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Mendeliome v0.5376 MYRF Zornitza Stark changed review comment from: Multiple affected individuals reported.
Sources: Expert list; to: Multiple affected individuals reported with nanophthalmos and high hyperopia and C-terminal frameshift variants, with or without dextrocardia or congenital diaphragmatic hernia.
Sources: Expert list
Mendeliome v0.5376 RLIM Zornitza Stark Marked gene: RLIM as ready
Mendeliome v0.5373 DNAH2 Zornitza Stark Marked gene: DNAH2 as ready
Mendeliome v0.5370 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) #301054
Mendeliome v0.5369 UBA1 Zornitza Stark edited their review of gene: UBA1: Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830, Autoinflammatory disease, adult onset: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) #301054
Mendeliome v0.5369 FGFR1 Zornitza Stark Marked gene: FGFR1 as ready
Mendeliome v0.5369 FGFR1 Zornitza Stark Phenotypes for gene: FGFR1 were changed from to Encephalocraniocutaneous lipomatosis, somatic mosaic 613001; Hartsfield syndrome 615465; Hypogonadotropic hypogonadism 2 with or without anosmia 147950; Jackson-Weiss syndrome 123150; Osteoglophonic dysplasia 166250; Pfeiffer syndrome 101600; Trigonocephaly 1 190440
Mendeliome v0.5365 B4GALT7 Zornitza Stark Marked gene: B4GALT7 as ready
Mendeliome v0.5361 KCNQ2 Zornitza Stark Marked gene: KCNQ2 as ready
Mendeliome v0.5361 KCNQ2 Zornitza Stark Phenotypes for gene: KCNQ2 were changed from to Epileptic encephalopathy, early infantile, 7, 613720; Seizures, benign neonatal, 1, 121200; Myokymia, 121200
Mendeliome v0.5357 KCNQ2 Elena Savva reviewed gene: KCNQ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 25959266, 32917465, 24318194; Phenotypes: Epileptic encephalopathy, early infantile, 7, 613720, Seizures, benign neonatal, 1, 121200, Myokymia, 121200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.5357 FGFR1 Elena Savva reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 18034870, 23812909, 26942290; Phenotypes: Encephalocraniocutaneous lipomatosis, somatic mosaic 613001, Hartsfield syndrome 615465, Hypogonadotropic hypogonadism 2 with or without anosmia 147950, Jackson-Weiss syndrome 123150, Osteoglophonic dysplasia 166250, Pfeiffer syndrome 101600, Trigonocephaly 1 190440; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5357 ADAR Zornitza Stark Marked gene: ADAR as ready
Mendeliome v0.5357 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Mendeliome v0.5357 ADAR Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010; Dyschromatosis symmetrica hereditaria, MIM# 127400
Mendeliome v0.5356 ADAR Zornitza Stark Mode of inheritance for gene: ADAR was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5355 ADAR Zornitza Stark reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM# 615010, Dyschromatosis symmetrica hereditaria, MIM# 127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5353 FOXJ1 Zornitza Stark Phenotypes for gene: FOXJ1 were changed from hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry to Ciliary dyskinesia, primary, 43, MIM#618699; hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry
Mendeliome v0.5352 FOXJ1 Zornitza Stark edited their review of gene: FOXJ1: Changed phenotypes: Ciliary dyskinesia, primary, 43, MIM#618699, hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry
Mendeliome v0.5352 MAPK1 Zornitza Stark Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, MIM#619087; Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Mendeliome v0.5351 MAPK1 Zornitza Stark edited their review of gene: MAPK1: Changed phenotypes: Noonan syndrome 13, MIM# 619087, Global developmental delay, Intellectual disability, Behavioral abnormality, Growth delay, Abnormality of the face, Abnormality of the neck, Abnormality of the cardiovascular system, Abnormality of the skin
Mendeliome v0.5351 SCD5 Zornitza Stark Marked gene: SCD5 as ready
Mendeliome v0.5351 SCD5 Zornitza Stark gene: SCD5 was added
gene: SCD5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SCD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCD5 were set to 31972369
Phenotypes for gene: SCD5 were set to Deafness, autosomal dominant 79, MIM#619086
Review for gene: SCD5 was set to RED
Added comment: Single 5-generation family reported with a missense variant segregating in 19 affected individuals. Variant is found at a low frequency in ExAC.
Sources: Expert list
Mendeliome v0.5350 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss to Delpire-McNeill syndrome, MIM# 619083; Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss
Mendeliome v0.5349 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss to Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Deafness, autosomal dominant 78, MIM#619081; Congenital, severe to profound hearing loss
Mendeliome v0.5348 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome: deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss to Kilquist syndrome, MIM#619080; deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss
Mendeliome v0.5347 OCLN Zornitza Stark Marked gene: OCLN as ready
Mendeliome v0.5344 JAM3 Zornitza Stark Marked gene: JAM3 as ready
Mendeliome v0.5344 JAM3 Zornitza Stark Phenotypes for gene: JAM3 were changed from to Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730
Mendeliome v0.5341 JAM3 Zornitza Stark reviewed gene: JAM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23255084, 21109224; Phenotypes: Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5341 NCKAP1 Zornitza Stark Marked gene: NCKAP1 as ready
Mendeliome v0.5338 ACAD9 Zornitza Stark Marked gene: ACAD9 as ready
Mendeliome v0.5338 ACAD9 Zornitza Stark Phenotypes for gene: ACAD9 were changed from to Mitochondrial complex I deficiency, nuclear type 20 MIM#611126
Mendeliome v0.5335 ACAD9 Zornitza Stark reviewed gene: ACAD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30025539; Phenotypes: Mitochondrial complex I deficiency, nuclear type 20 MIM#611126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5334 ALDOB Zornitza Stark Marked gene: ALDOB as ready
Mendeliome v0.5334 ALDOB Zornitza Stark Phenotypes for gene: ALDOB were changed from to Fructose intolerance, hereditary, 229600
Mendeliome v0.5331 ALDOB Elena Savva reviewed gene: ALDOB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 3083321; Phenotypes: Fructose intolerance, hereditary, 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5330 MYO1A Zornitza Stark Marked gene: MYO1A as ready
Mendeliome v0.5329 ARL2 Zornitza Stark Marked gene: ARL2 as ready
Mendeliome v0.5329 ARL2 Zornitza Stark Gene: arl2 has been classified as Red List (Low Evidence).
Mendeliome v0.5329 ARL2 Zornitza Stark gene: ARL2 was added
gene: ARL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARL2 were set to 30945270
Phenotypes for gene: ARL2 were set to Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma-1 (MRCS1), MIM#619082
Review for gene: ARL2 was set to RED
Added comment: Single family reported, missense variant segregating with structural eye abnormalities in 4 individuals (father and three daughters).
Sources: Expert list
Mendeliome v0.5327 LMX1B Zornitza Stark commented on gene: LMX1B: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. Some variants in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy).

>300 families reported.
Mendeliome v0.5326 UNC80 Zornitza Stark Marked gene: UNC80 as ready
Mendeliome v0.5326 UNC80 Zornitza Stark Phenotypes for gene: UNC80 were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; MONDO:0014777
Mendeliome v0.5323 UNC80 Zornitza Stark reviewed gene: UNC80: Rating: GREEN; Mode of pathogenicity: None; Publications: 26708751, 26708753, 26545877, 32620897, 30167850, 30167850; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801, MONDO:0014777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5321 AP2S1 Zornitza Stark Marked gene: AP2S1 as ready
Mendeliome v0.5320 CARD8 Zornitza Stark Marked gene: CARD8 as ready
Mendeliome v0.5320 CARD8 Zornitza Stark Gene: card8 has been classified as Red List (Low Evidence).
Mendeliome v0.5320 CARD8 Zornitza Stark gene: CARD8 was added
gene: CARD8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CARD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CARD8 were set to 29408806
Phenotypes for gene: CARD8 were set to Inflammatory bowel disease-30, MIM#619079
Review for gene: CARD8 was set to RED
Added comment: Two individuals from one family reported segregating a missense variant, dominant negative effect postulated.
Sources: Expert list
Mendeliome v0.5319 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830 to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Mendeliome v0.5317 UBA1 Zornitza Stark edited their review of gene: UBA1: Added comment: Association with VEXAS: 25 men reported with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation, and an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopaenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.; Changed publications: 18179898, 32181232, 31932168, 29034082, 27699224, 26028276, 23518311, 33108101; Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830, Autoinflammatory disease, adult onset: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Mendeliome v0.5317 ZFHX4 Bryony Thompson Marked gene: ZFHX4 as ready
Mendeliome v0.5315 ZFHX4 Bryony Thompson changed review comment from: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature; to: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 24038936 - a single case with developmental delay, macrocephaly, ventriculomegaly, hypermetropia, recurrent
infections, dysmorphism and a de novo deletion of the last 7 exons of the gene.
Sources: Literature
Mendeliome v0.5315 ZFHX4 Bryony Thompson gene: ZFHX4 was added
gene: ZFHX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to 33057194
Phenotypes for gene: ZFHX4 were set to Developmental disorders
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5314 UPF1 Bryony Thompson Marked gene: UPF1 as ready
Mendeliome v0.5313 UPF1 Bryony Thompson gene: UPF1 was added
gene: UPF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5311 U2AF2 Bryony Thompson gene: U2AF2 was added
gene: U2AF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5309 TCF7L2 Bryony Thompson Marked gene: TCF7L2 as ready
Mendeliome v0.5305 SRRM2 Bryony Thompson Marked gene: SRRM2 as ready
Mendeliome v0.5304 SRRM2 Bryony Thompson gene: SRRM2 was added
gene: SRRM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5303 SPEN Bryony Thompson Marked gene: SPEN as ready
Mendeliome v0.5302 SPEN Bryony Thompson gene: SPEN was added
gene: SPEN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5301 SATB1 Bryony Thompson Marked gene: SATB1 as ready
Mendeliome v0.5300 SATB1 Bryony Thompson gene: SATB1 was added
gene: SATB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB1 were set to 33057194
Phenotypes for gene: SATB1 were set to Developmental disorders
Review for gene: SATB1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo (2 frameshift, 7 missense, 1 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5299 RAB14 Bryony Thompson Marked gene: RAB14 as ready
Mendeliome v0.5298 RAB14 Bryony Thompson gene: RAB14 was added
gene: RAB14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5297 PSMC5 Bryony Thompson Marked gene: PSMC5 as ready
Mendeliome v0.5296 PSMC5 Bryony Thompson gene: PSMC5 was added
gene: PSMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5295 PRPF8 Bryony Thompson Marked gene: PRPF8 as ready
Mendeliome v0.5295 PRPF8 Bryony Thompson Added comment: Comment on phenotypes: Established Retinitis pigmentosa gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 29 de novo variants (2 frameshift, 19 missense, 1 stopgain, 7 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5292 MSL2 Bryony Thompson Marked gene: MSL2 as ready
Mendeliome v0.5291 PRKAR1B Bryony Thompson Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Mendeliome v0.5290 MSL2 Bryony Thompson gene: MSL2 was added
gene: MSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Mendeliome v0.5288 MMGT1 Bryony Thompson gene: MMGT1 was added
gene: MMGT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5286 MIB1 Bryony Thompson Added comment: Comment on phenotypes: Established congenital cardiac disease gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5286 MIB1 Bryony Thompson Phenotypes for gene: MIB1 were changed from to Left ventricular noncompaction 7 MIM#615092
Mendeliome v0.5284 MFN2 Bryony Thompson Added comment: Comment on phenotypes: Established cause of hereditary neuropathy.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 9 de novo variants (8 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5284 MFN2 Bryony Thompson Phenotypes for gene: MFN2 were changed from to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM #609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM #617087; Hereditary motor and sensory neuropathy VIA, OMIM #601152
Mendeliome v0.5282 KCNK3 Bryony Thompson Added comment: Comment on phenotypes: Established pulmonary hypertension gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (7 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5282 KCNK3 Bryony Thompson Phenotypes for gene: KCNK3 were changed from to Pulmonary hypertension, primary, 4 MIM#615344
Mendeliome v0.5280 HNRNPD Bryony Thompson Marked gene: HNRNPD as ready
Mendeliome v0.5279 HNRNPD Bryony Thompson gene: HNRNPD was added
gene: HNRNPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5278 PRKG2 Zornitza Stark Marked gene: PRKG2 as ready
Mendeliome v0.5277 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Mendeliome v0.5276 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLXND1 were set to 26068067
Phenotypes for gene: PLXND1 were set to Möbius syndrome
Review for gene: PLXND1 was set to GREEN
Added comment: De novo variants in 3 unrelated individuals with Moebius syndrome with some functional evidence.
Sources: Literature
Mendeliome v0.5275 ECEL1 Zornitza Stark Marked gene: ECEL1 as ready
Mendeliome v0.5275 ECEL1 Zornitza Stark Phenotypes for gene: ECEL1 were changed from to Arthrogryposis, distal, type 5D, MIM# 615065
Mendeliome v0.5274 MYMK Zornitza Stark changed review comment from: Sources: Expert list; to: Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. Intellect has been normal in molecularly confirmed cases. Defect in myoblast fusion. 6 unrelated families reported with CFZ phenotype and bi-allelic MYMK variants. p.Pro91Thr is a common founder variant, which is hypomorphic.
Mendeliome v0.5274 MYMK Zornitza Stark edited their review of gene: MYMK: Changed phenotypes: Carey-Fineman-Ziter syndrome, OMIM #254940
Mendeliome v0.5272 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261301, 23236030, 25099528, 24782201; Phenotypes: Arthrogryposis, distal, type 5D, MIM# 615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5272 PRKG2 Arina Puzriakova gene: PRKG2 was added
gene: PRKG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKG2 were set to 33106379
Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia
Review for gene: PRKG2 was set to GREEN
Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones.

Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper).
Sources: Literature
Mendeliome v0.5272 PRKACA Zornitza Stark Phenotypes for gene: PRKACA were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth
Mendeliome v0.5271 FOXP4 Zornitza Stark Marked gene: FOXP4 as ready
Mendeliome v0.5270 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to GREEN
Added comment: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays.
Sources: Literature
Mendeliome v0.5269 ASAH1 Zornitza Stark Marked gene: ASAH1 as ready
Mendeliome v0.5269 ASAH1 Zornitza Stark Phenotypes for gene: ASAH1 were changed from to Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950; Farber lipogranulomatosis, MIM# 228000
Mendeliome v0.5267 ASAH1 Zornitza Stark reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950, Farber lipogranulomatosis, MIM# 228000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5267 DHX32 Zornitza Stark Marked gene: DHX32 as ready
Mendeliome v0.5266 TNF Zornitza Stark Marked gene: TNF as ready
Mendeliome v0.5264 ALK Zornitza Stark Marked gene: ALK as ready
Mendeliome v0.5261 RHOB Zornitza Stark Marked gene: RHOB as ready
Mendeliome v0.5259 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979 to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant
Mendeliome v0.5258 DHX32 Dean Phelan gene: DHX32 was added
gene: DHX32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to PMID: 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
Mendeliome v0.5254 FBXO31 Kristin Rigbye changed review comment from: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.; to: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Extended patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Mendeliome v0.5254 NHLRC2 Zornitza Stark Marked gene: NHLRC2 as ready
Mendeliome v0.5251 RHOB Crystle Lee gene: RHOB was added
gene: RHOB was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RHOB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHOB were set to 32989326
Phenotypes for gene: RHOB were set to Cerebral Palsy (PMID:32989326)
Mode of pathogenicity for gene: RHOB was set to Other
Review for gene: RHOB was set to AMBER
Added comment: Candidate disease-causing gene for CP. Recurrent de novo missense variant reported in 2 unrelated families with supporting functional studies.
Sources: Expert list
Mendeliome v0.5251 CTLA4 Zornitza Stark Marked gene: CTLA4 as ready
Mendeliome v0.5249 VIM Zornitza Stark Marked gene: VIM as ready
Mendeliome v0.5249 VIM Zornitza Stark Phenotypes for gene: VIM were changed from to Cataract 30, pulverulent 116300; frontonasal dysostosis and premature aging
Mendeliome v0.5248 NHLRC2 Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.
Mendeliome v0.5248 NHLRC2 Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.
Mendeliome v0.5246 VIM Zornitza Stark reviewed gene: VIM: Rating: GREEN; Mode of pathogenicity: None; Publications: 19126778, 26694549, 28450710; Phenotypes: Cataract 30, pulverulent 116300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5244 ITPR3 Zornitza Stark Marked gene: ITPR3 as ready
Mendeliome v0.5243 ITPR3 Zornitza Stark gene: ITPR3 was added
gene: ITPR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to 32949214
Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease
Review for gene: ITPR3 was set to AMBER
Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect.
Sources: Literature
Mendeliome v0.5242 SOCS1 Zornitza Stark Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency to Common variable immunodeficiency; Early-onset autoimmunity
Mendeliome v0.5240 SOCS1 Zornitza Stark reviewed gene: SOCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33087723; Phenotypes: Early-onset autoimmunity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5240 AMOTL1 Zornitza Stark Marked gene: AMOTL1 as ready
Mendeliome v0.5240 AMOTL1 Zornitza Stark gene: AMOTL1 was added
gene: AMOTL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 33026150
Phenotypes for gene: AMOTL1 were set to Cleft lip and palate; imperforate anus; dysmorphism
Review for gene: AMOTL1 was set to RED
Added comment: Two unrelated families reported. In one, the variant was identified in parent and child who had orofacial cleft and cardiac abnormalities. Second report in PMID 33026150, de novo missense variant and cleft lip/palate, imperforate anus and dysmorphism. Mouse model does not recapitulate phenotype.
Sources: Literature
Mendeliome v0.5239 KIRREL1 Zornitza Stark Marked gene: KIRREL1 as ready
Mendeliome v0.5238 KIRREL1 Zornitza Stark gene: KIRREL1 was added
gene: KIRREL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIRREL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIRREL1 were set to 31472902
Phenotypes for gene: KIRREL1 were set to Steroid-resistant nephrotic syndrome
Review for gene: KIRREL1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants and limited functional data.
Sources: Literature
Mendeliome v0.5237 GFRA1 Zornitza Stark Marked gene: GFRA1 as ready
Mendeliome v0.5236 GFRA1 Zornitza Stark gene: GFRA1 was added
gene: GFRA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GFRA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFRA1 were set to 33020172
Phenotypes for gene: GFRA1 were set to Renal agenesis
Review for gene: GFRA1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic LOF variants identified in individuals with bilateral renal agenesis. GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system.
Sources: Literature
Mendeliome v0.5235 GNB2 Bryony Thompson reviewed gene: GNB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorder, sinus node dysfunction and atrioventricular block; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5235 GIGYF1 Bryony Thompson Marked gene: GIGYF1 as ready
Mendeliome v0.5234 GIGYF1 Bryony Thompson gene: GIGYF1 was added
gene: GIGYF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5233 FBXW7 Bryony Thompson Marked gene: FBXW7 as ready
Mendeliome v0.5232 FBXW7 Bryony Thompson gene: FBXW7 was added
gene: FBXW7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXW7 were set to 33057194
Phenotypes for gene: FBXW7 were set to Developmental disorder
Review for gene: FBXW7 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 12 de novo missense and 1 de novo synonymous variant identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5231 TKFC Zornitza Stark Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Developmental delay; cataracts; liver dysfunction
Mendeliome v0.5230 TKFC Zornitza Stark edited their review of gene: TKFC: Changed phenotypes: Triokinase and FMN cyclase deficiency syndrome, MIM#618805, Developmental delay, cataracts, liver dysfunction
Mendeliome v0.5230 PRKAR1B Zornitza Stark Marked gene: PRKAR1B as ready
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Mendeliome v0.5230 PRKAR1B Zornitza Stark Classified gene: PRKAR1B as Green List (high evidence)
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Mendeliome v0.5229 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Mendeliome v0.5229 NR1H4 Zornitza Stark Marked gene: NR1H4 as ready
Mendeliome v0.5226 PTF1A Zornitza Stark Marked gene: PTF1A as ready
Mendeliome v0.5226 PTF1A Zornitza Stark Phenotypes for gene: PTF1A were changed from to Pancreatic agenesis 2, MIM# 615935; Pancreatic and cerebellar agenesis, MIM# 609069
Mendeliome v0.5223 PTF1A Zornitza Stark reviewed gene: PTF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24212882, 21749365, 10507728, 15543146, 19650412; Phenotypes: Pancreatic agenesis 2, MIM# 615935, Pancreatic and cerebellar agenesis, MIM# 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5223 MPP5 Zornitza Stark Marked gene: MPP5 as ready
Mendeliome v0.5222 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous investigations not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Mendeliome v0.5222 AKR1D1 Zornitza Stark Marked gene: AKR1D1 as ready
Mendeliome v0.5219 SCYL1 Zornitza Stark Marked gene: SCYL1 as ready
Mendeliome v0.5219 SCYL1 Zornitza Stark Phenotypes for gene: SCYL1 were changed from to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
Mendeliome v0.5216 SCYL1 Zornitza Stark commented on gene: SCYL1: Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur. More than 5 unrelated families reported.
Mendeliome v0.5216 SLC30A10 Zornitza Stark Marked gene: SLC30A10 as ready
Mendeliome v0.5212 DDX23 Bryony Thompson gene: DDX23 was added
gene: DDX23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5210 ATP6V0A1 Bryony Thompson gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Marked gene: ARHGAP35 as ready
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Classified gene: ARHGAP35 as Amber List (moderate evidence)
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5208 ARHGAP35 Bryony Thompson gene: ARHGAP35 was added
gene: ARHGAP35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5207 AP2S1 Bryony Thompson Added comment: Comment on phenotypes: Established hypercalcaemia gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Mendeliome v0.5204 ASCL1 Zornitza Stark Marked gene: ASCL1 as ready
Mendeliome v0.5198 ODC1 Zornitza Stark commented on gene: ODC1: Fifth individual reported in PMID 30239107: de novo nonsense variant identified, molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce ODC degradation, leading to accumulation of active protein.
Mendeliome v0.5198 ODC1 Zornitza Stark changed review comment from: Four individuals with de novo GoF variants in this gene reported.
Sources: Literature; to: Four individuals with de novo GoF variants in this gene reported.
Sources: Literature
Mendeliome v0.5198 KDELR2 Zornitza Stark Marked gene: KDELR2 as ready
Mendeliome v0.5197 KDELR2 Zornitza Stark gene: KDELR2 was added
gene: KDELR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KDELR2 were set to 33053334
Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies.
Sources: Expert list
Mendeliome v0.5196 SCN8A Zornitza Stark Marked gene: SCN8A as ready
Mendeliome v0.5196 SCN8A Zornitza Stark Phenotypes for gene: SCN8A were changed from to Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive; Myoclonus, familial, 2, MIM# 618364; paroxysmal kinesigenic dyskinesias; Cognitive impairment with or without cerebellar ataxia, MIM# 614306
Mendeliome v0.5192 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31625145, 29726066, 27098556, 28702509, 16236810, 31904124, 31887642, 31675620; Phenotypes: Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive, Myoclonus, familial, 2, MIM# 618364, paroxysmal kinesigenic dyskinesias, Cognitive impairment with or without cerebellar ataxia, MIM# 614306; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5191 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5190 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979 to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5189 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979
Mendeliome v0.5188 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndromeROSAH syndrome, MIM#614979
Mendeliome v0.5188 NUS1 Zornitza Stark Phenotypes for gene: NUS1 were changed from Epilepsy; intellectual disability to Congenital disorder of glycosylation, type 1aa 617082; Mental retardation, autosomal dominant 55, with seizures 617831
Mendeliome v0.5185 COG8 Zornitza Stark Marked gene: COG8 as ready
Mendeliome v0.5182 HBB Zornitza Stark Marked gene: HBB as ready
Mendeliome v0.5182 HBB Zornitza Stark Phenotypes for gene: HBB were changed from to Delta-beta thalassemia 141749; Erythrocytosis 6 617980; Heinz body anemia 140700; Hereditary persistence of fetal hemoglobin 141749; Methemoglobinemia, beta type 617971; Sickle cell anemia 603903; Thalassemia-beta, dominant inclusion-body 603902; Thalassemia, beta 613985
Mendeliome v0.5180 SCN8A Elena Savva reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 30615093, 31904124; Phenotypes: ?Myoclonus, familial, 2 618364, Cognitive impairment with or without cerebellar ataxia 614306, Epileptic encephalopathy, early infantile, 13 614558, Seizures, benign familial infantile, 5 617080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5178 RAD51D Zornitza Stark Marked gene: RAD51D as ready
Mendeliome v0.5178 RAD51D Zornitza Stark Phenotypes for gene: RAD51D were changed from to {Breast-ovarian cancer, familial, susceptibility to, 4} 614291
Mendeliome v0.5174 NUS1 Elena Savva reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25066056, 29100083, 31656175, 32485575; Phenotypes: ?Congenital disorder of glycosylation, type 1aa 617082, Mental retardation, autosomal dominant 55, with seizures 617831; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5174 HBB Elena Savva reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31788855, 20301599, 29700171; Phenotypes: {Malaria, resistance to} 611162, Delta-beta thalassemia 141749, Erythrocytosis 6 617980, Heinz body anemia 140700, Hereditary persistence of fetal hemoglobin 141749, Methemoglobinemia, beta type 617971, Sickle cell anemia 603903, Thalassemia-beta, dominant inclusion-body 603902, Thalassemia, beta 613985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5174 ISPD Elena Savva reviewed gene: ISPD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28688748, 30060766, 22522420; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 614643, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7 616052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5174 TPO Zornitza Stark Marked gene: TPO as ready
Mendeliome v0.5171 RAD51D Elena Savva reviewed gene: RAD51D: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28646019, 31937788, 26057125; Phenotypes: {Breast-ovarian cancer, familial, susceptibility to, 4} 614291; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5171 SLC35A3 Zornitza Stark Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures; OMIM #615553 to Arthrogryposis, mental retardation, and seizures OMIM #615553; Skeletal dysplasia; Congenital disorder of glycosylation
Mendeliome v0.5168 SLC35A3 Zornitza Stark edited their review of gene: SLC35A3: Added comment: Third unrelated family reported in PMID 28777481 with prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus flammeus, and a cupped left ear. Unclear if this is a distinct phenotype (note Holstein cows with variants in this gene have a skeletal phenotype) or part of a spectrum for a CDG. However, abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter demonstrated, so overall, promoted to Green for CDG.; Changed rating: GREEN; Changed publications: 28777481, 28328131, 24031089; Changed phenotypes: Arthrogryposis, mental retardation, and seizures OMIM #615553, Skeletal dysplasia, Congenital disorder of glycosylation; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5168 VAC14 Zornitza Stark Marked gene: VAC14 as ready
Mendeliome v0.5164 PHOX2A Zornitza Stark reviewed gene: PHOX2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16815872; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5163 COL25A1 Zornitza Stark Marked gene: COL25A1 as ready
Mendeliome v0.5163 COL25A1 Zornitza Stark Phenotypes for gene: COL25A1 were changed from to Fibrosis of extraocular muscles, congenital, 5, MIM# 616219
Mendeliome v0.5159 COL25A1 Zornitza Stark reviewed gene: COL25A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25500261, 26486031; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, MIM# 616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5159 KIF21A Zornitza Stark Marked gene: KIF21A as ready
Mendeliome v0.5159 KIF21A Zornitza Stark Phenotypes for gene: KIF21A were changed from to Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700
Mendeliome v0.5156 KIF21A Zornitza Stark reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15621876, 15223798, 15621877, 18332320, 28930843, 27513105, 26190014, 24656932; Phenotypes: Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Marked gene: NDUFAF6 as ready
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Phenotypes for gene: NDUFAF6 were changed from to Mitochondrial complex I deficiency, nuclear type 17 (MIM#618239)
Mendeliome v0.5153 NDUFAF6 Ain Roesley reviewed gene: NDUFAF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 30642748; Phenotypes: Mitochondrial complex I deficiency, nuclear type 17 (MIM#618239); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5153 WNT5A Zornitza Stark Marked gene: WNT5A as ready
Mendeliome v0.5150 CYP3A4 Zornitza Stark Marked gene: CYP3A4 as ready
Mendeliome v0.5146 KCTD17 Zornitza Stark Marked gene: KCTD17 as ready
Mendeliome v0.5143 TAF1 Zornitza Stark Marked gene: TAF1 as ready
Mendeliome v0.5143 TAF1 Zornitza Stark Phenotypes for gene: TAF1 were changed from to Dystonia-Parkinsonism, X-linked, MIM# 314250; Mental retardation, X-linked, syndromic 33, MIM# 300966
Mendeliome v0.5140 TAF1 Zornitza Stark reviewed gene: TAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273961, 31646703; Phenotypes: Dystonia-Parkinsonism, X-linked, MIM# 314250, Mental retardation, X-linked, syndromic 33, MIM# 300966; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5140 CTNNA3 Bryony Thompson Marked gene: CTNNA3 as ready
Mendeliome v0.5139 CTNNA3 Bryony Thompson gene: CTNNA3 was added
gene: CTNNA3 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: CTNNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTNNA3 were set to 23136403; 21254927; 22421363; 30415094; 31539150
Phenotypes for gene: CTNNA3 were set to Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 13 MIM#615616
Review for gene: CTNNA3 was set to AMBER
Added comment: Gene is classified as Limited by the ClinGen ARVC GCEP (Classification - 08/06/2019). PMID: 23136403 - an assumed de novo missense (V94D) was identified in an Italian proband with arrhythmogenic right ventricular dysplasia. An inframe deletion (Leu765del) was identified in a proband with arrhythmogenic right ventricular dysplasia, and was also present in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. There was supporting in vitro functional assay evidence for both variants. PMID: 21254927 - a missense variant was found in one of 55 Danish ARVD patients, but was found 37 times in 276,338 (1 homozygous) reference alleles in gnomAD making it less likely as a causal variant. PMID: 22421363 - null mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC. Additional publications identified - PMID: 30415094 - a VUS identified in a sudden unexpected death case with slight LV hypertrophy. PMID: 31539150 - 2 VUS and a nonsense variant identified in 3 probands with atrial fibrillation, with the nonsense variant segregating in an affected first-degree relative.
Sources: ClinGen
Mendeliome v0.5138 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from Epileptic encephalopathy, early infantile, 4 612164; Rett syndrome; Rett-like phenotypes to Developmental and epileptic encephalopathy 4, MIM# 612164; Rett syndrome; Rett-like phenotypes
Mendeliome v0.5135 CHRNE Zornitza Stark Marked gene: CHRNE as ready
Mendeliome v0.5132 COLQ Zornitza Stark Marked gene: COLQ as ready
Mendeliome v0.5129 NDUFA4 Zornitza Stark Phenotypes for gene: NDUFA4 were changed from Leigh syndrome; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065; Leigh syndrome; Complex IV deficiency
Mendeliome v0.5128 NDUFA4 Zornitza Stark edited their review of gene: NDUFA4: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065, Leigh syndrome, Complex IV deficiency
Mendeliome v0.5128 COX5A Zornitza Stark Phenotypes for gene: COX5A were changed from pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064; pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Mendeliome v0.5127 COX5A Zornitza Stark edited their review of gene: COX5A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064, pulmonary arterial hypertension, lactic acidemia, failure to thrive, isolated complex IV deficiency
Mendeliome v0.5127 PET117 Zornitza Stark Phenotypes for gene: PET117 were changed from Developmental delay; Regression; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063; Developmental delay; Regression; Complex IV deficiency
Mendeliome v0.5126 PET117 Zornitza Stark edited their review of gene: PET117: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063, Developmental delay, Regression, Complex IV deficiency
Mendeliome v0.5126 COX6A2 Zornitza Stark Phenotypes for gene: COX6A2 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 18, MIM#619062
Mendeliome v0.5125 COX6A2 Zornitza Stark edited their review of gene: COX6A2: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 18, MIM#619062
Mendeliome v0.5125 APOPT1 Zornitza Stark Marked gene: APOPT1 as ready
Mendeliome v0.5125 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Mendeliome v0.5122 APOPT1 Zornitza Stark reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347]; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5122 COX4I1 Zornitza Stark Marked gene: COX4I1 as ready
Mendeliome v0.5121 COX4I1 Zornitza Stark gene: COX4I1 was added
gene: COX4I1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COX4I1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX4I1 were set to 28766551; 22592081; 31290619
Phenotypes for gene: COX4I1 were set to Mitochondrial complex IV deficiency, nuclear type 16, MIM#619060
Review for gene: COX4I1 was set to AMBER
Added comment: Two unrelated families reported.

Two more variants reported in PMID: 22592081: one is non-coding and the other rare missense, appear to have been identified in separate individuals, i.e. heterozygous in each individual.
Sources: Expert list
Mendeliome v0.5120 COX8A Zornitza Stark Phenotypes for gene: COX8A were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 15, MIM#619059
Mendeliome v0.5119 COX8A Zornitza Stark edited their review of gene: COX8A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 15, MIM#619059
Mendeliome v0.5119 COA3 Zornitza Stark Phenotypes for gene: COA3 were changed from Mitochondrial complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Mendeliome v0.5118 COA3 Zornitza Stark edited their review of gene: COA3: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 14, MIM# 619058
Mendeliome v0.5118 PET100 Zornitza Stark Marked gene: PET100 as ready
Mendeliome v0.5118 PET100 Zornitza Stark Phenotypes for gene: PET100 were changed from to Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Mendeliome v0.5115 PET100 Zornitza Stark reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5115 COX20 Zornitza Stark Marked gene: COX20 as ready
Mendeliome v0.5115 COX20 Zornitza Stark Phenotypes for gene: COX20 were changed from to Mitochondrial complex IV deficiency, nuclear type 11, MIM#619054
Mendeliome v0.5112 COX20 Zornitza Stark reviewed gene: COX20: Rating: GREEN; Mode of pathogenicity: None; Publications: 24202787, 31079202, 30656193, 23125284, 32606554; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 11, MIM#619054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5112 COX14 Zornitza Stark Phenotypes for gene: COX14 were changed from Mitochondrial complex IV deficiency, MIM#220110 to Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Mendeliome v0.5111 COX14 Zornitza Stark edited their review of gene: COX14: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Mendeliome v0.5111 TACO1 Zornitza Stark Marked gene: TACO1 as ready
Mendeliome v0.5111 TACO1 Zornitza Stark Phenotypes for gene: TACO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 8, MIM# 619052
Mendeliome v0.5108 TACO1 Zornitza Stark reviewed gene: TACO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19503089, 20727754, 25044680, 27319982; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 8, MIM# 619052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5108 PRKACA Zornitza Stark Marked gene: PRKACA as ready
Mendeliome v0.5106 CNGA2 Zornitza Stark Marked gene: CNGA2 as ready
Mendeliome v0.5106 CNGA2 Zornitza Stark gene: CNGA2 was added
gene: CNGA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNGA2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNGA2 were set to 28572688
Phenotypes for gene: CNGA2 were set to Congenital anosmia
Review for gene: CNGA2 was set to RED
Added comment: Single multiplex family with high-impact variant segregating with anosmia.
Sources: Literature
Mendeliome v0.5105 COX6B1 Zornitza Stark Marked gene: COX6B1 as ready
Mendeliome v0.5105 COX6B1 Zornitza Stark Phenotypes for gene: COX6B1 were changed from to Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051
Mendeliome v0.5102 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5102 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB 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: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 PRKACA Konstantinos Varvagiannis gene: PRKACA was added
gene: PRKACA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACA were set to 33058759; 31130284
Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACA were set to unknown
Mode of pathogenicity for gene: PRKACA 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: PRKACA was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 SCO1 Zornitza Stark Marked gene: SCO1 as ready
Mendeliome v0.5102 SCO1 Zornitza Stark Phenotypes for gene: SCO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048
Mendeliome v0.5099 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5099 COX10 Zornitza Stark Marked gene: COX10 as ready
Mendeliome v0.5099 COX10 Zornitza Stark Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046
Mendeliome v0.5096 COX10 Zornitza Stark reviewed gene: COX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 10767350, 12928484, 15455402, 27290639; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5096 GFPT1 Zornitza Stark Marked gene: GFPT1 as ready
Mendeliome v0.5096 GFPT1 Zornitza Stark Phenotypes for gene: GFPT1 were changed from to Myasthenia, congenital, 12, with tubular aggregates, 610542; Limb-girdle congenital myasthenic syndrome; Leukoencephalopathy
Mendeliome v0.5093 GFPT1 Zornitza Stark reviewed gene: GFPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21310273, 30635494; Phenotypes: Myasthenia, congenital, 12, with tubular aggregates, 610542, Limb-girdle congenital myasthenic syndrome, Leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5093 BMP7 Zornitza Stark Marked gene: BMP7 as ready
Mendeliome v0.5093 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 32266521; 24429398
Phenotypes for gene: BMP7 were set to Non-syndromic metopic craniosynostosis
Mode of pathogenicity for gene: BMP7 was set to Other
Review for gene: BMP7 was set to RED
Added comment: 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
Mendeliome v0.5092 SMARCC1 Zornitza Stark Publications for gene: