thrfs*56)) which segregated with the disease in three affected females.

Loss-of-function (homozygous) variants cause seizures in flies, and both heterozygous and homozygous mice showed behavioral abnormalities including altered social interaction, learning abnormalities, and behavioural inflexibility. PubMed: 21276947.; to: Six subjects from four unrelated families with neurodevelopmental delay, behavioural difficulties and epilepsy had heterozygous variants, either de novo or segregating with disease.
Two missense were de novo, c.122 C>T; p.(Pro41Leu) and c.680C>G; p.(Thr227Arg); one nonsense variant was de novo (c.214 C>T; p.(Arg72*); and one frameshift variant segregated with the disorder in three affected females (c.1286_1287delGT; p.(Ser429Thrfs*56)).

Loss-of-function (homozygous) variants have been shown to cause seizures in flies; and both heterozygous and homozygous mice have shown behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility (PubMed: 21276947).
Mendeliome v0.9088 FGF8 Zornitza Stark Gene: fgf8 has been classified as Green List (High Evidence).
Mendeliome v0.9088 FGF8 Zornitza Stark Phenotypes for gene: FGF8 were changed from to Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Femoral hypoplasia
Mendeliome v0.9085 UBE2U Zornitza Stark Gene: ube2u has been classified as Red List (Low Evidence).
Mendeliome v0.9085 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Mendeliome v0.9082 UBE2U Ee Ming Wong changed review comment from: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature; to: - one missense UBE2U variant identified in one family with five affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature
Mendeliome v0.9082 UBE2U Zornitza Stark Classified gene: UBE2U as Red List (low evidence)
Mendeliome v0.9082 UBE2U Zornitza Stark Gene: ube2u has been classified as Red List (Low Evidence).
Mendeliome v0.9081 FGF8 Dean Phelan reviewed gene: FGF8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34433009; Phenotypes: Femoral hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9081 LRP1 Seb Lunke Gene: lrp1 has been classified as Red List (Low Evidence).
Mendeliome v0.9081 LRP1 Seb Lunke Classified gene: LRP1 as Red List (low evidence)
Mendeliome v0.9081 LRP1 Seb Lunke Added comment: Comment on list classification: Two papers without related phenotypes and little overall evidence for gene disease association.
Mendeliome v0.9081 LRP1 Seb Lunke Gene: lrp1 has been classified as Red List (Low Evidence).
Mendeliome v0.9080 COPB2 Zornitza Stark Phenotypes for gene: COPB2 were changed from Microcephaly 19, primary, autosomal recessive, MIM# 617800 to Microcephaly 19, primary, autosomal recessive, MIM# 617800; Osteoporosis and developmental delay
Mendeliome v0.9077 COPB2 Zornitza Stark Classified gene: COPB2 as Green List (high evidence)
Mendeliome v0.9077 COPB2 Zornitza Stark Gene: copb2 has been classified as Green List (High Evidence).
Mendeliome v0.9076 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Mendeliome v0.9076 CACNA1I Seb Lunke Classified gene: CACNA1I as Green List (high evidence)
Mendeliome v0.9076 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Mendeliome v0.9075 UBE2U Ee Ming Wong gene: UBE2U was added
gene: UBE2U was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to PMID: 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Penetrance for gene: UBE2U were set to Complete
Review for gene: UBE2U was set to RED
gene: UBE2U was marked as current diagnostic
Added comment: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature
Mendeliome v0.9075 LRP1 Elena Savva reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26142438, 33776059; Phenotypes: ?Keratosis pilaris atrophicans MIM#604093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9075 COPB2 Belinda Chong reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34450031; Phenotypes: Osteoporosis and developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9075 GRIK2 Zornitza Stark Gene: grik2 has been classified as Green List (High Evidence).
Mendeliome v0.9075 CFAP206 Seb Lunke Gene: cfap206 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9075 GRIK2 Zornitza Stark Phenotypes for gene: GRIK2 were changed from to Mental retardation, autosomal recessive, 6 MIM# 611092; Nonsyndromic neurodevelopmental disorder, autosomal dominant
Mendeliome v0.9071 CFAP206 Seb Lunke Classified gene: CFAP206 as Amber List (moderate evidence)
Mendeliome v0.9071 CFAP206 Seb Lunke Gene: cfap206 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9069 ZNF668 Zornitza Stark Gene: znf668 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9069 ZNF668 Zornitza Stark Classified gene: ZNF668 as Amber List (moderate evidence)
Mendeliome v0.9069 ZNF668 Zornitza Stark Gene: znf668 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9068 GRIK2 Danielle Ariti reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, nonsyndromic neurodevelopmental disorder (NDD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9068 GLIS1 Seb Lunke Gene: glis1 has been classified as Red List (Low Evidence).
Mendeliome v0.9067 GLIS1 Seb Lunke changed review comment from: Functional studies in KO mice show increased intra-ocular pressure (IOT) caused by defects in the ocular drainage system. IOT is frequently associated with Glaucoma, however mice were not investigated for glaucoma, and no patients described.
Sources: Literature; to: Functional studies in KO mice show increased intra-ocular pressure (IOT) caused by defects in the ocular drainage system. IOT is frequently associated with Glaucoma, however mice were not investigated for glaucoma, and no patients described.

The authors did show dysregulation of GLIS1 in a human cell line study, and performed linkage analysis suggesting an association of the GLIS1 locus with Glaucoma in UK biobank samples.
Sources: Literature
Mendeliome v0.9067 CFAP206 Ain Roesley gene: CFAP206 was added
gene: CFAP206 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP206 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CFAP206 were set to Multiple morphological abnormalities of the fagella
Penetrance for gene: CFAP206 were set to unknown
Review for gene: CFAP206 was set to AMBER
Added comment: 1x hom with a fs variant

Sperm from knockout mouse model mainly had a fagellum of normal length but most of them showed abnormal forms including bent and coiled fagella. There was also a significant increase of sperm cells with absent or short fagella compared to the WT mice.
Sources: Literature
Mendeliome v0.9067 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Mendeliome v0.9066 SLC32A1 Zornitza Stark Classified gene: SLC32A1 as Green List (high evidence)
Mendeliome v0.9066 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Mendeliome v0.9065 SLC32A1 Zornitza Stark gene: SLC32A1 was added
gene: SLC32A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 34038384
Phenotypes for gene: SLC32A1 were set to Genetic epilepsy with febrile seizures plus
Review for gene: SLC32A1 was set to GREEN
Added comment: 8 unrelated families reported, including segregation evidence in two large pedigrees. Variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition.
Sources: Literature
Mendeliome v0.9064 G6PD Zornitza Stark Gene: g6pd has been classified as Green List (High Evidence).
Mendeliome v0.9060 EPB42 Zornitza Stark Gene: epb42 has been classified as Green List (High Evidence).
Mendeliome v0.9060 EPB42 Zornitza Stark Phenotypes for gene: EPB42 were changed from to Spherocytosis, type 5, MIM# 612690
Mendeliome v0.9057 EPB42 Zornitza Stark reviewed gene: EPB42: Rating: GREEN; Mode of pathogenicity: None; Publications: 1558976, 7803799, 7772513; Phenotypes: Spherocytosis, type 5, MIM# 612690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9057 EPB41 Zornitza Stark Gene: epb41 has been classified as Green List (High Evidence).
Mendeliome v0.9057 EPB41 Zornitza Stark Phenotypes for gene: EPB41 were changed from to Elliptocytosis-1, MIM# 611804
Mendeliome v0.9054 EPB41 Zornitza Stark reviewed gene: EPB41: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942936, 32807033, 27667160, 21839655; Phenotypes: Elliptocytosis-1, MIM# 611804; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9054 DHFR Zornitza Stark Gene: dhfr has been classified as Green List (High Evidence).
Mendeliome v0.9051 CYB5R3 Zornitza Stark Gene: cyb5r3 has been classified as Green List (High Evidence).
Mendeliome v0.9048 CD59 Zornitza Stark Gene: cd59 has been classified as Green List (High Evidence).
Mendeliome v0.9045 NEDD4L Zornitza Stark Gene: nedd4l has been classified as Green List (High Evidence).
Mendeliome v0.9041 GINS2 Zornitza Stark Gene: gins2 has been classified as Red List (Low Evidence).
Mendeliome v0.9041 GINS2 Zornitza Stark Classified gene: GINS2 as Red List (low evidence)
Mendeliome v0.9041 GINS2 Zornitza Stark Gene: gins2 has been classified as Red List (Low Evidence).
Mendeliome v0.9040 AMN Zornitza Stark Gene: amn has been classified as Green List (High Evidence).
Mendeliome v0.9037 AK1 Zornitza Stark Gene: ak1 has been classified as Green List (High Evidence).
Mendeliome v0.9034 ALAS2 Zornitza Stark Gene: alas2 has been classified as Green List (High Evidence).
Mendeliome v0.9034 ALAS2 Zornitza Stark Phenotypes for gene: ALAS2 were changed from to Anaemia, sideroblastic, 1, MIM# 300751; Protoporphyria, erythropoietic, X-linked, MIM# 300752
Mendeliome v0.9031 ALAS2 Zornitza Stark reviewed gene: ALAS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10029606, 7949148, 10029606, 25615817; Phenotypes: Anaemia, sideroblastic, 1, MIM# 300751, Protoporphyria, erythropoietic, X-linked, MIM# 300752; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9031 ABCG5 Zornitza Stark Gene: abcg5 has been classified as Green List (High Evidence).
Mendeliome v0.9031 ABCG5 Zornitza Stark Phenotypes for gene: ABCG5 were changed from to Sitosterolaemia 2, MIM# 618666
Mendeliome v0.9028 ABCG5 Zornitza Stark reviewed gene: ABCG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 34304999, 33907061, 32546081, 23556150; Phenotypes: Sitosterolaemia 2, MIM# 618666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9026 TOM1 Zornitza Stark Gene: tom1 has been classified as Red List (Low Evidence).
Mendeliome v0.9026 TOM1 Zornitza Stark gene: TOM1 was added
gene: TOM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOM1 were set to 31263572
Phenotypes for gene: TOM1 were set to Immunodeficiency 85 and autoimmunity, MIM# 619510
Review for gene: TOM1 was set to RED
Added comment: Parent and child reported with onset of atopic eczema and recurrent respiratory infections in the first decade of life; autoimmune enteropathy with vomiting, diarrhoea, and poor overall growth. More variable features included autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies showed hypogammaglobulinaemia and abnormal T-cell function, consistent with a combined immunodeficiency. Missense variant in TOM1, with limited functional data.
Sources: Expert list
Mendeliome v0.9025 GINS2 Arina Puzriakova gene: GINS2 was added
gene: GINS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis
Review for gene: GINS2 was set to RED
Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included.

GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date.
Sources: Literature
Mendeliome v0.9023 KIDINS220 Zornitza Stark Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; cerebral ventriculomegaly; limb contractures to Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; Ventriculomegaly and arthrogryposis, MIM# 619501
Mendeliome v0.9022 KIDINS220 Zornitza Stark edited their review of gene: KIDINS220: Changed phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296, Ventriculomegaly and arthrogryposis, MIM# 619501
Mendeliome v0.9022 CHRM1 Bryony Thompson Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9022 CHRM1 Bryony Thompson Classified gene: CHRM1 as Amber List (moderate evidence)
Mendeliome v0.9022 CHRM1 Bryony Thompson Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9021 CHRM1 Bryony Thompson gene: CHRM1 was added
gene: CHRM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Mendeliome v0.9020 FGF20 Zornitza Stark Gene: fgf20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9020 FGF20 Zornitza Stark Classified gene: FGF20 as Amber List (moderate evidence)
Mendeliome v0.9020 FGF20 Zornitza Stark Gene: fgf20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9019 FGF20 Zornitza Stark gene: FGF20 was added
gene: FGF20 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FGF20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF20 were set to 22698282
Phenotypes for gene: FGF20 were set to Renal hypodysplasia/aplasia 2, MIM#615721
Review for gene: FGF20 was set to AMBER
Added comment: Multiple affected fetuses in a consanguineous family; functional data.
Sources: Expert Review
Mendeliome v0.9018 ITGA8 Zornitza Stark Gene: itga8 has been classified as Green List (High Evidence).
Mendeliome v0.9018 ITGA8 Zornitza Stark Phenotypes for gene: ITGA8 were changed from to Renal hypodysplasia/aplasia 1, MIM# 191830
Mendeliome v0.9015 ITGA8 Zornitza Stark reviewed gene: ITGA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439109; Phenotypes: Renal hypodysplasia/aplasia 1, MIM# 191830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9015 NPR2 Zornitza Stark Gene: npr2 has been classified as Green List (High Evidence).
Mendeliome v0.9015 NPR2 Zornitza Stark Phenotypes for gene: NPR2 were changed from to Acromesomelic dysplasia, Maroteaux type MIM# 602875; Epiphyseal chondrodysplasia, Miura type, MIM# 615923; Short stature with nonspecific skeletal abnormalities, MIM# 616255
Mendeliome v0.9012 NPR2 Zornitza Stark edited their review of gene: NPR2: Changed publications: 31555216, 16384845, 15146390, 22870295, 24057292, 24259409, 16384845, 24471569; Changed phenotypes: Acromesomelic dysplasia, Maroteaux type MIM# 602875, Epiphyseal chondrodysplasia, Miura type, MIM# 615923, Short stature with nonspecific skeletal abnormalities, MIM# 616255; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9012 NPR2 Zornitza Stark reviewed gene: NPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555216, 16384845, 15146390; Phenotypes: Acromesomelic dysplasia, Maroteaux type MIM# 602875, Short stature, disproportionate, Oval vertebral bodies in infancy, Progressive shortening of humerus, radius and ulna in first year, dwarfism, Prominent forehead; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9012 RPS6KA3 Zornitza Stark Gene: rps6ka3 has been classified as Green List (High Evidence).
Mendeliome v0.9009 SHOX2 Zornitza Stark Gene: shox2 has been classified as Red List (Low Evidence).
Mendeliome v0.9009 SHOX2 Zornitza Stark gene: SHOX2 was added
gene: SHOX2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SHOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SHOX2 were set to 30443179
Phenotypes for gene: SHOX2 were set to Sinus Node Dysfunction; Atrial Fibrillation
Review for gene: SHOX2 was set to RED
Added comment: Single family reported with LoF in this gene and AF.
Sources: Expert Review
Mendeliome v0.9007 KCTD7 Zornitza Stark Gene: kctd7 has been classified as Green List (High Evidence).
Mendeliome v0.9007 KCTD7 Zornitza Stark Phenotypes for gene: KCTD7 were changed from to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726)
Mendeliome v0.9004 KCTD7 Kristin Rigbye reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693283, 22748208; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9003 ROR2 Zornitza Stark Gene: ror2 has been classified as Green List (High Evidence).
Mendeliome v0.9003 ROR2 Zornitza Stark Phenotypes for gene: ROR2 were changed from to Robinow syndrome, autosomal recessive MIM# 268310; hypertelorism; short stature; mesomelic shortening of the limbs; hypoplastic genitalia; rib/vertebral anomalies; abnormal morphogenesis of the face; Brachydactyly, type B1 MIM# 113000; hypoplasia/aplasia of distal phalanges and nails (2-5)
Mendeliome v0.9000 ROR2 Zornitza Stark reviewed gene: ROR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932186, 10932187, 10986040, 19461659; Phenotypes: Robinow syndrome, autosomal recessive MIM# 268310, hypertelorism, short stature, mesomelic shortening of the limbs, hypoplastic genitalia, rib/vertebral anomalies, abnormal morphogenesis of the face, Brachydactyly, type B1 MIM# 113000, hypoplasia/aplasia of distal phalanges and nails (2-5); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9000 PROP1 Zornitza Stark Gene: prop1 has been classified as Green List (High Evidence).
Mendeliome v0.9000 PROP1 Zornitza Stark Phenotypes for gene: PROP1 were changed from to Pituitary hormone deficiency, combined, 2 MIM# 262600; Ateliotic dwarfism with hypogonadism; growth failure; short stature; failure to thrive; absent sexual development at puberty; GH, PRL, TSH, LH, and FSH deficiency; pituitary hypoplasia
Mendeliome v0.8997 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301521, 31090814; Phenotypes: Pituitary hormone deficiency, combined, 2 MIM# 262600, Ateliotic dwarfism with hypogonadism, growth failure, short stature, failure to thrive, absent sexual development at puberty, GH, PRL, TSH, LH, and FSH deficiency, pituitary hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8997 WRN Zornitza Stark Gene: wrn has been classified as Green List (High Evidence).
Mendeliome v0.8994 POU1F1 Zornitza Stark Gene: pou1f1 has been classified as Green List (High Evidence).
Mendeliome v0.8994 POU1F1 Zornitza Stark Phenotypes for gene: POU1F1 were changed from to Pituitary hormone deficiency, combined, 1 MIM# 613038; pituitary hypoplasia; severe growth failure; combined GH, PRL and TSH deficiency; distinct facial features (prominent forehead, mid-facial hypoplasia, depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils)
Mendeliome v0.8991 POU1F1 Zornitza Stark reviewed gene: POU1F1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1302000, 1472057, 9392392, 15928241, 7833912, 12773133; Phenotypes: Pituitary hormone deficiency, combined, 1 MIM# 613038, pituitary hypoplasia, severe growth failure, combined GH, PRL and TSH deficiency, distinct facial features (prominent forehead, mid-facial hypoplasia, depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8991 OPDM2 Bryony Thompson Str: opdm2 has been classified as Green List (High Evidence).
Mendeliome v0.8991 OPDM2 Bryony Thompson Classified STR: OPDM2 as Green List (high evidence)
Mendeliome v0.8991 OPDM2 Bryony Thompson Str: opdm2 has been classified as Green List (High Evidence).
Mendeliome v0.8990 OPDM2 Bryony Thompson STR: OPDM2 was added
STR: OPDM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: OPDM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: OPDM2 were set to 32413282; 33374016
Phenotypes for STR: OPDM2 were set to Oculopharyngodistal myopathy 2 MIM#618940
Review for STR: OPDM2 was set to GREEN
STR: OPDM2 was marked as clinically relevant
Added comment: NM_005716.4:c.-211GGC[X]
>15 Chinese families/probands with a heterozygous trinucleotide repeat expansion (CGG(n)) in 5'UTR exon 1 of the GIPC1 gene. The expansion was found by a combination of linkage analysis, whole-exome sequencing, long-range sequencing, and PCR analysis, and segregated with the disorder in the family. Repeat lengths in the patients ranged from 70 to 138. Normal repeat lengths ranged from 12 to 32.
Sources: Literature
Mendeliome v0.8989 FAME2 Bryony Thompson Str: fame2 has been classified as Green List (High Evidence).
Mendeliome v0.8989 GIPC1 Bryony Thompson Classified gene: GIPC1 as No list
Mendeliome v0.8989 GIPC1 Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under OPDM2
Mendeliome v0.8988 FAME2 Bryony Thompson Classified STR: FAME2 as Green List (high evidence)
Mendeliome v0.8988 FAME2 Bryony Thompson Str: fame2 has been classified as Green List (High Evidence).
Mendeliome v0.8987 FAME2 Bryony Thompson STR: FAME2 was added
STR: FAME2 was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: FAME2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FAME2 were set to 11701600; 24114805; 31664034
Phenotypes for STR: FAME2 were set to Epilepsy, familial adult myoclonic, 2 MIM#607876
Review for STR: FAME2 was set to GREEN
STR: FAME2 was marked as clinically relevant
Added comment: NM_020151.3(STARD7):c.291-1572ATTTT[X]ATTTC[X]
158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy with a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat, similar molecular finding in other forms of FAME. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and no effect on STARD7 gene expression, suggesting ATTTC expansions may cause FAME irrespective of the genomic locus involved.
Sources: Literature
Mendeliome v0.8986 STARD7 Bryony Thompson Classified gene: STARD7 as No list
Mendeliome v0.8986 STARD7 Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under FAME2
Mendeliome v0.8984 PNPLA6 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.
Sources: Expert list; to: Variants in this gene are associated with multiple phenotypes.

Oliver-McFarlane syndrome is a rare congenital disorder characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies, including growth hormone. At least 10 families reported.

Laurence-Moon syndrome has a clinical presentation similar to that of Oliver-McFarlane syndrome, including chorioretinopathy and pituitary dysfunction, but with childhood onset of ataxia, peripheral neuropathy, and spastic paraplegia and without trichomegaly. Single family reported.
Mendeliome v0.8984 PI4KA Zornitza Stark Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531 to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531; Neurodevelopmental syndrome with hypomyelinating leukodystrophy
Mendeliome v0.8982 PI4KA Zornitza Stark Classified gene: PI4KA as Green List (high evidence)
Mendeliome v0.8982 PI4KA Zornitza Stark Gene: pi4ka has been classified as Green List (High Evidence).
Mendeliome v0.8981 PI4KA Zornitza Stark changed review comment from: Single family reported, aware of at least one other yet to be published family identified internally.; to: PMG: Single family reported, aware of at least one other yet to be published family identified internally.
Mendeliome v0.8981 PI4KA Zornitza Stark edited their review of gene: PI4KA: Added comment: Neurodevelopmental syndrome with hypomyelinating leukodystrophy: 10 unrelated patients harbouring biallelic variants in PI4KA reported with a spectrum of severe global neurodevelopmental delay, hypomyelination, and developmental brain abnormalities, and pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells.; Changed rating: GREEN; Changed publications: 25855803, 34415322; Changed phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531, Neurodevelopmental syndrome with hypomyelinating leukodystrophy
Mendeliome v0.8981 NIID Bryony Thompson Str: niid has been classified as Green List (High Evidence).
Mendeliome v0.8981 NIID Bryony Thompson Classified STR: NIID as Green List (high evidence)
Mendeliome v0.8981 NIID Bryony Thompson Str: niid has been classified as Green List (High Evidence).
Mendeliome v0.8980 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102; 34333668
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 4-40, 1 control had 61 repeats and may have been a presymptomatic carrier.
Intermediate range: 41-60 identified in Parkinson's disease
Pathogenic repeat range: >=60-520
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Mendeliome v0.8978 SUCO Bryony Thompson Gene: suco has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8978 SUCO Bryony Thompson Classified gene: SUCO as Amber List (moderate evidence)
Mendeliome v0.8978 SUCO Bryony Thompson Gene: suco has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8977 SUCO Bryony Thompson gene: SUCO was added
gene: SUCO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SUCO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCO were set to 29620724; 20440000
Phenotypes for gene: SUCO were set to Osteogenesis imperfecta
Review for gene: SUCO was set to AMBER
Added comment: A single case with diffuse osteopenia, multiple fractures with limb deformities, and short long bones, with biallelic variants (a missense and a splice site variant). Also, a null mouse model with acute onset skeletal defects that include impaired bone formation and spontaneous fractures.
Sources: Literature
Mendeliome v0.8976 IGFALS Zornitza Stark Gene: igfals has been classified as Green List (High Evidence).
Mendeliome v0.8973 FAME1 Bryony Thompson Str: fame1 has been classified as Green List (High Evidence).
Mendeliome v0.8973 FAME1 Bryony Thompson Classified STR: FAME1 as Green List (high evidence)
Mendeliome v0.8973 FAME1 Bryony Thompson Str: fame1 has been classified as Green List (High Evidence).
Mendeliome v0.8972 FAME1 Bryony Thompson STR: FAME1 was added
STR: FAME1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: FAME1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for STR: FAME1 were set to 30194086; 29507423
Phenotypes for STR: FAME1 were set to Epilepsy, familial adult myoclonic, 1 MIM#601068
Review for STR: FAME1 was set to GREEN
STR: FAME1 was marked as clinically relevant
Added comment: NC_000008.10:g.119379055_119379157TGAAA[X]TAAAA[X]
A heterozygous or homozygous 5-bp expanded TTTCA(n) insertion associated with an upstream 5-bp TTTTA(n) repeat expansion in a noncoding region within intron 4 of the SAMD12 gene, was identified in over 50 Chinese and Japanese families. 4 homozygous cases from 3 families had a more severe phenotype. The TTTTA repeat was present in controls, while the TTTCA was absent and only present in cases (100-3680 repeats reported). RNA toxicity is expected to be the mechanism of disease.
Sources: Expert list
Mendeliome v0.8971 SAMD12 Bryony Thompson Classified gene: SAMD12 as No list
Mendeliome v0.8971 SAMD12 Bryony Thompson Added comment: Comment on list classification: Added as an STR to panel under FAME1.
Mendeliome v0.8969 MYO1H Zornitza Stark Gene: myo1h has been classified as Red List (Low Evidence).
Mendeliome v0.8969 MYO1H Zornitza Stark gene: MYO1H was added
gene: MYO1H was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction, MIM#619482
Review for gene: MYO1H was set to RED
Added comment: Single family reported with three affected children, homozygous LoF variant.
Sources: Literature
Mendeliome v0.8968 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Mendeliome v0.8968 BLM Zornitza Stark Phenotypes for gene: BLM were changed from to Bloom Syndrome MIM# 210900; Short stature, dysmorphic facies; sun-sensitive; immunoglobulin deficiency (IgA, IgG, IgM); erythema; marrow failure; leukaemia; lymphoma; chromosomal instability; predisposition to malignancies
Mendeliome v0.8965 PRKDC Zornitza Stark Gene: prkdc has been classified as Green List (High Evidence).
Mendeliome v0.8962 TBX1 Zornitza Stark Gene: tbx1 has been classified as Green List (High Evidence).
Mendeliome v0.8962 TBX1 Zornitza Stark Phenotypes for gene: TBX1 were changed from to DiGeorge syndrome MIM# 188400; Velocardiofacial syndrome MIM# 192430; Decreased T cells; Hypoparathyroidism; Conotruncal cardiac malformation; velopalatal insufficiency; abnormal facies (cleft palate, prominent tubular nose etc); intellectual disability; Immunodeficiency; thymic hypoplasia or aplasia with resultant T‐cell dysfunction; renal anomalies; autoimmunity
Mendeliome v0.8959 TBX1 Zornitza Stark reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301696, 31830774, 16684884; Phenotypes: DiGeorge syndrome MIM# 188400, Velocardiofacial syndrome MIM# 192430, Decreased T cells, Hypoparathyroidism, Conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies (cleft palate, prominent tubular nose etc), intellectual disability, Immunodeficiency, thymic hypoplasia or aplasia with resultant T‐cell dysfunction, renal anomalies, autoimmunity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8959 RTEL1 Zornitza Stark Gene: rtel1 has been classified as Green List (High Evidence).
Mendeliome v0.8959 RTEL1 Zornitza Stark Phenotypes for gene: RTEL1 were changed from to Dyskeratosis congenita, autosomal dominant 4 MIM# 615190; Dyskeratosis congenita, autosomal recessive 5 MIM# 615190; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 MIM# 616373
Mendeliome v0.8956 RTEL1 Zornitza Stark reviewed gene: RTEL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301779, 23329068, 15210109, 23453664, 19461895, 25848748, 25607374; Phenotypes: Dyskeratosis congenita, autosomal dominant 4 MIM# 615190, Dyskeratosis congenita, autosomal recessive 5 MIM# 615190, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 MIM# 616373; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8956 RMRP Zornitza Stark changed review comment from: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models

Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function.
*Founder variant g.70A>G (Amish and Finnish populations)

CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency.; to: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models

Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function.
*Founder variant g.70A>G (Amish and Finnish populations)

CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency.

Anauxetic dysplasia 1, MIM# 607095 is a more severe phenotype, whereas Metaphyseal dysplasia without hypotrichosis, MIM# 250460 is milder.
Mendeliome v0.8956 RMRP Zornitza Stark edited their review of gene: RMRP: Changed phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, Anauxetic dysplasia 1, MIM# 607095, Metaphyseal dysplasia without hypotrichosis, MIM# 250460
Mendeliome v0.8956 RMRP Zornitza Stark Gene: rmrp has been classified as Green List (High Evidence).
Mendeliome v0.8956 RMRP Zornitza Stark Phenotypes for gene: RMRP were changed from to Cartilage-hair hypoplasia MIM#250250
Mendeliome v0.8953 RMRP Zornitza Stark reviewed gene: RMRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16244706, 21396580, 22420014; Phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities, CID, impaired lymphocyte proliferation, low Ig levels, antibodies variably decreased, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8953 BLM Danielle Ariti reviewed gene: BLM: Rating: GREEN; Mode of pathogenicity: None; Publications: 17407155, 9285778, 7585968, 8079989, 12242442, 11101838; Phenotypes: Bloom Syndrome MIM# 210900, Short stature, dysmorphic facies, sun-sensitive, immunoglobulin deficiency (IgA, IgG, IgM), erythema, marrow failure, leukaemia, lymphoma, chromosomal instability, predisposition to malignancies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8953 RFX5 Zornitza Stark Gene: rfx5 has been classified as Green List (High Evidence).
Mendeliome v0.8950 ELMOD3 Zornitza Stark Phenotypes for gene: ELMOD3 were changed from Deafness, autosomal recessive 88, MIM# 615429; Deafness, autosomal dominant to Deafness, autosomal recessive 88, MIM# 615429; Deafness, autosomal dominant 81, MIM# 619500
Mendeliome v0.8949 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Changed phenotypes: Deafness, autosomal recessive 88, MIM# 615429, Deafness, autosomal dominant 81, MIM# 619500
Mendeliome v0.8949 TYK2 Zornitza Stark Gene: tyk2 has been classified as Green List (High Evidence).
Mendeliome v0.8946 RAG1 Zornitza Stark Gene: rag1 has been classified as Green List (High Evidence).
Mendeliome v0.8946 RAG1 Zornitza Stark Phenotypes for gene: RAG1 were changed from to Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889; Combined cellular and humoral immune defects with granulomas MIM# 233650; Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457
Mendeliome v0.8943 RAG2 Zornitza Stark Gene: rag2 has been classified as Green List (High Evidence).
Mendeliome v0.8939 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
Mendeliome v0.8939 RAC2 Zornitza Stark Phenotypes for gene: RAC2 were changed from to Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203; Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987; Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986
Mendeliome v0.8937 RAG1 Danielle Ariti reviewed gene: RAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16276422, 18463379, 20489056, 9630231, 11313270, 17476359, 8810255, 6823332; Phenotypes: Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889, Combined cellular and humoral immune defects with granulomas MIM# 233650, Omenn syndrome MIM# 603554, Severe combined immunodeficiency, B cell-negative MIM# 601457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8935 RAC2 Danielle Ariti reviewed gene: RAC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21167572, 10758162, 10072071, 25512081, 32542921, 31919089; Phenotypes: Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203, Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987, Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8935 MTHFD1 Danielle Ariti reviewed gene: MTHFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780, Decreased Ig levels, poor antibody responses to conjugated polysaccharide antigens, low B/T/NK cells, Recurrent bacterial infection, megaloblastic anaemia, failure to thrive, neutropenia, seizures, intellectual disability, folate-responsive, Lymphopaenia; Phenotypes: 32414565, 19033438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8935 GLI2 Zornitza Stark Gene: gli2 has been classified as Green List (High Evidence).
Mendeliome v0.8932 GLI2 Zornitza Stark changed review comment from: Culler-Jones syndrome (CJS) is characterized by hypopituitarism, mainly growth hormone deficiency, and/or postaxial polydactyly. The phenotype is highly variable, and some individuals may have midline facial defects and developmental delay. The disorder shows incomplete penetrance and variable expressivity. Multiple families reported, short stature is a feature as a result of GH deficiency.

Variants in GLI2 are also associated with HPE, at least 5 families reported. Short stature is observed more rarely, as a result of midline defect.; to: Culler-Jones syndrome (CJS) is characterized by hypopituitarism, mainly growth hormone deficiency, and/or postaxial polydactyly. The phenotype is highly variable, and some individuals may have midline facial defects and developmental delay. The disorder shows incomplete penetrance and variable expressivity. Multiple families reported.

Variants in GLI2 are also associated with HPE, at least 5 families reported.
Mendeliome v0.8932 GHSR Zornitza Stark Gene: ghsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8929 GHSR Zornitza Stark Classified gene: GHSR as Amber List (moderate evidence)
Mendeliome v0.8929 GHSR Zornitza Stark Gene: ghsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8928 PDE6D Zornitza Stark Classified gene: PDE6D as Green List (high evidence)
Mendeliome v0.8928 PDE6D Zornitza Stark Gene: pde6d has been classified as Green List (High Evidence).
Mendeliome v0.8927 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
Mendeliome v0.8924 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
Mendeliome v0.8924 GHR Zornitza Stark Phenotypes for gene: GHR were changed from to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500
Mendeliome v0.8921 GHR Zornitza Stark reviewed gene: GHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 1999489, 8488849, 7565946; Phenotypes: Growth hormone insensitivity, partial, MIM# 604271, Laron dwarfism, MIM# 262500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8921 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.8921 SCA12 Bryony Thompson Classified STR: SCA12 as Green List (high evidence)
Mendeliome v0.8921 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.8920 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 27864267; 33811808
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Uncertain: ~40-50 repeats have been reported, 43 repeats is the lowest reported in an established affected individual in a family with SCA12
Established pathogenic (used as diagnostic cut-off): ≥51 repeats
Sources: Expert list
Mendeliome v0.8917 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Mendeliome v0.8913 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
Mendeliome v0.8910 EPHX1 Zornitza Stark Gene: ephx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8907 EPHX1 Zornitza Stark Classified gene: EPHX1 as Amber List (moderate evidence)
Mendeliome v0.8907 EPHX1 Zornitza Stark Gene: ephx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8906 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Mendeliome v0.8905 ATM Zornitza Stark Phenotypes for gene: ATM were changed from to Ataxia-telangiectasia, MIM# 208900
Mendeliome v0.8903 ATM Zornitza Stark reviewed gene: ATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 30137827; Phenotypes: Ataxia-telangiectasia, MIM# 208900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8900 RNU4ATAC Zornitza Stark edited their review of gene: RNU4ATAC: Added comment: Lowry-Wood syndrome (LWS) is characterized by multiple epiphyseal dysplasia and microcephaly. Patients exhibit intrauterine growth retardation and short stature, as well as developmental delay and intellectual disability. Retinal degeneration has been reported in some patients.

Four unrelated families reported.

Note features between the three RNU4ATAC-related conditions overlap and they may not represent distinct disorders.; Changed rating: GREEN; Changed publications: 29265708, 12605445; Changed phenotypes: Lowry-Wood syndrome, MIM# 226960; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8900 TRPS1 Zornitza Stark Gene: trps1 has been classified as Green List (High Evidence).
Mendeliome v0.8897 FGD1 Zornitza Stark Gene: fgd1 has been classified as Green List (High Evidence).
Mendeliome v0.8894 BRD4 Zornitza Stark Gene: brd4 has been classified as Green List (High Evidence).
Mendeliome v0.8890 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Mendeliome v0.8890 ZNF699 Zornitza Stark Classified gene: ZNF699 as Green List (high evidence)
Mendeliome v0.8890 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Mendeliome v0.8889 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Mendeliome v0.8886 DCLRE1B Zornitza Stark Gene: dclre1b has been classified as Red List (Low Evidence).
Mendeliome v0.8886 DCLRE1B Zornitza Stark Phenotypes for gene: DCLRE1B were changed from to Dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome
Mendeliome v0.8884 DCLRE1B Zornitza Stark Classified gene: DCLRE1B as Red List (low evidence)
Mendeliome v0.8884 DCLRE1B Zornitza Stark Gene: dclre1b has been classified as Red List (Low Evidence).
Mendeliome v0.8883 DCLRE1B Zornitza Stark reviewed gene: DCLRE1B: Rating: RED; Mode of pathogenicity: None; Publications: 20479256, 21647296; Phenotypes: Dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome; Mode of inheritance: Unknown
Mendeliome v0.8883 TOR1AIP1 Zornitza Stark Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Congenital myasthenic syndrome
Mendeliome v0.8881 TOR1AIP1 Zornitza Stark edited their review of gene: TOR1AIP1: Added comment: Gene is associated with multiple muscle phenotypes as already noted. Single family myasthenic syndrome and supportive mouse model data.; Changed rating: GREEN; Changed publications: 33215087; Changed phenotypes: Congenital myasthenic syndrome; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8881 PAPPA2 Zornitza Stark Gene: pappa2 has been classified as Green List (High Evidence).
Mendeliome v0.8881 PAPPA2 Zornitza Stark Classified gene: PAPPA2 as Green List (high evidence)
Mendeliome v0.8881 PAPPA2 Zornitza Stark Gene: pappa2 has been classified as Green List (High Evidence).
Mendeliome v0.8880 PAPPA2 Zornitza Stark gene: PAPPA2 was added
gene: PAPPA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAPPA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAPPA2 were set to 26902202; 34272725; 32739295
Phenotypes for gene: PAPPA2 were set to Short stature, Dauber-Argente type, MIM#619489
Review for gene: PAPPA2 was set to GREEN
Added comment: Short stature of the Dauber-Argente type (SSDA) is characterized by progressive postnatal growth failure, moderate microcephaly, thin long bones, and mildly decreased bone density. Patients have elevated circulating levels of total IGF1 due to impaired proteolysis of IGFBP3 and IGFBP5, resulting in reduced free IGF1.

7 individuals from 3 unrelated families reported, mouse model.
Sources: Literature
Mendeliome v0.8879 ATR Zornitza Stark Gene: atr has been classified as Green List (High Evidence).
Mendeliome v0.8876 SHOX Zornitza Stark Gene: shox has been classified as Green List (High Evidence).
Mendeliome v0.8876 SHOX Zornitza Stark Phenotypes for gene: SHOX were changed from to Langer mesomelic dysplasia, MIM# 249700; Leri-Weill dyschondrosteosis, MIM# 127300
Mendeliome v0.8874 SHOX Zornitza Stark reviewed gene: SHOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Langer mesomelic dysplasia, MIM# 249700, Leri-Weill dyschondrosteosis, MIM# 127300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8874 ORC4 Zornitza Stark Gene: orc4 has been classified as Green List (High Evidence).
Mendeliome v0.8871 ORC1 Zornitza Stark Gene: orc1 has been classified as Green List (High Evidence).
Mendeliome v0.8868 ORC6 Zornitza Stark Gene: orc6 has been classified as Green List (High Evidence).
Mendeliome v0.8865 IGF1 Zornitza Stark Gene: igf1 has been classified as Green List (High Evidence).
Mendeliome v0.8861 IGF2 Zornitza Stark changed review comment from: RSS phenotype.; to: Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay. Disruption of any gene in the HMGA2-PLAG1-IGF2 pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects.

Begemann et al. (2015) performed exome sequencing in 4 affected people with severe growth restriction in one family, and identified a heterozygous nonsense mutation in the IGF2 gene that segregated fully with the disorder. Affected individuals inherited the mutation from their healthy fathers, and it originated from the healthy paternal grandmother. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.

Many other cases reported since with de novo mutations in IGF2 present on the paternal allele.
Mendeliome v0.8861 OBSL1 Zornitza Stark Gene: obsl1 has been classified as Green List (High Evidence).
Mendeliome v0.8858 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Mendeliome v0.8854 PLAG1 Zornitza Stark Classified gene: PLAG1 as Green List (high evidence)
Mendeliome v0.8854 PLAG1 Zornitza Stark Gene: plag1 has been classified as Green List (High Evidence).
Mendeliome v0.8853 PLAG1 Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green.

Silver-Russell syndrome-4 (SRS4) is characterised by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed. So far 4 families have been reported with some functional studies of the role of the gene in the growth pathway.

Abi Habib et al. (2018) reported 1 family (child, sister and mother) patient with Silver-Russell syndrome (with normal methylation on chromosomes 7, 11, and 14, and exclusion of maternal UPD and chromosomal rearrangements). Using WES they identified a heterozygous 1-bp deletion in the PLAG1 gene. The variant segregated with disease, and was not present in polymorphism databases or ExAC. They also reported another patient with a different heterozygous 1-bp deletion in the PLAG1 gene. This was not found in her unaffected twin brother, older brother, or parents. Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 promoter P3, independently and via the HMGA2-PLAG1-IGF2 pathway. Disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus.

Inoue et al. (2020) reported 1 family with 2 affected people with Silver-Russell syndrome with a nonsense variant in the PLAG1 gene, which segregated with disease.

Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215
Mendeliome v0.8853 PACRG Zornitza Stark Gene: pacrg has been classified as Red List (Low Evidence).
Mendeliome v0.8852 PACRG Zornitza Stark Classified gene: PACRG as Red List (low evidence)
Mendeliome v0.8852 PACRG Zornitza Stark Gene: pacrg has been classified as Red List (Low Evidence).
Mendeliome v0.8851 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
Mendeliome v0.8848 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homozygous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8848 TCN2 Zornitza Stark Gene: tcn2 has been classified as Green List (High Evidence).
Mendeliome v0.8847 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8844 TAP2 Zornitza Stark Gene: tap2 has been classified as Green List (High Evidence).
Mendeliome v0.8844 TAP2 Zornitza Stark Phenotypes for gene: TAP2 were changed from to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis
Mendeliome v0.8841 TAP1 Zornitza Stark Gene: tap1 has been classified as Green List (High Evidence).
Mendeliome v0.8841 TAP1 Zornitza Stark Phenotypes for gene: TAP1 were changed from to Bare lymphocyte syndrome, type I MIM#604571; Low CD8; absent MHC I on lymphocytes; vasculitis; pyoderma gangrenosum; skin lesions; recurrent respiratory tract infections; bronchiectasis
Mendeliome v0.8836 PGRMC1 Bryony Thompson Classified gene: PGRMC1 as Amber List (moderate evidence)
Mendeliome v0.8836 PGRMC1 Bryony Thompson Gene: pgrmc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8835 TAP2 Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 TAP1 Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 ALS2 Teresa Zhao gene: ALS2 was added
gene: ALS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to PMID: 30128655; 33409823
Phenotypes for gene: ALS2 were set to Infantile onset ascending spastic paralysis (MIM#607225); Juvenile amyotrophic lateral sclerosis 2 (MIM#205100); Juvenile primary lateral sclerosis (MIM#606353)
Review for gene: ALS2 was set to GREEN
Added comment: >50 variants reported in multiple individuals with Infantile onset ascending spastic paralysis, mostly originated from the Middle East and Mediterranean countries.
Sources: Literature
Mendeliome v0.8835 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Mendeliome v0.8835 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Mendeliome v0.8835 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Mendeliome v0.8834 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Mendeliome v0.8833 NBAS Zornitza Stark Gene: nbas has been classified as Green List (High Evidence).
Mendeliome v0.8830 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8830 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Mendeliome v0.8830 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8829 ARF3 Zornitza Stark gene: ARF3 was added
gene: ARF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Mendeliome v0.8828 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Mendeliome v0.8825 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8825 PLXNA2 Zornitza Stark Classified gene: PLXNA2 as Amber List (moderate evidence)
Mendeliome v0.8825 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8824 PLXNA2 Zornitza Stark gene: PLXNA2 was added
gene: PLXNA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants possibly explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature
Mendeliome v0.8823 SLC51A Zornitza Stark Gene: slc51a has been classified as Red List (Low Evidence).
Mendeliome v0.8823 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Mendeliome v0.8821 MOCOS Zornitza Stark Gene: mocos has been classified as Green List (High Evidence).
Mendeliome v0.8818 HNMT Zornitza Stark Gene: hnmt has been classified as Green List (High Evidence).
Mendeliome v0.8818 HNMT Zornitza Stark Phenotypes for gene: HNMT were changed from to Mental retardation, autosomal recessive 51, MIM#616739
Mendeliome v0.8815 HNMT Zornitza Stark reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 26206890, 30744146, 33310825, 33739554; Phenotypes: Mental retardation, autosomal recessive 51, MIM#616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8815 BLNK Zornitza Stark Gene: blnk has been classified as Green List (High Evidence).
Mendeliome v0.8812 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
Mendeliome v0.8809 SLC51B Zornitza Stark Phenotypes for gene: SLC51B were changed from Congenital diarrhoea; Cholestasis to Bile acid malabsorption, primary, 2, MIM# 619481; Congenital diarrhoea; Cholestasis
Mendeliome v0.8808 SLC51B Zornitza Stark edited their review of gene: SLC51B: Changed phenotypes: Bile acid malabsorption, primary, 2, MIM# 619481, Congenital diarrhoea, Cholestasis
Mendeliome v0.8808 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8808 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Mendeliome v0.8808 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8807 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Mendeliome v0.8804 SP6 Zornitza Stark Classified gene: SP6 as Green List (high evidence)
Mendeliome v0.8804 SP6 Zornitza Stark Gene: sp6 has been classified as Green List (High Evidence).
Mendeliome v0.8803 SP6 Zornitza Stark reviewed gene: SP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33652941; Phenotypes: Hypoplastic amelogenesis imperfecta; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8803 AMTN Zornitza Stark Gene: amtn has been classified as Red List (Low Evidence).
Mendeliome v0.8803 AMTN Zornitza Stark gene: AMTN was added
gene: AMTN was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: AMTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMTN were set to 27412008; 25715379; 26620968
Phenotypes for gene: AMTN were set to Amelogenesis imperfecta, type IIIB
Mode of pathogenicity for gene: AMTN was set to Other
Review for gene: AMTN was set to RED
Added comment: In a Costa Rican family segregating autosomal dominant hypomineralized amelogenesis imperfecta, Smith et al. (2016) identified a heterozygous deletion/insertion mutation in the amelotin gene that segregated with the phenotype in the family. The mutation was predicted to result in an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 amino acids. Mode of pathogenicity not established. Toxic gain of function proposed as Atmn KO and +/- mice did not recapitulate the human phenotype.
Sources: Expert Review
Mendeliome v0.8802 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
Mendeliome v0.8802 WDR72 Zornitza Stark Phenotypes for gene: WDR72 were changed from to Amelogenesis imperfecta, type IIA3, MIM# 613211
Mendeliome v0.8799 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 21196691, 27259663, 20938048, 26502894, 23293580, 25008349, 19853237; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8799 SLC24A4 Zornitza Stark Gene: slc24a4 has been classified as Green List (High Evidence).
Mendeliome v0.8799 SLC24A4 Zornitza Stark Phenotypes for gene: SLC24A4 were changed from to Amelogenesis imperfecta, type IIA5, MIM# 615887
Mendeliome v0.8796 SLC24A4 Zornitza Stark reviewed gene: SLC24A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23375655, 24621671, 25442250, 24532815, 26502894, 27129268; Phenotypes: Amelogenesis imperfecta, type IIA5, MIM# 615887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8796 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Mendeliome v0.8793 RELT Zornitza Stark Gene: relt has been classified as Green List (High Evidence).
Mendeliome v0.8793 RELT Zornitza Stark Classified gene: RELT as Green List (high evidence)
Mendeliome v0.8793 RELT Zornitza Stark Gene: relt has been classified as Green List (High Evidence).
Mendeliome v0.8792 RELT Zornitza Stark gene: RELT was added
gene: RELT was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RELT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RELT were set to 30506946
Phenotypes for gene: RELT were set to Amelogenesis imperfecta, type IIIC, MIM# 618386
Review for gene: RELT was set to GREEN
Added comment: Amelogenesis imperfecta type IIIC is characterized by hypocalcified enamel in both the primary and secondary dentition. The enamel is rough and yellow-brown; under normal use, the enamel disintegrates from occlusal surfaces of the molars, leaving a ring of intact enamel remaining on the sides. At least 3 families and a mouse model.
Sources: Expert Review
Mendeliome v0.8791 LAMB3 Zornitza Stark Phenotypes for gene: LAMB3 were changed from Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650 to Amelogenesis imperfecta, type IA, MIM# 104530; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.8788 LAMB3 Zornitza Stark edited their review of gene: LAMB3: Changed publications: 11023379, 7706760, 23958762, 7706760, 23632796, 26502894, 27220909, 25769099, 24494736; Changed phenotypes: Amelogenesis imperfecta, type IA, MIM# 104530, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.8788 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome 38, MIM# 619476 to Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome 38, MIM# 619476; Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Mendeliome v0.8786 KIAA0753 Zornitza Stark edited their review of gene: KIAA0753: Added comment: At least 5 families reported with a skeletal ciliopathy.; Changed publications: 29138412, 31816441, 33875766, 34016807; Changed phenotypes: Orofaciodigital syndrome XV 617127, Joubert syndrome, Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Mendeliome v0.8785 NIID Zornitza Stark Phenotypes for STR: NIID were changed from Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866 to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866; Oculopharyngodistal myopathy 3, MIM# 619473
Mendeliome v0.8784 KLK4 Zornitza Stark Gene: klk4 has been classified as Green List (High Evidence).
Mendeliome v0.8784 KLK4 Zornitza Stark Phenotypes for gene: KLK4 were changed from to Amelogenesis imperfecta, type IIA1, MIM# 204700
Mendeliome v0.8781 KLK4 Zornitza Stark reviewed gene: KLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15235027, 23355523, 28611678, 27066511; Phenotypes: Amelogenesis imperfecta, type IIA1, MIM# 204700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8781 ITGB6 Zornitza Stark Gene: itgb6 has been classified as Green List (High Evidence).
Mendeliome v0.8781 ITGB6 Zornitza Stark Classified gene: ITGB6 as Green List (high evidence)
Mendeliome v0.8781 ITGB6 Zornitza Stark Gene: itgb6 has been classified as Green List (High Evidence).
Mendeliome v0.8780 ITGB6 Zornitza Stark gene: ITGB6 was added
gene: ITGB6 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ITGB6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGB6 were set to 25431241; 26695873; 24305999; 24319098
Phenotypes for gene: ITGB6 were set to Amelogenesis imperfecta, type IH, MIM# 616221
Review for gene: ITGB6 was set to GREEN
Added comment: At least 3 unrelated families reported.
Sources: Expert Review
Mendeliome v0.8779 STAT3 Zornitza Stark Gene: stat3 has been classified as Green List (High Evidence).
Mendeliome v0.8776 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Mendeliome v0.8776 STK4 Zornitza Stark Phenotypes for gene: STK4 were changed from to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts
Mendeliome v0.8773 SP110 Zornitza Stark Gene: sp110 has been classified as Green List (High Evidence).
Mendeliome v0.8773 SP110 Zornitza Stark Phenotypes for gene: SP110 were changed from to Hepatic veno-occlusive disease with immunodeficiency MIM#235550; Hepatic veno-occlusive disease; susceptibility to Pneumocystis jirovecii pneumonia; cytomegalovirus; thrombocytopaenia; hepatosplenomegaly; cerebrospinal leukodystrophy; memory T/B cell deficiency; low Ig levels; absent tissue plasma cells; absent lymph node germinal centers; hypogammaglobulinaemia
Mendeliome v0.8770 SMARCAL1 Zornitza Stark Gene: smarcal1 has been classified as Green List (High Evidence).
Mendeliome v0.8770 SMARCAL1 Zornitza Stark Phenotypes for gene: SMARCAL1 were changed from to Schimke immune-osseous dysplasia MIM# 242900; T cell deficiency; Short stature; spondyloepiphyseal dysplasia; renal dysfunction; lymphocytopaenia; nephropathy; bacterial/viral/fungal infections; may present as SCID; bone marrow failure
Mendeliome v0.8767 STK4 Danielle Ariti reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22294732, 26117625, 22174160, 22952854; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868, CD4/CD8 lymphopaenia, cardiac malformations, reduced naïve T cells, increased TEM and TEMRA cells, poor T cell Proliferation, Reduced memory B cells, Reduced IgM, increased IgG, IgA, IgE, impaired antibody responses, intermittent neutropaenia, bacterial/ viral/ fungal infections, autoimmune cytopaenias, mucocutaneous candidiasis, cutaneous warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SPINK5 Danielle Ariti reviewed gene: SPINK5: Rating: ; Mode of pathogenicity: None; Publications: 33534181, 20657595; Phenotypes: Netherton syndrome MIM# 256500, Low switched and non-switched B cells, High IgE and IgA, Antibody variably decreased, Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive, food allergies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SP110 Danielle Ariti reviewed gene: SP110: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic veno-occlusive disease with immunodeficiency MIM#235550, Hepatic veno-occlusive disease, susceptibility to Pneumocystis jirovecii pneumonia, cytomegalovirus, thrombocytopaenia, hepatosplenomegaly, cerebrospinal leukodystrophy, memory T/B cell deficiency, low Ig levels, absent tissue plasma cells, absent lymph node germinal centers, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SMARCAL1 Danielle Ariti reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301550, 17089404, 20036229; Phenotypes: Schimke immune-osseous dysplasia MIM# 242900, T cell deficiency, Short stature, spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopaenia, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 GPR68 Zornitza Stark Gene: gpr68 has been classified as Green List (High Evidence).
Mendeliome v0.8767 GPR68 Zornitza Stark Phenotypes for gene: GPR68 were changed from to Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217
Mendeliome v0.8764 GPR68 Zornitza Stark reviewed gene: GPR68: Rating: GREEN; Mode of pathogenicity: None; Publications: 27693231, 32279993; Phenotypes: Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8764 FAM83H Zornitza Stark Gene: fam83h has been classified as Green List (High Evidence).
Mendeliome v0.8764 FAM83H Zornitza Stark Phenotypes for gene: FAM83H were changed from to Amelogenesis imperfecta, type IIIA MIM#130900
Mendeliome v0.8761 FAM83H Zornitza Stark reviewed gene: FAM83H: Rating: GREEN; Mode of pathogenicity: None; Publications: 18484629, 19407157, 19825039, 26481691, 21702852, 20160442, 26142250, 22414746, 19828885, 19220331, 26502894, 18252228, 21597265, 21118793, 26788537, 26171361; Phenotypes: Amelogenesis imperfecta, type IIIA MIM#130900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8761 ENAM Zornitza Stark Gene: enam has been classified as Green List (High Evidence).
Mendeliome v0.8761 ENAM Zornitza Stark Phenotypes for gene: ENAM were changed from to Amelogenesis imperfecta, type IB, MIM# 104500; Amelogenesis imperfecta, type IC, MIM# 204650
Mendeliome v0.8758 ENAM Zornitza Stark reviewed gene: ENAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11487571, 28334996, 14684688, 33864320; Phenotypes: Amelogenesis imperfecta, type IB, MIM# 104500, Amelogenesis imperfecta, type IC, MIM# 204650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8758 FAM20A Zornitza Stark Gene: fam20a has been classified as Green List (High Evidence).
Mendeliome v0.8758 FAM20A Zornitza Stark Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690
Mendeliome v0.8755 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434854, 23697977, 23468644, 24756937, 21549343, 24259279, 24196488, 26502894, 25827751, 21990045; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8755 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Mendeliome v0.8755 C4orf26 Zornitza Stark Phenotypes for gene: C4orf26 were changed from to Amelogenesis imperfecta, type IIA4, MIM# 614832
Mendeliome v0.8752 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901946, 27558265; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8752 AMELX Zornitza Stark Gene: amelx has been classified as Green List (High Evidence).
Mendeliome v0.8752 AMELX Zornitza Stark Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, MIM# 301200 to Amelogenesis imperfecta, type 1E, MIM# 301200
Mendeliome v0.8752 AMELX Zornitza Stark Phenotypes for gene: AMELX were changed from to Amelogenesis imperfecta, type 1E, MIM# 301200
Mendeliome v0.8749 AMELX Zornitza Stark reviewed gene: AMELX: Rating: GREEN; Mode of pathogenicity: None; Publications: 17189466, 22243263, 7599636, 23251683, 1483698 1916828, 9188994, 15111628, 11201048, 26502894, 7782077, 11922869, 28130977, 8406474, 11839357, 25117480, 19610109; Phenotypes: Amelogenesis imperfecta, type 1E, MIM# 301200; 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 v0.8749 AMBN Zornitza Stark Gene: ambn has been classified as Green List (High Evidence).
Mendeliome v0.8749 AMBN Zornitza Stark Phenotypes for gene: AMBN were changed from to Amelogenesis imperfecta, type IF MIM#616270
Mendeliome v0.8746 AMBN Zornitza Stark reviewed gene: AMBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24858907, 26502894, 31402633, 30174330; Phenotypes: Amelogenesis imperfecta, type IF MIM#616270; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8746 ACP4 Zornitza Stark reviewed gene: ACP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513613, 27843125, 33552707; Phenotypes: Amelogenesis imperfecta, type IJ MIM#617297; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8742 TCF7L2 Zornitza Stark Classified gene: TCF7L2 as Green List (high evidence)
Mendeliome v0.8742 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Mendeliome v0.8741 TCF7L2 Zornitza Stark changed review comment from: 2 reviews
Konstantinos Varvagiannis (Other)
I don't know

Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.
Mendeliome v0.8741 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Green List (High Evidence).
Mendeliome v0.8741 LTBP3 Zornitza Stark Phenotypes for gene: LTBP3 were changed from to Dental anomalies and short stature, MIM# 601216; Geleophysic dysplasia 3, MIM# 617809; Thoracic aneurysm
Mendeliome v0.8738 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344874, 25899461, 25669657, 29625025, 27068007, 34150014; Phenotypes: Dental anomalies and short stature, MIM# 601216, Geleophysic dysplasia 3, MIM# 617809, Thoracic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8737 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Mendeliome v0.8737 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Mendeliome v0.8737 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Mendeliome v0.8736 PIDD1 Zornitza Stark gene: PIDD1 was added
gene: PIDD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.
Sources: Expert Review
Mendeliome v0.8735 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Mendeliome v0.8735 COLGALT1 Bryony Thompson Classified gene: COLGALT1 as Green List (high evidence)
Mendeliome v0.8735 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Mendeliome v0.8733 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8733 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Mendeliome v0.8733 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8732 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model.

Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H).

Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available.

KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Mendeliome v0.8731 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Mendeliome v0.8731 ARIH1 Bryony Thompson Classified gene: ARIH1 as Green List (high evidence)
Mendeliome v0.8731 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Mendeliome v0.8730 ARIH1 Bryony Thompson gene: ARIH1 was added
gene: ARIH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ARIH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a drosophila model.
Sources: Other
Mendeliome v0.8729 SLC41A1 Zornitza Stark Phenotypes for gene: SLC41A1 were changed from Nephronophthisis to Nephronophthisis-like nephropathy 2, MIM# 619468
Mendeliome v0.8728 SLC41A1 Zornitza Stark edited their review of gene: SLC41A1: Changed phenotypes: Nephronophthisis-like nephropathy 2, MIM# 619468
Mendeliome v0.8728 PRPF31 Zornitza Stark Gene: prpf31 has been classified as Green List (High Evidence).
Mendeliome v0.8725 RNF168 Zornitza Stark Gene: rnf168 has been classified as Green List (High Evidence).
Mendeliome v0.8725 RNF168 Zornitza Stark Phenotypes for gene: RNF168 were changed from to RIDDLE syndrome MIM# 611943; Radiosensitivity; Immune Deficiency; Dysmorphic Features; Learning difficulties; Low IgG or IgA; Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly
Mendeliome v0.8722 RFXAP Zornitza Stark Gene: rfxap has been classified as Green List (High Evidence).
Mendeliome v0.8722 RFXAP Zornitza Stark Phenotypes for gene: RFXAP were changed from to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Mendeliome v0.8719 RFXANK Zornitza Stark Gene: rfxank has been classified as Green List (High Evidence).
Mendeliome v0.8719 RFXANK Zornitza Stark Phenotypes for gene: RFXANK were changed from to MHC class II deficiency, complementation group B MIM# 209920; Bare Lymphocyte Syndrome, type II, complementation group B; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Mendeliome v0.8716 RBCK1 Zornitza Stark Gene: rbck1 has been classified as Green List (High Evidence).
Mendeliome v0.8713 RFXANK Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RFXAP Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RNF168 Danielle Ariti reviewed gene: RNF168: Rating: GREEN; Mode of pathogenicity: None; Publications: 19203578, 21394101, 29255463, 21552324; Phenotypes: RIDDLE syndrome MIM# 611943, Radiosensitivity, Immune Deficiency, Dysmorphic Features, Learning difficulties, Low IgG or IgA, Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 ABCC2 Zornitza Stark Gene: abcc2 has been classified as Green List (High Evidence).
Mendeliome v0.8710 CLDN9 Bryony Thompson Classified gene: CLDN9 as Green List (high evidence)
Mendeliome v0.8710 CLDN9 Bryony Thompson Gene: cldn9 has been classified as Green List (High Evidence).
Mendeliome v0.8709 CLDN9 Bryony Thompson reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19696885, 31175426, 34265170; Phenotypes: Deafness, autosomal recessive 116 MIM#619093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8709 UBR1 Zornitza Stark changed review comment from: >50 unrelated families reported, reviewed in PMID: 24599544.

Common clinical features include poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.; to: >50 unrelated families reported, reviewed in PMID: 24599544.

Common clinical features include poor growth, intellectual disability, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.
Mendeliome v0.8709 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Mendeliome v0.8706 ACTL6A Zornitza Stark Gene: actl6a has been classified as Green List (High Evidence).
Mendeliome v0.8703 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene. Part of the BAF complex. Only one confirmed de novo.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
PMID 31994175: fourth individual reported, recurrent de novo p.Arg377Trp
Mendeliome v0.8703 VAV1 Zornitza Stark Gene: vav1 has been classified as Red List (Low Evidence).
Mendeliome v0.8703 VAV1 Zornitza Stark gene: VAV1 was added
gene: VAV1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: VAV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VAV1 were set to 20638113; 23058036
Phenotypes for gene: VAV1 were set to Common variable immnodeficiency
Review for gene: VAV1 was set to RED
Added comment: Reduced VAV1 expression has been reported in multiple T-CVID cases, however only one large deletion (exon 2-27) has been reported in a single case in a publication from 2012. The CNV was detected using real-time qPCR, but was not confirmed by an orthogonal method.
Sources: Expert Review
Mendeliome v0.8702 TCF3 Zornitza Stark Gene: tcf3 has been classified as Green List (High Evidence).
Mendeliome v0.8699 PRKCD Zornitza Stark Gene: prkcd has been classified as Green List (High Evidence).
Mendeliome v0.8696 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
Mendeliome v0.8693 SNRPB Zornitza Stark Gene: snrpb has been classified as Green List (High Evidence).
Mendeliome v0.8690 RBM10 Zornitza Stark Gene: rbm10 has been classified as Green List (High Evidence).
Mendeliome v0.8686 POLR1D Zornitza Stark Gene: polr1d has been classified as Green List (High Evidence).
Mendeliome v0.8683 TP73 Zornitza Stark Phenotypes for gene: TP73 were changed from Cortical malformation; Lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Cortical malformation; Lissencephaly
Mendeliome v0.8682 TP73 Zornitza Stark reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Mode of inheritance: None
Mendeliome v0.8682 SYT2 Zornitza Stark Phenotypes for gene: SYT2 were changed from Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040 to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Mendeliome v0.8681 SYT2 Zornitza Stark edited their review of gene: SYT2: Changed phenotypes: Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040, Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Mendeliome v0.8681 POLR1C Zornitza Stark Gene: polr1c has been classified as Green List (High Evidence).
Mendeliome v0.8678 SF3B4 Zornitza Stark Gene: sf3b4 has been classified as Green List (High Evidence).
Mendeliome v0.8678 SF3B4 Zornitza Stark Phenotypes for gene: SF3B4 were changed from to Acrofacial dysostosis 1, Nager type, MIM# 154400
Mendeliome v0.8675 SF3B4 Zornitza Stark reviewed gene: SF3B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541558, 23568615, 24003905; Phenotypes: Acrofacial dysostosis 1, Nager type, MIM# 154400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8675 TMCO1 Zornitza Stark Gene: tmco1 has been classified as Green List (High Evidence).
Mendeliome v0.8671 RGS10 Zornitza Stark Gene: rgs10 has been classified as Red List (Low Evidence).
Mendeliome v0.8671 RGS10 Zornitza Stark gene: RGS10 was added
gene: RGS10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806; 34339853
Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature
Review for gene: RGS10 was set to RED
Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853.
Sources: Literature
Mendeliome v0.8670 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Mendeliome v0.8670 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Mendeliome v0.8670 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Mendeliome v0.8669 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Mendeliome v0.8668 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mendeliome v0.8668 SF3B2 Zornitza Stark Classified gene: SF3B2 as Green List (high evidence)
Mendeliome v0.8668 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mendeliome v0.8667 SF3B2 Zornitza Stark gene: SF3B2 was added
gene: SF3B2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

Targeted morpholino knockdown of SF3B2 in Xenopus resulted in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease.

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Mendeliome v0.8666 IMPG1 Zornitza Stark Gene: impg1 has been classified as Green List (High Evidence).
Mendeliome v0.8663 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome to Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome 20, MIM# 619471
Mendeliome v0.8662 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures
Mendeliome v0.8661 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures
Mendeliome v0.8661 CUL7 Zornitza Stark Gene: cul7 has been classified as Green List (High Evidence).
Mendeliome v0.8657 ACAN Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations.

Well established gene-disease association, multiple families reported.

Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813
Mendeliome v0.8657 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
Mendeliome v0.8657 NFKBIA Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth
Mendeliome v0.8654 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Mendeliome v0.8654 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577; Low serum IgG, IgA, IgM; low B cell numbers; low switched memory B cells; Recurrent sinopulmonary infections, Alopecia; endocrinopathies; ACTH deficiency
Mendeliome v0.8651 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Mendeliome v0.8648 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8645 MCM4 Zornitza Stark Classified gene: MCM4 as Amber List (moderate evidence)
Mendeliome v0.8645 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8644 MAP3K14 Zornitza Stark Gene: map3k14 has been classified as Green List (High Evidence).
Mendeliome v0.8641 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
Mendeliome v0.8638 NFKBIA Danielle Ariti reviewed gene: NFKBIA: 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: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 NFKB2 Danielle Ariti reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 AQP2 Zornitza Stark Gene: aqp2 has been classified as Green List (High Evidence).
Mendeliome v0.8638 AQP2 Zornitza Stark Phenotypes for gene: AQP2 were changed from to Diabetes insipidus, nephrogenic, MIM#125800
Mendeliome v0.8635 AQP2 Zornitza Stark reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7537761, 11536078; Phenotypes: Diabetes insipidus, nephrogenic, MIM#125800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8633 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Mendeliome v0.8633 GIMAP5 Zornitza Stark Classified gene: GIMAP5 as Green List (high evidence)
Mendeliome v0.8633 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Mendeliome v0.8632 GIMAP5 Zornitza Stark gene: GIMAP5 was added
gene: GIMAP5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GIMAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP5 were set to 33956074
Phenotypes for gene: GIMAP5 were set to Portal hypertension, noncirrhotic, 2, MIM# 619463
Review for gene: GIMAP5 was set to GREEN
Added comment: 8 individuals from 4 unrelated families reported with onset of disease in the first decade of life. Clinical features included jaundice, hyperbilirubinaemia, pancytopaenia, including neutropaenia, lymphopaenia, and thrombocytopaenia, hepatosplenomegaly, and oesophageal varices. Some individuals had recurrent infections or features suggestive of an immunodeficiency. Liver biopsy was notable for the absence of cirrhosis and the presence of nodular regeneration.
Sources: Expert list
Mendeliome v0.8631 ERBB2 Zornitza Stark Phenotypes for gene: ERBB2 were changed from to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465
Mendeliome v0.8630 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy to Lethal congenital contractural syndrome 2, MIM# 607598; Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy
Mendeliome v0.8629 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180, Complex neurocristinopathy
Mendeliome v0.8629 IL7R Zornitza Stark Gene: il7r has been classified as Green List (High Evidence).
Mendeliome v0.8629 IL7R Zornitza Stark Phenotypes for gene: IL7R were changed from to Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers.
Mendeliome v0.8626 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
Mendeliome v0.8626 MALT1 Zornitza Stark Phenotypes for gene: MALT1 were changed from to Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive
Mendeliome v0.8623 IL2RG Zornitza Stark Gene: il2rg has been classified as Green List (High Evidence).
Mendeliome v0.8623 IL2RG Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia
Mendeliome v0.8620 IL2RG Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8620 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Mendeliome v0.8617 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
Mendeliome v0.8614 MALT1 Danielle Ariti edited their review of gene: MALT1: Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.; Changed rating: GREEN
Mendeliome v0.8614 IL7R Danielle Ariti reviewed gene: IL7R: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843216, 19890784, 26123418, 11023514, 7964471; Phenotypes: Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971, fever, rash, failure to thrive, recurrent respiratory and gastric infections, diarrhoea, lymphadenopathy, pneumonitis, Pancytopaenia, low T-cell numbers, decreased immunoglobulins, normal-high B/NK-cell numbers.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 MALT1 Danielle Ariti reviewed gene: MALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23727036, 24332264, 14576442, 31037583; Phenotypes: Immunodeficiency 12 MIM# 615468, poor T-cell proliferation, normal T/B cell numbers, poor specific antibody response, recurrent bacterial/fungal/viral infections, bronchiectasis, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 PLCB4 Zornitza Stark Gene: plcb4 has been classified as Green List (High Evidence).
Mendeliome v0.8611 PBX1 Zornitza Stark Gene: pbx1 has been classified as Green List (High Evidence).
Mendeliome v0.8608 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia
Mendeliome v0.8606 VRK1 Zornitza Stark changed review comment from: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.; to: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.

Further delineation of phenotype 2021:
PMID 34169149: expanding spectrum of neurologic disorders associated with VRK1. Two Hispanic individuals, one homozygous (R321C: VUS and LP/P in ClinVar) and one cHet (R321C+V236M, latter P and more recently VUS in ClinVar), with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy WITHOUT pontocerebellar atrophy. No hom in gnomAD and both have been reported in cHet individuals with other features: R321C in association with adult-onset amyotrophic lateral sclerosis and V236M with rapidly progressive sensorimotor polyneuropathy and microcephaly. Authors suggest PMID 26583493 and 31837156 have similar reports. PMID 26583493 reports a 32yo Hispanic individual, cHet H119R+R321C, with early-onset amyotrophic lateral sclerosis, 5 years progressive weakness. PMID 31837156 reports two patients with adult-onset length-dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent, both hom for R387H.
Mendeliome v0.8606 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed publications: 19646678, 21937992, 25609612, 24126608, 27281532, 34169149, 26583493; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia
Mendeliome v0.8606 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Mendeliome v0.8605 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Mendeliome v0.8605 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Mendeliome v0.8604 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Mendeliome v0.8603 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Mendeliome v0.8603 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Mendeliome v0.8602 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Mendeliome v0.8602 DNAH10 Zornitza Stark Classified gene: DNAH10 as Green List (high evidence)
Mendeliome v0.8602 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Mendeliome v0.8601 CLCN3 Kristin Rigbye gene: CLCN3 was added
gene: CLCN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to PMID: 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Mendeliome v0.8601 TNPO2 Elena Savva gene: TNPO2 was added
gene: TNPO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to PMID: 34314705
Phenotypes for gene: TNPO2 were set to Developmental delays, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia).

Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF.

gnomAD: minimal PTCs present
Sources: Literature
Mendeliome v0.8601 DNAH10 Ain Roesley gene: DNAH10 was added
gene: DNAH10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to primary male infertility with asthenoteratozoospermia
Penetrance for gene: DNAH10 were set to unknown
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Literature
Mendeliome v0.8601 AP1G1 Zornitza Stark Added comment: Comment when marking as ready: Good evidence for association between mono-allelic variants and NDD, moderate evidence for bi-allelic variants causing disease.
Mendeliome v0.8601 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Mendeliome v0.8601 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Mendeliome v0.8601 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Mendeliome v0.8600 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Mode of pathogenicity for gene: AP1G1 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: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Mendeliome v0.8600 SEMA3D Zornitza Stark Gene: sema3d has been classified as Red List (Low Evidence).
Mendeliome v0.8599 SEMA3D Zornitza Stark Classified gene: SEMA3D as Red List (low evidence)
Mendeliome v0.8599 SEMA3D Zornitza Stark Gene: sema3d has been classified as Red List (Low Evidence).
Mendeliome v0.8598 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature; to: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29); behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8598 SPTBN4 Zornitza Stark Gene: sptbn4 has been classified as Green List (High Evidence).
Mendeliome v0.8597 TP73 Seb Lunke Classified gene: TP73 as Green List (high evidence)
Mendeliome v0.8597 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Mendeliome v0.8594 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Mendeliome v0.8594 HMGB1 Zornitza Stark Classified gene: HMGB1 as Red List (low evidence)
Mendeliome v0.8594 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Mendeliome v0.8593 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Mendeliome v0.8592 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Mendeliome v0.8591 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Mendeliome v0.8591 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Mendeliome v0.8590 EDEM3 Seb Lunke Classified gene: EDEM3 as Green List (high evidence)
Mendeliome v0.8590 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Mendeliome v0.8588 UBA2 Zornitza Stark Classified gene: UBA2 as Green List (high evidence)
Mendeliome v0.8588 UBA2 Zornitza Stark Gene: uba2 has been classified as Green List (High Evidence).
Mendeliome v0.8587 GCNA Zornitza Stark Gene: gcna has been classified as Green List (High Evidence).
Mendeliome v0.8587 GCNA Zornitza Stark Classified gene: GCNA as Green List (high evidence)
Mendeliome v0.8587 GCNA Zornitza Stark Gene: gcna has been classified as Green List (High Evidence).
Mendeliome v0.8586 TP73 Ee Ming Wong changed review comment from: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- Epithelial cells from TP73 variant carriers showed reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls; to: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls
Mendeliome v0.8586 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179; PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8586 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Mendeliome v0.8586 ANK2 Zornitza Stark Classified gene: ANK2 as Green List (high evidence)
Mendeliome v0.8586 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Mendeliome v0.8585 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 31983240; 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Long QT syndrome 4, MIM# 600919; Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
Added comment: Link with cardiac abnormalities such as LongQT is DISPUTED. More than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Expert Review
Mendeliome v0.8584 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mendeliome v0.8584 PRDX3 Zornitza Stark Classified gene: PRDX3 as Green List (high evidence)
Mendeliome v0.8584 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mendeliome v0.8583 PRDX3 Hazel Phillimore changed review comment from: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature; to: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 PRDX3 Hazel Phillimore gene: PRDX3 was added
gene: PRDX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to PMID: 33889951
Phenotypes for gene: PRDX3 were set to cerebellar ataxia (early onset, mild to moderate, progressive)
Penetrance for gene: PRDX3 were set to unknown
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 GSC Zornitza Stark Gene: gsc has been classified as Green List (High Evidence).
Mendeliome v0.8583 GSC Zornitza Stark Phenotypes for gene: GSC were changed from to Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471
Mendeliome v0.8580 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8580 GNAI3 Zornitza Stark Gene: gnai3 has been classified as Green List (High Evidence).
Mendeliome v0.8577 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Mendeliome v0.8574 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy
Mendeliome v0.8573 ERBB3 Zornitza Stark changed review comment from: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; to: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Mendeliome v0.8573 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility
Mendeliome v0.8571 ERBB3 Zornitza Stark changed review comment from: Two families reported with contractures, positional approach used in gene discovery (2007). Another family reported more recently with a multi-system disorder but without contractures.; to: Lethal congenital contractual syndrome: Two families reported with contractures, positional approach used in gene discovery (2007). Another family reported more recently with a multi-system disorder but without contractures.
Mendeliome v0.8571 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8571 PDCL3 Zornitza Stark Classified gene: PDCL3 as Amber List (moderate evidence)
Mendeliome v0.8571 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8570 PDCL3 Zornitza Stark gene: PDCL3 was added
gene: PDCL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PDCL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCL3 were set to 32621347
Phenotypes for gene: PDCL3 were set to Megacystis-microcolon
Review for gene: PDCL3 was set to AMBER
Added comment: Single publication (PMID 32621347): one family with two affected fetuses - one with megacystis and microcolon, and the other with megacystisis and bilateral diaphragmatic hernia (prune-belly phenotype). Compound het LOF variants in PDCL3 (one frameshift and one missense). Complete absence of PDLC3 expression demonstrated in one of the affected fetuses. No homozygous LOF PDCL3 variants in gnomAD. PCDL3 negatively modulates actin folding and is strongly expressed in smooth muscle of bladder and colon.
Sources: Expert Review
Mendeliome v0.8569 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8566 SGO1 Zornitza Stark Classified gene: SGO1 as Amber List (moderate evidence)
Mendeliome v0.8566 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8565 TYMP Zornitza Stark Gene: tymp has been classified as Green List (High Evidence).
Mendeliome v0.8565 TYMP Zornitza Stark Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041; MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy
Mendeliome v0.8562 TYMP Zornitza Stark reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9924029, 14757860; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041, MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8562 ZNF687 Zornitza Stark Gene: znf687 has been classified as Green List (High Evidence).
Mendeliome v0.8559 GRHPR Zornitza Stark Gene: grhpr has been classified as Green List (High Evidence).
Mendeliome v0.8556 AGXT Zornitza Stark Gene: agxt has been classified as Green List (High Evidence).
Mendeliome v0.8553 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
Mendeliome v0.8550 VPS45 Zornitza Stark Gene: vps45 has been classified as Green List (High Evidence).
Mendeliome v0.8550 VPS45 Zornitza Stark Phenotypes for gene: VPS45 were changed from to Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285
Mendeliome v0.8547 VPS45 Zornitza Stark reviewed gene: VPS45: Rating: GREEN; Mode of pathogenicity: None; Publications: 23738510, 23599270, 33623350, 32037586, 30294941; Phenotypes: Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8547 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8544 LAMTOR2 Zornitza Stark Classified gene: LAMTOR2 as Amber List (moderate evidence)
Mendeliome v0.8544 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8543 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8543 IKZF3 Zornitza Stark Classified gene: IKZF3 as Amber List (moderate evidence)
Mendeliome v0.8543 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8542 IKZF3 Zornitza Stark gene: IKZF3 was added
gene: IKZF3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF3 were set to 34155405
Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437
Review for gene: IKZF3 was set to AMBER
Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood. Mouse model recapitulated phenotype.
Sources: Expert Review
Mendeliome v0.8541 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Mendeliome v0.8538 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8538 LCK Zornitza Stark Phenotypes for gene: LCK were changed from to Immunodeficiency 22 MIM# 615758; Recurrent infections; Immune dysregulation; autoimmunity; Low CD4+; low CD8+; restricted T cell repertoire; poor TCR signaling; Normal IgG/IgA; high IgM; failure to thrive; diarrhoea; lymphopaenia; hypogammaglobulinaemia; anaemia; thrombocytopaenia; CD4+ T-cell lymphopaenia
Mendeliome v0.8535 LCK Zornitza Stark Classified gene: LCK as Amber List (moderate evidence)
Mendeliome v0.8535 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8534 LCK Zornitza Stark Classified gene: LCK as Amber List (moderate evidence)
Mendeliome v0.8534 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8533 LCK Zornitza Stark reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8533 DOCK8 Zornitza Stark Gene: dock8 has been classified as Green List (High Evidence).
Mendeliome v0.8533 DOCK8 Zornitza Stark Phenotypes for gene: DOCK8 were changed from to Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700; T cell Lymphopaenia; decraese T/B/NK cells; Eosinophilia; low IgM; elevated IgE; recurrent cutaneous/ viral/ bacterial/ fungal/ infections; severe atopy/allergic disease; autoimmune haemolytic anaemia; eczema; cancer diathesis
Mendeliome v0.8530 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
Mendeliome v0.8530 DOCK2 Zornitza Stark Phenotypes for gene: DOCK2 were changed from to Immunodeficiency 40 MIM# 616433; T/B-cell lymphopaenia; early-onset invasive herpes/viral/bacterial Infections; function defects in T/B/NK cells; immunodeficiency; defective IFN-mediated immunity; elevated IgM; normal IgG/IgA levels
Mendeliome v0.8527 DOCK2 Zornitza Stark reviewed gene: DOCK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968; Phenotypes: Immunodeficiency 40 MIM# 616433, T/B-cell lymphopaenia, early-onset invasive herpes/viral/bacterial Infections, function defects in T/B/NK cells, immunodeficiency, defective IFN-mediated immunity, elevated IgM, normal IgG/IgA levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DOCK8 Danielle Ariti reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700, T cell Lymphopaenia, decraese T/B/NK cells, Eosinophilia, low IgM, elevated IgE, recurrent cutaneous/ viral/ bacterial/ fungal/ infections, severe atopy/allergic disease, autoimmune haemolytic anaemia, eczema, cancer diathesisc; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DNMT3B Zornitza Stark Gene: dnmt3b has been classified as Green List (High Evidence).
Mendeliome v0.8527 DNMT3B Zornitza Stark Phenotypes for gene: DNMT3B were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells
Mendeliome v0.8524 DNMT3B Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8524 TMPO Bryony Thompson Gene: tmpo has been classified as Red List (Low Evidence).
Mendeliome v0.8524 TMPO Bryony Thompson Classified gene: TMPO as Red List (low evidence)
Mendeliome v0.8524 TMPO Bryony Thompson Gene: tmpo has been classified as Red List (Low Evidence).
Mendeliome v0.8523 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Mendeliome v0.8523 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Green List (high evidence)
Mendeliome v0.8523 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Mendeliome v0.8522 SYNCRIP Zornitza Stark gene: SYNCRIP was added
gene: SYNCRIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to GREEN
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.

The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.

Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.

Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)

[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]

SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.

Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.

The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.

There are no additional studies performed.

Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Mendeliome v0.8521 MSN Zornitza Stark Gene: msn has been classified as Green List (High Evidence).
Mendeliome v0.8518 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
Mendeliome v0.8518 JAGN1 Zornitza Stark Phenotypes for gene: JAGN1 were changed from to Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022
Mendeliome v0.8515 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8515 ITGB2 Zornitza Stark Gene: itgb2 has been classified as Green List (High Evidence).
Mendeliome v0.8515 ITGB2 Zornitza Stark Phenotypes for gene: ITGB2 were changed from to Leukocyte adhesion deficiency, MIM# 116920
Mendeliome v0.8512 ITGB2 Zornitza Stark reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8512 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Mendeliome v0.8512 CAMK4 Zornitza Stark Classified gene: CAMK4 as Green List (high evidence)
Mendeliome v0.8512 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Mendeliome v0.8511 CAMK4 Zornitza Stark gene: CAMK4 was added
gene: CAMK4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).
Sources: Expert Review
Mendeliome v0.8510 FERMT3 Zornitza Stark Gene: fermt3 has been classified as Green List (High Evidence).
Mendeliome v0.8510 FERMT3 Zornitza Stark Phenotypes for gene: FERMT3 were changed from to Leukocyte adhesion deficiency, type III, MIM# 612840
Mendeliome v0.8507 FERMT3 Zornitza Stark reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8506 CYBB Zornitza Stark Gene: cybb has been classified as Green List (High Evidence).
Mendeliome v0.8503 CSF3R Zornitza Stark Gene: csf3r has been classified as Green List (High Evidence).
Mendeliome v0.8503 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014 to Neutropaenia, severe congenital, 7, autosomal recessive, MIM# 617014
Mendeliome v0.8502 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from to Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014
Mendeliome v0.8499 CSF3R Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported. Some reports of progression to myelodysplasia.
Mendeliome v0.8499 CSF3R Zornitza Stark reviewed gene: CSF3R: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753537, 26324699, 33511998, 32966608; Phenotypes: Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8497 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Mendeliome v0.8496 RRP7A Zornitza Stark Phenotypes for gene: RRP7A were changed from Microcephaly to Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8495 RRP7A Zornitza Stark edited their review of gene: RRP7A: Changed phenotypes: Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8495 CEBPE Zornitza Stark Gene: cebpe has been classified as Green List (High Evidence).
Mendeliome v0.8492 NCF1 Zornitza Stark Gene: ncf1 has been classified as Green List (High Evidence).
Mendeliome v0.8492 NCF1 Zornitza Stark Phenotypes for gene: NCF1 were changed from to Chronic granulomatous disease 1, autosomal recessive, MIM# 233700
Mendeliome v0.8489 NCF1 Zornitza Stark reviewed gene: NCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2011585, 11133775, 10706888, 16972229, 16972229; Phenotypes: Chronic granulomatous disease 1, autosomal recessive, MIM# 233700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8488 COL25A1 Zornitza Stark Classified gene: COL25A1 as Green List (high evidence)
Mendeliome v0.8488 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Green List (High Evidence).
Mendeliome v0.8487 COL25A1 Zornitza Stark edited their review of gene: COL25A1: Added comment: PMID: 2643702 - Patient: 273182 reported in DECIPHER, chet COL25A1 missense variants (listed as Likely Pathogenic). Phenotype includes Duane anomaly of the eye.

PMID: 31875546 - Mouse models, including Col25a1 KO and muscle-specific KO mice showed a significant reduction in the number of motor neurons in the cranial nerve nuclei, including the oculomotor, trochlear, trigeminal, and facial motor nuclei. Abnormalities in motor innervation of muscles of the head, such as the extraocular and masseter muscles, were also observed

PMID: 31875546 - Functional studies in human cell lines showed that the reported COL25A1 variants (G382R and G497X) impaired the interaction of COL25A1 with receptor protein tyrosine phosphatases, thereby reducing the ability to attract motor axons.; Changed rating: GREEN; Changed publications: 25500261, 26486031, 31875546, 26437029
Mendeliome v0.8487 LTBP1 Zornitza Stark Phenotypes for gene: LTBP1 were changed from cutis laxa syndrome to Cutis laxa, autosomal recessive, type IIE MIM#619451
Mendeliome v0.8486 STX3 Zornitza Stark Phenotypes for gene: STX3 were changed from Microvillus inclusion disease, MIM#619445 to Microvillus inclusion disease, MIM#619445; Retinal dystrophy and microvillus inclusion disease, MIM#619446
Mendeliome v0.8485 STX3 Zornitza Stark edited their review of gene: STX3: Changed phenotypes: Microvillus inclusion disease, MIM#619445, Retinal dystrophy and microvillus inclusion disease, MIM#619446
Mendeliome v0.8485 STX3 Zornitza Stark Phenotypes for gene: STX3 were changed from Microvillus inclusion disease to Microvillus inclusion disease, MIM#619445
Mendeliome v0.8484 STX3 Zornitza Stark edited their review of gene: STX3: Changed phenotypes: Microvillus inclusion disease, MIM#619445
Mendeliome v0.8484 C1QA Zornitza Stark Gene: c1qa has been classified as Green List (High Evidence).
Mendeliome v0.8481 CIITA Zornitza Stark Gene: ciita has been classified as Green List (High Evidence).
Mendeliome v0.8478 CD40LG Zornitza Stark Gene: cd40lg has been classified as Green List (High Evidence).
Mendeliome v0.8475 CD3G Zornitza Stark Gene: cd3g has been classified as Green List (High Evidence).
Mendeliome v0.8472 WDR26 Zornitza Stark Gene: wdr26 has been classified as Green List (High Evidence).
Mendeliome v0.8467 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
Mendeliome v0.8464 ABCD1 Zornitza Stark Gene: abcd1 has been classified as Green List (High Evidence).
Mendeliome v0.8462 ABCD1 Zornitza Stark changed review comment from: Ataxia is a feature of this progressive disorder.
Sources: Expert list; to: Well established gene-disease association.
Sources: Expert list
Mendeliome v0.8460 CCBE1 Zornitza Stark Gene: ccbe1 has been classified as Green List (High Evidence).
Mendeliome v0.8460 CCBE1 Zornitza Stark Phenotypes for gene: CCBE1 were changed from to Hennekam lymphangiectasia- lymphoedema syndrome MIM# 235510; lymphangiectasia and lymphoedema; facial abnormalities; dysmorphic features; hypoalbuminaemia; intellectual disability; hypoglobulinaemia
Mendeliome v0.8457 CCBE1 Zornitza Stark reviewed gene: CCBE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19935664, 19911200, 19287381, 25925991, 27345729, 21778431; Phenotypes: Hennekam lymphangiectasia- lymphoedema syndrome MIM# 235510, lymphangiectasia and lymphoedema, facial abnormalities, dysmorphic features, hypoalbuminaemia, intellectual disability, hypoglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8457 CD27 Zornitza Stark Gene: cd27 has been classified as Green List (High Evidence).
Mendeliome v0.8454 ZNF148 Zornitza Stark Gene: znf148 has been classified as Green List (High Evidence).
Mendeliome v0.8454 ZNF148 Zornitza Stark Classified gene: ZNF148 as Green List (high evidence)
Mendeliome v0.8454 ZNF148 Zornitza Stark Gene: znf148 has been classified as Green List (High Evidence).
Mendeliome v0.8453 RAC3 Zornitza Stark Gene: rac3 has been classified as Green List (High Evidence).
Mendeliome v0.8453 RAC3 Zornitza Stark Classified gene: RAC3 as Green List (high evidence)
Mendeliome v0.8453 RAC3 Zornitza Stark Gene: rac3 has been classified as Green List (High Evidence).
Mendeliome v0.8452 PCLO Zornitza Stark Phenotypes for gene: PCLO were changed from to Pontocerebellar hypoplasia, type 3, MIM#608027
Mendeliome v0.8449 ZNF148 Natalie Tan gene: ZNF148 was added
gene: ZNF148 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF148 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF148 were set to PMID: 27964749
Phenotypes for gene: ZNF148 were set to Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies; MIM#617260
Review for gene: ZNF148 was set to GREEN
Added comment: Four unrelated individuals with de novo heterozygous nonsense or frameshift mutations (all resulting in premature termination codons in the last exon of ZNF148, predicted to escape nonsense-mediated mRNA decay and result in expression of a truncated protein). Phenotype characterised by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. No functional studies to date.
Sources: Literature
Mendeliome v0.8449 CHRNA4 Zornitza Stark Gene: chrna4 has been classified as Green List (High Evidence).
Mendeliome v0.8445 ZIC3 Zornitza Stark Gene: zic3 has been classified as Green List (High Evidence).
Mendeliome v0.8442 VPS13B Zornitza Stark Gene: vps13b has been classified as Green List (High Evidence).
Mendeliome v0.8440 TULP1 Zornitza Stark Gene: tulp1 has been classified as Green List (High Evidence).
Mendeliome v0.8440 TULP1 Zornitza Stark Phenotypes for gene: TULP1 were changed from to Retinitis pigmentosa 14 M(MIM#600132); Leber congenital amaurosis 15, MIM# 613843
Mendeliome v0.8437 TULP1 Zornitza Stark reviewed gene: TULP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 15, MIM# 613843; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8437 TOPORS Zornitza Stark Gene: topors has been classified as Green List (High Evidence).
Mendeliome v0.8434 SUFU Zornitza Stark Gene: sufu has been classified as Green List (High Evidence).
Mendeliome v0.8431 SUFU Zornitza Stark edited their review of gene: SUFU: Added comment: Mono-allelic variants are also associated with Basal cell nevus syndrome/predisposition to medulloblastoma.; Changed rating: GREEN; Changed publications: 28965847, 19533801, 31485359; Changed phenotypes: Joubert syndrome 32, MIM#617757, Basal cell nevus syndrome, MIM# 109400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8431 SCNN1G Zornitza Stark Gene: scnn1g has been classified as Green List (High Evidence).
Mendeliome v0.8428 SCNN1G Zornitza Stark edited their review of gene: SCNN1G: Added comment: Variants resulting in constitutive activation of epithelial sodium channel activity have been demonstrated in the beta and gamma subunits as the cause of the autosomal dominant form of hypertension, Liddle syndrome, which is characterized by volume expansion, hypokalemia, and alkalosis.

Variants causing loss of epithelial sodium channel activity cause the converse phenotype of volume depletion, hyperkalaemia and acidosis characteristic of patients with pseudohypoaldosteronism type I.

Well established gene-disease associations.; Changed rating: GREEN; Changed phenotypes: Liddle syndrome 2, MIM# 618114, Pseudohypoaldosteronism, type I, MIM# 264350; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8428 SCLT1 Zornitza Stark Gene: sclt1 has been classified as Green List (High Evidence).
Mendeliome v0.8425 RPGR Zornitza Stark Gene: rpgr has been classified as Green List (High Evidence).
Mendeliome v0.8422 PRKCSH Zornitza Stark Gene: prkcsh has been classified as Green List (High Evidence).
Mendeliome v0.8418 POC1B Zornitza Stark Gene: poc1b has been classified as Green List (High Evidence).
Mendeliome v0.8415 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Mendeliome v0.8412 PKHD1 Zornitza Stark Gene: pkhd1 has been classified as Green List (High Evidence).
Mendeliome v0.8410 PKHD1 Zornitza Stark changed review comment from: Included due to phenotypic overlap with nephronophthisis.; to: Well established gene-disease association.
Mendeliome v0.8410 MUC1 Zornitza Stark Gene: muc1 has been classified as Green List (High Evidence).
Mendeliome v0.8407 KIF7 Zornitza Stark Gene: kif7 has been classified as Green List (High Evidence).
Mendeliome v0.8404 KIAA0753 Zornitza Stark Gene: kiaa0753 has been classified as Green List (High Evidence).
Mendeliome v0.8401 KIAA0586 Zornitza Stark Gene: kiaa0586 has been classified as Green List (High Evidence).
Mendeliome v0.8401 KIAA0586 Zornitza Stark Phenotypes for gene: KIAA0586 were changed from to Joubert syndrome 23, MIM# 616490; Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546
Mendeliome v0.8398 KIAA0586 Zornitza Stark edited their review of gene: KIAA0586: Changed phenotypes: Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546, Joubert syndrome
Mendeliome v0.8398 IFT52 Zornitza Stark Gene: ift52 has been classified as Green List (High Evidence).
Mendeliome v0.8398 IFT52 Zornitza Stark Phenotypes for gene: IFT52 were changed from to Short-rib thoracic dysplasia 16 with or without polydactyly, MIM# 617102
Mendeliome v0.8395 IFT27 Zornitza Stark Gene: ift27 has been classified as Green List (High Evidence).
Mendeliome v0.8392 POLG2 Zornitza Stark Gene: polg2 has been classified as Green List (High Evidence).
Mendeliome v0.8392 POLG2 Zornitza Stark Phenotypes for gene: POLG2 were changed from to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MIM# 610131; Mitochondrial DNA depletion syndrome 16 , MIM# 618528
Mendeliome v0.8389 POLG2 Zornitza Stark reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16685652, 21555342, 27592148, 31778857; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MIM# 610131, Mitochondrial DNA depletion syndrome 16 , MIM# 618528; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8389 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Mendeliome v0.8389 PCDHGC4 Zornitza Stark Classified gene: PCDHGC4 as Green List (high evidence)
Mendeliome v0.8389 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Mendeliome v0.8388 PCDHGC4 Zornitza Stark gene: PCDHGC4 was added
gene: PCDHGC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Intellectual disability; Seizures
Review for gene: PCDHGC4 was set to GREEN
Added comment: Eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty in eight families and seizures in four families. Four of the variants were LoF, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Mendeliome v0.8387 ATP6V0A4 Zornitza Stark Gene: atp6v0a4 has been classified as Green List (High Evidence).
Mendeliome v0.8387 ATP6V0A4 Zornitza Stark Phenotypes for gene: ATP6V0A4 were changed from to Renal tubular acidosis, distal, autosomal recessive, MIM#602722
Mendeliome v0.8384 ATP6V0A4 Zornitza Stark reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12414817, 10973252; Phenotypes: Renal tubular acidosis, distal, autosomal recessive, MIM#602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8384 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Mendeliome v0.8384 ICK Zornitza Stark Phenotypes for gene: ICK were changed from to Endocrine-cerebroosteodysplasia (MIM#612651)
Mendeliome v0.8381 HNF1B Zornitza Stark Gene: hnf1b has been classified as Green List (High Evidence).
Mendeliome v0.8379 HNF1B Zornitza Stark changed review comment from: Included due to phenotypic overlap with nephronophthisis.; to: Well established gene-disease association, CNVs common.
Mendeliome v0.8379 GDF1 Zornitza Stark Gene: gdf1 has been classified as Green List (High Evidence).
Mendeliome v0.8376 GDF1 Zornitza Stark edited their review of gene: GDF1: Added comment: PMID: 32144877 - founder PTC in Arab population causing congenital heart detects AND right isomerism in 3 (unrelated?) families. Reviews other publications and reports additional chet (two PTC) or homozygous (missense) families with situs inversus and/or heart defects. No apparent genotype-phenotype correlation btw dominant and recessive disease.; Changed rating: GREEN; Changed publications: 32144877; Changed phenotypes: Congenital heart defects, multiple types, 6 613854, Right atrial isomerism (Ivemark) 208530; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8376 EVC2 Zornitza Stark Gene: evc2 has been classified as Green List (High Evidence).
Mendeliome v0.8373 EVC Zornitza Stark Gene: evc has been classified as Green List (High Evidence).
Mendeliome v0.8370 DCDC2 Zornitza Stark Gene: dcdc2 has been classified as Green List (High Evidence).
Mendeliome v0.8370 DCDC2 Zornitza Stark Phenotypes for gene: DCDC2 were changed from to Nephronophthisis 19, MIM# 616217; Sclerosing cholangitis, neonatal, MIM# 617394
Mendeliome v0.8367 DCDC2 Zornitza Stark changed review comment from: Only a single case with nephronophthisis, most reports are for cholangitis, though zebrafish model has renal cysts.; to: At least 5 families reported with cholangitis, and two with nephronophthisis, though zebrafish model has renal cysts.
Mendeliome v0.8367 DCDC2 Zornitza Stark edited their review of gene: DCDC2: Changed rating: GREEN; Changed publications: 25557784, 27319779, 27469900; Changed phenotypes: Nephronophthisis 19, MIM# 616217, Sclerosing cholangitis, neonatal, MIM# 617394; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8367 CRELD1 Zornitza Stark Gene: creld1 has been classified as Green List (High Evidence).
Mendeliome v0.8364 CRB2 Zornitza Stark Gene: crb2 has been classified as Green List (High Evidence).
Mendeliome v0.8364 CRB2 Zornitza Stark Phenotypes for gene: CRB2 were changed from to Ventriculomegaly with cystic kidney disease, MIM# 219730; Focal segmental glomerulosclerosis 9, MIM# 616220
Mendeliome v0.8361 CRB2 Zornitza Stark edited their review of gene: CRB2: Changed publications: 25557780, 33687977, 32051522, 30212996, 33575434, 31438467, 30593785, 25557779; Changed phenotypes: Ventriculomegaly with cystic kidney disease, MIM# 219730, Focal segmental glomerulosclerosis 9, MIM# 616220
Mendeliome v0.8361 CEP55 Zornitza Stark Gene: cep55 has been classified as Green List (High Evidence).
Mendeliome v0.8361 CEP55 Zornitza Stark Phenotypes for gene: CEP55 were changed from to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500
Mendeliome v0.8358 CEP55 Zornitza Stark reviewed gene: CEP55: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8358 CENPF Zornitza Stark Gene: cenpf has been classified as Green List (High Evidence).
Mendeliome v0.8355 C8orf37 Zornitza Stark Gene: c8orf37 has been classified as Green List (High Evidence).
Mendeliome v0.8352 C2CD3 Zornitza Stark Gene: c2cd3 has been classified as Green List (High Evidence).
Mendeliome v0.8348 CHRM3 Zornitza Stark Gene: chrm3 has been classified as Green List (High Evidence).
Mendeliome v0.8345 ARHGAP42 Zornitza Stark Gene: arhgap42 has been classified as Red List (Low Evidence).
Mendeliome v0.8345 ARHGAP42 Zornitza Stark gene: ARHGAP42 was added
gene: ARHGAP42 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP42 were set to 34232960
Phenotypes for gene: ARHGAP42 were set to Interstitial lung disease; systemic hypertension; immunological abnormalities
Review for gene: ARHGAP42 was set to RED
Added comment: Single individual reported with homozygous LoF variant, chILD disorder, systemic hypertension, and immunological findings.
Sources: Literature
Mendeliome v0.8344 KIAA0556 Zornitza Stark Gene: kiaa0556 has been classified as Green List (High Evidence).
Mendeliome v0.8341 IFT140 Zornitza Stark Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781 to Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; MONDO:0009964; Retinitis pigmentosa 80, MIM# 617781
Mendeliome v0.8340 IFT122 Zornitza Stark Phenotypes for gene: IFT122 were changed from Cranioectodermal dysplasia 1, MIM# MIM#218330 to Cranioectodermal dysplasia 1, MIM# MIM#218330; MONDO:0021093
Mendeliome v0.8339 LINGO4 Zornitza Stark Gene: lingo4 has been classified as Green List (High Evidence).
Mendeliome v0.8339 LINGO4 Zornitza Stark Classified gene: LINGO4 as Green List (high evidence)
Mendeliome v0.8339 LINGO4 Zornitza Stark Gene: lingo4 has been classified as Green List (High Evidence).
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Gene: arfgef3 has been classified as Green List (High Evidence).
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Classified gene: ARFGEF3 as Green List (high evidence)
Mendeliome v0.8338 ARFGEF3 Zornitza Stark Gene: arfgef3 has been classified as Green List (High Evidence).
Mendeliome v0.8337 IMPDH2 Zornitza Stark Gene: impdh2 has been classified as Green List (High Evidence).
Mendeliome v0.8336 IMPDH2 Zornitza Stark Classified gene: IMPDH2 as Green List (high evidence)
Mendeliome v0.8336 IMPDH2 Zornitza Stark Gene: impdh2 has been classified as Green List (High Evidence).
Mendeliome v0.8335 IMPDH2 Laura Raiti gene: IMPDH2 was added
gene: IMPDH2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to PMID: 33098801
Phenotypes for gene: IMPDH2 were set to Dystonia
Review for gene: IMPDH2 was set to GREEN
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Mendeliome v0.8334 DYNC2H1 Zornitza Stark changed review comment from: More than 50 unrelated families reported.; to: More than 50 unrelated families reported with predominantly skeletal dysplasia.

Association with RP: - Five affected probands with homozygous and compound heterozygous missense and PTC variants - Associated with the NM_001080463.1 transcript (predominant isoform in retina from retinal organoid studies). PMID 32753734
Mendeliome v0.8334 DYNC2H1 Zornitza Stark edited their review of gene: DYNC2H1: Changed publications: 19442771, 19361615, 22499340, 23456818, 27925158, 32753734; Changed phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM# 613091, MONDO:0013127, Non-syndromic retinitis pigmentosa
Mendeliome v0.8334 STK36 Zornitza Stark Phenotypes for gene: STK36 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 46, MIM# 619436
Mendeliome v0.8333 STK36 Zornitza Stark edited their review of gene: STK36: Changed phenotypes: Ciliary dyskinesia, primary, 46, MIM# 619436
Mendeliome v0.8333 KIF20A Zornitza Stark Gene: kif20a has been classified as Red List (Low Evidence).
Mendeliome v0.8333 KIF20A Zornitza Stark gene: KIF20A was added
gene: KIF20A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF20A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF20A were set to 29357359
Phenotypes for gene: KIF20A were set to Cardiomyopathy, familial restrictive, 6, MIM# 619433
Review for gene: KIF20A was set to GREEN
Added comment: Single family reported, two affected sibs, perinatal lethal cardiomyopathy, compound het variants in this gene.
Sources: Literature
Mendeliome v0.8332 ACTG2 Zornitza Stark Phenotypes for gene: ACTG2 were changed from Visceral myopathy, MIM#155310 to Visceral myopathy, MIM#155310; Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, MIM# 619431
Mendeliome v0.8331 ACTG2 Zornitza Stark edited their review of gene: ACTG2: Changed phenotypes: Visceral myopathy, MIM#155310, Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, MIM# 619431
Mendeliome v0.8331 B2M Zornitza Stark Gene: b2m has been classified as Green List (High Evidence).
Mendeliome v0.8331 B2M Zornitza Stark Phenotypes for gene: B2M were changed from to Immunodeficiency 43 MIM# 241600; Sinopulmonary infections; Purple-red skin lesions; Decreased serum IgG; Decreased B cells; Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c; MONDO:0009434; Amyloidosis, familial visceral, MIM# 105200
Mendeliome v0.8328 B2M Zornitza Stark reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 4186801, 16549777, 25702838, 11118151, 6165007, 22693999; Phenotypes: Immunodeficiency 43 MIM# 241600, Sinopulmonary infections, Purple-red skin lesions, Decreased serum IgG, Decreased B cells, Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c, MONDO:0009434, Amyloidosis, familial visceral, MIM# 105200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8328 AK2 Zornitza Stark Phenotypes for gene: AK2 were changed from Reticular dysgenesis, MIM# 267500 to Reticular dysgenesis, MIM# 267500; MONDO:0009973
Mendeliome v0.8326 AK2 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association.

PMID: 19043417 (2009). 6 affected individuals from 5 unrelated families (3 of the families showed evidence of consanguinity). Homozygous (5 individuals) and compound heterozygous (1 individual) variants in the AK2 gene. Variants included missense, deletion and inframe indel, resulting in protein LoF. Available parents were sequenced and found heterozygous for the variants, supporting bi-allelic inheritance.

PMID: 19043416 (2009). 7 affected individuals from 6 unrelated families (2 separate consanguineous & 4 non-consanguineous families). Homozygous and compound heterozygous variants detected (missense, deletion, inframe indel), resulting in protein LoF. Reticular dysgenesis phenotype including Leukopenia, lymphopenia and agranulocytosis in all affected individuals and sensorineural deafness in 7 individuals.
Mendeliome v0.8326 AK2 Zornitza Stark edited their review of gene: AK2: Changed phenotypes: Reticular dysgenesis, MIM# 267500, MONDO:0009973
Mendeliome v0.8326 TMEM126A Zornitza Stark Gene: tmem126a has been classified as Green List (High Evidence).
Mendeliome v0.8323 MYC Zornitza Stark Gene: myc has been classified as Red List (Low Evidence).
Mendeliome v0.8321 MYC Zornitza Stark Classified gene: MYC as Red List (low evidence)
Mendeliome v0.8321 MYC Zornitza Stark Gene: myc has been classified as Red List (Low Evidence).
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8318 ATG7 Zornitza Stark Gene: atg7 has been classified as Green List (High Evidence).
Mendeliome v0.8318 ATG7 Zornitza Stark Classified gene: ATG7 as Green List (high evidence)
Mendeliome v0.8318 ATG7 Zornitza Stark Gene: atg7 has been classified as Green List (High Evidence).
Mendeliome v0.8317 ATG7 Zornitza Stark gene: ATG7 was added
gene: ATG7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, SCAR31, MIM#619422
Review for gene: ATG7 was set to GREEN
Added comment: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature
Mendeliome v0.8316 ADA Zornitza Stark Gene: ada has been classified as Green List (High Evidence).
Mendeliome v0.8313 C2orf69 Zornitza Stark Gene: c2orf69 has been classified as Green List (High Evidence).
Mendeliome v0.8313 C2orf69 Zornitza Stark Classified gene: C2orf69 as Green List (high evidence)
Mendeliome v0.8313 C2orf69 Zornitza Stark Gene: c2orf69 has been classified as Green List (High Evidence).
Mendeliome v0.8312 C2orf69 Zornitza Stark gene: C2orf69 was added
gene: C2orf69 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency-53 (COXPD53), MIM#619423
Review for gene: C2orf69 was set to GREEN
Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model.

PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures.
Sources: Literature
Mendeliome v0.8310 NYNRIN Zornitza Stark Gene: nynrin has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8310 NYNRIN Zornitza Stark Phenotypes for gene: NYNRIN were changed from to Wilms tumour predisposition
Mendeliome v0.8309 NYNRIN Zornitza Stark Classified gene: NYNRIN as Amber List (moderate evidence)
Mendeliome v0.8309 NYNRIN Zornitza Stark Gene: nynrin has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8308 FBXW7 Zornitza Stark Phenotypes for gene: FBXW7 were changed from FBXW7-related neurodevelopmental syndrome to FBXW7-related neurodevelopmental syndrome; Wilms tumour predisposition
Mendeliome v0.8306 FBXW7 Zornitza Stark reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30885698, 26482194; Phenotypes: Wilms tumour predisposition; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8304 ZC3H14 Zornitza Stark edited their review of gene: ZC3H14: Added comment: Two families and a mouse model.; Changed phenotypes: Mental retardation, autosomal recessive 56, OMIM# 617125
Mendeliome v0.8302 ATP1A2 Zornitza Stark Gene: atp1a2 has been classified as Green List (High Evidence).
Mendeliome v0.8302 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8302 RNF2 Zornitza Stark Classified gene: RNF2 as Amber List (moderate evidence)
Mendeliome v0.8302 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8301 RING1 Zornitza Stark Gene: ring1 has been classified as Red List (Low Evidence).
Mendeliome v0.8301 RING1 Zornitza Stark Classified gene: RING1 as Red List (low evidence)
Mendeliome v0.8301 RING1 Zornitza Stark Gene: ring1 has been classified as Red List (Low Evidence).
Mendeliome v0.8300 IRX5 Zornitza Stark Gene: irx5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8297 IRX5 Zornitza Stark Classified gene: IRX5 as Amber List (moderate evidence)
Mendeliome v0.8297 IRX5 Zornitza Stark Gene: irx5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8296 IRX6 Zornitza Stark Gene: irx6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8296 IRX6 Zornitza Stark Classified gene: IRX6 as Amber List (moderate evidence)
Mendeliome v0.8296 IRX6 Zornitza Stark Gene: irx6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8293 RAB3GAP1 Zornitza Stark changed review comment from: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. Multiple families reported.; to: Warburg micro: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe ID, spastic diplegia, and hypogonadism. Multiple families reported.

Martsolf syndrome is characterised by cataracts, mild to severe ID, dysmorphic features. Two families reported.
Mendeliome v0.8293 CXCR2 Zornitza Stark Gene: cxcr2 has been classified as Red List (Low Evidence).
Mendeliome v0.8293 CXCR2 Zornitza Stark gene: CXCR2 was added
gene: CXCR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CXCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CXCR2 were set to 24777453
Phenotypes for gene: CXCR2 were set to WHIM syndrome 2, 619407
Review for gene: CXCR2 was set to RED
Added comment: 2 sisters with neutropaenia, myelokathexis, and recurrent bacterial infections and homozygous frameshift variant in this gene.
Sources: Expert list
Mendeliome v0.8292 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Mendeliome v0.8292 IRX6 Eleanor Williams changed review comment from: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature; to: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8292 SLCO2A1 Zornitza Stark Gene: slco2a1 has been classified as Green List (High Evidence).
Mendeliome v0.8291 GNB2 Zornitza Stark Classified gene: GNB2 as Green List (high evidence)
Mendeliome v0.8291 GNB2 Zornitza Stark Gene: gnb2 has been classified as Green List (High Evidence).
Mendeliome v0.8290 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Mendeliome v0.8290 HID1 Zornitza Stark Classified gene: HID1 as Green List (high evidence)
Mendeliome v0.8290 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Mendeliome v0.8288 KIF1B Zornitza Stark Gene: kif1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8288 KIF1B Zornitza Stark Phenotypes for gene: KIF1B were changed from to Charcot-Marie-Tooth disease, type 2A1 MIM#118210; Hypotonia, coloboma, hypoplasia of the corpus callosum, severe neurodevelopmental delay
Mendeliome v0.8285 NUF2 Zornitza Stark Gene: nuf2 has been classified as Red List (Low Evidence).
Mendeliome v0.8285 NUF2 Zornitza Stark Classified gene: NUF2 as Red List (low evidence)
Mendeliome v0.8285 NUF2 Zornitza Stark Gene: nuf2 has been classified as Red List (Low Evidence).
Mendeliome v0.8284 ERGIC3 Seb Lunke Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8284 ERGIC3 Seb Lunke Classified gene: ERGIC3 as Amber List (moderate evidence)
Mendeliome v0.8284 ERGIC3 Seb Lunke Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8283 FYCO1 Zornitza Stark Gene: fyco1 has been classified as Green List (High Evidence).
Mendeliome v0.8278 JPH3 Seb Lunke Gene: jph3 has been classified as Red List (Low Evidence).
Mendeliome v0.8277 MYT1 Zornitza Stark changed review comment from: Five unrelated individuals reported with variants in this gene and OAV spectrum.; to: Five unrelated individuals reported with variants in this gene and OAV spectrum.

Single individual reported with missense variant as part of an ID cohort, limited evidence for disease association.
Mendeliome v0.8277 JPH3 Seb Lunke Classified gene: JPH3 as Red List (low evidence)
Mendeliome v0.8277 JPH3 Seb Lunke Added comment: Comment on list classification: Only STRs disease causing, see separate STR list. No evidence for SNVs etc.
Mendeliome v0.8277 JPH3 Seb Lunke Gene: jph3 has been classified as Red List (Low Evidence).
Mendeliome v0.8276 MYT1 Zornitza Stark Gene: myt1 has been classified as Green List (High Evidence).
Mendeliome v0.8273 HEATR5B Seb Lunke Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia to pontocerebellar hypoplasia; intellectual disability; seizures
Mendeliome v0.8272 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from to Alternating hemiplegia of childhood 1, MIM#104290; Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations; Developmental and epileptic encephalopathy, polymicrogyria
Mendeliome v0.8269 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: Association with alternating hemiplegia is well established.

PMID 31608932: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities. Mouse model is perinatal lethal.

PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed rating: GREEN; Changed publications: 31608932, 33880529; Changed phenotypes: Alternating hemiplegia of childhood 1, MIM#104290, Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations, Developmental and epileptic encephalopathy, polymicrogyria; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8269 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8269 HEATR5B Seb Lunke Classified gene: HEATR5B as Amber List (moderate evidence)
Mendeliome v0.8269 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8266 SAMD9L Zornitza Stark changed review comment from: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism.; to: Ataxia-pancytopaenia: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism.

ID: single individual reported, limited evidence of association.
Mendeliome v0.8266 PITRM1 Zornitza Stark Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia-30 (SCAR30), MIM#619405; intellectual disability; cognitive decline; psychosis
Mendeliome v0.8265 VPS41 Zornitza Stark Phenotypes for gene: VPS41 were changed from Dystonia; intellectual disability to Spinocerebellar ataxia-29 (SCAR29), MIM#619389; Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Mendeliome v0.8264 IRX6 Eleanor Williams gene: IRX6 was added
gene: IRX6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IRX6 were set to 33891002
Phenotypes for gene: IRX6 were set to cone dystrophy, MONDO:0000455
Mode of pathogenicity for gene: IRX6 was set to Other
Review for gene: IRX6 was set to GREEN
Added comment: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8264 EPHA7 Zornitza Stark Gene: epha7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8264 EPHA7 Zornitza Stark Classified gene: EPHA7 as Amber List (moderate evidence)
Mendeliome v0.8264 EPHA7 Zornitza Stark Gene: epha7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8263 EPHA7 Zornitza Stark gene: EPHA7 was added
gene: EPHA7 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA7 were set to 34176129
Phenotypes for gene: EPHA7 were set to Intellectual disability
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.

9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].
Sources: Expert Review
Mendeliome v0.8262 DNM1 Zornitza Stark Gene: dnm1 has been classified as Green List (High Evidence).
Mendeliome v0.8259 GRK2 Zornitza Stark Gene: grk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8259 GRK2 Zornitza Stark Classified gene: GRK2 as Amber List (moderate evidence)
Mendeliome v0.8259 GRK2 Zornitza Stark Gene: grk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8257 WDR60 Zornitza Stark Gene: wdr60 has been classified as Green List (High Evidence).
Mendeliome v0.8257 WDR60 Zornitza Stark Phenotypes for gene: WDR60 were changed from to Short-rib thoracic dysplasia 8 with or without polydactyly, MIM# 615503; Retinitis pigmentosa
Mendeliome v0.8254 WDR60 Zornitza Stark reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910462, 29271569, 26874042; Phenotypes: Short-rib thoracic dysplasia 8 with or without polydactyly, MIM# 615503, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8254 WDR34 Zornitza Stark Gene: wdr34 has been classified as Green List (High Evidence).
Mendeliome v0.8254 WDR34 Zornitza Stark Phenotypes for gene: WDR34 were changed from to Short-rib thoracic dysplasia 11 with or without polydactyly, MIM# 615633; Retinitis pigmentosa
Mendeliome v0.8251 WDR34 Zornitza Stark reviewed gene: WDR34: Rating: GREEN; Mode of pathogenicity: None; Publications: 24183449, 24183451, 33124039, 30649997, 29241935, 28379358; Phenotypes: Short-rib thoracic dysplasia 11 with or without polydactyly, MIM# 615633, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8251 WDR19 Zornitza Stark Gene: wdr19 has been classified as Green List (High Evidence).
Mendeliome v0.8251 WDR19 Zornitza Stark Phenotypes for gene: WDR19 were changed from to Nephronophthisis 13, MIM# 614377; Senior-Loken syndrome 8, MIM# 616307; Short-rib thoracic dysplasia 5 with or without polydactyly, MIM# 614376; Cranioectodermal dysplasia 4, MIM# 614378
Mendeliome v0.8248 WDR19 Zornitza Stark reviewed gene: WDR19: Rating: GREEN; Mode of pathogenicity: None; Publications: 33946315, 33875766, 33606107, 22019273, 23559409, 23683095, 32055034; Phenotypes: Nephronophthisis 13, MIM# 614377, Senior-Loken syndrome 8, MIM# 616307, Short-rib thoracic dysplasia 5 with or without polydactyly, MIM# 614376, Cranioectodermal dysplasia 4, MIM# 614378; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8248 TXNDC15 Zornitza Stark Gene: txndc15 has been classified as Green List (High Evidence).
Mendeliome v0.8245 TTC8 Zornitza Stark Gene: ttc8 has been classified as Green List (High Evidence).
Mendeliome v0.8242 TTC21B Zornitza Stark Gene: ttc21b has been classified as Green List (High Evidence).
Mendeliome v0.8242 TTC21B Zornitza Stark Phenotypes for gene: TTC21B were changed from to Nephronophthisis 12, MIM# 613820; Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819; Joubert syndrome
Mendeliome v0.8239 TTC21B Zornitza Stark reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21258341, 25492405, 18327258, 33875766; Phenotypes: Nephronophthisis 12, MIM# 613820, Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819, Joubert syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8239 TRAF3IP1 Zornitza Stark Gene: traf3ip1 has been classified as Green List (High Evidence).
Mendeliome v0.8236 ATP9A Zornitza Stark Classified gene: ATP9A as Amber List (moderate evidence)
Mendeliome v0.8236 ATP9A Zornitza Stark Gene: atp9a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8235 ATP2C2 Zornitza Stark Classified gene: ATP2C2 as Red List (low evidence)
Mendeliome v0.8235 ATP2C2 Zornitza Stark Gene: atp2c2 has been classified as Red List (Low Evidence).
Mendeliome v0.8229 ATP9A Arina Puzriakova gene: ATP9A was added
gene: ATP9A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms
Review for gene: ATP9A was set to AMBER
Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Mendeliome v0.8229 ATP2C2 Eleanor Williams gene: ATP2C2 was added
gene: ATP2C2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment.

PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Mendeliome v0.8229 TMEM67 Zornitza Stark Gene: tmem67 has been classified as Green List (High Evidence).
Mendeliome v0.8229 TMEM67 Zornitza Stark Phenotypes for gene: TMEM67 were changed from to Joubert syndrome 6, MIM# 610688; Meckel syndrome 3, MIM# 607361; Nephronophthisis 11, MIM# 613550; COACH syndrome 1, MIM# 216360
Mendeliome v0.8226 TMEM67 Zornitza Stark edited their review of gene: TMEM67: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS, Meckel syndrome and nephronophthisis. Multiple families with each.; Changed publications: 16415887, 17377820, 17160906, 19508969; Changed phenotypes: Joubert syndrome 6, MIM# 610688, Meckel syndrome 3, MIM# 607361, Nephronophthisis 11, MIM# 613550, COACH syndrome 1, MIM# 216360
Mendeliome v0.8226 XDH Zornitza Stark Gene: xdh has been classified as Green List (High Evidence).
Mendeliome v0.8223 TCTEX1D2 Zornitza Stark Gene: tctex1d2 has been classified as Green List (High Evidence).
Mendeliome v0.8223 TCTEX1D2 Zornitza Stark Phenotypes for gene: TCTEX1D2 were changed from to Short-rib thoracic dysplasia 17 with or without polydactyly, MIM# 617405
Mendeliome v0.8220 TCTEX1D2 Zornitza Stark reviewed gene: TCTEX1D2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26044572, 25830415; Phenotypes: Short-rib thoracic dysplasia 17 with or without polydactyly, MIM# 617405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8220 TCTN3 Zornitza Stark Gene: tctn3 has been classified as Green List (High Evidence).
Mendeliome v0.8217 SDCCAG8 Zornitza Stark Gene: sdccag8 has been classified as Green List (High Evidence).
Mendeliome v0.8217 SDCCAG8 Zornitza Stark Phenotypes for gene: SDCCAG8 were changed from to Bardet-Biedl syndrome 16, MIM# 615993; MONDO:0014444; Senior-Loken syndrome 7, MIM# 613615; MONDO:0013326; Nephronophthisis
Mendeliome v0.8214 SDCCAG8 Zornitza Stark reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 20835237, 22626039, 22626039, 32432520, 31534065, 26968886; Phenotypes: Bardet-Biedl syndrome 16, MIM# 615993, MONDO:0014444, Senior-Loken syndrome 7, MIM# 613615, MONDO:0013326, Nephronophthisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8214 SBDS Zornitza Stark Gene: sbds has been classified as Green List (High Evidence).
Mendeliome v0.8212 RPGRIP1L Zornitza Stark Gene: rpgrip1l has been classified as Green List (High Evidence).
Mendeliome v0.8212 RPGRIP1L Zornitza Stark Phenotypes for gene: RPGRIP1L were changed from to Joubert syndrome 7, MIM# 611560; Meckel syndrome 5, MIM# 611561; COACH syndrome 3, MIM# 619113; Nephronophthisis
Mendeliome v0.8209 RPGRIP1L Zornitza Stark edited their review of gene: RPGRIP1L: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS and Meckel syndrome. Mouse model.; Changed publications: 17558409, 17558407, 17960139, 26071364, 19574260, 29991045; Changed phenotypes: Joubert syndrome 7, MIM# 611560, Meckel syndrome 5, MIM# 611561, COACH syndrome 3, MIM# 619113, Nephronophthisis
Mendeliome v0.8209 NPHP4 Zornitza Stark Gene: nphp4 has been classified as Green List (High Evidence).
Mendeliome v0.8209 NPHP4 Zornitza Stark Phenotypes for gene: NPHP4 were changed from to Nephronophthisis 4, MIM# 606966; Senior-Loken syndrome 4, MIM# 606996
Mendeliome v0.8206 NPHP4 Zornitza Stark reviewed gene: NPHP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12244321, 12205563, 34013113; Phenotypes: Nephronophthisis 4, MIM# 606966, Senior-Loken syndrome 4, MIM# 606996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8206 NPHP1 Zornitza Stark Gene: nphp1 has been classified as Green List (High Evidence).
Mendeliome v0.8206 NPHP1 Zornitza Stark Phenotypes for gene: NPHP1 were changed from to Joubert syndrome 4, MIM# 609583; Nephronophthisis 1, juvenile, MIM# 256100; Senior-Loken syndrome-1, MIM# 266900
Mendeliome v0.8203 NPHP1 Zornitza Stark reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15138899, 32139166, 28347285, 8852662, 9856524; Phenotypes: Joubert syndrome 4, MIM# 609583, Nephronophthisis 1, juvenile, MIM# 256100, Senior-Loken syndrome-1, MIM# 266900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8203 TIE1 Zornitza Stark Gene: tie1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8203 TIE1 Zornitza Stark Classified gene: TIE1 as Amber List (moderate evidence)
Mendeliome v0.8203 TIE1 Zornitza Stark Gene: tie1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8201 KIF1B Paul De Fazio reviewed gene: KIF1B: Rating: RED; Mode of pathogenicity: None; Publications: 33710394; Phenotypes: Hypotonia, coloboma, hypoplasia of the corpus callosum, severe neurodevelopmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8201 NUF2 Dean Phelan gene: NUF2 was added
gene: NUF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to PMID: 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Mendeliome v0.8201 ERGIC3 Elena Savva gene: ERGIC3 was added
gene: ERGIC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to PMID: 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Mendeliome v0.8201 HEATR5B Teresa Zhao gene: HEATR5B was added
gene: HEATR5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to PMID: 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay.

Two homozygous splice variants were reported ((c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated
with reduced levels of HEATR5B protein.

Homozygous knockout mice were not viable.

*NOTE: gene (and alias) not found in OMIM
Sources: Literature
Mendeliome v0.8201 NEK8 Zornitza Stark Gene: nek8 has been classified as Green List (High Evidence).
Mendeliome v0.8201 NEK8 Zornitza Stark Phenotypes for gene: NEK8 were changed from to Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174
Mendeliome v0.8198 NEK8 Zornitza Stark reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 33131162, 23418306, 26862157, 26697755, 26967905, 23274954, 31633649; Phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8198 MKKS Zornitza Stark Gene: mkks has been classified as Green List (High Evidence).
Mendeliome v0.8198 MKKS Zornitza Stark Phenotypes for gene: MKKS were changed from to Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome, MIM# 236700; Retinitis pigmentosa
Mendeliome v0.8195 MKKS Zornitza Stark reviewed gene: MKKS: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802661, 26900326, 10973251; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome, MIM# 236700, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8195 IQCB1 Zornitza Stark Gene: iqcb1 has been classified as Green List (High Evidence).
Mendeliome v0.8192 IFT80 Zornitza Stark Gene: ift80 has been classified as Green List (High Evidence).
Mendeliome v0.8192 IFT80 Zornitza Stark Phenotypes for gene: IFT80 were changed from to Short-rib thoracic dysplasia 2 with or without polydactyly, MIM# 611263; MONDO:0012644
Mendeliome v0.8189 IFT80 Zornitza Stark reviewed gene: IFT80: Rating: GREEN; Mode of pathogenicity: None; Publications: 17468754, 19648123, 30767363; Phenotypes: Short-rib thoracic dysplasia 2 with or without polydactyly, MIM# 611263, MONDO:0012644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8189 LZTFL1 Zornitza Stark Gene: lztfl1 has been classified as Green List (High Evidence).
Mendeliome v0.8186 TTC26 Zornitza Stark Gene: ttc26 has been classified as Green List (High Evidence).
Mendeliome v0.8186 TTC26 Zornitza Stark Classified gene: TTC26 as Green List (high evidence)
Mendeliome v0.8186 TTC26 Zornitza Stark Gene: ttc26 has been classified as Green List (High Evidence).
Mendeliome v0.8183 IFT43 Zornitza Stark changed review comment from: One family reported with cranioectodermal dysplasia, one with RP, and two with skeletal ciliopathy.; to: Two families reported with cranioectodermal dysplasia, one with RP, and two with skeletal ciliopathy.
Mendeliome v0.8183 IFT43 Zornitza Stark Gene: ift43 has been classified as Green List (High Evidence).
Mendeliome v0.8183 IFT43 Zornitza Stark Phenotypes for gene: IFT43 were changed from to Short-rib thoracic dysplasia 18 with polydactyly, MIM# 617866; Retinitis pigmentosa 81 , MIM#617871; Cranioectodermal dysplasia 3, MIM# 614099
Mendeliome v0.8180 IFT43 Zornitza Stark reviewed gene: IFT43: Rating: GREEN; Mode of pathogenicity: None; Publications: 28400947, 28973684, 21378380; Phenotypes: Short-rib thoracic dysplasia 18 with polydactyly, MIM# 617866, Retinitis pigmentosa 81 , MIM#617871, Cranioectodermal dysplasia 3, MIM# 614099; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8180 IFT140 Zornitza Stark Gene: ift140 has been classified as Green List (High Evidence).
Mendeliome v0.8180 IFT140 Zornitza Stark Phenotypes for gene: IFT140 were changed from to Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781
Mendeliome v0.8177 IFT140 Zornitza Stark reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: 22503633, 23418020, 28288023, 28724397, 26216056, 26968735; Phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920, Retinitis pigmentosa 80, MIM# 617781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8175 DYNC2H1 Zornitza Stark Gene: dync2h1 has been classified as Green List (High Evidence).
Mendeliome v0.8175 DYNC2H1 Zornitza Stark Phenotypes for gene: DYNC2H1 were changed from to Short-rib thoracic dysplasia 3 with or without polydactyly, MIM# 613091; MONDO:0013127
Mendeliome v0.8172 DYNC2H1 Zornitza Stark reviewed gene: DYNC2H1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19442771, 19361615, 22499340, 23456818, 27925158; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM# 613091, MONDO:0013127; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8172 DDX59 Zornitza Stark Gene: ddx59 has been classified as Green List (High Evidence).
Mendeliome v0.8169 CEP83 Zornitza Stark Gene: cep83 has been classified as Green List (High Evidence).
Mendeliome v0.8169 CEP83 Zornitza Stark Phenotypes for gene: CEP83 were changed from to Nephronophthisis 18, MIM# 615862; MONDO:0014374; Retinal dystrophy; ID
Mendeliome v0.8166 CEP83 Zornitza Stark reviewed gene: CEP83: Rating: GREEN; Mode of pathogenicity: None; Publications: 24882706, 33938610; Phenotypes: Nephronophthisis 18, MIM# 615862, MONDO:0014374, Retinal dystrophy, ID; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8166 RNU12 Bryony Thompson Gene: rnu12 has been classified as Green List (High Evidence).
Mendeliome v0.8166 RNU12 Bryony Thompson Classified gene: RNU12 as Green List (high evidence)
Mendeliome v0.8166 RNU12 Bryony Thompson Gene: rnu12 has been classified as Green List (High Evidence).
Mendeliome v0.8165 RNU12 Bryony Thompson gene: RNU12 was added
gene: RNU12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356; 27863452
Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations
Review for gene: RNU12 was set to GREEN
Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Also, limited evidence for an association with cerebellar ataxia with a single large consanguineous family reported with a homozygous variant.
Sources: Literature
Mendeliome v0.8164 FHOD3 Zornitza Stark Gene: fhod3 has been classified as Green List (High Evidence).
Mendeliome v0.8160 KCNJ16 Zornitza Stark Gene: kcnj16 has been classified as Green List (High Evidence).
Mendeliome v0.8160 KCNJ16 Zornitza Stark Classified gene: KCNJ16 as Green List (high evidence)
Mendeliome v0.8160 KCNJ16 Zornitza Stark Gene: kcnj16 has been classified as Green List (High Evidence).
Mendeliome v0.8158 KLHL7 Zornitza Stark Gene: klhl7 has been classified as Green List (High Evidence).
Mendeliome v0.8155 SLC34A3 Zornitza Stark Gene: slc34a3 has been classified as Green List (High Evidence).
Mendeliome v0.8152 TNC Zornitza Stark Gene: tnc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8149 TNC Zornitza Stark Classified gene: TNC as Amber List (moderate evidence)
Mendeliome v0.8149 TNC Zornitza Stark Gene: tnc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8148 RIPK4 Zornitza Stark Gene: ripk4 has been classified as Green List (High Evidence).
Mendeliome v0.8145 CEP290 Zornitza Stark Gene: cep290 has been classified as Green List (High Evidence).
Mendeliome v0.8145 CEP290 Zornitza Stark Phenotypes for gene: CEP290 were changed from to Bardet-Biedl syndrome 14, MIM# 615991; Joubert syndrome 5 610188; Leber congenital amaurosis 10, MIM# 611755; Meckel syndrome 4, MIM# 611134; Senior-Loken syndrome 6, MIM# 610189
Mendeliome v0.8142 CEP290 Zornitza Stark reviewed gene: CEP290: Rating: GREEN; Mode of pathogenicity: None; Publications: 18327255, 20690115, 16682973, 16682970, 17564967, 16909394, 17564974; Phenotypes: Bardet-Biedl syndrome 14, MIM# 615991, Joubert syndrome 5 610188, Leber congenital amaurosis 10, MIM# 611755, Meckel syndrome 4, MIM# 611134, Senior-Loken syndrome 6, MIM# 610189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8142 CEP164 Zornitza Stark Gene: cep164 has been classified as Green List (High Evidence).
Mendeliome v0.8142 CEP164 Zornitza Stark Phenotypes for gene: CEP164 were changed from to Bardet-Biedl syndrome; Nephronophthisis 15, MIM# 614845; Oro-facio-digital syndrome
Mendeliome v0.8139 CEP164 Zornitza Stark reviewed gene: CEP164: Rating: GREEN; Mode of pathogenicity: None; Publications: 34132027, 34013113, 32055034, 27708425, 22863007; Phenotypes: Bardet-Biedl syndrome, Nephronophthisis 15, MIM# 614845, Oro-facio-digital syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8139 CEP120 Zornitza Stark Gene: cep120 has been classified as Green List (High Evidence).
Mendeliome v0.8139 CEP120 Zornitza Stark Phenotypes for gene: CEP120 were changed from to Joubert syndrome 31, MIM# 617761; Short-rib thoracic dysplasia 13 with or without polydactyly, MIM# 616300
Mendeliome v0.8136 CEP120 Zornitza Stark reviewed gene: CEP120: Rating: GREEN; Mode of pathogenicity: None; Publications: 27208211, 33486889, 29847808, 25361962, 27208211; Phenotypes: Joubert syndrome 31, MIM# 617761, Short-rib thoracic dysplasia 13 with or without polydactyly, MIM# 616300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8136 CEP104 Zornitza Stark Gene: cep104 has been classified as Green List (High Evidence).
Mendeliome v0.8133 C5orf42 Zornitza Stark Gene: c5orf42 has been classified as Green List (High Evidence).
Mendeliome v0.8130 C21orf2 Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported.

7 families also reported with isolated retinal dystrophy.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported.

7 families also reported with isolated retinal dystrophy.

New HGNC approved name is CFAP410.
Mendeliome v0.8130 C21orf2 Zornitza Stark Gene: c21orf2 has been classified as Green List (High Evidence).
Mendeliome v0.8130 C21orf2 Zornitza Stark Phenotypes for gene: C21orf2 were changed from to Spondylometaphyseal dysplasia, axial, MIM# 602271; Retinal dystrophy with macular staphyloma, MIM# 617547
Mendeliome v0.8127 C21orf2 Zornitza Stark reviewed gene: C21orf2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26974433, 27548899, 28422394, 26294103, 23105016, 27548899; Phenotypes: Spondylometaphyseal dysplasia, axial, MIM# 602271, Retinal dystrophy with macular staphyloma, MIM# 617547; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8127 BBS9 Zornitza Stark Gene: bbs9 has been classified as Green List (High Evidence).
Mendeliome v0.8124 BBS7 Zornitza Stark Gene: bbs7 has been classified as Green List (High Evidence).
Mendeliome v0.8121 BBS5 Zornitza Stark Gene: bbs5 has been classified as Green List (High Evidence).
Mendeliome v0.8118 BBS4 Zornitza Stark Gene: bbs4 has been classified as Green List (High Evidence).
Mendeliome v0.8115 ARL6 Zornitza Stark Gene: arl6 has been classified as Green List (High Evidence).
Mendeliome v0.8111 SLCO2A1 Zornitza Stark Phenotypes for gene: SLCO2A1 were changed from to Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441
Mendeliome v0.8108 SLCO2A1 Zornitza Stark reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23509104, 27134495, 33852188, 22331663, 27134495]; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8108 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); MONDO:0026721 to Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952); MONDO:0010494; Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); MONDO:0026721; X-linked sideroblastic anaemia
Mendeliome v0.8106 NDUFB11 Zornitza Stark reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27488349; Phenotypes: X-linked sideroblastic anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8106 PPP2R1A Zornitza Stark Gene: ppp2r1a has been classified as Green List (High Evidence).
Mendeliome v0.8106 PPP2R1A Zornitza Stark Phenotypes for gene: PPP2R1A were changed from to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605
Mendeliome v0.8103 PPP2R1A Zornitza Stark reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 36, MIM#616362, Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8103 KIF1B Bryony Thompson Classified gene: KIF1B as Amber List (moderate evidence)
Mendeliome v0.8103 KIF1B Bryony Thompson Gene: kif1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Gene: arhgef10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Classified gene: ARHGEF10 as Amber List (moderate evidence)
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Added comment: Comment on list classification: ClinGen gene-disease clinical validity classification is limited for this gene.
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Gene: arhgef10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8100 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Mendeliome v0.8096 PON1 Zornitza Stark Gene: pon1 has been classified as Red List (Low Evidence).
Mendeliome v0.8095 PON1 Zornitza Stark Classified gene: PON1 as Red List (low evidence)
Mendeliome v0.8095 PON1 Zornitza Stark Gene: pon1 has been classified as Red List (Low Evidence).
Mendeliome v0.8094 ABCB4 Zornitza Stark Gene: abcb4 has been classified as Green List (High Evidence).
Mendeliome v0.8094 ABCB4 Zornitza Stark Phenotypes for gene: ABCB4 were changed from to Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism
Mendeliome v0.8091 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
Mendeliome v0.8091 OAS1 Zornitza Stark Phenotypes for gene: OAS1 were changed from to Autoinflammatory immunodeficiency; infantile-onset pulmonary alveolar proteinosis; hypogammaglobulinaemia
Mendeliome v0.8087 OAS1 Zornitza Stark reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34145065, 29455859; Phenotypes: Autoinflammatory immunodeficiency, infantile-onset pulmonary alveolar proteinosis, hypogammaglobulinaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8087 SLIT3 Zornitza Stark Gene: slit3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8087 SLIT3 Zornitza Stark Classified gene: SLIT3 as Amber List (moderate evidence)
Mendeliome v0.8087 SLIT3 Zornitza Stark Gene: slit3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8086 SLIT3 Zornitza Stark gene: SLIT3 was added
gene: SLIT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLIT3 were set to 33933663
Phenotypes for gene: SLIT3 were set to Congenital diaphragmatic hernia
Review for gene: SLIT3 was set to AMBER
Added comment: Two affected individuals, single family, supportive mouse model.
Sources: Literature
Mendeliome v0.8083 IQGAP3 Zornitza Stark Gene: iqgap3 has been classified as Red List (Low Evidence).
Mendeliome v0.8083 IQGAP3 Zornitza Stark gene: IQGAP3 was added
gene: IQGAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IQGAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IQGAP3 were set to Hereditary neuropathy
Review for gene: IQGAP3 was set to RED
Added comment: Single multiplex family, intronic variant, limited functional data.
Sources: Literature
Mendeliome v0.8082 TINF2 Zornitza Stark Gene: tinf2 has been classified as Green List (High Evidence).
Mendeliome v0.8082 TINF2 Zornitza Stark Phenotypes for gene: TINF2 were changed from to Dyskeratosis congenita, autosomal dominant 3, MIM# 613990; Revesz syndrome, MIM# 268130
Mendeliome v0.8079 TINF2 Zornitza Stark edited their review of gene: TINF2: Added comment: RS is a severe variant of DKC with early bone marrow failure and retinopathy. Well established gene-disease associations.; Changed publications: 18252230, 21477109, 18979121, 18669893, 21199492, 33097095; Changed phenotypes: Dyskeratosis congenita, autosomal dominant 3, MIM# 613990, Revesz syndrome, MIM# 268130
Mendeliome v0.8079 POPDC3 Zornitza Stark changed review comment from: 5 affected individuals from 3 unrelated families reported, supportive animal model data.
Sources: Literature; to: 5 affected individuals from 3 unrelated families reported, supportive animal model data. Presentation was between adolescence and 40s with proximal muscle weakness primarily affecting the lower limbs, resulting in increased falls and difficulty running. The disorder was slowly progressive, with later involvement of the upper limbs. MRI showed fatty replacement of the thigh muscles and medial gastrocnemius, with some paraspinal muscles also affected. Some patients had calf hypertrophy. Serum CK was markedly elevated.
Sources: Literature
Mendeliome v0.8079 POPDC3 Zornitza Stark Gene: popdc3 has been classified as Green List (High Evidence).
Mendeliome v0.8079 POPDC3 Zornitza Stark Classified gene: POPDC3 as Green List (high evidence)
Mendeliome v0.8079 POPDC3 Zornitza Stark Gene: popdc3 has been classified as Green List (High Evidence).
Mendeliome v0.8078 POPDC3 Zornitza Stark gene: POPDC3 was added
gene: POPDC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POPDC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC3 were set to 31610034
Phenotypes for gene: POPDC3 were set to Muscular dystrophy, limb-girdle, autosomal recessive 26, MIM# 618848
Review for gene: POPDC3 was set to GREEN
Added comment: 5 affected individuals from 3 unrelated families reported, supportive animal model data.
Sources: Literature
Mendeliome v0.8077 ACD Zornitza Stark Gene: acd has been classified as Red List (Low Evidence).
Mendeliome v0.8077 ACD Zornitza Stark Phenotypes for gene: ACD were changed from to Dyskeratosis congenita, MIM# 616553
Mendeliome v0.8074 ACD Zornitza Stark Classified gene: ACD as Red List (low evidence)
Mendeliome v0.8074 ACD Zornitza Stark Gene: acd has been classified as Red List (Low Evidence).
Mendeliome v0.8073 ACD Zornitza Stark reviewed gene: ACD: Rating: RED; Mode of pathogenicity: None; Publications: 25205116, 25233904; Phenotypes: Dyskeratosis congenita, MIM# 616553; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8071 WRAP53 Zornitza Stark Gene: wrap53 has been classified as Green List (High Evidence).
Mendeliome v0.8071 WRAP53 Zornitza Stark Phenotypes for gene: WRAP53 were changed from to Dyskeratosis congenita, autosomal recessive 3, MIM# 613988
Mendeliome v0.8068 WRAP53 Zornitza Stark reviewed gene: WRAP53: Rating: GREEN; Mode of pathogenicity: None; Publications: 21205863, 32303682, 29514627; Phenotypes: Dyskeratosis congenita, autosomal recessive 3, MIM# 613988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8068 EP300 Zornitza Stark Gene: ep300 has been classified as Green List (High Evidence).
Mendeliome v0.8065 PARN Zornitza Stark Gene: parn has been classified as Green List (High Evidence).
Mendeliome v0.8065 PARN Zornitza Stark Phenotypes for gene: PARN were changed from to Dyskeratosis congenita, autosomal recessive 6, MIM# 616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, MIM# 616371
Mendeliome v0.8062 PARN Zornitza Stark reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25893599, 26342108, 25848748; Phenotypes: Dyskeratosis congenita, autosomal recessive 6, MIM# 616353, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, MIM# 616371; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8062 KLF1 Zornitza Stark Gene: klf1 has been classified as Green List (High Evidence).
Mendeliome v0.8059 SPAG17 Zornitza Stark Gene: spag17 has been classified as Red List (Low Evidence).
Mendeliome v0.8059 SPAG17 Zornitza Stark gene: SPAG17 was added
gene: SPAG17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPAG17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPAG17 were set to 28548327
Phenotypes for gene: SPAG17 were set to Spermatogenic failure 55, MIM#619380
Review for gene: SPAG17 was set to RED
Added comment: Single family reported with two affected brothers, homozygous missense variant.
Sources: Literature
Mendeliome v0.8058 CATIP Zornitza Stark Gene: catip has been classified as Red List (Low Evidence).
Mendeliome v0.8058 CATIP Zornitza Stark gene: CATIP was added
gene: CATIP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CATIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CATIP were set to 32503832
Phenotypes for gene: CATIP were set to Spermatogenic failure 54, MIM# 619379
Review for gene: CATIP was set to RED
Added comment: Homozygous missense variant reported in a single consanguineous family with 4 affecteds. Limited functional data.
Sources: Expert list
Mendeliome v0.8056 HAX1 Zornitza Stark Gene: hax1 has been classified as Green List (High Evidence).
Mendeliome v0.8056 HAX1 Zornitza Stark Phenotypes for gene: HAX1 were changed from to Neutropaenia, severe congenital 3, autosomal recessive, MIM# 610738; Kostmann syndrome MONDO:0012548
Mendeliome v0.8053 HAX1 Zornitza Stark reviewed gene: HAX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17187068, 18611981, 19036076; Phenotypes: Neutropaenia, severe congenital 3, autosomal recessive, MIM# 610738, Kostmann syndrome MONDO:0012548; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8050 MYL9 Zornitza Stark Phenotypes for gene: MYL9 were changed from Megacystis-microcolon-intestinal hypoperistalsis syndrome to Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365
Mendeliome v0.8049 MYL9 Zornitza Stark edited their review of gene: MYL9: Changed phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365
Mendeliome v0.8046 NBEAL2 Zornitza Stark Gene: nbeal2 has been classified as Green List (High Evidence).
Mendeliome v0.8043 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
Mendeliome v0.8040 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Green List (High Evidence).
Mendeliome v0.8040 SLC13A5 Zornitza Stark Phenotypes for gene: SLC13A5 were changed from to Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905; MONDO:0014392
Mendeliome v0.8037 SLC13A5 Zornitza Stark reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24995870, 26384929; Phenotypes: Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905, MONDO:0014392; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8037 GATA2 Zornitza Stark Gene: gata2 has been classified as Green List (High Evidence).
Mendeliome v0.8034 GATA1 Zornitza Stark Gene: gata1 has been classified as Green List (High Evidence).
Mendeliome v0.8032 ELANE Zornitza Stark Gene: elane has been classified as Green List (High Evidence).
Mendeliome v0.8029 EFL1 Zornitza Stark Gene: efl1 has been classified as Green List (High Evidence).
Mendeliome v0.8026 CXCR4 Zornitza Stark Gene: cxcr4 has been classified as Green List (High Evidence).
Mendeliome v0.8023 CTC1 Zornitza Stark Gene: ctc1 has been classified as Green List (High Evidence).
Mendeliome v0.8020 ANKRD26 Zornitza Stark Gene: ankrd26 has been classified as Green List (High Evidence).
Mendeliome v0.8017 AK2 Zornitza Stark Gene: ak2 has been classified as Green List (High Evidence).
Mendeliome v0.8017 AK2 Zornitza Stark Phenotypes for gene: AK2 were changed from to Reticular dysgenesis, MIM# 267500
Mendeliome v0.8014 AK2 Zornitza Stark reviewed gene: AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19043416; Phenotypes: Reticular dysgenesis, MIM# 267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8014 ADA2 Zornitza Stark Gene: ada2 has been classified as Green List (High Evidence).
Mendeliome v0.8011 ADA2 Zornitza Stark commented on gene: ADA2: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits. Some affected individuals have immunodeficiency. At least 10 unrelated families reported, the p.Gly47Arg variant is a common founder variant in the Jewish population.
Mendeliome v0.8009 IFT74 Zornitza Stark edited their review of gene: IFT74: Added comment: PMID 33531668: Identified IFT74 as a JBTS-associated gene in 3 unrelated families through WES. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.; Changed publications: 27486776, 32144365, 33531668; Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 617119, Joubert syndrome
Mendeliome v0.8009 RFX4 Zornitza Stark Gene: rfx4 has been classified as Green List (High Evidence).
Mendeliome v0.8009 RFX4 Zornitza Stark Classified gene: RFX4 as Green List (high evidence)
Mendeliome v0.8009 RFX4 Zornitza Stark Gene: rfx4 has been classified as Green List (High Evidence).
Mendeliome v0.8008 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8007 RFX3 Zornitza Stark Gene: rfx3 has been classified as Green List (High Evidence).
Mendeliome v0.8007 RFX3 Zornitza Stark Classified gene: RFX3 as Green List (high evidence)
Mendeliome v0.8007 RFX3 Zornitza Stark Gene: rfx3 has been classified as Green List (High Evidence).
Mendeliome v0.8006 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8005 RFX7 Zornitza Stark Gene: rfx7 has been classified as Green List (High Evidence).
Mendeliome v0.8005 RFX7 Zornitza Stark Classified gene: RFX7 as Green List (high evidence)
Mendeliome v0.8005 RFX7 Zornitza Stark Gene: rfx7 has been classified as Green List (High Evidence).
Mendeliome v0.8004 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8003 SEMA3F Zornitza Stark Gene: sema3f has been classified as Green List (High Evidence).
Mendeliome v0.8003 SEMA3F Zornitza Stark Classified gene: SEMA3F as Green List (high evidence)
Mendeliome v0.8003 SEMA3F Zornitza Stark Gene: sema3f has been classified as Green List (High Evidence).
Mendeliome v0.8002 SEMA3F Zornitza Stark gene: SEMA3F was added
gene: SEMA3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3F were set to 33495532
Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism
Review for gene: SEMA3F was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates.
Sources: Literature
Mendeliome v0.8001 PLXNA3 Zornitza Stark Gene: plxna3 has been classified as Green List (High Evidence).
Mendeliome v0.8001 PLXNA3 Zornitza Stark Classified gene: PLXNA3 as Green List (high evidence)
Mendeliome v0.8001 PLXNA3 Zornitza Stark Gene: plxna3 has been classified as Green List (High Evidence).
Mendeliome v0.8000 PLXNA3 Zornitza Stark gene: PLXNA3 was added
gene: PLXNA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLXNA3 were set to 33495532
Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism
Review for gene: PLXNA3 was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants. In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3.
Sources: Literature
Mendeliome v0.7997 GNAI1 Zornitza Stark Gene: gnai1 has been classified as Green List (High Evidence).
Mendeliome v0.7994 FARSA Zornitza Stark Classified gene: FARSA as Green List (high evidence)
Mendeliome v0.7994 FARSA Zornitza Stark Gene: farsa has been classified as Green List (High Evidence).
Mendeliome v0.7993 LAMA5 Bryony Thompson Phenotypes for gene: LAMA5 were changed from to bent bone dysplasia; nephrotic syndrome; Presynaptic congenital myasthenic syndrome; multisystem syndrome; developmental delay
Mendeliome v0.7990 LAMA5 Bryony Thompson reviewed gene: LAMA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33242826, 29534211, 16790509, 30589377, 28735299, 30631761; Phenotypes: bent bone dysplasia, nephrotic syndrome, Presynaptic congenital myasthenic syndrome, multisystem syndrome, developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7990 ZNF81 Zornitza Stark Gene: znf81 has been classified as Red List (Low Evidence).
Mendeliome v0.7987 ZNF81 Zornitza Stark Classified gene: ZNF81 as Red List (low evidence)
Mendeliome v0.7987 ZNF81 Zornitza Stark Gene: znf81 has been classified as Red List (Low Evidence).
Mendeliome v0.7986 RELN Ee Ming Wong edited their review of gene: RELN: Added comment: - Six affected individuals carrying missense variants in RELN including
1. Two individuals with compound heterozygous variants
- One of the variants has 26 homozygotes in gnomAD and therefore pathogenicity of this variant is in question
- LoF demonstrated for three of the variants (reduced RELN secretion), except for p.Y1821H which demonstrated an apparently increased RELN secretion (GoF)
2. Two brothers carrying the maternally inherited variant (mother apparently healthy)
- LoF demonstrated for these variants
3. Two individuals de novo for RELN variants
- Dominant negative demonstrated for these variants where secretion of WT-RELN was impaired when co-transfected with mutant constructs in HEK293T cells; Changed rating: AMBER; Changed publications: Riva et al bioRxiv (pre-print, not peer-reviewed); Changed phenotypes: Pachygyria, Polymicrogyria, Heterotopia; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7986 NIID Bryony Thompson Str: niid has been classified as Green List (High Evidence).
Mendeliome v0.7986 NIID Bryony Thompson Classified STR: NIID as Green List (high evidence)
Mendeliome v0.7986 NIID Bryony Thompson Str: niid has been classified as Green List (High Evidence).
Mendeliome v0.7985 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)]
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 7-60
Pathogenic repeat range: >=61-500
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Mendeliome v0.7984 NOTCH2NL Bryony Thompson Classified gene: NOTCH2NL as No list
Mendeliome v0.7984 NOTCH2NL Bryony Thompson Added comment: Comment on list classification: STR is the only reported cause of disease for this gene. It has been added as an STR under NIID.
Mendeliome v0.7983 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
Mendeliome v0.7981 CNTNAP1 Zornitza Stark Gene: cntnap1 has been classified as Green List (High Evidence).
Mendeliome v0.7978 GLDN Zornitza Stark Gene: gldn has been classified as Green List (High Evidence).
Mendeliome v0.7975 ZBTB42 Zornitza Stark Gene: zbtb42 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7975 ZBTB42 Zornitza Stark Classified gene: ZBTB42 as Amber List (moderate evidence)
Mendeliome v0.7975 ZBTB42 Zornitza Stark Gene: zbtb42 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7974 ZBTB42 Zornitza Stark gene: ZBTB42 was added
gene: ZBTB42 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZBTB42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB42 were set to 25055871
Phenotypes for gene: ZBTB42 were set to Lethal congenital contracture syndrome 6, MIM# 616248
Review for gene: ZBTB42 was set to AMBER
Added comment: Homozygous missense variant reported in a family with three stillbirths and a phenotype consistent with LCCS. Supportive zebrafish model.
Sources: Expert Review
Mendeliome v0.7973 MYBPC1 Zornitza Stark Gene: mybpc1 has been classified as Green List (High Evidence).
Mendeliome v0.7973 MYBPC1 Zornitza Stark Phenotypes for gene: MYBPC1 were changed from to Arthrogryposis, distal, type 1B 614335; Lethal congenital contracture syndrome 4, MIM# 614915; Myopathy, congenital, with tremor MIM#618524
Mendeliome v0.7970 MYBPC1 Zornitza Stark reviewed gene: MYBPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20045868, 22610851, 23873045, 26661508, 31264822, 31025394; Phenotypes: Arthrogryposis, distal, type 1B 614335, Lethal congenital contracture syndrome 4, MIM# 614915, Myopathy, congenital, with tremor MIM#618524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7970 ERBB3 Zornitza Stark Gene: erbb3 has been classified as Green List (High Evidence).
Mendeliome v0.7970 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598 to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis
Mendeliome v0.7967 MUSK Zornitza Stark Gene: musk has been classified as Green List (High Evidence).
Mendeliome v0.7967 MUSK Zornitza Stark Phenotypes for gene: MUSK were changed from to Fetal akinesia deformation sequence 1, MIM# 208150; MONDO:0100101; Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency, MIM# 616325; MONDO:0014587
Mendeliome v0.7964 MUSK Zornitza Stark reviewed gene: MUSK: Rating: GREEN; Mode of pathogenicity: None; Publications: 25537362, 25612909, 8653786, 31750350, 15496425, 19949040, 20371544, 32253145; Phenotypes: Fetal akinesia deformation sequence 1, MIM# 208150, MONDO:0100101, Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency, MIM# 616325, MONDO:0014587; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7964 DOK7 Zornitza Stark Gene: dok7 has been classified as Green List (High Evidence).
Mendeliome v0.7964 DOK7 Zornitza Stark Phenotypes for gene: DOK7 were changed from to Myasthenic syndrome, congenital, 10, MIM# 254300; Fetal akinesia deformation sequence 3, MIM# 618389
Mendeliome v0.7961 DOK7 Zornitza Stark reviewed gene: DOK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16917026, 18626973, 20147321, 16794080, 31453852, 29395672, 32360404, 19261599, 31880392; Phenotypes: Myasthenic syndrome, congenital, 10, MIM# 254300, Fetal akinesia deformation sequence 3, MIM# 618389; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7961 TPM2 Zornitza Stark Gene: tpm2 has been classified as Green List (High Evidence).
Mendeliome v0.7961 TPM2 Zornitza Stark Phenotypes for gene: TPM2 were changed from to Arthrogryposis, distal, type 1A 108120; Arthrogryposis, distal, type 2B4 108120; CAP myopathy 2 609285; Nemaline myopathy 4, autosomal dominant 609285; Multiple pterygium syndrome
Mendeliome v0.7958 TPM2 Zornitza Stark reviewed gene: TPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32092148, 27726070, 32092148, 24692096; Phenotypes: Arthrogryposis, distal, type 1A 108120, Arthrogryposis, distal, type 2B4 108120, CAP myopathy 2 609285, Nemaline myopathy 4, autosomal dominant 609285, Multiple pterygium syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7958 CHRNG Zornitza Stark Gene: chrng has been classified as Green List (High Evidence).
Mendeliome v0.7955 CD207 Zornitza Stark Gene: cd207 has been classified as Red List (Low Evidence).
Mendeliome v0.7952 CD207 Zornitza Stark Classified gene: CD207 as Red List (low evidence)
Mendeliome v0.7952 CD207 Zornitza Stark Gene: cd207 has been classified as Red List (Low Evidence).
Mendeliome v0.7951 KIF17 Zornitza Stark Gene: kif17 has been classified as Red List (Low Evidence).
Mendeliome v0.7951 KIF17 Zornitza Stark gene: KIF17 was added
gene: KIF17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF17 were set to 33922911; 30458707; 28341548
Phenotypes for gene: KIF17 were set to Microphthalmia; Coloboma
Review for gene: KIF17 was set to RED
Added comment: Two siblings reported with MAC spectrum and homozygous missense variant in this gene. Some pre-existing data linking KIF17 to eye development.
Sources: Literature
Mendeliome v0.7950 SASH3 Zornitza Stark Gene: sash3 has been classified as Green List (High Evidence).
Mendeliome v0.7950 SASH3 Zornitza Stark Classified gene: SASH3 as Green List (high evidence)
Mendeliome v0.7950 SASH3 Zornitza Stark Gene: sash3 has been classified as Green List (High Evidence).
Mendeliome v0.7949 SASH3 Zornitza Stark gene: SASH3 was added
gene: SASH3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SASH3 were set to 33876203
Phenotypes for gene: SASH3 were set to Combined immunodeficiency; immune dysregulation
Review for gene: SASH3 was set to GREEN
Added comment: Four unrelated males reported presenting with combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopaenias. One missense variant, rest were nonsense.
Sources: Literature
Mendeliome v0.7945 MYBPC2 Zornitza Stark Gene: mybpc2 has been classified as Red List (Low Evidence).
Mendeliome v0.7945 MYBPC2 Zornitza Stark gene: MYBPC2 was added
gene: MYBPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC2 were set to 32732226
Phenotypes for gene: MYBPC2 were set to Fetal akinesia; Hydrops; Hygroma; Multiple pterygium
Review for gene: MYBPC2 was set to RED
Added comment: Novel candidate gene identified in a fetus with fetal akinesia detected by ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, hygroma, multiple pterygium. A homozygous variant (c.3394G>A/ p.Glu1132Lys) in MYBPC2 was found by exome sequencing with concordant segregation among one affected sib and two unaffected sibs.
Sources: Literature
Mendeliome v0.7944 SCN7A Zornitza Stark Gene: scn7a has been classified as Red List (Low Evidence).
Mendeliome v0.7944 SCN7A Zornitza Stark gene: SCN7A was added
gene: SCN7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Mendeliome v0.7943 SPTBN5 Zornitza Stark Gene: sptbn5 has been classified as Red List (Low Evidence).
Mendeliome v0.7943 SPTBN5 Zornitza Stark gene: SPTBN5 was added
gene: SPTBN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226; 28007035
Phenotypes for gene: SPTBN5 were set to Sacral agenesis; congenital anomalies
Review for gene: SPTBN5 was set to RED
Added comment: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature
Mendeliome v0.7942 WDR91 Zornitza Stark Phenotypes for gene: WDR91 were changed from to Hydrocephalus; cerebellar hypoplasia; hygroma
Mendeliome v0.7939 WDR91 Zornitza Stark Classified gene: WDR91 as Amber List (moderate evidence)
Mendeliome v0.7939 WDR91 Zornitza Stark Gene: wdr91 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7938 WDR91 Zornitza Stark commented on gene: WDR91: PMID 32732226: Novel candidate gene identified in a fetus with hygroma and hydrocephaly detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, and interventricular communication. A homozygous truncating variant was found by exome sequencing with concordant segregation among 4 affected fetus, 2 healthy sibs and both parents. Mouse models support role in brain development.
Mendeliome v0.7938 WDR91 Zornitza Stark reviewed gene: WDR91: Rating: AMBER; Mode of pathogenicity: None; Publications: 34028500, 28860274, 32732226; Phenotypes: Hydrocephalus, cerebellar hypoplasia, hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7938 PLEKHN1 Zornitza Stark Gene: plekhn1 has been classified as Red List (Low Evidence).
Mendeliome v0.7938 PLEKHN1 Zornitza Stark gene: PLEKHN1 was added
gene: PLEKHN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHN1 were set to 33884296
Phenotypes for gene: PLEKHN1 were set to Sensory Neuropathy
Review for gene: PLEKHN1 was set to RED
Added comment: Hom missense variant in single patient with severely reduced/absent pain and temperature sensation
Sources: Literature
Mendeliome v0.7937 ZNF3 Zornitza Stark Gene: znf3 has been classified as Red List (Low Evidence).
Mendeliome v0.7937 SMPDL3A Seb Lunke changed review comment from: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature; to: Hom missense variant in twin sisters with severely reduced pain and temperature sensation
Sources: Literature
Mendeliome v0.7937 ZNF3 Zornitza Stark gene: ZNF3 was added
gene: ZNF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF3 were set to 32732226
Phenotypes for gene: ZNF3 were set to Hydrocephalus; cleft palate; microphthalmia
Review for gene: ZNF3 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrocephaly and facial cleft detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including a median cleft palate, partial maxillar agenesis, bilateral severe microphthalmia, arhinencephaly, partial thalamic fusion. A homozygous truncating variant (c.396A>G/ p.*132Trpext*69) in ZNF3 was found by exome sequencing.
Sources: Literature
Mendeliome v0.7936 SMPDL3A Seb Lunke Gene: smpdl3a has been classified as Red List (Low Evidence).
Mendeliome v0.7936 WRAP73 Zornitza Stark Gene: wrap73 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7936 WRAP73 Zornitza Stark Classified gene: WRAP73 as Amber List (moderate evidence)
Mendeliome v0.7936 WRAP73 Zornitza Stark Gene: wrap73 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7936 SMPDL3A Seb Lunke gene: SMPDL3A was added
gene: SMPDL3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMPDL3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPDL3A were set to 33884296
Phenotypes for gene: SMPDL3A were set to Sensory Neuropathy
Added comment: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature
Mendeliome v0.7934 EIF2AK2 Zornitza Stark Phenotypes for gene: EIF2AK2 were changed from Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness; Dystonia
Mendeliome v0.7932 EIF2AK2 Zornitza Stark edited their review of gene: EIF2AK2: Added comment: Four unrelated families reported with dystonia, recurrent variant, (p.Gly130Arg); Changed publications: 32197074, 33866603; Changed phenotypes: Intellectual disability, white matter abnormalities, ataxia, regression with febrile illness, Dystonia
Mendeliome v0.7932 SLC37A4 Zornitza Stark Gene: slc37a4 has been classified as Green List (High Evidence).
Mendeliome v0.7929 TUBA1A Zornitza Stark Gene: tuba1a has been classified as Green List (High Evidence).
Mendeliome v0.7929 TUBA1A Zornitza Stark Phenotypes for gene: TUBA1A were changed from to Lissencephaly 3, MIM# 611603; Congenital fibrosis of the extraocular muscles, AD
Mendeliome v0.7926 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome; Deafness to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome AR; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD
Mendeliome v0.7921 ANGPTL8 Zornitza Stark Gene: angptl8 has been classified as Red List (Low Evidence).
Mendeliome v0.7921 ANGPTL8 Zornitza Stark Classified gene: ANGPTL8 as Red List (low evidence)
Mendeliome v0.7921 ANGPTL8 Zornitza Stark Gene: angptl8 has been classified as Red List (Low Evidence).
Mendeliome v0.7920 SRCAP Zornitza Stark Gene: srcap has been classified as Green List (High Evidence).
Mendeliome v0.7917 ADAMTSL2 Zornitza Stark Gene: adamtsl2 has been classified as Green List (High Evidence).
Mendeliome v0.7917 ADAMTSL2 Zornitza Stark Phenotypes for gene: ADAMTSL2 were changed from to Geleophysic dysplasia 1, MIM# 231050; Dermatosparaxic Ehlers Danlos syndrome
Mendeliome v0.7914 ADAMTSL2 Zornitza Stark reviewed gene: ADAMTSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33369194, 26879370, 21415077; Phenotypes: Geleophysic dysplasia 1, MIM# 231050, Dermatosparaxic Ehlers Danlos syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7914 UNC45A Zornitza Stark Phenotypes for gene: UNC45A were changed from Cholestasis; Diarrhoea; Bone fragility; Impaired hearing to Osteootohepatoenteric syndrome, MIM# 619377; Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Mendeliome v0.7913 UNC45A Zornitza Stark edited their review of gene: UNC45A: Changed phenotypes: Osteootohepatoenteric syndrome, MIM# 619377, Cholestasis, Diarrhoea, Bone fragility, Impaired hearing
Mendeliome v0.7912 HS3ST6 Zornitza Stark Gene: hs3st6 has been classified as Red List (Low Evidence).
Mendeliome v0.7912 HS3ST6 Zornitza Stark gene: HS3ST6 was added
gene: HS3ST6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HS3ST6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HS3ST6 were set to 33508266
Phenotypes for gene: HS3ST6 were set to Hereditary angioedema-8 (HAE8), MIM#619367
Review for gene: HS3ST6 was set to RED
Added comment: Three affected individuals from a single family reported, missense variant, no functional data.
Sources: Expert list
Mendeliome v0.7911 MYOF Zornitza Stark Gene: myof has been classified as Red List (Low Evidence).
Mendeliome v0.7910 KNG1 Zornitza Stark Gene: kng1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7907 KNG1 Zornitza Stark Classified gene: KNG1 as Amber List (moderate evidence)
Mendeliome v0.7907 KNG1 Zornitza Stark Gene: kng1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7906 ANGPT1 Zornitza Stark Gene: angpt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7905 PLG Zornitza Stark changed review comment from: Association between mono-allelic variants and HAE: Over 20 families reported with a recurrent variant, p.Lys330Glu. Single family reported with a different variant. Note bi-allelic variants are associated with a separate disorder.

Bi-allelic variants and plasminogen deficiency: congenital plasminogen deficiency is characterised clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. At least 3 unrelated families reported.; to: Association between mono-allelic variants and HAE: Over 20 families reported with a recurrent variant, p.Lys330Glu. Single family reported with a different variant. Note bi-allelic variants are associated with a separate disorder.

Bi-allelic variants and plasminogen deficiency: congenital plasminogen deficiency is characterised clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. Over 20 unrelated families reported.
Mendeliome v0.7905 PLG Zornitza Stark Gene: plg has been classified as Green List (High Evidence).
Mendeliome v0.7901 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from Congenital heart defects and ectodermal dysplasia, 617364 to Congenital heart defects and ectodermal dysplasia, 617364; Congenital heart disease, autosomal recessive
Mendeliome v0.7898 PIGF Zornitza Stark Phenotypes for gene: PIGF were changed from Glycosylphosphatidylinositol\ deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures to Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome, MIM# 619356
Mendeliome v0.7897 PRKD1 Zornitza Stark edited their review of gene: PRKD1: Added comment: Additional publications supporting association with bi-allelic disease:

PMID: 33919081: Three sisters with pulmonary stenosis, truncus arteriosis, and atrial septal defect were homozygous for c.265-1G>T. Their asymptomatic father was also homozygous, however he had two affected sisters (not genotyped), raising the possibility that PRKD1 may undergo autosomal recessive inheritance mode with gender limitation. PMID: 25713110: Two sisters with truncus arteriosis were homozygous for R618X.; Changed publications: 27479907, 32817298, 25713110, 33919081; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7897 ATXN2L Seb Lunke Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7897 ATXN2L Seb Lunke Classified gene: ATXN2L as Amber List (moderate evidence)
Mendeliome v0.7897 ATXN2L Seb Lunke Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7895 LTBP1 Seb Lunke Gene: ltbp1 has been classified as Green List (High Evidence).
Mendeliome v0.7895 LTBP1 Seb Lunke Classified gene: LTBP1 as Green List (high evidence)
Mendeliome v0.7895 LTBP1 Seb Lunke Gene: ltbp1 has been classified as Green List (High Evidence).
Mendeliome v0.7894 SLC30A5 Seb Lunke Classified gene: SLC30A5 as Amber List (moderate evidence)
Mendeliome v0.7894 SLC30A5 Seb Lunke Gene: slc30a5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7893 CADM3 Seb Lunke Added comment: Comment when marking as ready: Three families, but evidence not that great and missing segregation, so stays amber.
Mendeliome v0.7893 CADM3 Seb Lunke Gene: cadm3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7893 CADM3 Seb Lunke Classified gene: CADM3 as Amber List (moderate evidence)
Mendeliome v0.7893 CADM3 Seb Lunke Gene: cadm3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7892 PGM2L1 Sue White Gene: pgm2l1 has been classified as Green List (High Evidence).
Mendeliome v0.7892 PGM2L1 Sue White Classified gene: PGM2L1 as Green List (high evidence)
Mendeliome v0.7892 PGM2L1 Sue White Gene: pgm2l1 has been classified as Green List (High Evidence).
Mendeliome v0.7891 BCAS3 Sue White Gene: bcas3 has been classified as Green List (High Evidence).
Mendeliome v0.7891 TUBA1A Kristin Rigbye edited their review of gene: TUBA1A: Changed phenotypes: Congenital fibrosis of the extraocular muscles, AD
Mendeliome v0.7891 TUBA1A Kristin Rigbye reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30677308; Phenotypes: Congenital fibrosis of the extraocular muscles; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7891 LTBP1 Chern Lim gene: LTBP1 was added
gene: LTBP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to cutis laxa syndrome
Review for gene: LTBP1 was set to GREEN
gene: LTBP1 was marked as current diagnostic
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Mendeliome v0.7891 SLC30A5 Melanie Marty gene: SLC30A5 was added
gene: SLC30A5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919
Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy
Review for gene: SLC30A5 was set to AMBER
Added comment: Four affected children from two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. 2 different homozygous PTCs variants found. Knockout of SLC30A5 in mouse models showed reduced body growth and reduced bone density. About 60% of the mice died due to bradyarrhythmia.
Sources: Literature
Mendeliome v0.7891 COL9A3 Kristin Rigbye reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, AD, MIM# 600969, Stickler syndrome, AR, Deafness, AD, Peripheral vitreoretinal degeneration and retinal detachment, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7891 CADM3 Teresa Zhao gene: CADM3 was added
gene: CADM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CADM3 were set to PMID: 33889941
Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease
Review for gene: CADM3 was set to AMBER
Added comment: Three families reported with the same missense variant in CADM3 p.Tyr172Cys (one family de novo), with mice work to show reduced expression of the mutant protein in axons and abnormal axonal organization.
Sources: Literature
Mendeliome v0.7891 PGM2L1 Chern Lim gene: PGM2L1 was added
gene: PGM2L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris
Review for gene: PGM2L1 was set to GREEN
gene: PGM2L1 was marked as current diagnostic
Added comment: PMID: 33979636:
- Hom/chet PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Mendeliome v0.7891 KCNB1 Zornitza Stark Gene: kcnb1 has been classified as Green List (High Evidence).
Mendeliome v0.7888 SYT1 Zornitza Stark Gene: syt1 has been classified as Green List (High Evidence).
Mendeliome v0.7885 UBTF Zornitza Stark Gene: ubtf has been classified as Green List (High Evidence).
Mendeliome v0.7882 ZEB2 Zornitza Stark Gene: zeb2 has been classified as Green List (High Evidence).
Mendeliome v0.7881 SLC9A6 Zornitza Stark Gene: slc9a6 has been classified as Green List (High Evidence).
Mendeliome v0.7875 SATB2 Zornitza Stark Gene: satb2 has been classified as Green List (High Evidence).
Mendeliome v0.7870 MBD5 Zornitza Stark Gene: mbd5 has been classified as Green List (High Evidence).
Mendeliome v0.7867 IQSEC2 Zornitza Stark Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1/78, MIM#309530 to Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Mendeliome v0.7865 IQSEC2 Zornitza Stark reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33368194, 20473311, 23674175; Phenotypes: Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656, Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347; 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 v0.7863 MASP1 Zornitza Stark Gene: masp1 has been classified as Green List (High Evidence).
Mendeliome v0.7860 BRPF1 Zornitza Stark Gene: brpf1 has been classified as Green List (High Evidence).
Mendeliome v0.7860 BRPF1 Zornitza Stark Phenotypes for gene: BRPF1 were changed from to Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333; MONDO:0015022
Mendeliome v0.7857 BRPF1 Zornitza Stark reviewed gene: BRPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27939640, 27939639; Phenotypes: Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333, MONDO:0015022; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7857 TRAF7 Zornitza Stark Gene: traf7 has been classified as Green List (High Evidence).
Mendeliome v0.7854 UBE3B Zornitza Stark Gene: ube3b has been classified as Green List (High Evidence).
Mendeliome v0.7850 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11101850, 16927315, 11279527; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM# 255800, MONDO:0009717, Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410, MONDO:0009140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7850 HLA-DRB1 Zornitza Stark Gene: hla-drb1 has been classified as Red List (Low Evidence).
Mendeliome v0.7850 HLA-DRB1 Zornitza Stark Classified gene: HLA-DRB1 as Red List (low evidence)
Mendeliome v0.7850 HLA-DRB1 Zornitza Stark Gene: hla-drb1 has been classified as Red List (Low Evidence).
Mendeliome v0.7849 HLA-DRA Zornitza Stark Gene: hla-dra has been classified as Red List (Low Evidence).
Mendeliome v0.7849 HLA-DRA Zornitza Stark Classified gene: HLA-DRA as Red List (low evidence)
Mendeliome v0.7849 HLA-DRA Zornitza Stark Gene: hla-dra has been classified as Red List (Low Evidence).
Mendeliome v0.7848 HLA-C Zornitza Stark Gene: hla-c has been classified as Red List (Low Evidence).
Mendeliome v0.7848 HLA-C Zornitza Stark Classified gene: HLA-C as Red List (low evidence)
Mendeliome v0.7848 HLA-C Zornitza Stark Gene: hla-c has been classified as Red List (Low Evidence).
Mendeliome v0.7847 HLA-B Zornitza Stark Gene: hla-b has been classified as Red List (Low Evidence).
Mendeliome v0.7847 HLA-B Zornitza Stark Classified gene: HLA-B as Red List (low evidence)
Mendeliome v0.7847 HLA-B Zornitza Stark Gene: hla-b has been classified as Red List (Low Evidence).
Mendeliome v0.7846 HLA-A Zornitza Stark Gene: hla-a has been classified as Red List (Low Evidence).
Mendeliome v0.7846 HLA-A Zornitza Stark Classified gene: HLA-A as Red List (low evidence)
Mendeliome v0.7846 HLA-A Zornitza Stark Gene: hla-a has been classified as Red List (Low Evidence).
Mendeliome v0.7845 TAF6 Zornitza Stark Gene: taf6 has been classified as Green List (High Evidence).
Mendeliome v0.7841 SLC24A5 Zornitza Stark Gene: slc24a5 has been classified as Green List (High Evidence).
Mendeliome v0.7838 SLC45A2 Zornitza Stark Gene: slc45a2 has been classified as Green List (High Evidence).
Mendeliome v0.7835 TYR Zornitza Stark Gene: tyr has been classified as Green List (High Evidence).
Mendeliome v0.7833 TYRP1 Zornitza Stark Gene: tyrp1 has been classified as Green List (High Evidence).
Mendeliome v0.7830 MC1R Zornitza Stark Gene: mc1r has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7827 MC1R Zornitza Stark Classified gene: MC1R as Amber List (moderate evidence)
Mendeliome v0.7827 MC1R Zornitza Stark Gene: mc1r has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7826 LRMDA Zornitza Stark Gene: lrmda has been classified as Green List (High Evidence).
Mendeliome v0.7823 SERPINF2 Zornitza Stark Gene: serpinf2 has been classified as Green List (High Evidence).
Mendeliome v0.7820 SERPINE1 Zornitza Stark Gene: serpine1 has been classified as Green List (High Evidence).
Mendeliome v0.7817 TBXA2R Zornitza Stark Gene: tbxa2r has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7814 TBXA2R Zornitza Stark Classified gene: TBXA2R as Amber List (moderate evidence)
Mendeliome v0.7814 TBXA2R Zornitza Stark Gene: tbxa2r has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7813 P2RY12 Zornitza Stark Gene: p2ry12 has been classified as Green List (High Evidence).
Mendeliome v0.7810 MCFD2 Zornitza Stark Gene: mcfd2 has been classified as Green List (High Evidence).
Mendeliome v0.7807 LMAN1 Zornitza Stark Gene: lman1 has been classified as Green List (High Evidence).
Mendeliome v0.7804 ITGA2B Zornitza Stark Gene: itga2b has been classified as Green List (High Evidence).
Mendeliome v0.7801 LMOD1 Zornitza Stark Gene: lmod1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7801 LMOD1 Zornitza Stark Phenotypes for gene: LMOD1 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, MIM# 619362
Mendeliome v0.7798 LMOD1 Zornitza Stark Classified gene: LMOD1 as Amber List (moderate evidence)
Mendeliome v0.7798 LMOD1 Zornitza Stark Gene: lmod1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7797 LMOD1 Zornitza Stark reviewed gene: LMOD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28292896; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, MIM# 619362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7797 POU4F1 Bryony Thompson Gene: pou4f1 has been classified as Green List (High Evidence).
Mendeliome v0.7797 POU4F1 Bryony Thompson Classified gene: POU4F1 as Green List (high evidence)
Mendeliome v0.7797 POU4F1 Bryony Thompson Gene: pou4f1 has been classified as Green List (High Evidence).
Mendeliome v0.7795 HPS6 Zornitza Stark Gene: hps6 has been classified as Green List (High Evidence).
Mendeliome v0.7792 HPS4 Zornitza Stark Gene: hps4 has been classified as Green List (High Evidence).
Mendeliome v0.7789 HPS3 Zornitza Stark Gene: hps3 has been classified as Green List (High Evidence).
Mendeliome v0.7786 HPS1 Zornitza Stark Gene: hps1 has been classified as Green List (High Evidence).
Mendeliome v0.7783 GP9 Zornitza Stark Gene: gp9 has been classified as Green List (High Evidence).
Mendeliome v0.7780 GP6 Zornitza Stark Gene: gp6 has been classified as Green List (High Evidence).
Mendeliome v0.7777 GP1BB Zornitza Stark Gene: gp1bb has been classified as Green List (High Evidence).
Mendeliome v0.7774 CREB3L3 Zornitza Stark Gene: creb3l3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7772 SCNN1B Zornitza Stark Gene: scnn1b has been classified as Green List (High Evidence).
Mendeliome v0.7772 SCNN1B Zornitza Stark Phenotypes for gene: SCNN1B were changed from to Liddle syndrome 1, MIM# 177200; Pseudohypoaldosteronism, type I, MIM# 264350; Bronchiectasis with or without elevated sweat chloride 1 (MIM#211400)
Mendeliome v0.7770 SCNN1B Zornitza Stark reviewed gene: SCNN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Liddle syndrome 1, MIM# 177200, Pseudohypoaldosteronism, type I, MIM# 264350, Bronchiectasis with or without elevated sweat chloride 1 (MIM#211400); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7770 FGB Zornitza Stark Gene: fgb has been classified as Green List (High Evidence).
Mendeliome v0.7767 F9 Zornitza Stark Gene: f9 has been classified as Green List (High Evidence).
Mendeliome v0.7764 F8 Zornitza Stark Gene: f8 has been classified as Green List (High Evidence).
Mendeliome v0.7761 F7 Zornitza Stark Gene: f7 has been classified as Green List (High Evidence).
Mendeliome v0.7758 F5 Zornitza Stark Gene: f5 has been classified as Green List (High Evidence).
Mendeliome v0.7758 F5 Zornitza Stark Phenotypes for gene: F5 were changed from to Factor V deficiency, MIM# 227400; MONDO:0009210; Thrombophilia due to activated protein C resistance, MIM# 188055; MONDO:0008560; {Thrombophilia, susceptibility to, due to factor V Leiden}, MIM# 188055
Mendeliome v0.7756 F5 Zornitza Stark reviewed gene: F5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor V deficiency, MIM# 227400, MONDO:0009210, Thrombophilia due to activated protein C resistance, MIM# 188055, MONDO:0008560, {Thrombophilia, susceptibility to, due to factor V Leiden}, MIM# 188055; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7756 F13A1 Zornitza Stark Gene: f13a1 has been classified as Green List (High Evidence).
Mendeliome v0.7753 F10 Zornitza Stark Gene: f10 has been classified as Green List (High Evidence).
Mendeliome v0.7750 F10 Zornitza Stark commented on gene: F10: Factor X deficiency shows variable phenotypic severity. Affected individuals can manifest prolonged nasal and mucosal haemorrhage, menorrhagia, haematuria, and occasionally haemarthrosis. More than 20 unrelated families reported.
Mendeliome v0.7750 MCM7 Zornitza Stark Gene: mcm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7750 MCM7 Zornitza Stark Classified gene: MCM7 as Amber List (moderate evidence)
Mendeliome v0.7750 MCM7 Zornitza Stark Gene: mcm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7749 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. MCM7 is not associated with any phenotype in OMIM or G2P at present.
------
Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (see below). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
Mendeliome v0.7749 DTNBP1 Zornitza Stark Gene: dtnbp1 has been classified as Green List (High Evidence).
Mendeliome v0.7746 BLOC1S3 Zornitza Stark Gene: bloc1s3 has been classified as Green List (High Evidence).
Mendeliome v0.7743 AP3B1 Zornitza Stark Gene: ap3b1 has been classified as Green List (High Evidence).
Mendeliome v0.7740 LHCGR Zornitza Stark Gene: lhcgr has been classified as Green List (High Evidence).
Mendeliome v0.7740 LHCGR Zornitza Stark Phenotypes for gene: LHCGR were changed from to Luteinizing hormone resistance, female, (MIM#238320); Leydig cell hypoplasia with pseudohermaphroditism, (MIM#238320); Leydig cell hypoplasia with hypergonadotropic hypogonadism, (MIM#238320); Precocious puberty, male, (MIM#176410)
Mendeliome v0.7736 NEB Zornitza Stark Phenotypes for gene: NEB were changed from Nemaline myopathy 2, autosomal recessive 256030 to Nemaline myopathy 2, autosomal recessive 256030; MONDO:0009725; Arthrogryposis multiplex congenita 6, MIM# 619334
Mendeliome v0.7735 NEB Zornitza Stark reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 10051637, 22367672, 26578207, 33376055; Phenotypes: Arthrogryposis multiplex congenita 6, MIM# 619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7735 LHCGR Ain Roesley reviewed gene: LHCGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 11041448; Phenotypes: Luteinizing hormone resistance, female, (MIM#238320), Leydig cell hypoplasia with pseudohermaphroditism, (MIM#238320), Leydig cell hypoplasia with hypergonadotropic hypogonadism, (MIM#238320), Precocious puberty, male, (MIM#176410); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7735 GEMIN5 Zornitza Stark Gene: gemin5 has been classified as Green List (High Evidence).
Mendeliome v0.7735 GEMIN5 Zornitza Stark Classified gene: GEMIN5 as Green List (high evidence)
Mendeliome v0.7735 GEMIN5 Zornitza Stark Gene: gemin5 has been classified as Green List (High Evidence).
Mendeliome v0.7734 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy. 30 individuals from 22 unrelated families reported.
Sources: Literature
Mendeliome v0.7733 ANO6 Zornitza Stark Gene: ano6 has been classified as Green List (High Evidence).
Mendeliome v0.7730 KLHL3 Zornitza Stark Gene: klhl3 has been classified as Green List (High Evidence).
Mendeliome v0.7727 KCNJ5 Zornitza Stark Gene: kcnj5 has been classified as Green List (High Evidence).
Mendeliome v0.7727 KCNJ5 Zornitza Stark Classified gene: KCNJ5 as Green List (high evidence)
Mendeliome v0.7727 KCNJ5 Zornitza Stark Gene: kcnj5 has been classified as Green List (High Evidence).
Mendeliome v0.7725 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
Mendeliome v0.7722 CLCN2 Zornitza Stark Gene: clcn2 has been classified as Green List (High Evidence).
Mendeliome v0.7719 CACNA1D Zornitza Stark Gene: cacna1d has been classified as Green List (High Evidence).
Mendeliome v0.7719 CACNA1D Zornitza Stark Phenotypes for gene: CACNA1D were changed from to Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474; MONDO:0014200; Sinoatrial node dysfunction and deafness, MIM# 614896
Mendeliome v0.7716 CACNA1D Zornitza Stark reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913001, 32336187, 30698561, 21131953, 15357422, 22678062; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474, MONDO:0014200, Sinoatrial node dysfunction and deafness, MIM# 614896; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7716 CACNA1H Zornitza Stark Gene: cacna1h has been classified as Green List (High Evidence).
Mendeliome v0.7713 COX16 Zornitza Stark Phenotypes for gene: COX16 were changed from Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis to Mitochondrial complex IV deficiency, nuclear type 22, MIM# 619355; Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis
Mendeliome v0.7712 NSF Zornitza Stark Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, MIM# 619340; Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Mendeliome v0.7711 NSF Zornitza Stark edited their review of gene: NSF: Changed phenotypes: Developmental and epileptic encephalopathy 96, MIM# 619340, Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability
Mendeliome v0.7710 IPO8 Zornitza Stark Classified gene: IPO8 as Green List (high evidence)
Mendeliome v0.7710 IPO8 Zornitza Stark Gene: ipo8 has been classified as Green List (High Evidence).
Mendeliome v0.7709 NFU1 Zornitza Stark Gene: nfu1 has been classified as Green List (High Evidence).
Mendeliome v0.7706 RAB11B Zornitza Stark commented on gene: RAB11B: NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem.
Mendeliome v0.7706 RAB11B Zornitza Stark Gene: rab11b has been classified as Green List (High Evidence).
Mendeliome v0.7703 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Green List (High Evidence).
Mendeliome v0.7703 UFSP2 Zornitza Stark Phenotypes for gene: UFSP2 were changed from to Neurodevelopmental disorder; Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974
Mendeliome v0.7700 UFSP2 Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all.

Hip dysplasia: single 8 generation family reported.

Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all. Additional cases identified through the 100,000 Genomes project.

Hip dysplasia: single 8 generation family reported.

Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported.
Mendeliome v0.7700 KLHL13 Zornitza Stark Gene: klhl13 has been classified as Red List (Low Evidence).
Mendeliome v0.7700 KLHL13 Zornitza Stark gene: KLHL13 was added
gene: KLHL13 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLHL13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: KLHL13 were set to 24627108
Phenotypes for gene: KLHL13 were set to HMSN
Review for gene: KLHL13 was set to RED
Added comment: Single family (two affected males) with an inherited peripheral neuropathy, no functional analysis.
Sources: Expert Review
Mendeliome v0.7699 PRX Zornitza Stark Gene: prx has been classified as Green List (High Evidence).
Mendeliome v0.7696 PLEKHG5 Zornitza Stark Gene: plekhg5 has been classified as Green List (High Evidence).
Mendeliome v0.7696 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from to Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067
Mendeliome v0.7693 PLEKHG5 Zornitza Stark reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564964, 23777631, 23844677, 33492783, 33275839, 33220101, 23777631; Phenotypes: Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376, Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7693 NEFL Zornitza Stark Gene: nefl has been classified as Green List (High Evidence).
Mendeliome v0.7690 ADNP Zornitza Stark Gene: adnp has been classified as Green List (High Evidence).
Mendeliome v0.7687 CHUK Zornitza Stark Gene: chuk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7684 CHUK Zornitza Stark Classified gene: CHUK as Amber List (moderate evidence)
Mendeliome v0.7684 CHUK Zornitza Stark Gene: chuk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7683 TMEM251 Zornitza Stark Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex‐like skeletal dysplasia; severe short stature to Dysostosis multiplex, Ain-Naz type 619345
Mendeliome v0.7682 TMEM251 Zornitza Stark reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dysostosis multiplex, Ain-Naz type 619345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7681 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Mendeliome v0.7681 PARP6 Zornitza Stark Classified gene: PARP6 as Green List (high evidence)
Mendeliome v0.7681 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Mendeliome v0.7680 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PARP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Mendeliome v0.7679 MAPKBP1 Zornitza Stark Gene: mapkbp1 has been classified as Green List (High Evidence).
Mendeliome v0.7679 MAPKBP1 Zornitza Stark Phenotypes for gene: MAPKBP1 were changed from to Nephronophthisis 20, MIM# 617271; MONDO:0014997
Mendeliome v0.7676 MAPKBP1 Zornitza Stark reviewed gene: MAPKBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28089251, 33623699, 32505465, 32055034; Phenotypes: Nephronophthisis 20, MIM# 617271, MONDO:0014997; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7675 DNAJB2 Zornitza Stark Gene: dnajb2 has been classified as Green List (High Evidence).
Mendeliome v0.7675 DNAJB2 Zornitza Stark Phenotypes for gene: DNAJB2 were changed from to Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881; MONDO:0014866
Mendeliome v0.7672 DNAJB2 Zornitza Stark reviewed gene: DNAJB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22522442, 25274842, 33369814, 22522442; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881, MONDO:0014866; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7672 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from Occipital horn syndrome, 304150; X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489 to Menkes disease MIM#309400; Occipital horn syndrome MIM#304150; Spinal muscular atrophy, distal, X-linked 3, MIM# 300489
Mendeliome v0.7670 UFSP2 Zornitza Stark changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all.

Hip dysplasia: single 8 generation family reported.

Spondyloepimetaphyseal dysplasia, Di Rocco type: single 3-generation family reported.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)]. Likely founder variant in all.

Hip dysplasia: single 8 generation family reported.

Spondyloepimetaphyseal dysplasia, Di Rocco type: two families reported.
Mendeliome v0.7670 UFSP2 Zornitza Stark reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208, 26428751, 28892125; Phenotypes: Neurodevelopmental disorder, Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7670 TRPV6 Zornitza Stark Gene: trpv6 has been classified as Green List (High Evidence).
Mendeliome v0.7670 TRPV6 Zornitza Stark Phenotypes for gene: TRPV6 were changed from to Hyperparathyroidism, transient neonatal, MIM# 618188; Early onset chronic pancreatitis susceptibility
Mendeliome v0.7667 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383311, 31930989, 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188, Early onset chronic pancreatitis susceptibility; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7667 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7666 FAR1 Zornitza Stark edited their review of gene: FAR1: Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7665 BICRA Zornitza Stark Phenotypes for gene: BICRA were changed from Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features to Coffin-Siris syndrome-12, MIM#619325; Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Mendeliome v0.7664 BICRA Zornitza Stark reviewed gene: BICRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome-12, MIM#619325; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7664 RETREG1 Zornitza Stark Gene: retreg1 has been classified as Green List (High Evidence).
Mendeliome v0.7661 SBF1 Zornitza Stark Gene: sbf1 has been classified as Green List (High Evidence).
Mendeliome v0.7658 SBF2 Zornitza Stark Gene: sbf2 has been classified as Green List (High Evidence).
Mendeliome v0.7655 SCN10A Zornitza Stark Gene: scn10a has been classified as Green List (High Evidence).
Mendeliome v0.7651 COL5A1 Zornitza Stark Gene: col5a1 has been classified as Green List (High Evidence).
Mendeliome v0.7651 COL5A1 Zornitza Stark Phenotypes for gene: COL5A1 were changed from to Ehlers-Danlos syndrome, classic type, 1, MIM# 130000; Fibromuscular dysplasia, multifocal, MIM# 619329
Mendeliome v0.7648 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 32938213; Phenotypes: Ehlers-Danlos syndrome, classic type, 1, MIM# 130000, Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7648 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.7647 SCN1A Zornitza Stark edited their review of gene: SCN1A: Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.7646 DKC1 Zornitza Stark Gene: dkc1 has been classified as Green List (High Evidence).
Mendeliome v0.7646 DKC1 Zornitza Stark Phenotypes for gene: DKC1 were changed from to Dyskeratosis congenita, X-linked 305000; Hoyeraal-Hreidarsson Syndrome
Mendeliome v0.7643 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31269755, 26951492, 29081935, 25940403; Phenotypes: Dyskeratosis congenita, X-linked 305000, Hoyeraal-Hreidarsson Syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7643 THOC2 Zornitza Stark Gene: thoc2 has been classified as Green List (High Evidence).
Mendeliome v0.7640 FGA Zornitza Stark Gene: fga has been classified as Green List (High Evidence).
Mendeliome v0.7640 FGA Zornitza Stark Phenotypes for gene: FGA were changed from to Afibrinogenemia, congenital (MIM#202400), AR; Amyloidosis, familial visceral (MIM#105200), AD
Mendeliome v0.7637 FGA Chern Lim reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31064749, 17295221, 19073821, 11739173; Phenotypes: Afibrinogenemia, congenital (MIM#202400), AR, Amyloidosis, familial visceral (MIM#105200), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7637 GRHL2 Zornitza Stark Gene: grhl2 has been classified as Green List (High Evidence).
Mendeliome v0.7637 GRHL2 Zornitza Stark Phenotypes for gene: GRHL2 were changed from to Ectodermal dysplasia/short stature syndrome MIM#616029; Corneal dystrophy, posterior polymorphous, 4, MIM# 618031; Deafness, autosomal dominant 28, MIM# 608641
Mendeliome v0.7634 GRHL2 Zornitza Stark reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 29499165; Phenotypes: Ectodermal dysplasia/short stature syndrome MIM#616029, Corneal dystrophy, posterior polymorphous, 4, MIM# 618031, Deafness, autosomal dominant 28, MIM# 608641; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7634 ST14 Zornitza Stark Gene: st14 has been classified as Green List (High Evidence).
Mendeliome v0.7634 ST14 Zornitza Stark Phenotypes for gene: ST14 were changed from to Ichthyosis, congenital, autosomal recessive 11, MIM# MIM#602400
Mendeliome v0.7631 ST14 Zornitza Stark reviewed gene: ST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 18843291, 29611532, 17273967; Phenotypes: Ichthyosis, congenital, autosomal recessive 11 MIM#602400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7631 CPE Zornitza Stark Gene: cpe has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7631 CPE Zornitza Stark Classified gene: CPE as Amber List (moderate evidence)
Mendeliome v0.7631 CPE Zornitza Stark Gene: cpe has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7629 CELSR1 Zornitza Stark Gene: celsr1 has been classified as Green List (High Evidence).
Mendeliome v0.7629 CELSR1 Zornitza Stark Classified gene: CELSR1 as Green List (high evidence)
Mendeliome v0.7629 CELSR1 Zornitza Stark Gene: celsr1 has been classified as Green List (High Evidence).
Mendeliome v0.7627 SLC2A4RG Zornitza Stark Gene: slc2a4rg has been classified as Red List (Low Evidence).
Mendeliome v0.7627 SLC2A4RG Zornitza Stark Classified gene: SLC2A4RG as Red List (low evidence)
Mendeliome v0.7627 SLC2A4RG Zornitza Stark Gene: slc2a4rg has been classified as Red List (Low Evidence).
Mendeliome v0.7626 SLCO1B1 Zornitza Stark Gene: slco1b1 has been classified as Red List (Low Evidence).
Mendeliome v0.7624 SLCO1B1 Zornitza Stark Classified gene: SLCO1B1 as Red List (low evidence)
Mendeliome v0.7624 SLCO1B1 Zornitza Stark Gene: slco1b1 has been classified as Red List (Low Evidence).
Mendeliome v0.7623 SIAH1 Zornitza Stark Phenotypes for gene: SIAH1 were changed from Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia to Buratti-Harel syndrome, MIM# 619314; Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Mendeliome v0.7622 SIAH1 Zornitza Stark reviewed gene: SIAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Buratti-Harel syndrome, MIM# 619314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7622 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
Mendeliome v0.7622 SMARCA5 Zornitza Stark Classified gene: SMARCA5 as Green List (high evidence)
Mendeliome v0.7622 SMARCA5 Zornitza Stark Gene: smarca5 has been classified as Green List (High Evidence).
Mendeliome v0.7619 FBXW7 Zornitza Stark Classified gene: FBXW7 as Green List (high evidence)
Mendeliome v0.7619 FBXW7 Zornitza Stark Gene: fbxw7 has been classified as Green List (High Evidence).
Mendeliome v0.7615 SLC5A7 Zornitza Stark Gene: slc5a7 has been classified as Green List (High Evidence).
Mendeliome v0.7611 NR3C2 Zornitza Stark Gene: nr3c2 has been classified as Green List (High Evidence).
Mendeliome v0.7608 SCNN1A Zornitza Stark Gene: scnn1a has been classified as Green List (High Evidence).
Mendeliome v0.7608 SCNN1A Zornitza Stark Phenotypes for gene: SCNN1A were changed from to Liddle syndrome 3 618126, MIM# AD, MONDO:0029132; Bronchiectasis with or without elevated sweat chloride 2, MIM# 613021 AD, MONDO:0013087; Pseudohypoaldosteronism, type I, MIM# 264350 AR, MIM#0009917
Mendeliome v0.7605 SCNN1A Zornitza Stark reviewed gene: SCNN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31301676, 28710092, 19462466, 19017867; Phenotypes: Liddle syndrome 3 618126, MIM# AD, MONDO:0029132, Bronchiectasis with or without elevated sweat chloride 2, MIM# 613021 AD, MONDO:0013087, Pseudohypoaldosteronism, type I, MIM# 264350 AR, MIM#0009917; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7605 SPTLC1 Zornitza Stark Gene: sptlc1 has been classified as Green List (High Evidence).
Mendeliome v0.7605 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from to Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v0.7602 SPTLC2 Zornitza Stark Gene: sptlc2 has been classified as Green List (High Evidence).
Mendeliome v0.7602 SPTLC2 Zornitza Stark Phenotypes for gene: SPTLC2 were changed from to Neuropathy, hereditary sensory and autonomic, type IC, 613640; MONDO:0013337; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v0.7599 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Red List (Low Evidence).
Mendeliome v0.7598 SPEN Zornitza Stark Gene: spen has been classified as Green List (High Evidence).
Mendeliome v0.7596 AFF3 Zornitza Stark Gene: aff3 has been classified as Green List (High Evidence).
Mendeliome v0.7593 KDR Zornitza Stark Gene: kdr has been classified as Green List (High Evidence).
Mendeliome v0.7593 KDR Zornitza Stark Phenotypes for gene: KDR were changed from to Pulmonary hypertension; Haemangioma, capillary infantile, somatic 602089
Mendeliome v0.7590 KDR Zornitza Stark reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31980491, 29650961, 18931684; Phenotypes: Pulmonary hypertension, Haemangioma, capillary infantile, somatic 602089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7590 TRIM2 Zornitza Stark Gene: trim2 has been classified as Green List (High Evidence).
Mendeliome v0.7587 RAB7A Zornitza Stark Gene: rab7a has been classified as Green List (High Evidence).
Mendeliome v0.7584 PRDM12 Zornitza Stark Gene: prdm12 has been classified as Green List (High Evidence).
Mendeliome v0.7581 FIP1L1 Zornitza Stark Gene: fip1l1 has been classified as Red List (Low Evidence).
Mendeliome v0.7581 FIP1L1 Zornitza Stark Classified gene: FIP1L1 as Red List (low evidence)
Mendeliome v0.7581 FIP1L1 Zornitza Stark Gene: fip1l1 has been classified as Red List (Low Evidence).
Mendeliome v0.7580 THBS2 Zornitza Stark Gene: thbs2 has been classified as Red List (Low Evidence).
Mendeliome v0.7579 THBS2 Zornitza Stark Classified gene: THBS2 as Red List (low evidence)
Mendeliome v0.7579 THBS2 Zornitza Stark Gene: thbs2 has been classified as Red List (Low Evidence).
Mendeliome v0.7578 ADIPOQ Zornitza Stark Gene: adipoq has been classified as Red List (Low Evidence).
Mendeliome v0.7576 ADIPOQ Zornitza Stark Classified gene: ADIPOQ as Red List (low evidence)
Mendeliome v0.7576 ADIPOQ Zornitza Stark Gene: adipoq has been classified as Red List (Low Evidence).
Mendeliome v0.7575 INTU Zornitza Stark Gene: intu has been classified as Green List (High Evidence).
Mendeliome v0.7575 INTU Zornitza Stark Phenotypes for gene: INTU were changed from to ?Orofaciodigital syndrome XVII MIM#617926; ?Short-rib thoracic dysplasia 20 with polydactyly
Mendeliome v0.7572 INTU Elena Savva reviewed gene: INTU: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27158779, 29451301, 20067783; Phenotypes: ?Orofaciodigital syndrome XVII MIM#617926, ?Short-rib thoracic dysplasia 20 with polydactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7572 NGF Zornitza Stark Gene: ngf has been classified as Green List (High Evidence).
Mendeliome v0.7567 NDUFB3 Zornitza Stark Gene: ndufb3 has been classified as Green List (High Evidence).
Mendeliome v0.7563 EXOSC1 Zornitza Stark Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia, type 1F, MIM# 619304
Mendeliome v0.7562 EXOSC1 Zornitza Stark edited their review of gene: EXOSC1: Changed phenotypes: Pontocerebellar hypoplasia, type 1F, MIM# 619304
Mendeliome v0.7562 SLC25A46 Zornitza Stark Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505 to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303
Mendeliome v0.7561 SLC25A46 Zornitza Stark changed review comment from: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. New disease entity added by OMIM in 2021 to reflect this more severe end of the spectrum.

At least 10 unrelated families reported, supportive functional data.
Mendeliome v0.7561 SLC25A46 Zornitza Stark edited their review of gene: SLC25A46: Changed phenotypes: Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303
Mendeliome v0.7559 EXOC2 Zornitza Stark Phenotypes for gene: EXOC2 were changed from Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology to Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306; Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Mendeliome v0.7558 EXOC2 Zornitza Stark edited their review of gene: EXOC2: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, MIM# 619306, Global developmental delay, Intellectual disability, Abnormality of the face, Abnormality of brain morphology
Mendeliome v0.7558 SPI1 Zornitza Stark Gene: spi1 has been classified as Green List (High Evidence).
Mendeliome v0.7558 SPI1 Zornitza Stark Classified gene: SPI1 as Green List (high evidence)
Mendeliome v0.7558 SPI1 Zornitza Stark Gene: spi1 has been classified as Green List (High Evidence).
Mendeliome v0.7557 SPI1 Zornitza Stark gene: SPI1 was added
gene: SPI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to Agammaglobulinaemia
Review for gene: SPI1 was set to GREEN
Added comment: Six unrelated individuals reported, four with de novo variants, two unphased. Some functional data.
Sources: Literature
Mendeliome v0.7556 NDRG1 Zornitza Stark Gene: ndrg1 has been classified as Green List (High Evidence).
Mendeliome v0.7553 MTMR2 Zornitza Stark Gene: mtmr2 has been classified as Green List (High Evidence).
Mendeliome v0.7550 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Mendeliome v0.7550 TMEM222 Zornitza Stark Classified gene: TMEM222 as Green List (high evidence)
Mendeliome v0.7550 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Mendeliome v0.7549 TMEM222 Zornitza Stark gene: TMEM222 was added
gene: TMEM222 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants. The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17.
Sources: Literature
Mendeliome v0.7548 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Mendeliome v0.7548 CHD5 Zornitza Stark Classified gene: CHD5 as Green List (high evidence)
Mendeliome v0.7548 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Mendeliome v0.7546 MME Zornitza Stark Gene: mme has been classified as Green List (High Evidence).
Mendeliome v0.7543 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant to Mental retardation, autosomal recessive 45, MIM#615979; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v0.7542 FBXO31 Zornitza Stark Classified gene: FBXO31 as Green List (high evidence)
Mendeliome v0.7542 FBXO31 Zornitza Stark Gene: fbxo31 has been classified as Green List (High Evidence).
Mendeliome v0.7541 FBXO31 Zornitza Stark changed review comment from: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list; to: AR intellectual disability: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list
Mendeliome v0.7541 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP.; Changed rating: GREEN; Changed publications: 24623383, 33675180, 32989326; Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Spastic-dystonic cerebral palsy, de novo dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7541 RCAN1 Zornitza Stark Gene: rcan1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7541 RCAN1 Zornitza Stark Classified gene: RCAN1 as Amber List (moderate evidence)
Mendeliome v0.7541 RCAN1 Zornitza Stark Gene: rcan1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7539 ZNFX1 Zornitza Stark Gene: znfx1 has been classified as Green List (High Evidence).
Mendeliome v0.7539 ZNFX1 Zornitza Stark Phenotypes for gene: ZNFX1 were changed from Multisystem inflammation; susceptibility to viral infections to Multisystem inflammation; susceptibility to viral infections; monocytosis; susceptibility to mycobacterial infection
Mendeliome v0.7538 ZNFX1 Zornitza Stark Classified gene: ZNFX1 as Green List (high evidence)
Mendeliome v0.7538 ZNFX1 Zornitza Stark Gene: znfx1 has been classified as Green List (High Evidence).
Mendeliome v0.7537 ZNFX1 Zornitza Stark gene: ZNFX1 was added
gene: ZNFX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33872655; 33876776
Phenotypes for gene: ZNFX1 were set to Multisystem inflammation; susceptibility to viral infections
Review for gene: ZNFX1 was set to GREEN
Added comment: 15 individuals from 8 families reported with multi-system inflammation and susceptibility to viral infections.

In addition, four indviduals from two unrelated kindreds reported with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis.
Sources: Literature
Mendeliome v0.7536 STXBP3 Zornitza Stark Gene: stxbp3 has been classified as Green List (High Evidence).
Mendeliome v0.7536 STXBP3 Zornitza Stark Classified gene: STXBP3 as Green List (high evidence)
Mendeliome v0.7536 STXBP3 Zornitza Stark Gene: stxbp3 has been classified as Green List (High Evidence).
Mendeliome v0.7534 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
Mendeliome v0.7531 SCD Zornitza Stark Gene: scd has been classified as Red List (Low Evidence).
Mendeliome v0.7531 SCD Zornitza Stark Classified gene: SCD as Red List (low evidence)
Mendeliome v0.7531 SCD Zornitza Stark Gene: scd has been classified as Red List (Low Evidence).
Mendeliome v0.7530 DPYSL5 Zornitza Stark Gene: dpysl5 has been classified as Green List (High Evidence).
Mendeliome v0.7530 DPYSL5 Zornitza Stark Classified gene: DPYSL5 as Green List (high evidence)
Mendeliome v0.7530 DPYSL5 Zornitza Stark Gene: dpysl5 has been classified as Green List (High Evidence).
Mendeliome v0.7529 SIN3B Zornitza Stark Marked gene: SIN3B as ready
Mendeliome v0.7529 SIN3B Zornitza Stark Gene: sin3b has been classified as Green List (High Evidence).
Mendeliome v0.7529 SIN3B Zornitza Stark Mode of inheritance for gene: SIN3B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7528 SIN3B Zornitza Stark Classified gene: SIN3B as Green List (high evidence)
Mendeliome v0.7528 SIN3B Zornitza Stark Gene: sin3b has been classified as Green List (High Evidence).
Mendeliome v0.7526 VPS41 Zornitza Stark Classified gene: VPS41 as Green List (high evidence)
Mendeliome v0.7526 VPS41 Zornitza Stark Gene: vps41 has been classified as Green List (High Evidence).
Mendeliome v0.7524 ANKRD17 Zornitza Stark Classified gene: ANKRD17 as Green List (high evidence)
Mendeliome v0.7524 ANKRD17 Zornitza Stark Gene: ankrd17 has been classified as Green List (High Evidence).
Mendeliome v0.7523 JAG2 Zornitza Stark Gene: jag2 has been classified as Green List (High Evidence).
Mendeliome v0.7523 JAG2 Zornitza Stark Classified gene: JAG2 as Green List (high evidence)
Mendeliome v0.7523 JAG2 Zornitza Stark Gene: jag2 has been classified as Green List (High Evidence).
Mendeliome v0.7522 NEPRO Zornitza Stark Gene: nepro has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7522 NEPRO Zornitza Stark Classified gene: NEPRO as Amber List (moderate evidence)
Mendeliome v0.7522 NEPRO Zornitza Stark Gene: nepro has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7521 LRSAM1 Zornitza Stark Gene: lrsam1 has been classified as Green List (High Evidence).
Mendeliome v0.7518 LITAF Zornitza Stark Gene: litaf has been classified as Green List (High Evidence).
Mendeliome v0.7515 SLC3A1 Zornitza Stark Gene: slc3a1 has been classified as Green List (High Evidence).
Mendeliome v0.7512 LSM7 Bryony Thompson Gene: lsm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7512 LSM7 Bryony Thompson Classified gene: LSM7 as Amber List (moderate evidence)
Mendeliome v0.7512 LSM7 Bryony Thompson Gene: lsm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7510 PTPN4 Bryony Thompson Gene: ptpn4 has been classified as Green List (High Evidence).
Mendeliome v0.7510 PTPN4 Bryony Thompson Classified gene: PTPN4 as Green List (high evidence)
Mendeliome v0.7510 PTPN4 Bryony Thompson Gene: ptpn4 has been classified as Green List (High Evidence).
Mendeliome v0.7509 PTPN4 Bryony Thompson gene: PTPN4 was added
gene: PTPN4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability; developmental delay
Review for gene: PTPN4 was set to GREEN
Added comment: >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
Mendeliome v0.7507 POLR3K Zornitza Stark Gene: polr3k has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7507 POLR3K Zornitza Stark Classified gene: POLR3K as Amber List (moderate evidence)
Mendeliome v0.7507 POLR3K Zornitza Stark Gene: polr3k has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7506 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes. Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Expert Review
Mendeliome v0.7505 SAG Zornitza Stark Gene: sag has been classified as Green List (High Evidence).
Mendeliome v0.7502 YWHAG Zornitza Stark Gene: ywhag has been classified as Green List (High Evidence).
Mendeliome v0.7498 OCRL Zornitza Stark Gene: ocrl has been classified as Green List (High Evidence).
Mendeliome v0.7495 APOL1 Zornitza Stark Phenotypes for gene: APOL1 were changed from {Glomerulosclerosis, focal segmental, 4, susceptibility to} 612551 to {Glomerulosclerosis, focal segmental, 4, susceptibility to} 612551; {End-stage renal disease, nondiabetic, susceptibility to} OMIM:612551
Mendeliome v0.7493 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from Premature aging syndrome, Penttinen type, 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
Mendeliome v0.7491 PDGFRB Zornitza Stark reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 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; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7491 NEK1 Zornitza Stark Gene: nek1 has been classified as Green List (High Evidence).
Mendeliome v0.7491 NEK1 Zornitza Stark Phenotypes for gene: NEK1 were changed from to Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892
Mendeliome v0.7488 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21211617, 22499340, 25492405, 28123176; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520, Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7488 OCRL Eleanor Williams changed review comment from: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients.; to: Genotype/Phenotype information:
PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients.
Mendeliome v0.7488 APOL1 Eleanor Williams reviewed gene: APOL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33517446; Phenotypes: {Focal Segmental Glomerulosclerosis 4, Susceptibility to} OMIM:612551, {End-stage renal disease, nondiabetic, susceptibility to} OMIM:612551; Mode of inheritance: None
Mendeliome v0.7488 PDGFRB Eleanor Williams reviewed gene: PDGFRB: Rating: ; Mode of pathogenicity: None; Publications: 33450762; Phenotypes: Ocular pterygium-digital keloid dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7488 NEK1 Eleanor Williams reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33445179; Phenotypes: {Amyotrophic lateral sclerosis, susceptibility to, 24}, OMIM:617892; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7488 INF2 Zornitza Stark Gene: inf2 has been classified as Green List (High Evidence).
Mendeliome v0.7488 INF2 Zornitza Stark Phenotypes for gene: INF2 were changed from to Charcot-Marie-Tooth disease, dominant intermediate E, MIM# 614455; Glomerulosclerosis, focal segmental, 5, MIM# 613237
Mendeliome v0.7485 INF2 Zornitza Stark reviewed gene: INF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22187985, 30680856, 25943269, 20023659; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate E, MIM# 614455, Glomerulosclerosis, focal segmental, 5, MIM# 613237; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7485 MED25 Zornitza Stark changed review comment from: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities.

7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.; to: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in intellectual disability, as well as variable eye, brain, cardiac, and palatal abnormalities.

7 individuals from 4 families reported initially, founder variant p.Tyr39Cys. Over 20 individuals reported since, including other variants.
Mendeliome v0.7485 MED25 Zornitza Stark Gene: med25 has been classified as Green List (High Evidence).
Mendeliome v0.7482 HSPB1 Zornitza Stark Gene: hspb1 has been classified as Green List (High Evidence).
Mendeliome v0.7479 HINT1 Zornitza Stark Gene: hint1 has been classified as Green List (High Evidence).
Mendeliome v0.7479 HINT1 Zornitza Stark Phenotypes for gene: HINT1 were changed from to Neuromyotonia and axonal neuropathy, autosomal recessive, MIM# 137200; Gamstorp-Wohlfart syndrome, MONDO:0007646
Mendeliome v0.7476 HINT1 Zornitza Stark reviewed gene: HINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22961002, 33663550, 33404983, 31848916; Phenotypes: Neuromyotonia and axonal neuropathy, autosomal recessive, MIM# 137200, Gamstorp-Wohlfart syndrome, MONDO:0007646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7476 GNB4 Zornitza Stark Gene: gnb4 has been classified as Green List (High Evidence).
Mendeliome v0.7473 GJB1 Zornitza Stark Gene: gjb1 has been classified as Green List (High Evidence).
Mendeliome v0.7473 GJB1 Zornitza Stark Phenotypes for gene: GJB1 were changed from to Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM# 302800; MONDO:0010549; reversible posterior leukoencephalopathy
Mendeliome v0.7470 NEPRO Chern Lim gene: NEPRO was added
gene: NEPRO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant.

PMID 31250547: 1 family with homozygous novel missense

All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
Mendeliome v0.7470 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8266101, 17100997, 17353473, 31842800; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM# 302800, MONDO:0010549, reversible posterior leukoencephalopathy; 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 v0.7470 FGD4 Zornitza Stark Gene: fgd4 has been classified as Green List (High Evidence).
Mendeliome v0.7467 COX6A1 Zornitza Stark Gene: cox6a1 has been classified as Green List (High Evidence).
Mendeliome v0.7467 COX6A1 Zornitza Stark Phenotypes for gene: COX6A1 were changed from to Charcot Marie Tooth disease, recessive intermediate D, MIM# 616039; MONDO:0014467
Mendeliome v0.7464 COX6A1 Zornitza Stark reviewed gene: COX6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152455, 26302975, 25152455; Phenotypes: Charcot Marie Tooth disease, recessive intermediate D, MIM# 616039, MONDO:0014467; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7464 JAG2 Belinda Chong gene: JAG2 was added
gene: JAG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to PMID: 33861953
Phenotypes for gene: JAG2 were set to muscular dystrophy
Review for gene: JAG2 was set to GREEN
Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy.
Sources: Literature
Mendeliome v0.7464 VPS41 Kristin Rigbye edited their review of gene: VPS41: Changed phenotypes: Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Mendeliome v0.7464 VPS41 Kristin Rigbye changed review comment from: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."; to: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."

"Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay. Two siblings further presented with therapy-resistant epilepsy. No major dysmorphic features were found. In two individuals, retinal pigment alterations were noticed. Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals while in one case (Subject 9) bilateral hyperintensities at the nucleus caudatus area were noted. No hearing or vision problems were noted and in cases where nerve conduction studies were performed, these were normal. Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells."
Mendeliome v0.7464 SIN3B Elena Savva gene: SIN3B was added
gene: SIN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIN3B were set to PMID: 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability/autism spectrum disorder
Review for gene: SIN3B was set to GREEN
Added comment: PMID: 33811806
- 9 affected patients, all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
- CNVs encompassing the gene have been found
Sources: Literature
Mendeliome v0.7464 DPYSL5 Michelle Torres gene: DPYSL5 was added
gene: DPYSL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development
Sources: Literature
Mendeliome v0.7464 VPS41 Kristin Rigbye reviewed gene: VPS41: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33764426; Phenotypes: Progressive neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7464 CDC40 Zornitza Stark Phenotypes for gene: CDC40 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 15, MIM# 619302; microcephaly; seizures
Mendeliome v0.7463 CDC40 Zornitza Stark edited their review of gene: CDC40: Changed phenotypes: Pontocerebellar hypoplasia, type 15, MIM# 619302, microcephaly, seizures
Mendeliome v0.7463 PPIL1 Zornitza Stark Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures
Mendeliome v0.7462 PPIL1 Zornitza Stark edited their review of gene: PPIL1: Changed phenotypes: Pontocerebellar hypoplasia, type 14, MIM# 619301, microcephaly, seizures
Mendeliome v0.7462 BICD2 Zornitza Stark Gene: bicd2 has been classified as Green List (High Evidence).
Mendeliome v0.7459 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome, MIM#619293
Mendeliome v0.7457 KCNQ5 Zornitza Stark Gene: kcnq5 has been classified as Green List (High Evidence).
Mendeliome v0.7454 KCNK9 Zornitza Stark Gene: kcnk9 has been classified as Green List (High Evidence).
Mendeliome v0.7451 ATL1 Zornitza Stark Gene: atl1 has been classified as Green List (High Evidence).
Mendeliome v0.7447 COQ2 Zornitza Stark Gene: coq2 has been classified as Green List (High Evidence).
Mendeliome v0.7444 COA6 Zornitza Stark Gene: coa6 has been classified as Green List (High Evidence).
Mendeliome v0.7441 CARS2 Zornitza Stark Gene: cars2 has been classified as Green List (High Evidence).
Mendeliome v0.7438 PPP2R5C Zornitza Stark Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7438 PPP2R5C Sue White Classified gene: PPP2R5C as Amber List (moderate evidence)
Mendeliome v0.7438 PPP2R5C Sue White Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7437 PPP2R5C Sue White gene: PPP2R5C was added
gene: PPP2R5C was added to Mendeliome. Sources: Research
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PPP2R5C were set to macrocephaly; intellectual disability
Penetrance for gene: PPP2R5C were set to Complete
Review for gene: PPP2R5C was set to AMBER
Added comment: Emerging unpublished evidence of monoallelic missense variants causing intellectual disability and macrocephaly
Sources: Research
Mendeliome v0.7436 SLX4 Zornitza Stark Gene: slx4 has been classified as Green List (High Evidence).
Mendeliome v0.7432 SGCE Zornitza Stark Gene: sgce has been classified as Green List (High Evidence).
Mendeliome v0.7429 PRKRA Zornitza Stark Gene: prkra has been classified as Green List (High Evidence).
Mendeliome v0.7426 KMT2B Zornitza Stark Gene: kmt2b has been classified as Green List (High Evidence).
Mendeliome v0.7423 CIZ1 Zornitza Stark Gene: ciz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7420 CIZ1 Zornitza Stark Classified gene: CIZ1 as Amber List (moderate evidence)
Mendeliome v0.7420 CIZ1 Zornitza Stark Gene: ciz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7419 NPAS2 Zornitza Stark Gene: npas2 has been classified as Red List (Low Evidence).
Mendeliome v0.7416 NPAS2 Zornitza Stark Classified gene: NPAS2 as Red List (low evidence)
Mendeliome v0.7416 NPAS2 Zornitza Stark Gene: npas2 has been classified as Red List (Low Evidence).
Mendeliome v0.7415 NPAS2 Alison Compton changed review comment from: The brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to in a functional domain. Not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Paper did not include any functional work.; to: Three brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Found to be heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to be within a functional domain. Gene not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Publication did not include any functional work as support.
Mendeliome v0.7415 PNKD Zornitza Stark Gene: pnkd has been classified as Green List (High Evidence).
Mendeliome v0.7415 PNKD Zornitza Stark Phenotypes for gene: PNKD were changed from to Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800; MONDO:0007326
Mendeliome v0.7412 PNKD Zornitza Stark reviewed gene: PNKD: Rating: GREEN; Mode of pathogenicity: None; Publications: 15262732, 15496428, 15824259, 19124534, 21487022; Phenotypes: Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800, MONDO:0007326; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7412 MECR Zornitza Stark Gene: mecr has been classified as Green List (High Evidence).
Mendeliome v0.7409 HPCA Zornitza Stark Gene: hpca has been classified as Green List (High Evidence).
Mendeliome v0.7409 HPCA Zornitza Stark Phenotypes for gene: HPCA were changed from to Dystonia 2, torsion, autosomal recessive, MIM# 224500; MONDO:0009141
Mendeliome v0.7406 HPCA Zornitza Stark reviewed gene: HPCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25799108, 30991467, 30145809; Phenotypes: Dystonia 2, torsion, autosomal recessive, MIM# 224500, MONDO:0009141; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7406 GNAL Zornitza Stark Gene: gnal has been classified as Green List (High Evidence).
Mendeliome v0.7403 ADCY5 Zornitza Stark Gene: adcy5 has been classified as Green List (High Evidence).
Mendeliome v0.7403 ADCY5 Zornitza Stark Phenotypes for gene: ADCY5 were changed from to Dyskinesia, familial, with facial myokymia, MIM# 606703; MONDO:0011707
Mendeliome v0.7400 ADCY5 Zornitza Stark reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22782511, 24700542, 33051786, 32647899, 33704598; Phenotypes: Dyskinesia, familial, with facial myokymia, MIM# 606703, MONDO:0011707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7400 XPNPEP3 Zornitza Stark Classified gene: XPNPEP3 as Green List (high evidence)
Mendeliome v0.7400 XPNPEP3 Zornitza Stark Gene: xpnpep3 has been classified as Green List (High Evidence).
Mendeliome v0.7399 THAP1 Zornitza Stark Gene: thap1 has been classified as Green List (High Evidence).
Mendeliome v0.7399 THAP1 Zornitza Stark Phenotypes for gene: THAP1 were changed from to Dystonia 6, torsion, 602629; MONDO:0011264
Mendeliome v0.7396 THAP1 Zornitza Stark reviewed gene: THAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21793105, 22377579; Phenotypes: Dystonia 6, torsion, 602629, MONDO:0011264; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7395 CHST11 Zornitza Stark Gene: chst11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7395 CHST11 Zornitza Stark Classified gene: CHST11 as Amber List (moderate evidence)
Mendeliome v0.7395 CHST11 Zornitza Stark Gene: chst11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7394 CHST11 Zornitza Stark gene: CHST11 was added
gene: CHST11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST11 were set to 26436107; 29514872
Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167
Review for gene: CHST11 was set to AMBER
Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum.

Two unrelated families reported, note one had a homozygous deletion. One family had 10 affected individuals.
Sources: Expert Review
Mendeliome v0.7392 PSMB8 Zornitza Stark Gene: psmb8 has been classified as Green List (High Evidence).
Mendeliome v0.7388 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Added comment: PMID 33807164: third unrelated family reported with CTD phenotype, single affected individual with bi-alllelic LoF variant, cutis laxa and multiple herniations.; Changed publications: 32006683, 31792352, 33807164
Mendeliome v0.7388 PPARG Zornitza Stark Gene: pparg has been classified as Green List (High Evidence).
Mendeliome v0.7385 POLD1 Zornitza Stark Gene: pold1 has been classified as Green List (High Evidence).
Mendeliome v0.7385 POLD1 Zornitza Stark Phenotypes for gene: POLD1 were changed from to Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157
Mendeliome v0.7382 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23770608, 33618333, 33369179, 32826474, 30023403, 29199204, 28791128; Phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381, MONDO:0014157; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7382 PLIN1 Zornitza Stark Gene: plin1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7379 PLIN1 Zornitza Stark Classified gene: PLIN1 as Amber List (moderate evidence)
Mendeliome v0.7379 PLIN1 Zornitza Stark Gene: plin1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7378 PCYT1A Zornitza Stark Gene: pcyt1a has been classified as Green List (High Evidence).
Mendeliome v0.7378 PCYT1A Zornitza Stark Phenotypes for gene: PCYT1A were changed from to Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Congenital lipodystrophy
Mendeliome v0.7375 PCYT1A Zornitza Stark reviewed gene: PCYT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24387990, 24387991, 24889630; Phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940, Congenital lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7374 KCNJ6 Zornitza Stark Gene: kcnj6 has been classified as Green List (High Evidence).
Mendeliome v0.7371 EIF4G1 Zornitza Stark Gene: eif4g1 has been classified as Red List (Low Evidence).
Mendeliome v0.7368 EIF4G1 Zornitza Stark Classified gene: EIF4G1 as Red List (low evidence)
Mendeliome v0.7368 EIF4G1 Zornitza Stark Gene: eif4g1 has been classified as Red List (Low Evidence).
Mendeliome v0.7367 CIDEC Zornitza Stark Gene: cidec has been classified as Red List (Low Evidence).
Mendeliome v0.7364 CIDEC Zornitza Stark Classified gene: CIDEC as Red List (low evidence)
Mendeliome v0.7364 CIDEC Zornitza Stark Gene: cidec has been classified as Red List (Low Evidence).
Mendeliome v0.7363 LIG3 Zornitza Stark Gene: lig3 has been classified as Green List (High Evidence).
Mendeliome v0.7363 LIG3 Zornitza Stark Classified gene: LIG3 as Green List (high evidence)
Mendeliome v0.7363 LIG3 Zornitza Stark Gene: lig3 has been classified as Green List (High Evidence).
Mendeliome v0.7361 HNRNPDL Bryony Thompson Gene: hnrnpdl has been classified as Green List (High Evidence).
Mendeliome v0.7361 HNRNPDL Bryony Thompson Classified gene: HNRNPDL as Green List (high evidence)
Mendeliome v0.7361 HNRNPDL Bryony Thompson Gene: hnrnpdl has been classified as Green List (High Evidence).
Mendeliome v0.7359 JMJD1C Zornitza Stark Gene: jmjd1c has been classified as Green List (High Evidence).
Mendeliome v0.7359 JMJD1C Zornitza Stark Classified gene: JMJD1C as Green List (high evidence)
Mendeliome v0.7359 JMJD1C Zornitza Stark Gene: jmjd1c has been classified as Green List (High Evidence).
Mendeliome v0.7357 CAVIN1 Zornitza Stark Gene: cavin1 has been classified as Green List (High Evidence).
Mendeliome v0.7354 CAV1 Zornitza Stark Gene: cav1 has been classified as Green List (High Evidence).
Mendeliome v0.7354 CAV1 Zornitza Stark Phenotypes for gene: CAV1 were changed from to Lipodystrophy, familial partial, type 7, autosomal dominant MIM# 606721; Lipodystrophy, congenital generalized, type 3, autosomal recessive, MIM# 612526
Mendeliome v0.7351 CAV1 Zornitza Stark reviewed gene: CAV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18237401, 25898808, 11739396, 18211975, 27717241, 26176221, 33836561, 33776068, 32502478, 22474227, 28768485; Phenotypes: Lipodystrophy, familial partial, type 7, autosomal dominant MIM# 606721, Lipodystrophy, congenital generalized, type 3, autosomal recessive, MIM# 612526; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7351 AFF4 Zornitza Stark Gene: aff4 has been classified as Green List (High Evidence).
Mendeliome v0.7348 DNAJB13 Zornitza Stark Classified gene: DNAJB13 as Green List (high evidence)
Mendeliome v0.7348 DNAJB13 Zornitza Stark Gene: dnajb13 has been classified as Green List (High Evidence).
Mendeliome v0.7347 GCGR Zornitza Stark Gene: gcgr has been classified as Green List (High Evidence).
Mendeliome v0.7347 GCGR Zornitza Stark Classified gene: GCGR as Green List (high evidence)
Mendeliome v0.7347 GCGR Zornitza Stark Gene: gcgr has been classified as Green List (High Evidence).
Mendeliome v0.7346 GCGR Zornitza Stark gene: GCGR was added
gene: GCGR was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GCGR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCGR were set to 19657311; 25695890; 27933176; 30032256; 30294546
Phenotypes for gene: GCGR were set to Mahvash disease, MIM# 619290
Review for gene: GCGR was set to GREEN
Added comment: Mahvash disease (MVAH) is caused by inactivating mutations in the glucagon receptor, leading to alpha-cell hyperplasia of the pancreas, hyperglucagonaemia without glucagonoma syndrome, and occasional hypoglycaemia. The disease may lead to glucagonomas and/or primitive neuroectodermal tumours.

More than 5 unrelated families reported.
Sources: Expert list
Mendeliome v0.7344 MED27 Zornitza Stark Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286
Mendeliome v0.7343 MED27 Zornitza Stark reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7343 ABCB6 Zornitza Stark Gene: abcb6 has been classified as Green List (High Evidence).
Mendeliome v0.7343 ABCB6 Zornitza Stark Phenotypes for gene: ABCB6 were changed from to Pseudohyperkalemia, familial, 2, due to red cell leak, MIM# 609153; Microphthalmia, isolated, with coloboma 7, MIM# 614497; Dyschromatosis universalis hereditaria 3, MIM# 615402
Mendeliome v0.7340 ABCB6 Zornitza Stark reviewed gene: ABCB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23180570; Phenotypes: Pseudohyperkalemia, familial, 2, due to red cell leak, MIM# 609153, Microphthalmia, isolated, with coloboma 7, MIM# 614497, Dyschromatosis universalis hereditaria 3, MIM# 615402; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7340 ABCA1 Zornitza Stark Gene: abca1 has been classified as Green List (High Evidence).
Mendeliome v0.7340 PRDM15 Zornitza Stark Gene: prdm15 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7340 PRDM15 Zornitza Stark Classified gene: PRDM15 as Amber List (moderate evidence)
Mendeliome v0.7340 PRDM15 Zornitza Stark Gene: prdm15 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7339 PRDM15 Zornitza Stark gene: PRDM15 was added
gene: PRDM15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to 31950080
Phenotypes for gene: PRDM15 were set to Steroid resistant nephrotic syndrome; Holoprosencephaly
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic SRNS including HPE, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data focused on the brain phenotype. Two additional homozygous missense identified with isolated SRNS.
Sources: Literature
Mendeliome v0.7338 ZIC2 Zornitza Stark Gene: zic2 has been classified as Green List (High Evidence).
Mendeliome v0.7335 TGIF1 Zornitza Stark Gene: tgif1 has been classified as Green List (High Evidence).
Mendeliome v0.7332 SIX3 Zornitza Stark Marked gene: SIX3 as ready
Mendeliome v0.7332 SIX3 Zornitza Stark Gene: six3 has been classified as Green List (High Evidence).
Mendeliome v0.7332 SIX3 Zornitza Stark Phenotypes for gene: SIX3 were changed from to Holoprosencephaly 2, MIM# 157170; MONDO:0007999
Mendeliome v0.7331 SIX3 Zornitza Stark Publications for gene: SIX3 were set to
Mendeliome v0.7330 SIX3 Zornitza Stark Mode of inheritance for gene: SIX3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7329 SIX3 Zornitza Stark reviewed gene: SIX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10369266, 16323008, 19346217; Phenotypes: Holoprosencephaly 2, MIM# 157170, MONDO:0007999; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7329 DISP1 Zornitza Stark Gene: disp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7326 DISP1 Zornitza Stark Classified gene: DISP1 as Amber List (moderate evidence)
Mendeliome v0.7326 DISP1 Zornitza Stark Gene: disp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7325 TBX3 Zornitza Stark Gene: tbx3 has been classified as Green List (High Evidence).
Mendeliome v0.7322 SALL1 Zornitza Stark Gene: sall1 has been classified as Green List (High Evidence).
Mendeliome v0.7317 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
Mendeliome v0.7314 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Green List (High Evidence).
Mendeliome v0.7311 CDCA7 Zornitza Stark Gene: cdca7 has been classified as Green List (High Evidence).
Mendeliome v0.7307 XPC Zornitza Stark Gene: xpc has been classified as Green List (High Evidence).
Mendeliome v0.7304 XPA Zornitza Stark Gene: xpa has been classified as Green List (High Evidence).
Mendeliome v0.7301 RMI2 Zornitza Stark Gene: rmi2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7298 RMI2 Zornitza Stark Classified gene: RMI2 as Amber List (moderate evidence)
Mendeliome v0.7298 RMI2 Zornitza Stark Gene: rmi2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7297 RAD51 Zornitza Stark Gene: rad51 has been classified as Green List (High Evidence).
Mendeliome v0.7294 POLH Zornitza Stark Gene: polh has been classified as Green List (High Evidence).
Mendeliome v0.7289 MRE11 Zornitza Stark Gene: mre11 has been classified as Green List (High Evidence).
Mendeliome v0.7289 MRE11 Zornitza Stark Phenotypes for gene: MRE11 were changed from to Ataxia-telangiectasia-like disorder 1, MIM# 604391; MONDO:0024557
Mendeliome v0.7286 MRE11 Zornitza Stark reviewed gene: MRE11: Rating: GREEN; Mode of pathogenicity: None; Publications: 10612394, 11371508, 15269180, 22863007, 24332946, 21227757; Phenotypes: Ataxia-telangiectasia-like disorder 1, MIM# 604391, MONDO:0024557; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7286 MPLKIP Zornitza Stark Gene: mplkip has been classified as Green List (High Evidence).
Mendeliome v0.7286 MPLKIP Zornitza Stark Phenotypes for gene: MPLKIP were changed from to Trichothiodystrophy 4, nonphotosensitive, MIM# 234050; MONDO:0021013
Mendeliome v0.7283 MPLKIP Zornitza Stark reviewed gene: MPLKIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 15645389, 16977596; Phenotypes: Trichothiodystrophy 4, nonphotosensitive, MIM# 234050, MONDO:0021013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7283 PIK3CD Zornitza Stark Gene: pik3cd has been classified as Green List (High Evidence).
Mendeliome v0.7283 PIK3CD Zornitza Stark Phenotypes for gene: PIK3CD were changed from to Immunodeficiency 14B, autosomal recessive, MIM# 619281; Immunodeficiency 14A, autosomal dominant, MIM# 615513
Mendeliome v0.7280 PIK3CD Zornitza Stark reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30040974, 30336224, 29180244, 16984281, 24136356, 24165795, 24610295; Phenotypes: Immunodeficiency 14B, autosomal recessive, MIM# 619281, Immunodeficiency 14A, autosomal dominant, MIM# 615513; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7280 GTF2H5 Zornitza Stark Gene: gtf2h5 has been classified as Green List (High Evidence).
Mendeliome v0.7280 GTF2H5 Zornitza Stark Phenotypes for gene: GTF2H5 were changed from to Trichothiodystrophy 3, photosensitive, MIM# 616395; MONDO:0014619
Mendeliome v0.7277 GTF2H5 Zornitza Stark reviewed gene: GTF2H5: Rating: GREEN; Mode of pathogenicity: None; Publications: 15220921, 30359777, 24986372; Phenotypes: Trichothiodystrophy 3, photosensitive, MIM# 616395, MONDO:0014619; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7277 GTF2E2 Zornitza Stark Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7277 GTF2E2 Zornitza Stark Phenotypes for gene: GTF2E2 were changed from to Trichothiodystrophy 6, nonphotosensitive, MIM# 616943; MONDO:0014841
Mendeliome v0.7274 GTF2E2 Zornitza Stark Classified gene: GTF2E2 as Amber List (moderate evidence)
Mendeliome v0.7274 GTF2E2 Zornitza Stark Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7273 GTF2E2 Zornitza Stark reviewed gene: GTF2E2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26996949; Phenotypes: Trichothiodystrophy 6, nonphotosensitive, MIM# 616943, MONDO:0014841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7273 FANCL Zornitza Stark Gene: fancl has been classified as Green List (High Evidence).
Mendeliome v0.7270 FANCI Zornitza Stark Gene: fanci has been classified as Green List (High Evidence).
Mendeliome v0.7267 FANCG Zornitza Stark Gene: fancg has been classified as Green List (High Evidence).
Mendeliome v0.7264 FANCF Zornitza Stark Gene: fancf has been classified as Green List (High Evidence).
Mendeliome v0.7261 FANCE Zornitza Stark Gene: fance has been classified as Green List (High Evidence).
Mendeliome v0.7258 MDM2 Zornitza Stark Gene: mdm2 has been classified as Red List (Low Evidence).
Mendeliome v0.7255 MDM2 Zornitza Stark Classified gene: MDM2 as Red List (low evidence)
Mendeliome v0.7255 MDM2 Zornitza Stark Gene: mdm2 has been classified as Red List (Low Evidence).
Mendeliome v0.7252 NDUFB11 Zornitza Stark Gene: ndufb11 has been classified as Green List (High Evidence).
Mendeliome v0.7249 NDUFB11 Kristin Rigbye changed review comment from: Variable syndromic features have been observed in affected individuals, however anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349).

Affected females have previously been reported with inherited pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic or external factors (PMID: 28050600).

Affected females have been reported with null alleles, whereas affected males have only been identified with missense variants or a recurrent single residue in-frame deletion, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443).
Note: female carriers of missense variants have not been reported as clinically affected.

Western blots from cells of male patients with the recurrent F93del variant showed reduced protein levels, and recombinant cells demonstrated a proliferation defect, consistent with the anaemia phenotype (PMID: 27488349).; to: Variable syndromic features have been observed in affected individuals, however anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349).

It has been suggested that heterozygous females do not display the severe phenotype associated with mitochondrial complex 1 deficiency due to highly skewed XCI favouring expression of the wild type allele, whereas these null variants result in a severe lethal disorder in hemizygous males (PMID: 25772934).

Affected females have previously been reported with inherited pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic or external factors (PMID: 28050600).

Affected females have been reported with null alleles, whereas affected males have only been identified with missense variants or a recurrent single residue in-frame deletion, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443).
Note: female carriers of missense variants have not been reported as clinically affected.

Western blots from cells of male patients with the recurrent F93del variant showed reduced protein levels, and recombinant cells demonstrated a proliferation defect, consistent with the anaemia phenotype (PMID: 27488349).
Mendeliome v0.7249 FANCC Zornitza Stark Gene: fancc has been classified as Green List (High Evidence).
Mendeliome v0.7243 MFAP5 Zornitza Stark Classified gene: MFAP5 as Amber List (moderate evidence)
Mendeliome v0.7243 MFAP5 Zornitza Stark Gene: mfap5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7242 FANCB Zornitza Stark Gene: fancb has been classified as Green List (High Evidence).
Mendeliome v0.7238 FANCA Zornitza Stark Gene: fanca has been classified as Green List (High Evidence).
Mendeliome v0.7235 ERCC8 Zornitza Stark Gene: ercc8 has been classified as Green List (High Evidence).
Mendeliome v0.7235 ERCC8 Zornitza Stark Phenotypes for gene: ERCC8 were changed from to Cockayne syndrome, type A, MIM# 216400; MONDO:0019569; UV-sensitive syndrome 2, MIM# 614621; MONDO:0013829
Mendeliome v0.7232 ERCC8 Zornitza Stark reviewed gene: ERCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 7664335, 19894250; Phenotypes: Cockayne syndrome, type A, MIM# 216400, MONDO:0019569, UV-sensitive syndrome 2, MIM# 614621, MONDO:0013829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7231 GP1BA Zornitza Stark Gene: gp1ba has been classified as Green List (High Evidence).
Mendeliome v0.7231 GP1BA Zornitza Stark Phenotypes for gene: GP1BA were changed from to Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS); von Willebrand disease, platelet-type, (MIM#177820), AD (VWD); MONDO:0008332; Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); MONDO:0007930
Mendeliome v0.7229 GP1BA Zornitza Stark reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), MONDO:0008332, Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS), MONDO:0007930; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7229 GP1BA Ain Roesley reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24934643; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7227 ERCC4 Zornitza Stark Gene: ercc4 has been classified as Green List (High Evidence).
Mendeliome v0.7224 ERCC3 Zornitza Stark Gene: ercc3 has been classified as Green List (High Evidence).
Mendeliome v0.7224 ERCC3 Zornitza Stark Phenotypes for gene: ERCC3 were changed from to Trichothiodystrophy 2, photosensitive, MIM# 616390; Xeroderma pigmentosum, group B 61, MIM#0651
Mendeliome v0.7221 ERCC3 Zornitza Stark reviewed gene: ERCC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 2167179, 10447254, 16947863, 9012405, 32557569, 27004399; Phenotypes: Trichothiodystrophy 2, photosensitive, MIM# 616390, Xeroderma pigmentosum, group B 61, MIM#0651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7221 DAAM2 Zornitza Stark Phenotypes for gene: DAAM2 were changed from steroid-resistant nephrotic syndrome (SRNS) to Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS)
Mendeliome v0.7220 DAAM2 Zornitza Stark edited their review of gene: DAAM2: Changed phenotypes: Nephrotic syndrome, type 24, MIM# 619263, Steroid-resistant nephrotic syndrome (SRNS)
Mendeliome v0.7219 SDHA Zornitza Stark Gene: sdha has been classified as Green List (High Evidence).
Mendeliome v0.7217 SLC19A1 Zornitza Stark Gene: slc19a1 has been classified as Red List (Low Evidence).
Mendeliome v0.7217 SLC19A1 Zornitza Stark gene: SLC19A1 was added
gene: SLC19A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275
Phenotypes for gene: SLC19A1 were set to Megaloblastic anemia, folate-responsive, MIM# 601775
Review for gene: SLC19A1 was set to RED
Added comment: Single individual reported with in-frame deletion, some functional data.
Sources: Expert list
Mendeliome v0.7216 ERCC2 Zornitza Stark Gene: ercc2 has been classified as Green List (High Evidence).
Mendeliome v0.7216 ERCC2 Zornitza Stark Phenotypes for gene: ERCC2 were changed from to Cerebrooculofacioskeletal syndrome 2, MIM# 610756; MONDO:0012553; Trichothiodystrophy 1, photosensitive, MIM# 601675; MONDO:0011125; Xeroderma pigmentosum, group D, MIM# 278730; MONDO:0010212
Mendeliome v0.7213 ERCC2 Zornitza Stark reviewed gene: ERCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7849702, 9758621, 11443545, 33733458; Phenotypes: Cerebrooculofacioskeletal syndrome 2, MIM# 610756, MONDO:0012553, Trichothiodystrophy 1, photosensitive, MIM# 601675, MONDO:0011125, Xeroderma pigmentosum, group D, MIM# 278730, MONDO:0010212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7212 ERCC1 Zornitza Stark changed review comment from: Three unrelated families reported, variable severity reported from a Cockayne phenotype with congenital onset and early mortality, through to adolescent presentation with short stature, photosensitivity and progressive liver and renal dysfunction.; to: More than three unrelated families reported, variable severity reported from a Cockayne phenotype with congenital onset and early mortality, through to adolescent presentation with short stature, photosensitivity and progressive liver and renal dysfunction.
Mendeliome v0.7210 NDUFA8 Zornitza Stark Classified gene: NDUFA8 as Amber List (moderate evidence)
Mendeliome v0.7210 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7209 NDUFA8 Zornitza Stark commented on gene: NDUFA8: Second family reported with pair of affected siblings and homozygous missense variant, some functional data.
Mendeliome v0.7206 KCNH1 Zornitza Stark Gene: kcnh1 has been classified as Green List (High Evidence).
Mendeliome v0.7203 GREB1L Zornitza Stark Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, OMIM# 617805 to Renal hypodysplasia/aplasia 3, OMIM# 617805; Deafness, autosomal dominant 80, MIM# 619274
Mendeliome v0.7201 GREB1L Zornitza Stark edited their review of gene: GREB1L: Added comment: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves. Four unrelated families reported, no comment on a renal phenotype. Note variants in this gene are also associated with renal agenesis.; Changed publications: 29100091, 29955957, 32585897; Changed phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805, Deafness, autosomal dominant 80, MIM# 619274
Mendeliome v0.7200 EMC10 Zornitza Stark Classified gene: EMC10 as Green List (high evidence)
Mendeliome v0.7200 EMC10 Zornitza Stark Gene: emc10 has been classified as Green List (High Evidence).
Mendeliome v0.7199 ITGB3 Zornitza Stark Gene: itgb3 has been classified as Green List (High Evidence).
Mendeliome v0.7196 KRT8 Seb Lunke reviewed gene: KRT8: Rating: RED; Mode of pathogenicity: None; Publications: 15235035, 11372009, 12724528; Phenotypes: CIRRHOSIS, FAMILIAL, MIM #215600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7194 UNC50 Zornitza Stark Gene: unc50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7194 UNC50 Zornitza Stark Classified gene: UNC50 as Amber List (moderate evidence)
Mendeliome v0.7194 UNC50 Zornitza Stark Gene: unc50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7192 ADCY6 Zornitza Stark changed review comment from: Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies.
Sources: Literature; to: - PMID: 33820833 (2021) - Further 2 sibs reported with a homozygous c.3346C>T:p.Arg1116Cys variant in the ADCY6 gene. The family was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and IUGR were detected prenatally.

Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies.
Sources: Literature
Mendeliome v0.7192 PLCH1 Zornitza Stark Gene: plch1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7192 PLCH1 Zornitza Stark Classified gene: PLCH1 as Amber List (moderate evidence)
Mendeliome v0.7192 PLCH1 Zornitza Stark Gene: plch1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7191 UNC50 Arina Puzriakova gene: UNC50 was added
gene: UNC50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC50 were set to 29016857; 33820833
Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita
Review for gene: UNC50 was set to AMBER
Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype.

- PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle.

- PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally.

-- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity.
Sources: Literature
Mendeliome v0.7191 PLCH1 Arina Puzriakova gene: PLCH1 was added
gene: PLCH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCH1 were set to 33820834
Phenotypes for gene: PLCH1 were set to Holoprosencephaly spectrum; Severe developmental delay; Brain malformations
Review for gene: PLCH1 was set to AMBER
Added comment: PLCH1 is currently not associated with any phenotype in OMIM (last edited on 16/06/2009) or Gene2Phenotype.

- PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease.
Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
Sources: Literature
Mendeliome v0.7191 DDX11 Zornitza Stark Gene: ddx11 has been classified as Green List (High Evidence).
Mendeliome v0.7188 PDIA6 Zornitza Stark Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7188 PDIA6 Zornitza Stark Classified gene: PDIA6 as Amber List (moderate evidence)
Mendeliome v0.7188 PDIA6 Zornitza Stark Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7187 PDIA6 Zornitza Stark gene: PDIA6 was added
gene: PDIA6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes
Review for gene: PDIA6 was set to AMBER
Added comment: Amber in view of the good quality functional data.

1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans.
Sources: Literature
Mendeliome v0.7186 EXOSC1 Zornitza Stark Gene: exosc1 has been classified as Red List (Low Evidence).
Mendeliome v0.7186 EXOSC1 Zornitza Stark gene: EXOSC1 was added
gene: EXOSC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOSC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC1 were set to 33463720
Phenotypes for gene: EXOSC1 were set to Pontocerebellar hypoplasia
Review for gene: EXOSC1 was set to RED
Added comment: An 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism, hypotonia, pontocerebellar hypoplasia and delayed myelination. Similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Exome sequencing revealed a homozygous missense variant (c.104C >T, p.Ser35Leu) in EXOSC1. In silico mutagenesis revealed loss of a polar contact with neighbouring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. Of note, bi‐allelic variants in other exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively.
Sources: Literature
Mendeliome v0.7183 UBE4A Zornitza Stark Gene: ube4a has been classified as Green List (High Evidence).
Mendeliome v0.7183 UBE4A Zornitza Stark Classified gene: UBE4A as Green List (high evidence)
Mendeliome v0.7183 UBE4A Zornitza Stark Gene: ube4a has been classified as Green List (High Evidence).
Mendeliome v0.7182 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability and global developmental delay
Review for gene: UBE4A was set to GREEN
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Mendeliome v0.7181 MAPKAPK5 Zornitza Stark Gene: mapkapk5 has been classified as Green List (High Evidence).
Mendeliome v0.7181 MAPKAPK5 Zornitza Stark Classified gene: MAPKAPK5 as Green List (high evidence)
Mendeliome v0.7181 MAPKAPK5 Zornitza Stark Gene: mapkapk5 has been classified as Green List (High Evidence).
Mendeliome v0.7180 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic
Review for gene: MAPKAPK5 was set to GREEN
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.
Sources: Literature
Mendeliome v0.7179 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts
Mendeliome v0.7176 FAR1 Zornitza Stark Classified gene: FAR1 as Green List (high evidence)
Mendeliome v0.7176 FAR1 Zornitza Stark Gene: far1 has been classified as Green List (High Evidence).
Mendeliome v0.7175 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7175 GRIA3 Zornitza Stark Gene: gria3 has been classified as Green List (High Evidence).
Mendeliome v0.7172 SLC17A5 Zornitza Stark Gene: slc17a5 has been classified as Green List (High Evidence).
Mendeliome v0.7172 SLC17A5 Zornitza Stark Phenotypes for gene: SLC17A5 were changed from to Salla disease 604369; MONDO:0011449; Sialic acid storage disorder, infantile 269920; MONDO:0010027
Mendeliome v0.7169 SLC17A5 Zornitza Stark edited their review of gene: SLC17A5: Added comment: Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form or a slowly progressive adult form, which is prevalent in Finland and referred to as Salla disease. p.Arg39Cys is a founder Finnish variant. Multiple families reported.; Changed publications: 10581036, 10947946; Changed phenotypes: Salla disease 604369, MONDO:0011449, Sialic acid storage disorder, infantile 269920, MONDO:0010027
Mendeliome v0.7169 SGSH Zornitza Stark Gene: sgsh has been classified as Green List (High Evidence).
Mendeliome v0.7169 SGSH Zornitza Stark Phenotypes for gene: SGSH were changed from to Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900; MONDO:0009655
Mendeliome v0.7166 SGSH Zornitza Stark reviewed gene: SGSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7493035, 9158154, 9401012, 9554748; Phenotypes: Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900, MONDO:0009655; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7166 SMPD1 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Niemann-Pick disease (NPD) refers to a group of disorders that present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings.

Well established gene-disease association.
Mendeliome v0.7166 SMPD1 Zornitza Stark Gene: smpd1 has been classified as Green List (High Evidence).
Mendeliome v0.7163 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270 to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; MONDO:0008769; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270; MONDO:0012235
Mendeliome v0.7161 TPP1 Zornitza Stark reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9295267, 18684116, 23418007, 26224725, 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, MIM# 204500, MONDO:0008769, Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270, MONDO:0012235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7161 PSAP Zornitza Stark changed review comment from: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.; to: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.

The PSAP gene encodes saposins A, B, C and D. Variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A-D) or whole prosaposin. The patient's phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles.
Mendeliome v0.7161 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson disease, AD; Combined SAP deficiency 611721; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900 to Parkinson disease, AD; Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722; MONDO:0012720; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; MONDO:0009590; Gaucher disease, atypical, MIM# 610539; MONDO:0012517
Mendeliome v0.7160 PSAP Zornitza Stark edited their review of gene: PSAP: Changed phenotypes: Combined SAP deficiency, MIM# 611721, Encephalopathy due to prosaposin deficiency, MONDO:0012719, Krabbe disease, atypical, MIM# 611722, MONDO:0012720, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, MONDO:0009590, Gaucher disease, atypical, MIM# 610539, MONDO:0012517
Mendeliome v0.7160 PPT1 Zornitza Stark Gene: ppt1 has been classified as Green List (High Evidence).
Mendeliome v0.7160 PPT1 Zornitza Stark Phenotypes for gene: PPT1 were changed from to Ceroid lipofuscinosis, neuronal, 1, MIM# 256730; MONDO:0009744
Mendeliome v0.7157 PPT1 Zornitza Stark reviewed gene: PPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7637805, 9425237, 9664077; Phenotypes: Ceroid lipofuscinosis, neuronal, 1, MIM# 256730, MONDO:0009744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7157 NEU1 Zornitza Stark Gene: neu1 has been classified as Green List (High Evidence).
Mendeliome v0.7157 NEU1 Zornitza Stark Phenotypes for gene: NEU1 were changed from to Sialidosis, type I and type II, MIM# 256550; MONDO:0009738
Mendeliome v0.7154 NEU1 Zornitza Stark reviewed gene: NEU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8985184, 9054950, 11063730; Phenotypes: Sialidosis, type I and type II, MIM# 256550, MONDO:0009738; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7154 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491 to Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; MONDO:0009656; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491; MONDO:0014665
Mendeliome v0.7153 NAGLU Zornitza Stark Gene: naglu has been classified as Green List (High Evidence).
Mendeliome v0.7153 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from to Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491
Mendeliome v0.7150 NAGLU Zornitza Stark reviewed gene: NAGLU: Rating: GREEN; Mode of pathogenicity: None; Publications: 25818867, 8650226; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920, Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7148 MIA3 Zornitza Stark Gene: mia3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7148 MIA3 Zornitza Stark Classified gene: MIA3 as Amber List (moderate evidence)
Mendeliome v0.7148 MIA3 Zornitza Stark Gene: mia3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7147 MIA3 Zornitza Stark changed review comment from: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported. Mouse model has absence of bone mineralization.
Sources: Expert list; to: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization.
Sources: Expert list
Mendeliome v0.7147 MIA3 Zornitza Stark gene: MIA3 was added
gene: MIA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163; 33778321
Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269
Review for gene: MIA3 was set to AMBER
Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported. Mouse model has absence of bone mineralization.
Sources: Expert list
Mendeliome v0.7146 MFSD8 Zornitza Stark Phenotypes for gene: MFSD8 were changed from Ceroid lipofuscinosis, neuronal, 7 610951; Macular dystrophy with central cone involvement 616170 to Ceroid lipofuscinosis, neuronal, 7, MIM# 610951; MONDO:0012588; Macular dystrophy with central cone involvement, MIM# 616170; MONDO:0014515
Mendeliome v0.7144 MFSD8 Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763, 25227500; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588, Macular dystrophy with central cone involvement, MIM# 616170, MONDO:0014515; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7144 MCOLN1 Zornitza Stark Gene: mcoln1 has been classified as Green List (High Evidence).
Mendeliome v0.7144 MCOLN1 Zornitza Stark Phenotypes for gene: MCOLN1 were changed from to Mucolipidosis IV, MIM# 252650; MONDO:0009653
Mendeliome v0.7142 MCOLN1 Zornitza Stark reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7142 MANBA Zornitza Stark Gene: manba has been classified as Green List (High Evidence).
Mendeliome v0.7142 MANBA Zornitza Stark Phenotypes for gene: MANBA were changed from to Mannosidosis, beta, MIM# 248510; MONDO:0009562
Mendeliome v0.7140 MANBA Zornitza Stark reviewed gene: MANBA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, beta, MIM# 248510, MONDO:0009562; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7140 MAN2B1 Zornitza Stark Gene: man2b1 has been classified as Green List (High Evidence).
Mendeliome v0.7140 MAN2B1 Zornitza Stark Phenotypes for gene: MAN2B1 were changed from to Mannosidosis, alpha-, types I and II, MIM# 248500; MONDO:0009561
Mendeliome v0.7138 MAN2B1 Zornitza Stark reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, alpha-, types I and II, MIM# 248500, MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7138 LIPA Zornitza Stark Gene: lipa has been classified as Green List (High Evidence).
Mendeliome v0.7135 LAMP2 Zornitza Stark changed review comment from: XLD. Vacuolar cardiomyopathy and myopathy. Gene encodes lysosome-associated membrane protein-2.; to: XLD. Gene encodes lysosome-associated membrane protein-2.

Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease) with 'normal acid maltase' or alpha-glucosidase, however, it may be more accurately classified as a lysosomal disorder.
Mendeliome v0.7135 LAMP2 Zornitza Stark Gene: lamp2 has been classified as Green List (High Evidence).
Mendeliome v0.7133 IDUA Zornitza Stark Phenotypes for gene: IDUA were changed from Mucopolysaccharidosis Ih (MIM#607014); Mucopolysaccharidosis Ih/s (MIM#607015); Mucopolysaccharidosis Is (MIM#6070) to Mucopolysaccharidosis Ih (MIM#607014); Mucopolysaccharidosis Ih/s (MIM#607015); Mucopolysaccharidosis Is (MIM#6070); Mucopolysaccharidosis type 1, MONDO:0001586
Mendeliome v0.7132 IDUA Zornitza Stark reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type 1, MONDO:0001586; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7132 IDS Zornitza Stark Gene: ids has been classified as Green List (High Evidence).
Mendeliome v0.7132 IDS Zornitza Stark Phenotypes for gene: IDS were changed from to Mucopolysaccharidosis II, MIM# 309900; MONDO:0010674; Hunter syndrome
Mendeliome v0.7129 IDS Zornitza Stark reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921913, 9762601, 8940265, 1901826; Phenotypes: Mucopolysaccharidosis II, MIM# 309900, MONDO:0010674, Hunter syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7129 ERBB2 Alison Yeung Classified gene: ERBB2 as Red List (low evidence)
Mendeliome v0.7129 ERBB2 Alison Yeung Gene: erbb2 has been classified as Red List (Low Evidence).
Mendeliome v0.7128 VWA1 Alison Yeung Gene: vwa1 has been classified as Green List (High Evidence).
Mendeliome v0.7128 VWA1 Alison Yeung Classified gene: VWA1 as Green List (high evidence)
Mendeliome v0.7128 VWA1 Alison Yeung Gene: vwa1 has been classified as Green List (High Evidence).
Mendeliome v0.7127 VWA1 Melanie Marty gene: VWA1 was added
gene: VWA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to 33459760; 33693694; 33559681
Phenotypes for gene: VWA1 were set to Hereditary motor neuropathy
Review for gene: VWA1 was set to GREEN
Added comment: Six different truncating variants identified in 15 affected individuals from six families (biallelic inheritance). Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed.

An additional 17 individuals from 15 families with hereditary motor neuropathy were identified. A 10-bp repeat expansion at the end of exon 1 was observed in 14 families and was homozygous in 10 of them. This mutation, c.62_71dup [p.Gly25Argfs*74], leads to a frameshift that results in a reduction in VWA1 transcript levels via nonsense-mediated decay.
Sources: Literature
Mendeliome v0.7127 GIPC1 Alison Yeung Classified gene: GIPC1 as Amber List (moderate evidence)
Mendeliome v0.7127 GIPC1 Alison Yeung Gene: gipc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7126 TSPOAP1 Tiong Tan Gene: tspoap1 has been classified as Green List (High Evidence).
Mendeliome v0.7126 TSPOAP1 Tiong Tan Classified gene: TSPOAP1 as Green List (high evidence)
Mendeliome v0.7126 TSPOAP1 Tiong Tan Added comment: Comment on list classification: Need to add to HSP gene lists too - dystonia/HSP
Mendeliome v0.7126 TSPOAP1 Tiong Tan Gene: tspoap1 has been classified as Green List (High Evidence).
Mendeliome v0.7125 CLDN11 Alison Yeung Gene: cldn11 has been classified as Green List (High Evidence).
Mendeliome v0.7125 CLDN11 Alison Yeung Classified gene: CLDN11 as Green List (high evidence)
Mendeliome v0.7125 CLDN11 Alison Yeung Gene: cldn11 has been classified as Green List (High Evidence).
Mendeliome v0.7124 ERBB3 Alison Yeung Classified gene: ERBB3 as Green List (high evidence)
Mendeliome v0.7124 ERBB3 Alison Yeung Gene: erbb3 has been classified as Green List (High Evidence).
Mendeliome v0.7123 SYK Alison Yeung Gene: syk has been classified as Green List (High Evidence).
Mendeliome v0.7123 SYK Alison Yeung Classified gene: SYK as Green List (high evidence)
Mendeliome v0.7123 SYK Alison Yeung Gene: syk has been classified as Green List (High Evidence).
Mendeliome v0.7122 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Mendeliome v0.7122 NCDN Alison Yeung Classified gene: NCDN as Green List (high evidence)
Mendeliome v0.7122 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Mendeliome v0.7121 TSPOAP1 Ain Roesley gene: TSPOAP1 was added
gene: TSPOAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Penetrance for gene: TSPOAP1 were set to unknown
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted)

mice KO models were investigated
Sources: Literature
Mendeliome v0.7121 CLDN11 Melanie Marty gene: CLDN11 was added
gene: CLDN11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy
Review for gene: CLDN11 was set to GREEN
Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.
Sources: Literature
Mendeliome v0.7121 SLC5A5 Zornitza Stark Gene: slc5a5 has been classified as Green List (High Evidence).
Mendeliome v0.7121 SLC5A5 Zornitza Stark Phenotypes for gene: SLC5A5 were changed from to Thyroid dyshormonogenesis 1, MIM# 274400; MONDO:0020716
Mendeliome v0.7118 SLC5A5 Zornitza Stark reviewed gene: SLC5A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9745458, 9171822, 33815280, 32319661; Phenotypes: Thyroid dyshormonogenesis 1, MIM# 274400, MONDO:0020716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7118 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7115 SLC45A1 Zornitza Stark Classified gene: SLC45A1 as Amber List (moderate evidence)
Mendeliome v0.7115 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7114 MESP1 Zornitza Stark Gene: mesp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7114 MESP1 Zornitza Stark Classified gene: MESP1 as Amber List (moderate evidence)
Mendeliome v0.7114 MESP1 Zornitza Stark Gene: mesp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7113 MESP1 Zornitza Stark gene: MESP1 was added
gene: MESP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203
Phenotypes for gene: MESP1 were set to Congenital heart disease
Review for gene: MESP1 was set to AMBER
Added comment: Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development.
Sources: Expert list
Mendeliome v0.7112 HYAL1 Zornitza Stark Gene: hyal1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7112 HYAL1 Zornitza Stark Phenotypes for gene: HYAL1 were changed from to Mucopolysaccharidosis type IX, MIM# 601492; MONDO:0011093
Mendeliome v0.7109 HYAL1 Zornitza Stark Classified gene: HYAL1 as Amber List (moderate evidence)
Mendeliome v0.7109 HYAL1 Zornitza Stark Gene: hyal1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7108 HYAL1 Zornitza Stark reviewed gene: HYAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 10339581, 18344557, 21559944; Phenotypes: Mucopolysaccharidosis type IX, MIM# 601492, MONDO:0011093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7108 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930 MONDO:0009657 Retinitis pigmentosa 73, MIM# 616544 MONDO:0014687 to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930; MONDO:0009657; Retinitis pigmentosa 73, MIM# 616544; MONDO:0014687
Mendeliome v0.7106 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from Mucopolysaccharidosis type IIIC (Sanfilippo C) (MIM #252930); Retinitis pigmentosa 73 (MIM # 616544) to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930 MONDO:0009657 Retinitis pigmentosa 73, MIM# 616544 MONDO:0014687
Mendeliome v0.7105 HEXB Zornitza Stark Gene: hexb has been classified as Green List (High Evidence).
Mendeliome v0.7103 HEXA Zornitza Stark Phenotypes for gene: HEXA were changed from GM2-gangliosidosis, several forms 272800; Tay-Sachs disease 272800 to GM2-gangliosidosis, several forms 272800; Tay-Sachs disease 272800; MONDO:0010100
Mendeliome v0.7102 GUSB Zornitza Stark Gene: gusb has been classified as Green List (High Evidence).
Mendeliome v0.7102 GUSB Zornitza Stark Phenotypes for gene: GUSB were changed from to Mucopolysaccharidosis VII, MIM# 253220; MONDO:0009662
Mendeliome v0.7100 GUSB Zornitza Stark reviewed gene: GUSB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis VII, MIM# 253220, MONDO:0009662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7100 GNS Zornitza Stark Gene: gns has been classified as Green List (High Evidence).
Mendeliome v0.7100 GNS Zornitza Stark Phenotypes for gene: GNS were changed from to Mucopolysaccharidosis type IIID, MIM# 252940; Sanfilippo syndrome type D, MONDO:0009658
Mendeliome v0.7097 GNS Zornitza Stark reviewed gene: GNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12573255, 12624138, 31536183, 25851924; Phenotypes: Mucopolysaccharidosis type IIID, MIM# 252940, Sanfilippo syndrome type D, MONDO:0009658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7097 GNPTG Zornitza Stark Gene: gnptg has been classified as Green List (High Evidence).
Mendeliome v0.7097 GNPTG Zornitza Stark Phenotypes for gene: GNPTG were changed from to Mucolipidosis III gamma, MIM# 252605; MONDO:0009652
Mendeliome v0.7094 GNPTG Zornitza Stark reviewed gene: GNPTG: Rating: GREEN; Mode of pathogenicity: None; Publications: 10712439, 19370764, 19659762, 33507475, 33023972, 32651481; Phenotypes: Mucolipidosis III gamma, MIM# 252605, MONDO:0009652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7094 CHD7 Zornitza Stark Gene: chd7 has been classified as Green List (High Evidence).
Mendeliome v0.7091 ALDH1A2 Bryony Thompson Phenotypes for gene: ALDH1A2 were changed from to congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features
Mendeliome v0.7089 NDUFA12 Bryony Thompson Classified gene: NDUFA12 as Green List (high evidence)
Mendeliome v0.7089 NDUFA12 Bryony Thompson Gene: ndufa12 has been classified as Green List (High Evidence).
Mendeliome v0.7088 ALDH1A2 Bryony Thompson Gene: aldh1a2 has been classified as Green List (High Evidence).
Mendeliome v0.7086 ALDH1A2 Bryony Thompson reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33565183, 10192400; Phenotypes: congenital heart defects, diaphragmatic eventration, pulmonary hypoplasia, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7086 MMP20 Bryony Thompson Gene: mmp20 has been classified as Green List (High Evidence).
Mendeliome v0.7084 FBN2 Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy.

Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7084 MMP20 Bryony Thompson Phenotypes for gene: MMP20 were changed from to Amelogenesis imperfecta, type IIA2 MIM#612529
Mendeliome v0.7081 MMP20 Bryony Thompson reviewed gene: MMP20: Rating: GREEN; Mode of pathogenicity: None; Publications: 15744043, 33600052; Phenotypes: Amelogenesis imperfecta, type IIA2 MIM#612529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7081 NDUFB7 Bryony Thompson Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7081 NDUFB7 Bryony Thompson Classified gene: NDUFB7 as Amber List (moderate evidence)
Mendeliome v0.7081 NDUFB7 Bryony Thompson Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7080 NDUFB7 Bryony Thompson gene: NDUFB7 was added
gene: NDUFB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFB7 were set to 33502047; 27626371
Phenotypes for gene: NDUFB7 were set to Congenital lactic acidosis; hypertrophic cardiomyopathy
Review for gene: NDUFB7 was set to AMBER
Added comment: Single patient with a homozygous variant impacting RNA splicing (c.113-10C>G) with intrauterine growth restriction and anaemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Also, a supporting knockout cell line model demonstrating impaired complex I assembly.
Sources: Literature
Mendeliome v0.7079 CELA3B Bryony Thompson Gene: cela3b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7079 CELA3B Bryony Thompson Classified gene: CELA3B as Amber List (moderate evidence)
Mendeliome v0.7079 CELA3B Bryony Thompson Gene: cela3b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7078 CDH11 Zornitza Stark Gene: cdh11 has been classified as Green List (High Evidence).
Mendeliome v0.7074 SLC10A1 Zornitza Stark Gene: slc10a1 has been classified as Green List (High Evidence).
Mendeliome v0.7074 SLC10A1 Zornitza Stark Classified gene: SLC10A1 as Green List (high evidence)
Mendeliome v0.7074 SLC10A1 Zornitza Stark Gene: slc10a1 has been classified as Green List (High Evidence).
Mendeliome v0.7073 SLC10A1 Zornitza Stark gene: SLC10A1 was added
gene: SLC10A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC10A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC10A1 were set to 24867799; 27882152; 28835676; 29290974; 31201272
Phenotypes for gene: SLC10A1 were set to Familial hypercholanemia-2, MIM#619256
Review for gene: SLC10A1 was set to GREEN
Added comment: IEM characterised by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT). Some variants are recurrent (founder effect likely) but at least 3 different variants reported, mouse model.
Sources: Expert list
Mendeliome v0.7072 GALNS Zornitza Stark Gene: galns has been classified as Green List (High Evidence).
Mendeliome v0.7072 GALNS Zornitza Stark Phenotypes for gene: GALNS were changed from to Mucopolysaccharidosis IVA, MIM# 253000; MONDO:0009659
Mendeliome v0.7069 GALNS Zornitza Stark reviewed gene: GALNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9298823; Phenotypes: Mucopolysaccharidosis IVA, MIM# 253000, MONDO:0009659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7069 GALC Zornitza Stark Gene: galc has been classified as Green List (High Evidence).
Mendeliome v0.7065 FUCA1 Zornitza Stark Gene: fuca1 has been classified as Green List (High Evidence).
Mendeliome v0.7065 FUCA1 Zornitza Stark Phenotypes for gene: FUCA1 were changed from to Fucosidosis, MIM# 230000; MONDO:0009254
Mendeliome v0.7062 FUCA1 Zornitza Stark reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094192; Phenotypes: Fucosidosis, MIM# 230000, MONDO:0009254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7062 CTSD Zornitza Stark Gene: ctsd has been classified as Green List (High Evidence).
Mendeliome v0.7062 CTSD Zornitza Stark Phenotypes for gene: CTSD were changed from to Ceroid lipofuscinosis, neuronal, 10, MIM# 610127; MONDO:0012414
Mendeliome v0.7059 CTSD Zornitza Stark reviewed gene: CTSD: Rating: GREEN; Mode of pathogenicity: None; Publications: 16685649, 16670177, 25298308, 33681191, 29284168, 27072142; Phenotypes: Ceroid lipofuscinosis, neuronal, 10, MIM# 610127, MONDO:0012414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7059 CCDC88C Zornitza Stark Phenotypes for gene: CCDC88C were changed from Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Eearly-onset pure hereditary spastic paraplegia to Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Early-onset pure hereditary spastic paraplegia
Mendeliome v0.7058 CCDC88C Zornitza Stark Phenotypes for gene: CCDC88C were changed from Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600 AR to Spinocerebellar ataxia 40, MIM#616053; Hydrocephalus, nonsyndromic, autosomal recessive 236600; Eearly-onset pure hereditary spastic paraplegia
Mendeliome v0.7056 CCDC88C Paul De Fazio changed review comment from: Heterozygous missense variant (gnomad: 1 het) reported in a 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. In contrast to previous reports, she developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Functional studies showed the varaint induced JNK hyper-phosphorylation and enhanced apoptosis. 4 unaffected family members did not have the variant.

This phenotype appears to be sufficiently dissimilar to the 2 previously reported SCA families to not constitute a 3rd supporting report in that context.; to: Heterozygous missense variant (gnomad: 1 het) reported in a 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. In contrast to previous reports, she developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Functional studies showed the varaint induced JNK hyper-phosphorylation and enhanced apoptosis. 4 unaffected family members did not have the variant.

NB: Rated Amber as this phenotype appears to be sufficiently dissimilar to the 2 previously reported SCA families to not constitute a 3rd supporting report in that context. Gene remains Green for the AR ID phenotype.
Mendeliome v0.7055 NMNAT1 Zornitza Stark Phenotypes for gene: NMNAT1 were changed from to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553
Mendeliome v0.7053 NMNAT1 Zornitza Stark Gene: nmnat1 has been classified as Green List (High Evidence).
Mendeliome v0.7053 NMNAT1 Zornitza Stark reviewed gene: NMNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32533184, 33668384, 22842230, 22842229; Phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260, Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7053 ZMPSTE24 Zornitza Stark Phenotypes for gene: ZMPSTE24 were changed from Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612; MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210 to Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612; MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210; MONDO:0010143
Mendeliome v0.7052 ZMPSTE24 Zornitza Stark Gene: zmpste24 has been classified as Green List (High Evidence).
Mendeliome v0.7052 ZMPSTE24 Zornitza Stark Phenotypes for gene: ZMPSTE24 were changed from to Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612; MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210
Mendeliome v0.7049 ZMPSTE24 Zornitza Stark reviewed gene: ZMPSTE24: Rating: GREEN; Mode of pathogenicity: None; Publications: 11923874, 22718200, 29794150, 29208544, 12913070, 27410998, 27409638, 15937076, 16671095, 22718200, 29794150, 24169522; Phenotypes: Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, MONDO:0012074, Restrictive dermopathy, lethal, MIM# 275210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7049 WDR35 Zornitza Stark reviewed gene: WDR35: Rating: GREEN; Mode of pathogenicity: None; Publications: 33421337, 29134781, 28870638, 26691894, 24027799, 21473986; Phenotypes: Cranioectodermal dysplasia 2, MIM#613610, MONDO:0013323, Short-rib thoracic dysplasia 7 with or without polydactyly, MIM#614091, MONDO:0013569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7049 WDR35 Zornitza Stark Phenotypes for gene: WDR35 were changed from Cranioectodermal dysplasia 2, MIM#613610; Short-rib thoracic dysplasia 7 with or without polydactyly, MIM#614091 to Cranioectodermal dysplasia 2, MIM#613610; MONDO:0013323; Short-rib thoracic dysplasia 7 with or without polydactyly, MIM#614091; MONDO:0013569
Mendeliome v0.7048 EDN1 Zornitza Stark Gene: edn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7045 EDN1 Zornitza Stark Classified gene: EDN1 as Amber List (moderate evidence)
Mendeliome v0.7045 EDN1 Zornitza Stark Gene: edn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7044 CLN5 Zornitza Stark Gene: cln5 has been classified as Green List (High Evidence).
Mendeliome v0.7044 CLN5 Zornitza Stark Phenotypes for gene: CLN5 were changed from to Ceroid lipofuscinosis, neuronal, 5, MIM# 256731; MONDO:0009745
Mendeliome v0.7041 CLN5 Zornitza Stark reviewed gene: CLN5: Rating: GREEN; Mode of pathogenicity: None; Publications: 20157158; Phenotypes: Ceroid lipofuscinosis, neuronal, 5, MIM# 256731, MONDO:0009745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7041 CLN3 Zornitza Stark Gene: cln3 has been classified as Green List (High Evidence).
Mendeliome v0.7041 CLN3 Zornitza Stark Phenotypes for gene: CLN3 were changed from to Ceroid lipofuscinosis, neuronal, 3, MIM# 204200; MONDO:0008767
Mendeliome v0.7038 CLN3 Zornitza Stark reviewed gene: CLN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7553855; Phenotypes: Ceroid lipofuscinosis, neuronal, 3, MIM# 204200, MONDO:0008767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7038 ARSB Zornitza Stark Gene: arsb has been classified as Green List (High Evidence).
Mendeliome v0.7038 ARSB Zornitza Stark Phenotypes for gene: ARSB were changed from to Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200; MONDO:0009661
Mendeliome v0.7035 ARSB Zornitza Stark reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 11668612; Phenotypes: Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200, MONDO:0009661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7035 AGA Zornitza Stark Gene: aga has been classified as Green List (High Evidence).
Mendeliome v0.7032 AGA Zornitza Stark edited their review of gene: AGA: Added comment: Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. Multiple families and mouse model.; Changed publications: 1703489, 1904874, 8064811, 8946839; Changed phenotypes: Aspartylglucosaminuria, MIM# 208400, MONDO:0008830
Mendeliome v0.7032 ATCAY Zornitza Stark Gene: atcay has been classified as Green List (High Evidence).
Mendeliome v0.7028 ARAP3 Zornitza Stark Gene: arap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7028 ARAP3 Zornitza Stark Classified gene: ARAP3 as Amber List (moderate evidence)
Mendeliome v0.7028 ARAP3 Zornitza Stark Gene: arap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7026 RORC Zornitza Stark edited their review of gene: RORC: Added comment: Association with lymphoedema: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency.; Changed publications: 26160376, 32960152; Changed phenotypes: Immunodeficiency 42, MIM# 616622, Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710, Lymphoedema; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7026 RORC Zornitza Stark Gene: rorc has been classified as Green List (High Evidence).
Mendeliome v0.7026 RORC Zornitza Stark Phenotypes for gene: RORC were changed from to Immunodeficiency 42, MIM# 616622; Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710
Mendeliome v0.7023 RORC Zornitza Stark reviewed gene: RORC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26160376; Phenotypes: Immunodeficiency 42, MIM# 616622, Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7023 IL17RC Zornitza Stark Gene: il17rc has been classified as Green List (High Evidence).
Mendeliome v0.7023 IL17RC Zornitza Stark Phenotypes for gene: IL17RC were changed from to Candidiasis, familial, 9, MIM# 616445; MONDO:0014642
Mendeliome v0.7020 IL17RC Zornitza Stark reviewed gene: IL17RC: Rating: GREEN; Mode of pathogenicity: None; Publications: 25918342; Phenotypes: Candidiasis, familial, 9, MIM# 616445, MONDO:0014642; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7018 IL17RA Zornitza Stark Gene: il17ra has been classified as Green List (High Evidence).
Mendeliome v0.7017 CARD9 Zornitza Stark Gene: card9 has been classified as Green List (High Evidence).
Mendeliome v0.7017 CARD9 Zornitza Stark Phenotypes for gene: CARD9 were changed from to Candidiasis, familial, 2, autosomal recessive, MIM# 212050; Predisposition to invasive fungal disease, MONDO:0008905
Mendeliome v0.7014 CARD9 Zornitza Stark reviewed gene: CARD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19864672, 23335372, 24131138, 33789983, 33558980, 33180249; Phenotypes: Candidiasis, familial, 2, autosomal recessive, MIM# 212050, Predisposition to invasive fungal disease, MONDO:0008905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7014 CYP24A1 Zornitza Stark Gene: cyp24a1 has been classified as Green List (High Evidence).
Mendeliome v0.7009 ABCB7 Zornitza Stark Gene: abcb7 has been classified as Green List (High Evidence).
Mendeliome v0.7009 ABCB7 Zornitza Stark Phenotypes for gene: ABCB7 were changed from to Anaemia, sideroblastic, with ataxia, MIM# 301310
Mendeliome v0.7006 ABCB7 Zornitza Stark reviewed gene: ABCB7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10196363, 10196363, 33157103, 31772327, 31511561, 26242992; Phenotypes: Anaemia, sideroblastic, with ataxia, MIM# 301310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7006 PORCN Zornitza Stark Gene: porcn has been classified as Green List (High Evidence).
Mendeliome v0.7006 PORCN Zornitza Stark Phenotypes for gene: PORCN were changed from to Focal dermal hypoplasia, MIM# 305600
Mendeliome v0.7004 PORCN Zornitza Stark reviewed gene: PORCN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal dermal hypoplasia, MIM# 305600; 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 v0.7004 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7004 PRIM1 Zornitza Stark Gene: prim1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7004 PRIM1 Zornitza Stark Classified gene: PRIM1 as Amber List (moderate evidence)
Mendeliome v0.7004 PRIM1 Zornitza Stark Gene: prim1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark gene: PRIM1 was added
gene: PRIM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
Added comment: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.6998 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: second family reported, three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.; Changed publications: 32865517, 33712616; Changed phenotypes: Susceptibility to CMV, Restrictive cardiomyopathy
Mendeliome v0.6998 CYBA Zornitza Stark Gene: cyba has been classified as Green List (High Evidence).
Mendeliome v0.6998 CYBA Zornitza Stark Phenotypes for gene: CYBA were changed from to Chronic granulomatous disease 4, autosomal recessive, MIM# 233690; MONDO:0009308
Mendeliome v0.6995 CYBA Zornitza Stark reviewed gene: CYBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 2770793; Phenotypes: Chronic granulomatous disease 4, autosomal recessive, MIM# 233690, MONDO:0009308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6995 NUP37 Zornitza Stark Phenotypes for gene: NUP37 were changed from Nephrotic syndrome to Nephrotic syndrome; Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 NUP37 Zornitza Stark changed review comment from: Single family reported with nephrotic syndrome.
Sources: Literature; to: Single family reported with nephrotic syndrome and microcephaly.
Sources: Literature
Mendeliome v0.6994 NUP37 Zornitza Stark edited their review of gene: NUP37: Changed phenotypes: Nephrotic syndrome, Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 COPB2 Zornitza Stark Gene: copb2 has been classified as Red List (Low Evidence).
Mendeliome v0.6994 COPB2 Zornitza Stark gene: COPB2 was added
gene: COPB2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly 19, primary, autosomal recessive, MIM# 617800
Review for gene: COPB2 was set to RED
Added comment: Two sibs with homozygous missense variant in this gene, mice homozygous for this variant had normal brain size however. Mice compound het for null allele and missense variant had some brain features, suggesting the missense variant is hypomorphic.
Sources: Expert list
Mendeliome v0.6993 WDR62 Zornitza Stark Gene: wdr62 has been classified as Green List (High Evidence).
Mendeliome v0.6993 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Mendeliome v0.6990 WDR62 Zornitza Stark reviewed gene: WDR62: Rating: GREEN; Mode of pathogenicity: None; Publications: 20890279, 20729831, 20890278, 21496009, 21834044, 22775483, 32677750, 31788460; Phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6990 TRMT10A Zornitza Stark Gene: trmt10a has been classified as Green List (High Evidence).
Mendeliome v0.6987 TRAIP Zornitza Stark Gene: traip has been classified as Green List (High Evidence).
Mendeliome v0.6983 TOP3A Zornitza Stark Gene: top3a has been classified as Green List (High Evidence).
Mendeliome v0.6983 TOP3A Zornitza Stark Phenotypes for gene: TOP3A were changed from to Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, MIM#618098
Mendeliome v0.6980 TOP3A Zornitza Stark reviewed gene: TOP3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057030, 33631320; Phenotypes: Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, MIM#618098; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6980 STIL Zornitza Stark Gene: stil has been classified as Green List (High Evidence).
Mendeliome v0.6980 STIL Zornitza Stark Phenotypes for gene: STIL were changed from to Microcephaly 7, primary, autosomal recessive, MIM# 612703; MONDO:0012989
Mendeliome v0.6977 STIL Zornitza Stark reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive, MIM# 612703, MONDO:0012989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6975 STAMBP Zornitza Stark Gene: stambp has been classified as Green List (High Evidence).
Mendeliome v0.6972 PCNT Zornitza Stark Gene: pcnt has been classified as Green List (High Evidence).
Mendeliome v0.6969 NHEJ1 Zornitza Stark Gene: nhej1 has been classified as Green List (High Evidence).
Mendeliome v0.6969 NHEJ1 Zornitza Stark Phenotypes for gene: NHEJ1 were changed from to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650
Mendeliome v0.6966 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6966 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Mendeliome v0.6963 MSMO1 Zornitza Stark Gene: msmo1 has been classified as Green List (High Evidence).
Mendeliome v0.6963 MSMO1 Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793; Disorders of the metabolism of sterols
Mendeliome v0.6960 MSMO1 Zornitza Stark reviewed gene: MSMO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21285510, 24144731, 28673550, 33161406; Phenotypes: Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834, MONDO:0014793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6960 MCPH1 Zornitza Stark Gene: mcph1 has been classified as Green List (High Evidence).
Mendeliome v0.6960 MCPH1 Zornitza Stark Phenotypes for gene: MCPH1 were changed from to Microcephaly 1, primary, autosomal recessive, MIM# 251200; MONDO:0009617
Mendeliome v0.6957 MCPH1 Zornitza Stark reviewed gene: MCPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12046007, 15199523, 16311745, 20978018, 32294449, 30351297, 29026105; Phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200, MONDO:0009617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6957 ATP1A3 Zornitza Stark Gene: atp1a3 has been classified as Green List (High Evidence).
Mendeliome v0.6953 LARP7 Zornitza Stark Gene: larp7 has been classified as Green List (High Evidence).
Mendeliome v0.6950 KNL1 Zornitza Stark Gene: knl1 has been classified as Green List (High Evidence).
Mendeliome v0.6950 KNL1 Zornitza Stark Phenotypes for gene: KNL1 were changed from to Microcephaly 4, primary, autosomal recessive, MIM# 604321; MONDO:0011437
Mendeliome v0.6947 KNL1 Zornitza Stark reviewed gene: KNL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22983954, 26626498, 27149178, 30304678, 27784895; Phenotypes: Microcephaly 4, primary, autosomal recessive, MIM# 604321, MONDO:0011437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6946 BAAT Zornitza Stark Gene: baat has been classified as Green List (High Evidence).
Mendeliome v0.6943 KIF11 Zornitza Stark Gene: kif11 has been classified as Green List (High Evidence).
Mendeliome v0.6940 IER3IP1 Zornitza Stark Gene: ier3ip1 has been classified as Green List (High Evidence).
Mendeliome v0.6937 EFTUD2 Zornitza Stark Gene: eftud2 has been classified as Green List (High Evidence).
Mendeliome v0.6937 EFTUD2 Zornitza Stark Phenotypes for gene: EFTUD2 were changed from to Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536; Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516
Mendeliome v0.6934 EFTUD2 Zornitza Stark reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305528, 23188108, 33601405, 33262786, 26507355; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536, Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6934 CEP152 Zornitza Stark Gene: cep152 has been classified as Green List (High Evidence).
Mendeliome v0.6934 CEP152 Zornitza Stark Phenotypes for gene: CEP152 were changed from to Microcephaly 9, primary, autosomal recessive, MIM# 614852; MONDO:0013923; Seckel syndrome 5, MIM# 613823; MONDO:0013443
Mendeliome v0.6931 CEP152 Zornitza Stark reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6931 GNPAT Zornitza Stark Gene: gnpat has been classified as Green List (High Evidence).
Mendeliome v0.6931 GNPAT Zornitza Stark Phenotypes for gene: GNPAT were changed from to Rhizomelic chondrodysplasia punctata, type 2, MIM# 222765; MONDO:0009112
Mendeliome v0.6928 GNPAT Zornitza Stark reviewed gene: GNPAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536089, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 2, MIM# 222765, MONDO:0009112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6927 CD4 Zornitza Stark Gene: cd4 has been classified as Green List (High Evidence).
Mendeliome v0.6927 CD4 Zornitza Stark Phenotypes for gene: CD4 were changed from to Immunodeficiency 79, MIM# 619238; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 CD4 Zornitza Stark changed review comment from: Single individual reported, functional data, emerging gene.; to: Two individuals reported, functional data.
Mendeliome v0.6924 CD4 Zornitza Stark edited their review of gene: CD4: Changed rating: GREEN; Changed publications: 31781092, 33471124; Changed phenotypes: Immunodeficiency 79, MIM# 619238, Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 TMEM231 Zornitza Stark Gene: tmem231 has been classified as Green List (High Evidence).
Mendeliome v0.6921 TMEM216 Zornitza Stark Gene: tmem216 has been classified as Green List (High Evidence).
Mendeliome v0.6918 TMEM138 Zornitza Stark Gene: tmem138 has been classified as Green List (High Evidence).
Mendeliome v0.6915 TCTN2 Zornitza Stark Gene: tctn2 has been classified as Green List (High Evidence).
Mendeliome v0.6912 TCTN1 Zornitza Stark Gene: tctn1 has been classified as Green List (High Evidence).
Mendeliome v0.6908 SMCHD1 Zornitza Stark edited their review of gene: SMCHD1: Added comment: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Choanal atresia is a feature. More than 30 unrelated individuals reported. Caused by gain of function missense variants with the extended ATPase domain.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: 28067909; Changed phenotypes: Bosma arhinia microphthalmia syndrome, MIM# 603457, Arhinia, choanal atresia, microphthalmia MONDO:0011323; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6908 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic to Bosma arhinia microphthalmia syndrome, MIM 603457; Arhinia, choanal atresia, microphthalmia MONDO:0011323; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.6906 TXNL4A Zornitza Stark Gene: txnl4a has been classified as Green List (High Evidence).
Mendeliome v0.6906 TXNL4A Zornitza Stark Phenotypes for gene: TXNL4A were changed from to Burn-McKeown syndrome, MIM# 608572; Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064
Mendeliome v0.6903 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25434003; Phenotypes: Burn-McKeown syndrome, MIM# 608572, Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6901 SPINT2 Zornitza Stark changed review comment from: More than 15 unrelated families reported.; to: Well established gene-disease association. PMID 30445423 reviews 34 patients from 26 families: 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation. Choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhoea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhoea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients.
Mendeliome v0.6901 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
Mendeliome v0.6898 MIB1 Zornitza Stark Gene: mib1 has been classified as Green List (High Evidence).
Mendeliome v0.6897 ANO3 Zornitza Stark Gene: ano3 has been classified as Green List (High Evidence).
Mendeliome v0.6894 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6894 IPO8 Zornitza Stark Classified gene: IPO8 as Amber List (moderate evidence)
Mendeliome v0.6894 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6893 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to AMBER
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Expert Review
Mendeliome v0.6891 FAM20C Zornitza Stark Gene: fam20c has been classified as Green List (High Evidence).
Mendeliome v0.6886 ANKS6 Zornitza Stark Gene: anks6 has been classified as Green List (High Evidence).
Mendeliome v0.6886 ANKS6 Zornitza Stark Phenotypes for gene: ANKS6 were changed from to Nephronophthisis 16, MIM# 615382; MONDO:0014158
Mendeliome v0.6883 ANKS6 Zornitza Stark reviewed gene: ANKS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23793029, 31678577, 31635528, 26039630, 24610927; Phenotypes: Nephronophthisis 16, MIM# 615382, MONDO:0014158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6883 GLIS2 Zornitza Stark Phenotypes for gene: GLIS2 were changed from Nephronophthisis 7, OMIM#611498 to Nephronophthisis 7, OMIM#611498; MONDO:0012680
Mendeliome v0.6881 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed publications: 17618285, 23559409, 31676329; Changed phenotypes: Nephronophthisis 7, OMIM#611498, MONDO:0012680
Mendeliome v0.6881 CLDN2 Zornitza Stark Phenotypes for gene: CLDN2 were changed from Susceptibility to pancreatitis to Susceptibility to pancreatitis; Azoospermia, obstructive, with nephrolithiasis, MIM# 301060
Mendeliome v0.6878 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Added comment: Azoospermia: single multigenerational family reported.; Changed publications: 29884332, 31163246, 31320686; Changed phenotypes: Susceptibility to pancreatitis, Azoospermia, obstructive, with nephrolithiasis, MIM# 301060; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6877 FLII Zornitza Stark Classified gene: FLII as Green List (high evidence)
Mendeliome v0.6877 FLII Zornitza Stark Gene: flii has been classified as Green List (High Evidence).
Mendeliome v0.6876 POLR3A Elena Savva commented on gene: POLR3A: c.1909+22G>A is a recurring variant that results in a leaky splice site

Bi-allelic variants associated with Leukodystrophy and with Wiedemann-Rautenstrauch syndrome; note association between mono-allelic variants and susceptibility to severe VZV infection.

Deep intronic variants commonly pathogenic

No clear gen-phen correlation
Mendeliome v0.6876 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Red List (Low Evidence).
Mendeliome v0.6876 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Expert list
Mendeliome v0.6875 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Red List (Low Evidence).
Mendeliome v0.6872 COL4A6 Zornitza Stark Classified gene: COL4A6 as Red List (low evidence)
Mendeliome v0.6872 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Red List (Low Evidence).
Mendeliome v0.6871 RNF6 Zornitza Stark Gene: rnf6 has been classified as Red List (Low Evidence).
Mendeliome v0.6871 RNF6 Zornitza Stark Classified gene: RNF6 as Red List (low evidence)
Mendeliome v0.6871 RNF6 Zornitza Stark Gene: rnf6 has been classified as Red List (Low Evidence).
Mendeliome v0.6870 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Mendeliome v0.6867 BMPR2 Zornitza Stark Gene: bmpr2 has been classified as Green List (High Evidence).
Mendeliome v0.6867 BMPR2 Zornitza Stark Phenotypes for gene: BMPR2 were changed from to Pulmonary venoocclusive disease 1 MIM#265450; Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600
Mendeliome v0.6863 BMPR2 Elena Savva reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33380512; Phenotypes: Pulmonary venoocclusive disease 1 MIM#265450, Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600, Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6863 ZNF711 Zornitza Stark Gene: znf711 has been classified as Green List (High Evidence).
Mendeliome v0.6860 SLC35A2 Zornitza Stark Gene: slc35a2 has been classified as Green List (High Evidence).
Mendeliome v0.6860 SLC35A2 Zornitza Stark Phenotypes for gene: SLC35A2 were changed from to Congenital disorder of glycosylation, type IIm (MIM #300896) 30817854; Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)
Mendeliome v0.6857 SLC35A2 Zornitza Stark reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561849, 24115232, 27743886, 25778940, 33407896; Phenotypes: Congenital disorder of glycosylation, type IIm (MIM #300896) 30817854, Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE); 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 v0.6856 MEF2A Zornitza Stark Gene: mef2a has been classified as Red List (Low Evidence).
Mendeliome v0.6855 MEF2A Zornitza Stark Classified gene: MEF2A as Red List (low evidence)
Mendeliome v0.6855 MEF2A Zornitza Stark Gene: mef2a has been classified as Red List (Low Evidence).
Mendeliome v0.6854 FN1 Zornitza Stark Gene: fn1 has been classified as Green List (High Evidence).
Mendeliome v0.6854 FN1 Zornitza Stark Phenotypes for gene: FN1 were changed from to Glomerulopathy with fibronectin deposits 2 (MIM#601894); Spondylometaphyseal dysplasia, corner fracture type (MIM#184255)
Mendeliome v0.6851 IL37 Zornitza Stark Gene: il37 has been classified as Red List (Low Evidence).
Mendeliome v0.6851 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Mendeliome v0.6850 PEX10 Teresa Zhao reviewed gene: PEX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30640048; Phenotypes: Peroxisome biogenesis disorder 6A (Zellweger) (MIM#614870), Peroxisome biogenesis disorder 6B (MIM#614871); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6850 FN1 Ain Roesley reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100092; Phenotypes: Glomerulopathy with fibronectin deposits 2 (MIM#601894), Spondylometaphyseal dysplasia, corner fracture type (MIM#184255); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6850 CHRDL1 Zornitza Stark Gene: chrdl1 has been classified as Green List (High Evidence).
Mendeliome v0.6847 HDL2 Bryony Thompson Str: hdl2 has been classified as Green List (High Evidence).
Mendeliome v0.6847 HDL2 Bryony Thompson Classified STR: HDL2 as Green List (high evidence)
Mendeliome v0.6847 HDL2 Bryony Thompson Str: hdl2 has been classified as Green List (High Evidence).
Mendeliome v0.6846 HDL2 Bryony Thompson STR: HDL2 was added
STR: HDL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: HDL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: HDL2 were set to 20301701
Phenotypes for STR: HDL2 were set to Huntington disease-like 2 MIM#606438
Review for STR: HDL2 was set to GREEN
STR: HDL2 was marked as clinically relevant
Added comment: NM_001271604.2:c.431CTG[X] or NM_020655.4:c.382+760CTG[X]
In an alternatively spliced exon, the repeat can be transcribed in both directions, leading to CUG (more common) or CAG (less common) repeat-containing transcripts. While a dominant RNA toxic effect may occur, the repeat expansion also reduces levels of the Junctophilin-3 protein
Normal: ≤28 repeats
Questionable significance: 29-39 repeats, mutable normal or reduced penetrance included
Full penetrance: ≥40 repeats
Sources: Expert list
Mendeliome v0.6845 JPH3 Bryony Thompson Classified gene: JPH3 as No list
Mendeliome v0.6845 JPH3 Bryony Thompson Added comment: Comment on list classification: See STRs for this panel
Mendeliome v0.6844 DM2 Bryony Thompson Str: dm2 has been classified as Green List (High Evidence).
Mendeliome v0.6844 DM2 Bryony Thompson Classified STR: DM2 as Green List (high evidence)
Mendeliome v0.6844 DM2 Bryony Thompson Str: dm2 has been classified as Green List (High Evidence).
Mendeliome v0.6843 DM2 Bryony Thompson STR: DM2 was added
STR: DM2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM2 were set to 20301639; 29325606
Phenotypes for STR: DM2 were set to Myotonic dystrophy 2 MIM#602668
Review for STR: DM2 was set to GREEN
STR: DM2 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_003418.4:c.-14-833_-14-830[X]
Toxic gain of function RNA expected mechanism of disease
Normal: ≤30 uninterrupted CCTG repeats, 11-26 CCTG repeats with any GCTC or TCTG interruptions
Unknown significance (normal vs. mutable): 27-29 CCTG repeats
Mutable normal (premutation) alleles. ~30-~54 CCTG repeats
Unknown significance (premutation vs pathogenic): ~55-74 CCTG repeats
Pathogenic: ~75-11,000 CCTG repeats
Sources: Expert list
Mendeliome v0.6842 CNBP Bryony Thompson Classified gene: CNBP as No list
Mendeliome v0.6842 CNBP Bryony Thompson Added comment: Comment on list classification: Condition is caused by a CCTG expansion in intron 1. No reported SNVs or indels reported in association with disease. Present under STRs on this panel
Mendeliome v0.6841 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Mendeliome v0.6841 DM1 Bryony Thompson Classified STR: DM1 as Green List (high evidence)
Mendeliome v0.6841 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Mendeliome v0.6840 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Mendeliome v0.6839 DMPK Bryony Thompson Classified gene: DMPK as No list
Mendeliome v0.6839 DMPK Bryony Thompson Added comment: Comment on list classification: STR is the only cause of condition for this gene and is present in STRs for this panel.
Mendeliome v0.6838 SCA17 Bryony Thompson Str: sca17 has been classified as Green List (High Evidence).
Mendeliome v0.6838 SCA17 Bryony Thompson Classified STR: SCA17 as Green List (high evidence)
Mendeliome v0.6838 SCA17 Bryony Thompson Str: sca17 has been classified as Green List (High Evidence).
Mendeliome v0.6836 TBP Bryony Thompson Classified gene: TBP as No list
Mendeliome v0.6836 TBP Bryony Thompson Added comment: Comment on list classification: See STRs
Mendeliome v0.6835 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.6835 SCA12 Bryony Thompson Classified STR: SCA12 as Green List (high evidence)
Mendeliome v0.6835 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.6834 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 29325606; 20301381
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Reduced penetrance: ~40-66 repeats
Full penetrance: ≥66 repeats
Sources: Expert list
Mendeliome v0.6833 PPP2R2B Bryony Thompson Classified gene: PPP2R2B as No list
Mendeliome v0.6832 SCA36 Bryony Thompson Str: sca36 has been classified as Green List (High Evidence).
Mendeliome v0.6832 SCA36 Bryony Thompson Classified STR: SCA36 as Green List (high evidence)
Mendeliome v0.6832 SCA36 Bryony Thompson Str: sca36 has been classified as Green List (High Evidence).
Mendeliome v0.6831 SCA36 Bryony Thompson STR: SCA36 was added
STR: SCA36 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA36 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA36 were set to 25101480
Phenotypes for STR: SCA36 were set to Spinocerebellar ataxia 36 MIM#614153
Review for STR: SCA36 was set to GREEN
STR: SCA36 was marked as clinically relevant
Added comment: NM_006392​.3:c.3+71GGCCTG[X]
Toxic RNA effect is suggested mechanism of disease
Normal: 3-14 repeats
Uncertain significance: 15-650 repeats
Pathogenic: ≥650 repeats
Sources: Expert list
Mendeliome v0.6830 NOP56 Bryony Thompson Classified gene: NOP56 as No list
Mendeliome v0.6830 NOP56 Bryony Thompson Added comment: Comment on list classification: A hexanucleotide (GGCCTG) repeat expansion in the first intron of the NOP56 gene is the only reported cause of disease. See STRS
Mendeliome v0.6829 SCA37 Bryony Thompson Str: sca37 has been classified as Green List (High Evidence).
Mendeliome v0.6829 SCA37 Bryony Thompson Classified STR: SCA37 as Green List (high evidence)
Mendeliome v0.6829 SCA37 Bryony Thompson Str: sca37 has been classified as Green List (High Evidence).
Mendeliome v0.6828 SCA37 Bryony Thompson STR: SCA37 was added
STR: SCA37 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA37 were set to 28686858; 31145571
Phenotypes for STR: SCA37 were set to Spinocerebellar ataxia 37 MIM#615945
Review for STR: SCA37 was set to GREEN
STR: SCA37 was marked as clinically relevant
Added comment: NC_000001.10:g.57832716_57832797ins[(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90]
Located in a 5'UTR intron, flanked by (ATTTT)n on both sides
Non-pathogenic allele: (ATTTT)7–400
Pathogenic allele: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90]
Sources: Expert list
Mendeliome v0.6827 DAB1 Bryony Thompson Classified gene: DAB1 as No list
Mendeliome v0.6826 SCA31 Bryony Thompson Str: sca31 has been classified as Green List (High Evidence).
Mendeliome v0.6826 SCA31 Bryony Thompson Classified STR: SCA31 as Green List (high evidence)
Mendeliome v0.6826 SCA31 Bryony Thompson Str: sca31 has been classified as Green List (High Evidence).
Mendeliome v0.6825 SCA31 Bryony Thompson STR: SCA31 was added
STR: SCA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA31 were set to 19878914; 31755042
Phenotypes for STR: SCA31 were set to Spinocerebellar ataxia 31 MIM#117210
Review for STR: SCA31 was set to GREEN
STR: SCA31 was marked as clinically relevant
Added comment: Complex repeat insertion (TGGAA)n, (TAGAA)n, (TAAAA)n, (TAAAATAGAA)n, TGGAA is present only in affected cases. Sequencing showed that the insertion consisted of a preceding TCAC sequence, and 3 pentanucleotide repeat components (TGGAA)n, (TAGAA)n, and (TAAAA)n in all patients tested.
2.5-3.8 KB insertion is associated with disease and RNA toxicity expected to be mechanism of disease
Normal and pathogenic cut-offs are based on animal model experiments (PMID: 31755042)
Sources: Expert list
Mendeliome v0.6824 BEAN1 Bryony Thompson Classified gene: BEAN1 as No list
Mendeliome v0.6823 SCA7 Bryony Thompson Str: sca7 has been classified as Green List (High Evidence).
Mendeliome v0.6823 SCA7 Bryony Thompson Classified STR: SCA7 as Green List (high evidence)
Mendeliome v0.6823 SCA7 Bryony Thompson Str: sca7 has been classified as Green List (High Evidence).
Mendeliome v0.6821 ATXN7 Bryony Thompson Classified gene: ATXN7 as No list
Mendeliome v0.6820 SCA3 Bryony Thompson Str: sca3 has been classified as Green List (High Evidence).
Mendeliome v0.6820 SCA3 Bryony Thompson Classified STR: SCA3 as Green List (high evidence)
Mendeliome v0.6820 SCA3 Bryony Thompson Str: sca3 has been classified as Green List (High Evidence).
Mendeliome v0.6819 SCA3 Bryony Thompson STR: SCA3 was added
STR: SCA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA3 were set to 20301375; 29325606
Phenotypes for STR: SCA3 were set to Machado-Joseph disease MIM#109150; Spinocerebellar ataxia type 3
Review for STR: SCA3 was set to GREEN
STR: SCA3 was marked as clinically relevant
Added comment: NM_004993​.5:c.886_888CAG[X]
Toxic aggregation and mislocalization in neurons is mechanism of disease
Normal: ≤44 repeats, mostly <31 repeats
Intermediate: 45-59 repeats, some intermediate alleles are not associated with classic clinical features of SCA3
Pathogenic (full penetrance): ≥60 repeats
Sources: Expert list
Mendeliome v0.6818 ATXN3 Bryony Thompson Classified gene: ATXN3 as No list
Mendeliome v0.6817 SCA2 Bryony Thompson Str: sca2 has been classified as Green List (High Evidence).
Mendeliome v0.6817 SCA2 Bryony Thompson Classified STR: SCA2 as Green List (high evidence)
Mendeliome v0.6817 SCA2 Bryony Thompson Str: sca2 has been classified as Green List (High Evidence).
Mendeliome v0.6816 SCA2 Bryony Thompson STR: SCA2 was added
STR: SCA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA2 were set to 29325606; 20301452
Phenotypes for STR: SCA2 were set to Spinocerebellar ataxia 2 MIM#183090
Review for STR: SCA2 was set to GREEN
STR: SCA2 was marked as clinically relevant
Added comment: NM_002973​.3:c.496_498CAG[X]
Toxic protein aggregation is mechanism of disease
Benign: ≤31 repeats (homozygous 31/31 repeats reported for recessive SCA2)
Uncertain: 32 repeats
ALS risk allele: 30-32 repeats
Reduced penetrance: 33-34 repeats, may not develop symptoms or only very late in life
Full penetrance: ≥35 repeats
Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size, but may enhance the meiotic stability of the repeat
Sources: Expert list
Mendeliome v0.6815 ATXN2 Bryony Thompson Classified gene: ATXN2 as No list
Mendeliome v0.6814 SCA10 Bryony Thompson Str: sca10 has been classified as Green List (High Evidence).
Mendeliome v0.6814 SCA10 Bryony Thompson Classified STR: SCA10 as Green List (high evidence)
Mendeliome v0.6814 SCA10 Bryony Thompson Str: sca10 has been classified as Green List (High Evidence).
Mendeliome v0.6813 SCA10 Bryony Thompson STR: SCA10 was added
STR: SCA10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA10 were set to 20301354
Phenotypes for STR: SCA10 were set to Spinocerebellar ataxia 10 MIM#603516
Review for STR: SCA10 was set to GREEN
STR: SCA10 was marked as clinically relevant
Added comment: NM_013236​.2:c.1430+54822ATTCT[X]
Toxic RNA gain-of-function mechanism of disease
Normal alleles: 10-32 ATTCT repeats
Alleles of questionable significance: 33-280 ATTCT repeats
Reduced-penetrance alleles: 33-850 repeats
Full-penetrance alleles: 800-4,500 ATTCT repeats
Sources: Expert list
Mendeliome v0.6812 ATXN10 Bryony Thompson Classified gene: ATXN10 as No list
Mendeliome v0.6811 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6811 INPP4A Zornitza Stark Classified gene: INPP4A as Amber List (moderate evidence)
Mendeliome v0.6811 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6810 INPP4A Zornitza Stark gene: INPP4A was added
gene: INPP4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Phenotypes for gene: INPP4A were set to Intellectual disability
Review for gene: INPP4A was set to AMBER
Added comment: Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.
Sources: Literature
Mendeliome v0.6808 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.; Changed phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228, Kohlschutter-Tonz syndrome-like, MIM# 619229
Mendeliome v0.6808 SATB1 Zornitza Stark commented on gene: SATB1: Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present. 12 individuals from 11 families reported (one inherited variant, affected parent).
Mendeliome v0.6805 MKS1 Zornitza Stark Gene: mks1 has been classified as Green List (High Evidence).
Mendeliome v0.6802 FLII Zornitza Stark Gene: flii has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6802 FLII Zornitza Stark Classified gene: FLII as Amber List (moderate evidence)
Mendeliome v0.6802 FLII Zornitza Stark Gene: flii has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6800 RHBDF1 Zornitza Stark Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6800 RHBDF1 Zornitza Stark Classified gene: RHBDF1 as Amber List (moderate evidence)
Mendeliome v0.6800 RHBDF1 Zornitza Stark Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6798 MYLK3 Zornitza Stark Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6798 MYLK3 Zornitza Stark Classified gene: MYLK3 as Amber List (moderate evidence)
Mendeliome v0.6798 MYLK3 Zornitza Stark Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6797 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Mendeliome v0.6796 NRAP Zornitza Stark Gene: nrap has been classified as Green List (High Evidence).
Mendeliome v0.6796 NRAP Zornitza Stark Classified gene: NRAP as Green List (high evidence)
Mendeliome v0.6796 NRAP Zornitza Stark Gene: nrap has been classified as Green List (High Evidence).
Mendeliome v0.6794 MPEG1 Zornitza Stark Gene: mpeg1 has been classified as Green List (High Evidence).
Mendeliome v0.6794 MPEG1 Zornitza Stark Classified gene: MPEG1 as Green List (high evidence)
Mendeliome v0.6794 MPEG1 Zornitza Stark Gene: mpeg1 has been classified as Green List (High Evidence).
Mendeliome v0.6793 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Expert list
Mendeliome v0.6791 INPP5E Zornitza Stark Gene: inpp5e has been classified as Green List (High Evidence).
Mendeliome v0.6791 INPP5E Zornitza Stark Phenotypes for gene: INPP5E were changed from to Joubert syndrome 1, MIM# 213300; MONDO:0008944; Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156; MONDO:0012423
Mendeliome v0.6788 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6788 CSPP1 Zornitza Stark Gene: cspp1 has been classified as Green List (High Evidence).
Mendeliome v0.6785 CSPP1 Zornitza Stark changed review comment from: More than 20 unrelated families reported.; to: More than 20 unrelated families reported. Classically associated with Joubert syndrome; however, note 4 individuals reported with features consistent with Jeune asphyxiating thoracic dystrophy, including short ribs, bell-shaped chest, and pulmonary hypoplasia.
Mendeliome v0.6785 CEP41 Zornitza Stark Gene: cep41 has been classified as Green List (High Evidence).
Mendeliome v0.6782 SCA1 Bryony Thompson Str: sca1 has been classified as Green List (High Evidence).
Mendeliome v0.6782 SCA1 Bryony Thompson Classified STR: SCA1 as Green List (high evidence)
Mendeliome v0.6782 SCA1 Bryony Thompson Str: sca1 has been classified as Green List (High Evidence).
Mendeliome v0.6780 ATXN1 Bryony Thompson Classified gene: ATXN1 as No list
Mendeliome v0.6779 RANBP2 Bryony Thompson Gene: ranbp2 has been classified as Green List (High Evidence).
Mendeliome v0.6779 NCSTN Bryony Thompson Gene: ncstn has been classified as Green List (High Evidence).
Mendeliome v0.6779 PSENEN Bryony Thompson Gene: psenen has been classified as Green List (High Evidence).
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Gene: aldh1l2 has been classified as Red List (Low Evidence).
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Classified gene: ALDH1L2 as Red List (low evidence)
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Gene: aldh1l2 has been classified as Red List (Low Evidence).
Mendeliome v0.6775 ESCO2 Zornitza Stark Gene: esco2 has been classified as Green List (High Evidence).
Mendeliome v0.6771 RNF113A Bryony Thompson Classified gene: RNF113A as Green List (high evidence)
Mendeliome v0.6771 RNF113A Bryony Thompson Added comment: Comment on list classification: Additional cases published
Mendeliome v0.6771 RNF113A Bryony Thompson Gene: rnf113a has been classified as Green List (High Evidence).
Mendeliome v0.6769 ALDH1L2 Naomi Baker gene: ALDH1L2 was added
gene: ALDH1L2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1L2 were set to PMID: 31341639; 33168096
Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks
Review for gene: ALDH1L2 was set to RED
Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease.
Sources: Literature
Mendeliome v0.6769 FAM57B Zornitza Stark Gene: fam57b has been classified as Green List (High Evidence).
Mendeliome v0.6769 FAM57B Zornitza Stark Classified gene: FAM57B as Green List (high evidence)
Mendeliome v0.6769 FAM57B Zornitza Stark Gene: fam57b has been classified as Green List (High Evidence).
Mendeliome v0.6768 FAM57B Zornitza Stark gene: FAM57B was added
gene: FAM57B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM57B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM57B were set to 33077892
Phenotypes for gene: FAM57B were set to Cone–rod dystrophy; Maculopathy
Review for gene: FAM57B was set to GREEN
Added comment: 4 patients with cone-rod dystrophy or maculopathy from 3 families, with LOF pathogenic variants in TLCD3B (ceramide synthase gene). Ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. Variants segregated with disease. TLCD3B showed high expression in the adult retina with higher expression in the macular than in the peripheral region. Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.
Sources: Literature
Mendeliome v0.6767 LRRC8A Bryony Thompson Gene: lrrc8a has been classified as Red List (Low Evidence).
Mendeliome v0.6767 LRRC8A Bryony Thompson Classified gene: LRRC8A as Red List (low evidence)
Mendeliome v0.6767 LRRC8A Bryony Thompson Gene: lrrc8a has been classified as Red List (Low Evidence).
Mendeliome v0.6766 LRRC8A Bryony Thompson changed review comment from: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence; to: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence could be identified.
Mendeliome v0.6766 SIAE Bryony Thompson Marked gene: SIAE as ready
Mendeliome v0.6766 SIAE Bryony Thompson Gene: siae has been classified as Red List (Low Evidence).
Mendeliome v0.6766 SIAE Bryony Thompson Classified gene: SIAE as Red List (low evidence)
Mendeliome v0.6766 SIAE Bryony Thompson Gene: siae has been classified as Red List (Low Evidence).
Mendeliome v0.6765 SIAE Bryony Thompson reviewed gene: SIAE: Rating: RED; Mode of pathogenicity: None; Publications: 20555325, 28900629, 22200769; Phenotypes: {Autoimmune disease, susceptibility to, 6} MIM#613551; Mode of inheritance: Unknown
Mendeliome v0.6765 TAOK2 Bryony Thompson Gene: taok2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6765 TAOK2 Bryony Thompson edited their review of gene: TAOK2: Changed phenotypes: Generalized verrucosis, abnormal T cell activation, autism
Mendeliome v0.6765 TAOK2 Bryony Thompson Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation to Generalized verrucosis; abnormal T cell activation; autism
Mendeliome v0.6764 TAOK2 Bryony Thompson Classified gene: TAOK2 as Amber List (moderate evidence)
Mendeliome v0.6764 TAOK2 Bryony Thompson Gene: taok2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6763 TAOK2 Bryony Thompson gene: TAOK2 was added
gene: TAOK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAOK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TAOK2 were set to 28385331; 29467497
Phenotypes for gene: TAOK2 were set to Generalized verrucosis; abnormal T cell activation
Review for gene: TAOK2 was set to AMBER
Added comment: PMID: 28385331 - A single consanguineous family with generalized verrucosis and abnormal T cell activation, and a homozygous missense (p.R700C), with some assays on patient fibroblasts.
PMID: 29467497 - One of the several genes in the 16p11.2 microdeletion region associated with autism. Taok2 heterozygous and knockout mice had gene dosage-dependent impairments in cognition, anxiety, social interaction, brain size, and neural connectivity. 3 de novo variants and 3 predicted loss of function variants identified in 6 unrelated autism cases. 2 of the de novo variants have supporting functional assays, but 1 of them co-occurs in an individual with a CHD8 frameshift. 1 of the predicted loss of function variants was also identified in the unaffected father and sibling.
Sources: Literature
Mendeliome v0.6762 CC2D2A Zornitza Stark Gene: cc2d2a has been classified as Green List (High Evidence).
Mendeliome v0.6759 POLR3GL Zornitza Stark Phenotypes for gene: POLR3GL were changed from endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy to Short stature, oligodontia, dysmorphic facies, and motor delay (SOFM), MIM#619234; endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Mendeliome v0.6758 INVS Zornitza Stark Gene: invs has been classified as Green List (High Evidence).
Mendeliome v0.6758 INVS Zornitza Stark Phenotypes for gene: INVS were changed from to Nephronophthisis 2, infantile, (MIM#602088)
Mendeliome v0.6755 INVS Paul De Fazio reviewed gene: INVS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872123, 19177160; Phenotypes: Nephronophthisis 2, infantile, (MIM#602088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Classified gene: ZCCHC8 as Amber List (moderate evidence)
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6754 ZCCHC8 Bryony Thompson gene: ZCCHC8 was added
gene: ZCCHC8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Mendeliome v0.6753 KDM5B Zornitza Stark reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, Intellectual disability and/or autism, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6753 KDM5B Zornitza Stark Gene: kdm5b has been classified as Green List (High Evidence).
Mendeliome v0.6753 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from to Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant
Mendeliome v0.6750 TPP2 Zornitza Stark Gene: tpp2 has been classified as Green List (High Evidence).
Mendeliome v0.6747 DOCK7 Zornitza Stark Gene: dock7 has been classified as Green List (High Evidence).
Mendeliome v0.6742 UBAP1 Zornitza Stark changed review comment from: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.; to: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.

PMID 32934340: additional 7 families. Median age of onset 10yrs.
Mendeliome v0.6742 RTN2 Zornitza Stark Gene: rtn2 has been classified as Green List (High Evidence).
Mendeliome v0.6739 KDM5B Elena Savva reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29276005, 30217758, 30409806; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, autosomal dominant autism spectrum disorder or intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6739 NIPA1 Zornitza Stark Gene: nipa1 has been classified as Green List (High Evidence).
Mendeliome v0.6736 DDHD1 Zornitza Stark Gene: ddhd1 has been classified as Green List (High Evidence).
Mendeliome v0.6736 DDHD1 Zornitza Stark Phenotypes for gene: DDHD1 were changed from to Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256
Mendeliome v0.6733 DDHD1 Zornitza Stark reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6730 CAPN1 Zornitza Stark Phenotypes for gene: CAPN1 were changed from Spastic paraplegia 76, autosomal recessive, MIM#616907 to Spastic paraplegia 76, autosomal recessive, MIM#616907; MONDO:0014827
Mendeliome v0.6729 AP5Z1 Zornitza Stark Gene: ap5z1 has been classified as Green List (High Evidence).
Mendeliome v0.6729 AP5Z1 Zornitza Stark Phenotypes for gene: AP5Z1 were changed from to Spastic paraplegia 48, autosomal recessive, MIM# 613647; MONDO:0013342
Mendeliome v0.6726 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26085577, 33543803, 27606357; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647, MONDO:0013342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6726 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6726 COPB1 Zornitza Stark Classified gene: COPB1 as Amber List (moderate evidence)
Mendeliome v0.6726 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6724 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; MONDO:0014725
Mendeliome v0.6723 SLC1A4 Zornitza Stark Gene: slc1a4 has been classified as Green List (High Evidence).
Mendeliome v0.6723 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657
Mendeliome v0.6720 TFG Zornitza Stark Gene: tfg has been classified as Green List (High Evidence).
Mendeliome v0.6720 TFG Zornitza Stark Phenotypes for gene: TFG were changed from to Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484; Spastic paraplegia 57, autosomal recessive, MIM# 615658
Mendeliome v0.6718 TFG Zornitza Stark reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30467354, 30157421, 28124177, 27601211, 27492651, 23479643, 25098539, 23553329, 22883144, 31449671, 31111683; Phenotypes: Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484, Spastic paraplegia 57, autosomal recessive, MIM# 615658; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6718 WDR45B Zornitza Stark Gene: wdr45b has been classified as Green List (High Evidence).
Mendeliome v0.6715 REEP2 Zornitza Stark Gene: reep2 has been classified as Green List (High Evidence).
Mendeliome v0.6715 REEP2 Zornitza Stark Phenotypes for gene: REEP2 were changed from to Spastic paraplegia 72, dominant and recessive, MIM# 615625; MONDO:0014282
Mendeliome v0.6712 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33526816, 28491902, 24388663; Phenotypes: Spastic paraplegia 72, dominant and recessive, MIM# 615625, MONDO:0014282; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6712 NT5C2 Zornitza Stark Gene: nt5c2 has been classified as Green List (High Evidence).
Mendeliome v0.6712 NT5C2 Zornitza Stark Phenotypes for gene: NT5C2 were changed from to Spastic paraplegia 45, autosomal recessive, MIM# 613162; MONDO:0013165
Mendeliome v0.6709 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 32153630, 29123918, 28884889, 28327087; Phenotypes: Spastic paraplegia 45, autosomal recessive, MIM# 613162, MONDO:0013165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6709 HACE1 Zornitza Stark Gene: hace1 has been classified as Green List (High Evidence).
Mendeliome v0.6706 NKX6-2 Zornitza Stark Gene: nkx6-2 has been classified as Green List (High Evidence).
Mendeliome v0.6706 NKX6-2 Zornitza Stark Phenotypes for gene: NKX6-2 were changed from to Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, MIM# 617560; MONDO:0033043
Mendeliome v0.6703 NKX6-2 Zornitza Stark reviewed gene: NKX6-2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28575651, 15601927, 32246862, 32004679; Phenotypes: Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, MIM# 617560, MONDO:0033043; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6703 ARPC1B Zornitza Stark Gene: arpc1b has been classified as Green List (High Evidence).
Mendeliome v0.6703 ARPC1B Zornitza Stark Phenotypes for gene: ARPC1B were changed from to Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718
Mendeliome v0.6700 ARPC1B Zornitza Stark reviewed gene: ARPC1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28368018, 33679784; Phenotypes: Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6699 KDM5C Zornitza Stark changed review comment from: Progressive lower limb spasticity is a feature of this ID syndrome. More than 5 unrelated families reported.; to: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.
Mendeliome v0.6699 KDM5C Zornitza Stark Gene: kdm5c has been classified as Green List (High Evidence).
Mendeliome v0.6696 ENTPD1 Zornitza Stark Gene: entpd1 has been classified as Green List (High Evidence).
Mendeliome v0.6696 ENTPD1 Zornitza Stark Phenotypes for gene: ENTPD1 were changed from to Spastic paraplegia 64, autosomal recessive MIM#615683
Mendeliome v0.6693 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive MIM#615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6693 C12orf65 Zornitza Stark Gene: c12orf65 has been classified as Green List (High Evidence).
Mendeliome v0.6693 C12orf65 Zornitza Stark Phenotypes for gene: C12orf65 were changed from to Spastic paraplegia 55, autosomal recessive, MIM#615035; Combined oxidative phosphorylation deficiency 7, MIM# 613559
Mendeliome v0.6690 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23188110, 24080142, 24198383, 20598281, 32808965, 32478789, 28804760; Phenotypes: Spastic paraplegia 55, autosomal recessive, MIM#615035, Combined oxidative phosphorylation deficiency 7, MIM# 613559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6690 C19orf12 Zornitza Stark Gene: c19orf12 has been classified as Green List (High Evidence).
Mendeliome v0.6690 C19orf12 Zornitza Stark Phenotypes for gene: C19orf12 were changed from to Neurodegeneration with brain iron accumulation 4, MIM# 614298; Spastic paraplegia 43, autosomal recessive, MIM# 615043
Mendeliome v0.6687 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33688131, 21981780, 22508347, 23269600, 31804703, 30088953, 20039086; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298, Spastic paraplegia 43, autosomal recessive, MIM# 615043; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6687 CYP2U1 Zornitza Stark Gene: cyp2u1 has been classified as Green List (High Evidence).
Mendeliome v0.6687 CYP2U1 Zornitza Stark Phenotypes for gene: CYP2U1 were changed from to Spastic paraplegia 56, autosomal recessive, MIM#615030
Mendeliome v0.6684 CYP2U1 Zornitza Stark edited their review of gene: CYP2U1: Added comment: SPG56 is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy. Onset is typically in the first decade. More than 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 23176821, 32006740, 29034544
Mendeliome v0.6684 IFRD1 Zornitza Stark Gene: ifrd1 has been classified as Red List (Low Evidence).
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6683 KLC4 Zornitza Stark Gene: klc4 has been classified as Red List (Low Evidence).
Mendeliome v0.6683 KLC4 Zornitza Stark gene: KLC4 was added
gene: KLC4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC4 were set to 26423925
Phenotypes for gene: KLC4 were set to Complicated hereditary spastic paraplegia
Review for gene: KLC4 was set to RED
Added comment: Single family reported.
Sources: Expert Review
Mendeliome v0.6682 AP4M1 Zornitza Stark Gene: ap4m1 has been classified as Green List (High Evidence).
Mendeliome v0.6682 AP4M1 Zornitza Stark Phenotypes for gene: AP4M1 were changed from to Spastic paraplegia 50, autosomal recessive, MIM# 612936
Mendeliome v0.6679 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559397, 21937992, 21937992, 32979048, 31915823, 29096665, 28464862, 25496299; Phenotypes: Spastic paraplegia 50, autosomal recessive, MIM# 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6679 ADAMTS13 Zornitza Stark Gene: adamts13 has been classified as Green List (High Evidence).
Mendeliome v0.6676 AP4S1 Zornitza Stark Gene: ap4s1 has been classified as Green List (High Evidence).
Mendeliome v0.6676 AP4S1 Zornitza Stark Phenotypes for gene: AP4S1 were changed from to Spastic paraplegia 52, autosomal recessive, MIM# 614067
Mendeliome v0.6673 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 25552650, 32979048, 32216065, 31915823, 30283821, 27444738; Phenotypes: Spastic paraplegia 52, autosomal recessive, MIM# 614067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6673 AIMP1 Zornitza Stark Gene: aimp1 has been classified as Green List (High Evidence).
Mendeliome v0.6667 CC2D1A Zornitza Stark Gene: cc2d1a has been classified as Green List (High Evidence).
Mendeliome v0.6667 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from to Autosomal recessive mental retardation, (MIM#608443)
Mendeliome v0.6664 CC2D1A Zornitza Stark reviewed gene: CC2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066123; Phenotypes: Autosomal recessive mental retardation, (MIM#608443); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6664 ZAP70 Zornitza Stark Gene: zap70 has been classified as Green List (High Evidence).
Mendeliome v0.6660 GDF5 Michelle Torres reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: 8589725, 33333243; Phenotypes: ? Hunter-Thompson type acromesomelic dysplasia (MIM#201250) AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6660 CST3 Zornitza Stark Gene: cst3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6657 CST3 Zornitza Stark Classified gene: CST3 as Amber List (moderate evidence)
Mendeliome v0.6657 CST3 Zornitza Stark Gene: cst3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6656 NR3C1 Zornitza Stark Gene: nr3c1 has been classified as Green List (High Evidence).
Mendeliome v0.6656 NR3C1 Zornitza Stark Phenotypes for gene: NR3C1 were changed from to Glucocorticoid resistance, OMIM # 615962
Mendeliome v0.6653 NR3C1 Zornitza Stark reviewed gene: NR3C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12754700, 1704018, 8445027, 31995340, 30158362; Phenotypes: Glucocorticoid resistance, OMIM # 615962; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6652 YY1AP1 Zornitza Stark commented on gene: YY1AP1: Grange syndrome: multiple arterial stenoses, severe early onset hypertension, fibromuscular dysplasia, variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Missense variant reported PMID: 31633303 with moyamoya like phenotype in adult case; fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein but most LOF. PMID: 30556293 non coding variants reported (intronic variants leading to aberrant splicing)
Mendeliome v0.6652 NOS3 Zornitza Stark Gene: nos3 has been classified as Red List (Low Evidence).
Mendeliome v0.6652 NOS3 Zornitza Stark Phenotypes for gene: NOS3 were changed from to {Hypertension, susceptibility to}, MIM#145500; {Ischemic stroke, susceptibility to}, MIM# 601367; {Hypertension, pregnancy-induced}, MIM# 189800
Mendeliome v0.6650 NOS3 Zornitza Stark Classified gene: NOS3 as Red List (low evidence)
Mendeliome v0.6650 NOS3 Zornitza Stark Gene: nos3 has been classified as Red List (Low Evidence).
Mendeliome v0.6649 NOS3 Zornitza Stark reviewed gene: NOS3: Rating: RED; Mode of pathogenicity: None; Publications: 24986538, 28084234, 33652340; Phenotypes: {Hypertension, susceptibility to}, MIM#145500, {Ischemic stroke, susceptibility to}, MIM# 601367, {Hypertension, pregnancy-induced}, MIM# 189800; Mode of inheritance: Unknown
Mendeliome v0.6649 CDT1 Zornitza Stark Gene: cdt1 has been classified as Green List (High Evidence).
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Gene: cdk5rap2 has been classified as Green List (High Evidence).
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Phenotypes for gene: CDK5RAP2 were changed from to Microcephaly 3, primary, autosomal recessive, MIM# 604804; MONDO:0011488
Mendeliome v0.6643 CDK5RAP2 Zornitza Stark reviewed gene: CDK5RAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15793586, 22887808, 23995685, 23726037, 27761245, 20460369, 32677750, 32015000; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM# 604804, MONDO:0011488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6643 UGT2B17 Zornitza Stark Gene: ugt2b17 has been classified as Red List (Low Evidence).
Mendeliome v0.6643 UGT2B17 Zornitza Stark Classified gene: UGT2B17 as Red List (low evidence)
Mendeliome v0.6643 UGT2B17 Zornitza Stark Gene: ugt2b17 has been classified as Red List (Low Evidence).
Mendeliome v0.6640 PLD1 Zornitza Stark Classified gene: PLD1 as Green List (high evidence)
Mendeliome v0.6640 PLD1 Zornitza Stark Gene: pld1 has been classified as Green List (High Evidence).
Mendeliome v0.6639 DONSON Zornitza Stark Gene: donson has been classified as Green List (High Evidence).
Mendeliome v0.6636 SQOR Zornitza Stark Gene: sqor has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6635 SQOR Zornitza Stark Classified gene: SQOR as Amber List (moderate evidence)
Mendeliome v0.6635 SQOR Zornitza Stark Gene: sqor has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6633 PGK1 Zornitza Stark Gene: pgk1 has been classified as Green List (High Evidence).
Mendeliome v0.6630 PGM1 Zornitza Stark Gene: pgm1 has been classified as Green List (High Evidence).
Mendeliome v0.6626 PHKA1 Zornitza Stark Gene: phka1 has been classified as Green List (High Evidence).
Mendeliome v0.6626 PHKA1 Zornitza Stark Phenotypes for gene: PHKA1 were changed from to Muscle glycogenosis, MIM# 300559
Mendeliome v0.6623 PHKA1 Zornitza Stark reviewed gene: PHKA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7874115, 12825073, 9731190; Phenotypes: Muscle glycogenosis, MIM# 300559; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6623 PHKB Zornitza Stark Gene: phkb has been classified as Green List (High Evidence).
Mendeliome v0.6623 PHKB Zornitza Stark Phenotypes for gene: PHKB were changed from to Phosphorylase kinase deficiency of liver and muscle, autosomal recessive 261750; Glycogen storage disease IXb, MONDO:0009868
Mendeliome v0.6620 PHKB Zornitza Stark reviewed gene: PHKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9215682, 25266922, 30659246; Phenotypes: Phosphorylase kinase deficiency of liver and muscle, autosomal recessive 261750, Glycogen storage disease IXb, MONDO:0009868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6620 PHKG2 Zornitza Stark Gene: phkg2 has been classified as Green List (High Evidence).
Mendeliome v0.6617 PYGL Zornitza Stark Gene: pygl has been classified as Green List (High Evidence).
Mendeliome v0.6614 NHLRC1 Zornitza Stark Gene: nhlrc1 has been classified as Green List (High Evidence).
Mendeliome v0.6614 NHLRC1 Zornitza Stark Phenotypes for gene: NHLRC1 were changed from to Epilepsy, progressive myoclonic 2B (Lafora) 254780
Mendeliome v0.6611 NHLRC1 Zornitza Stark reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21505799, 12958597; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora) 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6611 LDHA Zornitza Stark Gene: ldha has been classified as Green List (High Evidence).
Mendeliome v0.6608 SIAH1 Zornitza Stark Marked gene: SIAH1 as ready
Mendeliome v0.6608 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Mendeliome v0.6608 SIAH1 Zornitza Stark Classified gene: SIAH1 as Green List (high evidence)
Mendeliome v0.6608 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Mendeliome v0.6607 RPL18 Zornitza Stark Gene: rpl18 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6607 RPL18 Zornitza Stark Classified gene: RPL18 as Amber List (moderate evidence)
Mendeliome v0.6607 RPL18 Zornitza Stark Gene: rpl18 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6605 RPS15A Zornitza Stark Gene: rps15a has been classified as Red List (Low Evidence).
Mendeliome v0.6605 RPS15A Zornitza Stark gene: RPS15A was added
gene: RPS15A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPS15A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS15A were set to 27909223
Phenotypes for gene: RPS15A were set to Diamond-Blackfan anemia 20, MIM# 618313
Review for gene: RPS15A was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6604 RPL35 Zornitza Stark Gene: rpl35 has been classified as Red List (Low Evidence).
Mendeliome v0.6604 RPL35 Zornitza Stark gene: RPL35 was added
gene: RPL35 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL35 were set to 28280134
Phenotypes for gene: RPL35 were set to Diamond-Blackfan anemia 19, MIM# 618312
Review for gene: RPL35 was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6603 RPS7 Zornitza Stark Gene: rps7 has been classified as Green List (High Evidence).
Mendeliome v0.6600 RPS26 Zornitza Stark Gene: rps26 has been classified as Green List (High Evidence).
Mendeliome v0.6597 RPS24 Zornitza Stark Gene: rps24 has been classified as Green List (High Evidence).
Mendeliome v0.6593 RPS19 Zornitza Stark Gene: rps19 has been classified as Green List (High Evidence).
Mendeliome v0.6590 ACKR3 Zornitza Stark Phenotypes for gene: ACKR3 were changed from Oculomotor synkinesis; Ptosis to Oculomotor-abducens synkinesis, MIM# 619215
Mendeliome v0.6589 ACKR3 Zornitza Stark reviewed gene: ACKR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculomotor-abducens synkinesis, MIM# 619215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6589 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Mendeliome v0.6589 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6589 SYCP2L Zornitza Stark Classified gene: SYCP2L as Amber List (moderate evidence)
Mendeliome v0.6589 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6588 RPL5 Zornitza Stark Gene: rpl5 has been classified as Green List (High Evidence).
Mendeliome v0.6585 RPL35A Zornitza Stark Gene: rpl35a has been classified as Green List (High Evidence).
Mendeliome v0.6582 SYCP2L Arina Puzriakova gene: SYCP2L was added
gene: SYCP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603
Phenotypes for gene: SYCP2L were set to Premature ovarian insufficiency
Review for gene: SYCP2L was set to AMBER
Added comment: - PMID: 32303603 (2021) - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L.
In vitro assays revealed that mutant SYCP2L proteins induced mislocalisation and reduced expression. Sycp2l knockout mice exhibit accelerated reproductive ageing.
Sources: Literature
Mendeliome v0.6582 RPL27 Zornitza Stark Gene: rpl27 has been classified as Red List (Low Evidence).
Mendeliome v0.6579 RPL27 Zornitza Stark Classified gene: RPL27 as Red List (low evidence)
Mendeliome v0.6579 RPL27 Zornitza Stark Gene: rpl27 has been classified as Red List (Low Evidence).
Mendeliome v0.6578 RPL11 Zornitza Stark Gene: rpl11 has been classified as Green List (High Evidence).
Mendeliome v0.6572 CLCN4 Zornitza Stark Gene: clcn4 has been classified as Green List (High Evidence).
Mendeliome v0.6572 CLCN4 Zornitza Stark Phenotypes for gene: CLCN4 were changed from to Raynaud-Claes syndrome, MIM#300114; intellectual disability; epilepsy; autistic features; mood disorders; cerebral white matter changes; progressive appendicular spasticity
Mendeliome v0.6569 CLCN4 Zornitza Stark reviewed gene: CLCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27550844; Phenotypes: Raynaud-Claes syndrome, MIM#300114, intellectual disability, epilepsy, autistic features, mood disorders, cerebral white matter changes, progressive appendicular spasticity; 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 v0.6569 KIRREL1 Zornitza Stark Phenotypes for gene: KIRREL1 were changed from Steroid-resistant nephrotic syndrome to Nephrotic syndrome, type 23, MIM# 619201
Mendeliome v0.6567 EN1 Zornitza Stark changed review comment from: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature; to: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.

An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant.
Sources: Literature
Mendeliome v0.6567 EN1 Zornitza Stark Gene: en1 has been classified as Green List (High Evidence).
Mendeliome v0.6567 EN1 Zornitza Stark Classified gene: EN1 as Green List (high evidence)
Mendeliome v0.6567 EN1 Zornitza Stark Gene: en1 has been classified as Green List (High Evidence).
Mendeliome v0.6566 EN1 Zornitza Stark gene: EN1 was added
gene: EN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217
Review for gene: EN1 was set to GREEN
Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v0.6560 EEF2 Zornitza Stark Classified gene: EEF2 as Green List (high evidence)
Mendeliome v0.6560 EEF2 Zornitza Stark Gene: eef2 has been classified as Green List (High Evidence).
Mendeliome v0.6559 MKRN3 Zornitza Stark Gene: mkrn3 has been classified as Green List (High Evidence).
Mendeliome v0.6556 ACSL5 Zornitza Stark Gene: acsl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6556 ACSL5 Zornitza Stark gene: ACSL5 was added
gene: ACSL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACSL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACSL5 were set to 33191500
Phenotypes for gene: ACSL5 were set to severe FTT (no OMIM #)
Review for gene: ACSL5 was set to RED
Added comment: 6 individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Autozygosity mapping and WES identified homozygous variant (c.1358C>A:p.(Thr453Lys) in ACSL5. Segregated with affected individuals. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity. Affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. They responded well and follow up suggests that treatment is only required during early life.
Sources: Literature
Mendeliome v0.6555 GDF5 Zornitza Stark Gene: gdf5 has been classified as Green List (High Evidence).
Mendeliome v0.6555 GDF5 Zornitza Stark Phenotypes for gene: GDF5 were changed from to Type A1C brachydactyly (MIM#615072); Type A2 brachydactyly, (MIM#112600); Type C brachydactyly (MIM#113100); Grebe type chondrodysplasia (MIM#200700); Du Pan syndrome (MIM#228900); Multiple synostoses syndrome 2 (MIM#610017); Proximal Symphalangism 1B (MIM#615298)
Mendeliome v0.6554 GDF5 Zornitza Stark reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6552 KIDINS220 Zornitza Stark Gene: kidins220 has been classified as Green List (High Evidence).
Mendeliome v0.6552 KIDINS220 Zornitza Stark Phenotypes for gene: KIDINS220 were changed from to Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; cerebral ventriculomegaly; limb contractures
Mendeliome v0.6549 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: None; Publications: 27005418; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6549 MYO15A Zornitza Stark Phenotypes for gene: MYO15A were changed from Deafness, autosomal recessive 3, MIM# 600316 to Deafness, autosomal recessive 3, MIM# 600316; autosomal recessive nonsyndromic deafness 3 MONDO:0010860
Mendeliome v0.6547 MYO3A Zornitza Stark Phenotypes for gene: MYO3A were changed from to Deafness, autosomal recessive 30 OMIM:607101; autosomal recessive nonsyndromic deafness 30 MONDO:0011774; dominant deafness
Mendeliome v0.6544 MYO3A Zornitza Stark reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21165622, 26754646, 23990876; Phenotypes: Deafness, autosomal recessive 30, MIM# 607101; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6544 COL9A3 Zornitza Stark Gene: col9a3 has been classified as Green List (High Evidence).
Mendeliome v0.6544 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome; Deafness
Mendeliome v0.6541 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450842, 31090205, 24273071, 10090888, 15551337; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969, Stickler syndrome, Deafness; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6541 DLK1 Zornitza Stark Gene: dlk1 has been classified as Green List (High Evidence).
Mendeliome v0.6541 DLK1 Zornitza Stark Classified gene: DLK1 as Green List (high evidence)
Mendeliome v0.6541 DLK1 Zornitza Stark Gene: dlk1 has been classified as Green List (High Evidence).
Mendeliome v0.6540 DLK1 Zornitza Stark gene: DLK1 was added
gene: DLK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DLK1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: DLK1 were set to 28324015; 30462238
Phenotypes for gene: DLK1 were set to central precocious puberty
Review for gene: DLK1 was set to GREEN
Added comment: PMID: 30462238 "three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1". PMID: 28324015 single large family, only affected females, central precocious puberty all carrying paternally inherited LOF variant (del/dup of 5'UTR and exon 1) absent DLK1 expression in all affected. Unclear if males affected as none reported to date.
Sources: Expert Review
Mendeliome v0.6539 GDF5 Ain Roesley reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33333243; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6539 MYO15A Eleanor Williams reviewed gene: MYO15A: Rating: ; Mode of pathogenicity: None; Publications: 33078831; Phenotypes: Deafness, autosomal recessive 3 OMIM:600316, autosomal recessive nonsyndromic deafness 3 MONDO:0010860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 MYO3A Eleanor Williams reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 26841241, 29880844; Phenotypes: Deafness, autosomal recessive 30 OMIM:607101, autosomal recessive nonsyndromic deafness 30 MONDO:0011774; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 COL9A3 Eleanor Williams reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 15917166; Phenotypes: autosomal recessive non-syndromic hearing impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Mendeliome v0.6539 EIF5A Zornitza Stark Classified gene: EIF5A as Green List (high evidence)
Mendeliome v0.6539 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Mendeliome v0.6537 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Mendeliome v0.6537 POLRMT Zornitza Stark Classified gene: POLRMT as Green List (high evidence)
Mendeliome v0.6537 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Mendeliome v0.6536 POLRMT Zornitza Stark gene: POLRMT was added
gene: POLRMT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 33602924
Phenotypes for gene: POLRMT were set to Mitochondrial disorder; intellectual disability; hypotonia
Review for gene: POLRMT was set to GREEN
Added comment: 8 individuals from 7 families reported. 5 families with bi-allelic variants and 2 with heterozygous variants. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Sources: Literature
Mendeliome v0.6535 PERP Zornitza Stark Phenotypes for gene: PERP were changed from Erythrokeratoderma, no OMIM # yet to Olmsted syndrome 2, MIM# 619208; Erythrokeratodermia variabilis et progressiva 7, MIM# 619209
Mendeliome v0.6532 PERP Zornitza Stark Classified gene: PERP as Green List (high evidence)
Mendeliome v0.6532 PERP Zornitza Stark Gene: perp has been classified as Green List (High Evidence).
Mendeliome v0.6531 PERP Zornitza Stark edited their review of gene: PERP: Added comment: Four families reported with heterozygous variants and Olmsted syndrome-2 (OLMS2), which is characterised by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. The lesions are progressive, becoming thicker with verrucous fissures on the palms and soles over time. In addition, affected individuals exhibit perioral hyperkeratosis, and may have lesions around other orifices as well, such as the nostrils, perineum, and anus. Most patients also have hyperkeratotic nails and light-colored woolly hair.

Two families reported with bi-allelic variants and Erythrokeratodermia variabilis et progressiva-7 (EKVP7), which is characterised by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present.; Changed rating: GREEN; Changed publications: 31898316, 30321533, 31361044; Changed phenotypes: Olmsted syndrome 2, MIM# 619208, Erythrokeratodermia variabilis et progressiva 7, MIM# 619209; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6531 KARS Zornitza Stark edited their review of gene: KARS: Changed phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916, Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6531 KARS Zornitza Stark Phenotypes for gene: KARS were changed from Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916 to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916; Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6530 KARS Zornitza Stark Gene: kars has been classified as Green List (High Evidence).
Mendeliome v0.6530 KARS Zornitza Stark Phenotypes for gene: KARS were changed from to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916
Mendeliome v0.6527 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 31618474, 28887846, 25330800, 29615062, 30252186, 28496994, 23768514, 14975237; Phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6527 APOO Zornitza Stark reviewed gene: APOO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6527 APOO Zornitza Stark Gene: apoo has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6527 APOO Zornitza Stark Classified gene: APOO as Amber List (moderate evidence)
Mendeliome v0.6527 APOO Zornitza Stark Gene: apoo has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6526 APOO Arina Puzriakova gene: APOO was added
gene: APOO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOO 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: APOO were set to 32439808
Phenotypes for gene: APOO were set to Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Review for gene: APOO was set to RED
Added comment: - PMID: 32439808 (2021) - Three generation family with c.350T>C variant in APOO, encoding a component of the MICOS complex which plays a role in maintaining inner mitochondrial membrane architecture.
Phenotypes include fatigue and muscle weakness (6/8), learning difficulties and cognitive impairment (4/8), and increased blood lactate (2/8). Four individuals were asymptomatic carriers, including one male (authors indicate variability in female carriers was due to skewed X-inactivation, although skewing studies were inconclusive in some cases). Variability in clinical presentation suggests reduced penetrance or possible contribution of additional factors.
Functional studies showed altered MICOS assembly and abnormalities in mitochondria ultrastructure in patient-derived fibroblasts. Knockdown studies in Drosophila and yeast demonstrated mitochondrial structural and functional deficiencies.
Sources: Literature
Mendeliome v0.6526 ECE1 Zornitza Stark Gene: ece1 has been classified as Red List (Low Evidence).
Mendeliome v0.6523 ECE1 Zornitza Stark Classified gene: ECE1 as Red List (low evidence)
Mendeliome v0.6523 ECE1 Zornitza Stark Gene: ece1 has been classified as Red List (Low Evidence).
Mendeliome v0.6522 AMH Seb Lunke Gene: amh has been classified as Green List (High Evidence).
Mendeliome v0.6522 AMH Seb Lunke Phenotypes for gene: AMH were changed from to Persistent Mullerian duct syndrome, type I (MIM#261550)
Mendeliome v0.6519 AMH Seb Lunke reviewed gene: AMH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32172781; Phenotypes: Persistent Mullerian duct syndrome, type I (MIM#261550); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6519 PAX4 Zornitza Stark Gene: pax4 has been classified as Green List (High Evidence).
Mendeliome v0.6516 PCBD1 Zornitza Stark Gene: pcbd1 has been classified as Green List (High Evidence).
Mendeliome v0.6513 SPTAN1 Zornitza Stark Gene: sptan1 has been classified as Green List (High Evidence).
Mendeliome v0.6510 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion with early-onset PD reported.; to: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.
Mendeliome v0.6508 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion reported with early-onset PD reported.; to: Well established gene-disease association. Phenotype expansion with early-onset PD reported.
Mendeliome v0.6508 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Mendeliome v0.6505 IRF4 Bryony Thompson Gene: irf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6502 IRF4 Bryony Thompson Classified gene: IRF4 as Amber List (moderate evidence)
Mendeliome v0.6502 IRF4 Bryony Thompson Added comment: Comment on list classification: Single case and mouse model for recessive combined immunodeficiency
Mendeliome v0.6502 IRF4 Bryony Thompson Gene: irf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6501 PCBD1 Michelle Torres edited their review of gene: PCBD1: Added comment: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; Changed phenotypes: MODY, Hyperphenylalaninemia, BH4-deficient, D 264070
Mendeliome v0.6501 SPEN Alison Yeung Classified gene: SPEN as Green List (high evidence)
Mendeliome v0.6501 SPEN Alison Yeung Gene: spen has been classified as Green List (High Evidence).
Mendeliome v0.6500 SPTAN1 Alison Yeung Added comment: Comment on mode of inheritance: phenotype expansion
Mendeliome v0.6499 PSAP Seb Lunke Gene: psap has been classified as Green List (High Evidence).
Mendeliome v0.6497 ACTL9 Alison Yeung Classified gene: ACTL9 as Green List (high evidence)
Mendeliome v0.6497 ACTL9 Alison Yeung Gene: actl9 has been classified as Green List (High Evidence).
Mendeliome v0.6496 MAST2 Seb Lunke Gene: mast2 has been classified as Red List (Low Evidence).
Mendeliome v0.6496 MAST2 Seb Lunke Classified gene: MAST2 as Red List (low evidence)
Mendeliome v0.6496 MAST2 Seb Lunke Gene: mast2 has been classified as Red List (Low Evidence).
Mendeliome v0.6495 SPEN Chern Lim reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596411; Phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6495 ANGPTL6 Alison Yeung Classified gene: ANGPTL6 as Green List (high evidence)
Mendeliome v0.6495 ANGPTL6 Alison Yeung Gene: angptl6 has been classified as Green List (High Evidence).
Mendeliome v0.6494 PCBD1 Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY
Mendeliome v0.6494 EPAS1 Seb Lunke Gene: epas1 has been classified as Green List (High Evidence).
Mendeliome v0.6494 EPAS1 Seb Lunke Phenotypes for gene: EPAS1 were changed from to Familial erythrocytosis (MIM#4611783), AD
Mendeliome v0.6492 NLRP3 Alison Yeung Classified gene: NLRP3 as Green List (high evidence)
Mendeliome v0.6492 NLRP3 Alison Yeung Gene: nlrp3 has been classified as Green List (High Evidence).
Mendeliome v0.6490 PCBD1 Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY
Mendeliome v0.6487 NLRP3 Alison Yeung Gene: nlrp3 has been classified as Green List (High Evidence).
Mendeliome v0.6487 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Mendeliome v0.6487 MED27 Alison Yeung Classified gene: MED27 as Green List (high evidence)
Mendeliome v0.6487 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Mendeliome v0.6486 MED27 Alison Yeung gene: MED27 was added
gene: MED27 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families with balletic variants
Sources: Literature
Mendeliome v0.6485 ACTL9 Elena Savva gene: ACTL9 was added
gene: ACTL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to PMID: 33626338
Phenotypes for gene: ACTL9 were set to Fertilization failure; male infertility
Review for gene: ACTL9 was set to GREEN
Added comment: Three families with homozygous pathogenic variants (two missense, one PTC). Single affected in each family. Functional analysis from patients shows all sperm had morphological defects, protein had reduced binding to ACTL7A
All variants very rare in gnomAD.
Sources: Literature
Mendeliome v0.6485 MAST2 Elena Savva gene: MAST2 was added
gene: MAST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to PMID: 33465109
Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis
Review for gene: MAST2 was set to RED
Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression.

RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets
Sources: Literature
Mendeliome v0.6485 EPAS1 Teresa Zhao reviewed gene: EPAS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27292716, 19208626; Phenotypes: Familial erythrocytosis (MIM#4611783), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6485 AGPS Zornitza Stark Gene: agps has been classified as Green List (High Evidence).
Mendeliome v0.6485 AGPS Zornitza Stark Phenotypes for gene: AGPS were changed from to Rhizomelic chondrodysplasia punctata, type 3, MIM# 600121
Mendeliome v0.6482 AGPS Zornitza Stark reviewed gene: AGPS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9553082, 8611652, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, MIM# 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6482 BANF1 Zornitza Stark Gene: banf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6479 BANF1 Zornitza Stark Classified gene: BANF1 as Amber List (moderate evidence)
Mendeliome v0.6479 BANF1 Zornitza Stark Gene: banf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6478 FOXP2 Zornitza Stark Gene: foxp2 has been classified as Green List (High Evidence).
Mendeliome v0.6475 GLI3 Zornitza Stark Gene: gli3 has been classified as Green List (High Evidence).
Mendeliome v0.6472 KIF22 Zornitza Stark Gene: kif22 has been classified as Green List (High Evidence).
Mendeliome v0.6471 KIF22 Zornitza Stark reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: 25256152; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2, MIM# 603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6471 KIF22 Zornitza Stark Phenotypes for gene: KIF22 were changed from to Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546
Mendeliome v0.6468 ANKZF1 Bryony Thompson Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6468 ANKZF1 Bryony Thompson Classified gene: ANKZF1 as Amber List (moderate evidence)
Mendeliome v0.6468 ANKZF1 Bryony Thompson Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6466 ANGPT1 Bryony Thompson Classified gene: ANGPT1 as Amber List (moderate evidence)
Mendeliome v0.6466 ANGPT1 Bryony Thompson Gene: angpt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6465 ANGPT1 Bryony Thompson gene: ANGPT1 was added
gene: ANGPT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ANGPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT1 were set to 28601681; 24852101; 30689269; 10617467; 8980224
Phenotypes for gene: ANGPT1 were set to Hereditary angioedema
Review for gene: ANGPT1 was set to AMBER
Added comment: A missense variant (A119S) identified in 4 affected individuals in a single family. Supportive data in patient cells, functional assays of the variant, and animal models (both overexpression and null) for the gene.
Sources: Other
Mendeliome v0.6464 CLTCL1 Bryony Thompson Gene: cltcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6464 CLTCL1 Bryony Thompson Classified gene: CLTCL1 as Amber List (moderate evidence)
Mendeliome v0.6464 CLTCL1 Bryony Thompson Added comment: Comment on list classification: A single family, but also some compelling functional data for an association with insensitivity to pain.
Mendeliome v0.6464 CLTCL1 Bryony Thompson Gene: cltcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6463 CLTCL1 Bryony Thompson changed review comment from: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature; to: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system.

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature
Mendeliome v0.6463 CLTCL1 Bryony Thompson gene: CLTCL1 was added
gene: CLTCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784
Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain
Review for gene: CLTCL1 was set to AMBER
Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature
Mendeliome v0.6462 KIF22 Elena Savva reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22152677, 22152678; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6461 SLC7A6OS Zornitza Stark Phenotypes for gene: SLC7A6OS were changed from Progressive myoclonus epilepsy to Epilepsy, progressive myoclonic, 12, MIM# 619191
Mendeliome v0.6460 SLC7A6OS Zornitza Stark edited their review of gene: SLC7A6OS: Changed phenotypes: Epilepsy, progressive myoclonic, 12, MIM# 619191
Mendeliome v0.6460 G6PC Zornitza Stark Gene: g6pc has been classified as Green List (High Evidence).
Mendeliome v0.6457 ALPI Zornitza Stark Classified gene: ALPI as Amber List (moderate evidence)
Mendeliome v0.6457 ALPI Zornitza Stark Gene: alpi has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Classified gene: NMNAT2 as Amber List (moderate evidence)
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6455 NMNAT2 Bryony Thompson gene: NMNAT2 was added
gene: NMNAT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT2 were set to 31132363; 25271157; 20126265
Phenotypes for gene: NMNAT2 were set to polyneuropathy; erythromelalgia
Review for gene: NMNAT2 was set to AMBER
Added comment: A single family with siblings with a homozygous variant that confers a partial loss of function. Strong supporting functional evidence that the gene plays a key role in axonal survival.
Sources: Literature
Mendeliome v0.6451 USF1 Bryony Thompson Gene: usf1 has been classified as Red List (Low Evidence).
Mendeliome v0.6451 USF1 Bryony Thompson Classified gene: USF1 as Red List (low evidence)
Mendeliome v0.6451 USF1 Bryony Thompson Gene: usf1 has been classified as Red List (Low Evidence).
Mendeliome v0.6449 PDXK Bryony Thompson Classified gene: PDXK as Green List (high evidence)
Mendeliome v0.6449 PDXK Bryony Thompson Added comment: Comment on list classification: Additional family published in 2020
Mendeliome v0.6449 PDXK Bryony Thompson Gene: pdxk has been classified as Green List (High Evidence).
Mendeliome v0.6447 LIPI Bryony Thompson Gene: lipi has been classified as Red List (Low Evidence).
Mendeliome v0.6447 LIPI Bryony Thompson Classified gene: LIPI as Red List (low evidence)
Mendeliome v0.6447 LIPI Bryony Thompson Gene: lipi has been classified as Red List (Low Evidence).
Mendeliome v0.6446 GALNT12 Bryony Thompson Gene: galnt12 has been classified as Red List (Low Evidence).
Mendeliome v0.6446 GALNT12 Bryony Thompson Classified gene: GALNT12 as Red List (low evidence)
Mendeliome v0.6446 GALNT12 Bryony Thompson Gene: galnt12 has been classified as Red List (Low Evidence).
Mendeliome v0.6445 ABCG2 Bryony Thompson Gene: abcg2 has been classified as Red List (Low Evidence).
Mendeliome v0.6445 ABCG2 Bryony Thompson Classified gene: ABCG2 as Red List (low evidence)
Mendeliome v0.6445 ABCG2 Bryony Thompson Gene: abcg2 has been classified as Red List (Low Evidence).
Mendeliome v0.6444 SAT1 Bryony Thompson Gene: sat1 has been classified as Red List (Low Evidence).
Mendeliome v0.6444 SAT1 Bryony Thompson Classified gene: SAT1 as Red List (low evidence)
Mendeliome v0.6444 SAT1 Bryony Thompson Gene: sat1 has been classified as Red List (Low Evidence).
Mendeliome v0.6443 SAT1 Bryony Thompson reviewed gene: SAT1: Rating: RED; Mode of pathogenicity: None; Publications: 12215835, 20672378, 9228047; Phenotypes: Keratosis follicularis spinulosa decalvans; 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 v0.6442 ALPI Zornitza Stark Classified gene: ALPI as Green List (high evidence)
Mendeliome v0.6442 ALPI Zornitza Stark Gene: alpi has been classified as Green List (High Evidence).
Mendeliome v0.6441 MIR5004 Bryony Thompson Gene: mir5004 has been classified as Red List (Low Evidence).
Mendeliome v0.6441 MIR5004 Bryony Thompson Classified gene: MIR5004 as Red List (low evidence)
Mendeliome v0.6441 MIR5004 Bryony Thompson Gene: mir5004 has been classified as Red List (Low Evidence).
Mendeliome v0.6440 TOGARAM1 Zornitza Stark Phenotypes for gene: TOGARAM1 were changed from Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus to Joubert syndrome 37, MIM# 619185
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Green List (high evidence)
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Green List (High Evidence).
Mendeliome v0.6437 ALDOA Zornitza Stark Gene: aldoa has been classified as Green List (High Evidence).
Mendeliome v0.6434 RDH5 Zornitza Stark Gene: rdh5 has been classified as Green List (High Evidence).
Mendeliome v0.6431 RPGRIP1 Zornitza Stark Gene: rpgrip1 has been classified as Green List (High Evidence).
Mendeliome v0.6431 RPGRIP1 Zornitza Stark Phenotypes for gene: RPGRIP1 were changed from to Cone-rod dystrophy 13 (MIM#608194) , Leber congenital amaurosis (MIM#61382)
Mendeliome v0.6428 RPGRIP1 Ain Roesley reviewed gene: RPGRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33308271, 31666973; Phenotypes: Cone-rod dystrophy 13 (MIM#608194) , Leber congenital amaurosis (MIM#61382); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6428 IRX4 Zornitza Stark Gene: irx4 has been classified as Red List (Low Evidence).
Mendeliome v0.6425 IRX4 Zornitza Stark Classified gene: IRX4 as Red List (low evidence)
Mendeliome v0.6425 IRX4 Zornitza Stark Gene: irx4 has been classified as Red List (Low Evidence).
Mendeliome v0.6424 AKAP6 Zornitza Stark Gene: akap6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6421 AKAP6 Zornitza Stark Classified gene: AKAP6 as Amber List (moderate evidence)
Mendeliome v0.6421 AKAP6 Zornitza Stark Gene: akap6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6420 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Mendeliome v0.6420 ASCC3 Bryony Thompson Classified gene: ASCC3 as Green List (high evidence)
Mendeliome v0.6420 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Mendeliome v0.6418 HS2ST1 Zornitza Stark Phenotypes for gene: HS2ST1 were changed from Intellectual disability; dysmorphic features; congenital anomalies to Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Intellectual disability; dysmorphic features; congenital anomalies
Mendeliome v0.6417 HS2ST1 Zornitza Stark reviewed gene: HS2ST1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6414 ARSG Bryony Thompson Classified gene: ARSG as Green List (high evidence)
Mendeliome v0.6414 ARSG Bryony Thompson Added comment: Comment on list classification: 2 additional families reported, upgraded to green
Mendeliome v0.6414 ARSG Bryony Thompson Gene: arsg has been classified as Green List (High Evidence).
Mendeliome v0.6412 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from 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
Mendeliome v0.6411 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
Mendeliome v0.6410 CRYM Zornitza Stark Gene: crym has been classified as Green List (High Evidence).
Mendeliome v0.6407 HARS Zornitza Stark Gene: hars has been classified as Green List (High Evidence).
Mendeliome v0.6401 PMVK Zornitza Stark Gene: pmvk has been classified as Green List (High Evidence).
Mendeliome v0.6401 PMVK Zornitza Stark Classified gene: PMVK as Green List (high evidence)
Mendeliome v0.6401 PMVK Zornitza Stark Gene: pmvk has been classified as Green List (High Evidence).
Mendeliome v0.6400 PMVK Zornitza Stark gene: PMVK was added
gene: PMVK was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, MIM# 175800
Review for gene: PMVK was set to GREEN
Added comment: At least 9 individuals reported.
Sources: Expert Review
Mendeliome v0.6399 MVD Zornitza Stark Gene: mvd has been classified as Green List (High Evidence).
Mendeliome v0.6399 MVD Zornitza Stark Classified gene: MVD as Green List (high evidence)
Mendeliome v0.6399 MVD Zornitza Stark Gene: mvd has been classified as Green List (High Evidence).
Mendeliome v0.6398 MVD Zornitza Stark gene: MVD was added
gene: MVD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MVD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVD were set to 30942823; 33491095
Phenotypes for gene: MVD were set to Porokeratosis 7, multiple types, MIM# 614714
Review for gene: MVD was set to GREEN
Added comment: Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. At least 5 individuals reported.
Sources: Expert list
Mendeliome v0.6396 UNC45B Zornitza Stark Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Myofibrillar myopathy 11, MIM# 619178; Progressive Myopathy with Eccentric Cores
Mendeliome v0.6395 SHROOM3 Zornitza Stark Gene: shroom3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6395 SHROOM3 Zornitza Stark Classified gene: SHROOM3 as Amber List (moderate evidence)
Mendeliome v0.6395 SHROOM3 Zornitza Stark Gene: shroom3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6394 SHROOM3 Zornitza Stark gene: SHROOM3 was added
gene: SHROOM3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SHROOM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHROOM3 were set to 32621286
Phenotypes for gene: SHROOM3 were set to Anencephaly; cleft lip and palate
Review for gene: SHROOM3 was set to AMBER
Added comment: Animal model and other functional data link SHROOM3 to neural tube development. Single family reported with bi-allelic LoF in a fetus with anencephaly and CL/P.
Sources: Expert Review
Mendeliome v0.6393 FLT3 Zornitza Stark Gene: flt3 has been classified as Red List (Low Evidence).
Mendeliome v0.6393 FLT3 Zornitza Stark Classified gene: FLT3 as Red List (low evidence)
Mendeliome v0.6393 FLT3 Zornitza Stark Gene: flt3 has been classified as Red List (Low Evidence).
Mendeliome v0.6392 MSL3 Zornitza Stark Gene: msl3 has been classified as Green List (High Evidence).
Mendeliome v0.6392 MSL3 Zornitza Stark Phenotypes for gene: MSL3 were changed from to Basilicata-Akhtar syndrome, OMIM # 301032
Mendeliome v0.6389 MSL3 Zornitza Stark reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33173220; Phenotypes: Basilicata-Akhtar syndrome, OMIM # 301032; 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 v0.6389 TOE1 Zornitza Stark Gene: toe1 has been classified as Green List (High Evidence).
Mendeliome v0.6389 TOE1 Zornitza Stark Phenotypes for gene: TOE1 were changed from to Pontocerebellar hypoplasia, type 7, MIM# 614969
Mendeliome v0.6386 TOE1 Zornitza Stark reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28092684; Phenotypes: Pontocerebellar hypoplasia, type 7, MIM# 614969; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6386 VRK1 Zornitza Stark Gene: vrk1 has been classified as Green List (High Evidence).
Mendeliome v0.6386 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from to Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA
Mendeliome v0.6383 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed rating: GREEN; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, SMA
Mendeliome v0.6383 SPTBN2 Zornitza Stark Gene: sptbn2 has been classified as Green List (High Evidence).
Mendeliome v0.6383 SPTBN2 Zornitza Stark Phenotypes for gene: SPTBN2 were changed from to Spinocerebellar ataxia, autosomal recessive 14, MIM# 615386; Spinocerebellar ataxia 5, MIM# 600224
Mendeliome v0.6380 SEPSECS Zornitza Stark Gene: sepsecs has been classified as Green List (High Evidence).
Mendeliome v0.6380 SEPSECS Zornitza Stark Phenotypes for gene: SEPSECS were changed from to Pontocerebellar hypoplasia type 2D, 613811; cerebellar ataxia and cognitive impairment
Mendeliome v0.6377 SEPSECS Zornitza Stark reviewed gene: SEPSECS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20920667, 25044680, 31748115, 29464431; Phenotypes: Pontocerebellar hypoplasia type 2D, MIM# 613811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6377 ITPR1 Zornitza Stark changed review comment from: Gillespie syndrome is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.; to: Gillespie syndrome: usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.
Mendeliome v0.6377 ITPR1 Zornitza Stark Gene: itpr1 has been classified as Green List (High Evidence).
Mendeliome v0.6377 ITPR1 Zornitza Stark Phenotypes for gene: ITPR1 were changed from to Gillespie syndrome, MIM# 206700; Spinocerebellar ataxia 15 MIM#606658; Spinocerebellar ataxia 29, congenital nonprogressive MIM#117360
Mendeliome v0.6374 EXOSC8 Zornitza Stark Gene: exosc8 has been classified as Green List (High Evidence).
Mendeliome v0.6374 EXOSC8 Zornitza Stark Phenotypes for gene: EXOSC8 were changed from to Pontocerebellar hypoplasia, type 1C, MIM# 616081
Mendeliome v0.6371 EXOSC8 Zornitza Stark reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia, type 1C, MIM# 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6371 EXOSC3 Zornitza Stark Gene: exosc3 has been classified as Green List (High Evidence).
Mendeliome v0.6371 EXOSC3 Zornitza Stark Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, MIM# 614678
Mendeliome v0.6368 EXOSC3 Zornitza Stark reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544365, 23284067, 24524299; Phenotypes: Pontocerebellar hypoplasia, type 1B, MIM# 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6368 CLP1 Zornitza Stark Gene: clp1 has been classified as Green List (High Evidence).
Mendeliome v0.6368 CLP1 Zornitza Stark Phenotypes for gene: CLP1 were changed from to Pontocerebellar hypoplasia type 10, MIM# 615803
Mendeliome v0.6365 CLP1 Zornitza Stark reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809, 29307788; Phenotypes: Pontocerebellar hypoplasia type 10, MIM# 615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6365 CHMP1A Zornitza Stark Gene: chmp1a has been classified as Green List (High Evidence).
Mendeliome v0.6365 CHMP1A Zornitza Stark Phenotypes for gene: CHMP1A were changed from to Pontocerebellar hypoplasia, type 8, MIM# 614961
Mendeliome v0.6362 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6362 BRF1 Zornitza Stark Gene: brf1 has been classified as Green List (High Evidence).
Mendeliome v0.6359 DHODH Zornitza Stark Gene: dhodh has been classified as Green List (High Evidence).
Mendeliome v0.6356 ITGB4 Zornitza Stark Gene: itgb4 has been classified as Green List (High Evidence).
Mendeliome v0.6356 ITGB4 Zornitza Stark Phenotypes for gene: ITGB4 were changed from to Epidermolysis bullosa of hands and feet, MIM# 131800; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730
Mendeliome v0.6353 ITGB4 Zornitza Stark reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11328943, 9670011, 33225458, 30079450, 29380424, 29198538, 28557647; Phenotypes: Epidermolysis bullosa of hands and feet, MIM# 131800, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650, Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6353 LAMA3 Zornitza Stark Gene: lama3 has been classified as Green List (High Evidence).
Mendeliome v0.6353 LAMA3 Zornitza Stark Phenotypes for gene: LAMA3 were changed from to Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700
Mendeliome v0.6350 LAMA3 Zornitza Stark reviewed gene: LAMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, generalized atrophic benign, MIM# 226650, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6350 LAMB3 Zornitza Stark Gene: lamb3 has been classified as Green List (High Evidence).
Mendeliome v0.6350 LAMB3 Zornitza Stark Phenotypes for gene: LAMB3 were changed from to Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.6347 LAMB3 Zornitza Stark reviewed gene: LAMB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11023379, 7706760; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6347 LAMC2 Zornitza Stark Gene: lamc2 has been classified as Green List (High Evidence).
Mendeliome v0.6347 LAMC2 Zornitza Stark Phenotypes for gene: LAMC2 were changed from to Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.6344 LAMC2 Zornitza Stark reviewed gene: LAMC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11810295, 25888738, 24533970; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6344 KRT5 Zornitza Stark Gene: krt5 has been classified as Green List (High Evidence).
Mendeliome v0.6344 KRT5 Zornitza Stark Phenotypes for gene: KRT5 were changed from to Dowling-Degos disease 1, MIM# 179850; Epidermolysis bullosa simplex-MCR, MIM# 609352; Epidermolysis bullosa simplex-MP 131960; Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760; Epidermolysis bullosa simplex, Koebner type, MIM# 131900; Epidermolysis bullosa simplex, recessive 1, MIM# 601001; Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800
Mendeliome v0.6342 KRT5 Zornitza Stark reviewed gene: KRT5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dowling-Degos disease 1, MIM# 179850, Epidermolysis bullosa simplex-MCR, MIM# 609352, Epidermolysis bullosa simplex-MP 131960, Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760, Epidermolysis bullosa simplex, Koebner type, MIM# 131900, Epidermolysis bullosa simplex, recessive 1, MIM# 601001, Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6340 ITGA6 Zornitza Stark Gene: itga6 has been classified as Green List (High Evidence).
Mendeliome v0.6340 ITGA6 Zornitza Stark Phenotypes for gene: ITGA6 were changed from to Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730
Mendeliome v0.6337 ITGA6 Zornitza Stark reviewed gene: ITGA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31502654, 27607025, 9158140; Phenotypes: Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6337 ITGA3 Zornitza Stark Gene: itga3 has been classified as Green List (High Evidence).
Mendeliome v0.6337 ITGA3 Zornitza Stark Phenotypes for gene: ITGA3 were changed from to Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, MIM# 614748
Mendeliome v0.6334 ITGA3 Zornitza Stark reviewed gene: ITGA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22512483, 25810266, 27717396, 32198874, 26854491; Phenotypes: Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, MIM# 614748; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6334 FERMT1 Zornitza Stark Gene: fermt1 has been classified as Green List (High Evidence).
Mendeliome v0.6331 EXPH5 Zornitza Stark Gene: exph5 has been classified as Green List (High Evidence).
Mendeliome v0.6331 EXPH5 Zornitza Stark Phenotypes for gene: EXPH5 were changed from to Epidermolysis bullosa, nonspecific, autosomal recessive, MIM# 615028
Mendeliome v0.6328 EXPH5 Zornitza Stark reviewed gene: EXPH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176819, 32176379, 27730671, 27384765; Phenotypes: Epidermolysis bullosa, nonspecific, autosomal recessive, MIM# 615028; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6328 COL7A1 Zornitza Stark Gene: col7a1 has been classified as Green List (High Evidence).
Mendeliome v0.6328 COL7A1 Zornitza Stark Phenotypes for gene: COL7A1 were changed from to EBD inversa, MIM# 226600; EBD, Bart type MIM# 132000; EBD, localisata variant; Epidermolysis bullosa dystrophica, MIM# 131750; Epidermolysis bullosa dystrophica, 226600; Epidermolysis bullosa pruriginosa 604129; Epidermolysis bullosa, pretibial, MIM# 131850; Transient bullous of the newborn 131705
Mendeliome v0.6326 COL7A1 Zornitza Stark reviewed gene: COL7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: EBD inversa, MIM# 226600, EBD, Bart type MIM# 132000, EBD, localisata variant, Epidermolysis bullosa dystrophica, MIM# 131750, Epidermolysis bullosa dystrophica, 226600, Epidermolysis bullosa pruriginosa 604129, Epidermolysis bullosa, pretibial, MIM# 131850, Transient bullous of the newborn 131705; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6326 IGSF1 Zornitza Stark Gene: igsf1 has been classified as Green List (High Evidence).
Mendeliome v0.6323 FSTL5 Zornitza Stark Gene: fstl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6323 FSTL5 Zornitza Stark Classified gene: FSTL5 as Red List (low evidence)
Mendeliome v0.6323 FSTL5 Zornitza Stark Gene: fstl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6322 NCOA3 Zornitza Stark Gene: ncoa3 has been classified as Red List (Low Evidence).
Mendeliome v0.6322 NCOA3 Zornitza Stark Classified gene: NCOA3 as Red List (low evidence)
Mendeliome v0.6322 NCOA3 Zornitza Stark Gene: ncoa3 has been classified as Red List (Low Evidence).
Mendeliome v0.6321 FCHO1 Zornitza Stark Phenotypes for gene: FCHO1 were changed from Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis to Immunodeficiency 76, MIM# 619164; Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis
Mendeliome v0.6320 FCHO1 Zornitza Stark edited their review of gene: FCHO1: Changed phenotypes: Immunodeficiency 76, MIM# 619164, Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis
Mendeliome v0.6320 FSTL5 Eleanor Williams gene: FSTL5 was added
gene: FSTL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSTL5 was set to Unknown
Publications for gene: FSTL5 were set to 33105483
Phenotypes for gene: FSTL5 were set to isolated club-foot; iTEV; Talipes equinovarus
Review for gene: FSTL5 was set to RED
Added comment: PMID: 33105483 - Khanshour et al 20201 - GWAS study of isolated Talipes equinovarus (clubfoot, iTEV) identified an associated locus within FSTL5. They show that Fstl5 is expressed in the embryonic hindlimb in bats, chicks and mice. However, Fstl5 was expressed more highly in neural tissues in mice, and rats lacking Fstl5 showed no gross developmental malformations. Conditional overexpression of Fstl5 in osteochondroprogenitors resulted in sexually dimorphic differences in skeletal development in mice.
Sources: Literature
Mendeliome v0.6320 NCOA3 Eleanor Williams gene: NCOA3 was added
gene: NCOA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCOA3 were set to 33326993
Phenotypes for gene: NCOA3 were set to non-syndromic hearing loss
Review for gene: NCOA3 was set to RED
Added comment: PMID: 33326993 - Salazar da Silva et al 2020 - report a 5 generation Brazilian family with 15 individuals with non-syndromic, bilateral and progressive hearing loss. Using linkage analysis and then exome sequencing they identified a heterozygous variant in NCOA3 (NM_181659, c.2810C > G; p.Ser937Cys) that was found in the 7 analysed affected individuals. It was also found in 4 unaffected individuals but they are within the range of onset of hearing loss observed in the family. Expression of nco3 was found in the inner ear of mice and zebrafish. ncoa3-/- zebrafish showed subtle alterations in cartilage, mineral density and abnormal adult swimming behaviour, which may suggest the mechanism of pathogenicity.
Sources: Literature
Mendeliome v0.6320 CFHR3 Zornitza Stark Gene: cfhr3 has been classified as Green List (High Evidence).
Mendeliome v0.6317 CFHR1 Zornitza Stark Gene: cfhr1 has been classified as Green List (High Evidence).
Mendeliome v0.6312 OTUD5 Zornitza Stark Classified gene: OTUD5 as Green List (high evidence)
Mendeliome v0.6312 OTUD5 Zornitza Stark Gene: otud5 has been classified as Green List (High Evidence).
Mendeliome v0.6311 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931; Changed phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Mendeliome v0.6311 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6311 SCARB1 Bryony Thompson Phenotypes for gene: SCARB1 were changed from to High density lipoprotein cholesterol level QTL6 MIM#610762; Scavenger receptor class B type I deficiency; Inherited hypolipidaemias
Mendeliome v0.6308 SCARB1 Bryony Thompson Classified gene: SCARB1 as Amber List (moderate evidence)
Mendeliome v0.6308 SCARB1 Bryony Thompson Added comment: Comment on list classification: Benign clinical phenotype
Mendeliome v0.6308 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6307 SCARB1 Bryony Thompson reviewed gene: SCARB1: Rating: ; Mode of pathogenicity: None; Publications: 21226579, 30720493, 21480869, 26965621, 27604308; Phenotypes: High density lipoprotein cholesterol level QTL6 MIM#610762, Scavenger receptor class B type I deficiency, Inherited hypolipidaemias; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6307 CETP Bryony Thompson Gene: cetp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6307 CETP Bryony Thompson Phenotypes for gene: CETP were changed from to Hyperalphalipoproteinemia MIM#143470; Disorders of high density lipoprotein metabolism
Mendeliome v0.6304 CETP Bryony Thompson Classified gene: CETP as Amber List (moderate evidence)
Mendeliome v0.6304 CETP Bryony Thompson Added comment: Comment on list classification: Benign metabolic condition
Mendeliome v0.6304 CETP Bryony Thompson Gene: cetp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6303 CETP Bryony Thompson reviewed gene: CETP: Rating: ; Mode of pathogenicity: None; Publications: 12070157, 2586614, 27604308, 2215607, 2390095; Phenotypes: Hyperalphalipoproteinemia MIM#143470, Disorders of high density lipoprotein metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6302 DMGDH Bryony Thompson Classified gene: DMGDH as Amber List (moderate evidence)
Mendeliome v0.6302 DMGDH Bryony Thompson Gene: dmgdh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6301 CD320 Bryony Thompson Gene: cd320 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6301 CD320 Bryony Thompson Phenotypes for gene: CD320 were changed from to Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646; Disorders of cobalamin absorption, transport and metabolism
Mendeliome v0.6299 CD320 Bryony Thompson Classified gene: CD320 as Amber List (moderate evidence)
Mendeliome v0.6299 CD320 Bryony Thompson Added comment: Comment on list classification: Benign clinical condition
Mendeliome v0.6299 CD320 Bryony Thompson Gene: cd320 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6298 CD320 Bryony Thompson reviewed gene: CD320: Rating: ; Mode of pathogenicity: None; Publications: 29663633, 27604308, 30303736; Phenotypes: Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646, Disorders of cobalamin absorption, transport and metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6298 SHPK Bryony Thompson Gene: shpk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6298 SHPK Bryony Thompson Classified gene: SHPK as Amber List (moderate evidence)
Mendeliome v0.6298 SHPK Bryony Thompson Added comment: Comment on list classification: Likely benign disorder
Mendeliome v0.6298 SHPK Bryony Thompson Gene: shpk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6297 SHPK Bryony Thompson gene: SHPK was added
gene: SHPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHPK were set to 25647543; 27604308
Phenotypes for gene: SHPK were set to Sedoheptulokinase deficiency MIM#617213
Review for gene: SHPK was set to AMBER
Added comment: 2 unrelated cases reported, with elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense variant. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Due to inconsistency in phenotypes, likely SHPK deficiency is a benign disorder.
Sources: Literature
Mendeliome v0.6296 PNLIP Bryony Thompson Gene: pnlip has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6296 PNLIP Bryony Thompson Classified gene: PNLIP as Amber List (moderate evidence)
Mendeliome v0.6296 PNLIP Bryony Thompson Added comment: Comment on list classification: Appears to be a clinically benign metabolic condition
Mendeliome v0.6296 PNLIP Bryony Thompson Gene: pnlip has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6294 TDO2 Zornitza Stark Gene: tdo2 has been classified as Red List (Low Evidence).
Mendeliome v0.6294 TDO2 Zornitza Stark gene: TDO2 was added
gene: TDO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TDO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDO2 were set to 28285122; 27604308
Phenotypes for gene: TDO2 were set to Hypertryptophanemia MIM#600627; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: TDO2 was set to RED
Added comment: Single case reported, biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences
Sources: Expert list
Mendeliome v0.6293 SUGCT Zornitza Stark Gene: sugct has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6290 SUGCT Zornitza Stark Classified gene: SUGCT as Amber List (moderate evidence)
Mendeliome v0.6290 SUGCT Zornitza Stark Gene: sugct has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6289 SLC36A2 Zornitza Stark Gene: slc36a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6286 SLC36A2 Zornitza Stark Classified gene: SLC36A2 as Amber List (moderate evidence)
Mendeliome v0.6286 SLC36A2 Zornitza Stark Gene: slc36a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6285 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6285 SARDH Zornitza Stark Phenotypes for gene: SARDH were changed from to Sarcosinemia MIM#268900; Disorders of serine, glycine or glycerate metabolism
Mendeliome v0.6282 SARDH Zornitza Stark Classified gene: SARDH as Amber List (moderate evidence)
Mendeliome v0.6282 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6281 SARDH Zornitza Stark reviewed gene: SARDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 22825317, 27604308; Phenotypes: Sarcosinemia MIM#268900, Disorders of serine, glycine or glycerate metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6281 OPLAH Zornitza Stark Gene: oplah has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6278 OPLAH Zornitza Stark Classified gene: OPLAH as Amber List (moderate evidence)
Mendeliome v0.6278 OPLAH Zornitza Stark Gene: oplah has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6277 KHK Zornitza Stark Gene: khk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6274 KHK Zornitza Stark Classified gene: KHK as Amber List (moderate evidence)
Mendeliome v0.6274 KHK Zornitza Stark Gene: khk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6273 HAL Zornitza Stark Gene: hal has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6273 HAL Zornitza Stark Phenotypes for gene: HAL were changed from to Histidinemia MIM#235800; Disorders of histidine, tryptophan or lysine metabolism
Mendeliome v0.6270 HAL Zornitza Stark Classified gene: HAL as Amber List (moderate evidence)
Mendeliome v0.6270 HAL Zornitza Stark Gene: hal has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6269 HAL Zornitza Stark reviewed gene: HAL: Rating: AMBER; Mode of pathogenicity: None; Publications: 27604308, 15806399, 20156889; Phenotypes: Histidinemia MIM#235800, Disorders of histidine, tryptophan or lysine metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6268 GGT1 Zornitza Stark Classified gene: GGT1 as Amber List (moderate evidence)
Mendeliome v0.6268 GGT1 Zornitza Stark Gene: ggt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6267 DCXR Zornitza Stark Gene: dcxr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6267 DCXR Zornitza Stark Classified gene: DCXR as Amber List (moderate evidence)
Mendeliome v0.6267 DCXR Zornitza Stark Gene: dcxr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6265 CTH Zornitza Stark Gene: cth has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6262 CTH Zornitza Stark Classified gene: CTH as Amber List (moderate evidence)
Mendeliome v0.6262 CTH Zornitza Stark Gene: cth has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6261 ACSF3 Zornitza Stark Gene: acsf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6258 ACSF3 Zornitza Stark Classified gene: ACSF3 as Amber List (moderate evidence)
Mendeliome v0.6258 ACSF3 Zornitza Stark Gene: acsf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6257 PHGDH Zornitza Stark Gene: phgdh has been classified as Green List (High Evidence).
Mendeliome v0.6253 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
Mendeliome v0.6253 PNP Zornitza Stark Phenotypes for gene: PNP were changed from to Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179
Mendeliome v0.6250 PNP Zornitza Stark reviewed gene: PNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 3029074, 1384322, 11453975, 32695102, 32514656; Phenotypes: Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6250 PNPLA2 Zornitza Stark Gene: pnpla2 has been classified as Green List (High Evidence).
Mendeliome v0.6247 ESRP2 Zornitza Stark Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6244 ESRP2 Zornitza Stark Classified gene: ESRP2 as Amber List (moderate evidence)
Mendeliome v0.6244 ESRP2 Zornitza Stark Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6243 ACBD5 Zornitza Stark Gene: acbd5 has been classified as Green List (High Evidence).
Mendeliome v0.6240 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
Mendeliome v0.6237 SC5D Zornitza Stark Gene: sc5d has been classified as Green List (High Evidence).
Mendeliome v0.6237 SC5D Zornitza Stark Phenotypes for gene: SC5D were changed from to Lathosterolosis, MIM# 607330
Mendeliome v0.6234 SC5D Zornitza Stark reviewed gene: SC5D: Rating: GREEN; Mode of pathogenicity: None; Publications: 17853487, 12189593, 12812989, 24142275; Phenotypes: Lathosterolosis, MIM# 607330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6234 SLC39A14 Zornitza Stark Gene: slc39a14 has been classified as Green List (High Evidence).
Mendeliome v0.6231 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Mendeliome v0.6228 SLC46A1 Zornitza Stark changed review comment from: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.; to: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhoea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Gene: st3gal3 has been classified as Green List (High Evidence).
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from to Mental retardation, autosomal recessive 12 MIM# 611090
Mendeliome v0.6225 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23252400, 21907012, 31584066; Phenotypes: Mental retardation, autosomal recessive 12 MIM# 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6221 DDX58 Zornitza Stark edited their review of gene: DDX58: Added comment: Prasov et al. 2021 (PMID: 33495304) - A heterozygous DDX58 variant (c.1529A>T) was identified in 5 individuals from 2 unrelated families from different ethnic backgrounds. Phenotypes varied with some being severely affected by systemic features and others solely with glaucoma.Functional analysis demonstrated the variant confers a dominant gain-of-function effect on interferon activity.; Changed mode of pathogenicity: Other; Changed publications: 25620203, 33495304
Mendeliome v0.6221 KL Bryony Thompson Gene: kl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6220 KL Bryony Thompson Phenotypes for gene: KL were changed from to Tumoral calcinosis, hyperphosphatemic, familial, 3 MIM#617994; Hyperphosphatemia
Mendeliome v0.6219 KL Bryony Thompson Classified gene: KL as Amber List (moderate evidence)
Mendeliome v0.6219 KL Bryony Thompson Gene: kl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6218 KL Bryony Thompson reviewed gene: KL: Rating: AMBER; Mode of pathogenicity: None; Publications: 17710231, 31013726, 9363890; Phenotypes: Tumoral calcinosis, hyperphosphatemic, familial, 3 MIM#617994, Hyperphosphatemia; Mode of inheritance: None
Mendeliome v0.6218 GLRX2 Bryony Thompson Gene: glrx2 has been classified as Red List (Low Evidence).
Mendeliome v0.6218 GLRX2 Bryony Thompson Classified gene: GLRX2 as Red List (low evidence)
Mendeliome v0.6218 GLRX2 Bryony Thompson Gene: glrx2 has been classified as Red List (Low Evidence).
Mendeliome v0.6217 GLRX3 Bryony Thompson Classified gene: GLRX3 as Red List (low evidence)
Mendeliome v0.6217 GLRX3 Bryony Thompson Gene: glrx3 has been classified as Red List (Low Evidence).
Mendeliome v0.6216 GSTO2 Bryony Thompson Gene: gsto2 has been classified as Red List (Low Evidence).
Mendeliome v0.6216 GSTO2 Bryony Thompson Classified gene: GSTO2 as Red List (low evidence)
Mendeliome v0.6216 GSTO2 Bryony Thompson Gene: gsto2 has been classified as Red List (Low Evidence).
Mendeliome v0.6215 SIX1 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.; to: Deafness/BOS: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.
Mendeliome v0.6215 SIX1 Zornitza Stark Phenotypes for gene: SIX1 were changed from Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389 to Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389; Sagittal synostosis; Multi-suture synostosis
Mendeliome v0.6214 SIX1 Zornitza Stark Publications for gene: SIX1 were set to 15141091; 18330911; 21254961; 17637804; 29500469; 21700001; 24164807
Mendeliome v0.6213 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark changed review comment from: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature; to: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature

PMID 33434492: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS.
Mendeliome v0.6211 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract, Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 SIX1 Arina Puzriakova reviewed gene: SIX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33436522; Phenotypes: Sagittal synostosis, Multi-suture synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6210 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Mendeliome v0.6210 WBP11 Zornitza Stark Classified gene: WBP11 as Green List (high evidence)
Mendeliome v0.6210 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Mendeliome v0.6208 CLRN2 Zornitza Stark Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6208 CLRN2 Zornitza Stark Phenotypes for gene: CLRN2 were changed from Non-syndromic hearing loss to Non-syndromic hearing loss; Deafness, autosomal recessive 117, MIM# 619174
Mendeliome v0.6207 WBP11 Eleanor Williams gene: WBP11 was added
gene: WBP11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
Mendeliome v0.6207 TTF2 Zornitza Stark Gene: ttf2 has been classified as Red List (Low Evidence).
Mendeliome v0.6207 TTF2 Zornitza Stark gene: TTF2 was added
gene: TTF2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TTF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTF2 were set to 30022773
Phenotypes for gene: TTF2 were set to congenital hypothyroidism, thyroid dysgenesis, No OMIM #
Review for gene: TTF2 was set to RED
Added comment: 1 case only
Sources: Expert Review
Mendeliome v0.6206 DUOXA1 Zornitza Stark Gene: duoxa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6206 DUOXA1 Zornitza Stark Classified gene: DUOXA1 as Amber List (moderate evidence)
Mendeliome v0.6206 DUOXA1 Zornitza Stark Gene: duoxa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6204 DUOX1 Zornitza Stark Gene: duox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6204 DUOX1 Zornitza Stark Classified gene: DUOX1 as Amber List (moderate evidence)
Mendeliome v0.6204 DUOX1 Zornitza Stark Gene: duox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6202 TTF1 Zornitza Stark Gene: ttf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6202 TTF1 Zornitza Stark Phenotypes for gene: TTF1 were changed from to congenital hypothyroidism, thyroid dysgenesis, No OMIM #
Mendeliome v0.6199 TTF1 Zornitza Stark Classified gene: TTF1 as Amber List (moderate evidence)
Mendeliome v0.6199 TTF1 Zornitza Stark Gene: ttf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6198 TTF1 Zornitza Stark reviewed gene: TTF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30022773; Phenotypes: congenital hypothyroidism, thyroid dysgenesis, No OMIM #; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6198 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Mendeliome v0.6198 CDCA8 Zornitza Stark Classified gene: CDCA8 as Green List (high evidence)
Mendeliome v0.6198 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Mendeliome v0.6197 CDCA8 Zornitza Stark gene: CDCA8 was added
gene: CDCA8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, thyroid dysgenesis, no OMIM #
Mode of pathogenicity for gene: CDCA8 was set to Other
Review for gene: CDCA8 was set to GREEN
Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. GREEN for mono allelic, RED for biallelic.
Sources: Expert Review
Mendeliome v0.6196 DNAJC30 Zornitza Stark Gene: dnajc30 has been classified as Green List (High Evidence).
Mendeliome v0.6196 DNAJC30 Zornitza Stark Classified gene: DNAJC30 as Green List (high evidence)
Mendeliome v0.6196 DNAJC30 Zornitza Stark Gene: dnajc30 has been classified as Green List (High Evidence).
Mendeliome v0.6195 DNAJC30 Zornitza Stark gene: DNAJC30 was added
gene: DNAJC30 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC30 were set to 33465056
Phenotypes for gene: DNAJC30 were set to Leber Hereditary Optic Neuropathy
Review for gene: DNAJC30 was set to GREEN
Added comment: 33 individuals from 29 families had homozygous DNAJC30 missense variants. Three different variants identified (one responsible for most cases). All three variants absent from gnomAD. Incomplete penetrance and male predominance in affected individuals both typical of LHON due to mtDNA mutations. All 3 variants in the J domain of the protein. Functional evidence.
Sources: Literature
Mendeliome v0.6194 NFS1 Zornitza Stark Classified gene: NFS1 as Green List (high evidence)
Mendeliome v0.6194 NFS1 Zornitza Stark Gene: nfs1 has been classified as Green List (High Evidence).
Mendeliome v0.6192 SLC7A6OS Zornitza Stark Gene: slc7a6os has been classified as Red List (Low Evidence).
Mendeliome v0.6192 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Mendeliome v0.6191 TLR8 Zornitza Stark Gene: tlr8 has been classified as Green List (High Evidence).
Mendeliome v0.6191 TLR8 Zornitza Stark Classified gene: TLR8 as Green List (high evidence)
Mendeliome v0.6191 TLR8 Zornitza Stark Gene: tlr8 has been classified as Green List (High Evidence).
Mendeliome v0.6190 TLR8 Zornitza Stark gene: TLR8 was added
gene: TLR8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TLR8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR8 were set to 33512449
Phenotypes for gene: TLR8 were set to Immunodeficiency; bone marrow failure
Mode of pathogenicity for gene: TLR8 was set to Other
Review for gene: TLR8 was set to GREEN
Added comment: Six unrelated males reported with a phenotype comprising neutropaenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure. Three different variants reported, the variant was somatic in 5/6 individuals. GoF mechanism demonstrated.
Sources: Literature
Mendeliome v0.6189 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Mendeliome v0.6189 PIGF Zornitza Stark Classified gene: PIGF as Red List (low evidence)
Mendeliome v0.6189 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Mendeliome v0.6188 BRWD1 Zornitza Stark Gene: brwd1 has been classified as Green List (High Evidence).
Mendeliome v0.6188 BRWD1 Zornitza Stark Classified gene: BRWD1 as Green List (high evidence)
Mendeliome v0.6188 BRWD1 Zornitza Stark Gene: brwd1 has been classified as Green List (High Evidence).
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness - only one of the two had seizures (GTCS), the other was 14mo and noted to have tonic posturing.

Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated by flow cytometry and a rescue assay. Alkaline phosphatase in both individuals was normal.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio edited their review of gene: PIGF: Changed phenotypes: Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: Identified in 2 individuals with a phenotype similar to DOORS (syndrome
Sources: Literature; to: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio gene: PIGF was added
gene: PIGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol\ deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
gene: PIGF was marked as current diagnostic
Added comment: Identified in 2 individuals with a phenotype similar to DOORS (syndrome
Sources: Literature
Mendeliome v0.6187 BRWD1 Paul De Fazio gene: BRWD1 was added
gene: BRWD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRWD1 were set to 33389130
Phenotypes for gene: BRWD1 were set to Asthenoteratozoospermia, likely primary ciliary dyskinesia
Review for gene: BRWD1 was set to GREEN
gene: BRWD1 was marked as current diagnostic
Added comment: Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-likely" symptoms of re-occurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls).

Rated Green as there are three unrelated individuals reported.
Sources: Literature
Mendeliome v0.6187 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Mendeliome v0.6187 HIRA Zornitza Stark Classified gene: HIRA as Green List (high evidence)
Mendeliome v0.6187 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Mendeliome v0.6186 EYA3 Zornitza Stark Gene: eya3 has been classified as Red List (Low Evidence).
Mendeliome v0.6186 EYA3 Zornitza Stark Classified gene: EYA3 as Red List (low evidence)
Mendeliome v0.6186 EYA3 Zornitza Stark Gene: eya3 has been classified as Red List (Low Evidence).
Mendeliome v0.6185 CLRN2 Zornitza Stark Classified gene: CLRN2 as Amber List (moderate evidence)
Mendeliome v0.6185 CLRN2 Zornitza Stark Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6184 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Mendeliome v0.6181 CFAP47 Zornitza Stark Gene: cfap47 has been classified as Green List (High Evidence).
Mendeliome v0.6181 CFAP47 Zornitza Stark Classified gene: CFAP47 as Green List (high evidence)
Mendeliome v0.6181 CFAP47 Zornitza Stark Gene: cfap47 has been classified as Green List (High Evidence).
Mendeliome v0.6180 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Mendeliome v0.6180 C14orf39 Zornitza Stark Classified gene: C14orf39 as Green List (high evidence)
Mendeliome v0.6180 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Mendeliome v0.6179 ENO1 Zornitza Stark Gene: eno1 has been classified as Red List (Low Evidence).
Mendeliome v0.6179 ENO1 Zornitza Stark Classified gene: ENO1 as Red List (low evidence)
Mendeliome v0.6179 ENO1 Zornitza Stark Gene: eno1 has been classified as Red List (Low Evidence).
Mendeliome v0.6178 HEY2 Zornitza Stark gene: HEY2 was added
gene: HEY2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance). Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Mendeliome v0.6177 FGF9 Zornitza Stark edited their review of gene: FGF9: Changed phenotypes: Multiple synostoses syndrome 3, OMIM # 612961, Craniosynostosis
Mendeliome v0.6177 FGF9 Zornitza Stark Gene: fgf9 has been classified as Green List (High Evidence).
Mendeliome v0.6177 FGF9 Zornitza Stark Phenotypes for gene: FGF9 were changed from to Multiple synostoses syndrome 3, OMIM # 612961; Craniosynostosis
Mendeliome v0.6174 OTUD5 Zornitza Stark Gene: otud5 has been classified as Red List (Low Evidence).
Mendeliome v0.6174 OTUD5 Zornitza Stark gene: OTUD5 was added
gene: OTUD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies.
Sources: Literature
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6173 BCAT2 Bryony Thompson Classified gene: BCAT2 as Green List (high evidence)
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6172 BCAT2 Bryony Thompson changed review comment from: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS; to: 6 cases from 5 unrelated families with homozygous or compound heterozygous variant, and supporting functional studies demonstrating decreased BCAT2 enzyme activity for some of the variants. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6172 BCAT2 Bryony Thompson gene: BCAT2 was added
gene: BCAT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: BCAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT2 were set to 14755340; 25653144
Phenotypes for gene: BCAT2 were set to Hypervalinemia or hyperleucine-isoleucinemia MIM#618850; disorder of branched-chain amino acid metabolism
Review for gene: BCAT2 was set to AMBER
Added comment: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6170 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Mendeliome v0.6169 SATB1 Zornitza Stark Classified gene: SATB1 as Green List (high evidence)
Mendeliome v0.6169 SATB1 Zornitza Stark Gene: satb1 has been classified as Green List (High Evidence).
Mendeliome v0.6168 KCNN2 Sebastian Lunke Classified gene: KCNN2 as Green List (high evidence)
Mendeliome v0.6168 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Mendeliome v0.6167 ENO1 Kristin Rigbye gene: ENO1 was added
gene: ENO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ENO1 were set to 32488097
Phenotypes for gene: ENO1 were set to Polymicrogyria
Review for gene: ENO1 was set to RED
Added comment: ENO1 identified as a polymicrogyria candidate gene from the smallest case of 1p36 duplication reported to date, in a 35yo F (onset at 8mo) presenting intellectual disability, microcephaly, epilepsy and perisylvian polymicrogyria. The duplication only encompassed 2 genes, ENO1 and RERE, and gene expression analysis performed using the patient cells revealed reduced expression, mimicking haploinsufficiency. Eno1 inactivation in rats was shown to cause a brain development defect. According to OMIM, ENO1 is deleted in glioblastoma, which is tolerated by the expression of ENO2.
Sources: Literature
Mendeliome v0.6167 METAP1 Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence).
Mendeliome v0.6167 METAP1 Zornitza Stark Classified gene: METAP1 as Red List (low evidence)
Mendeliome v0.6167 METAP1 Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence).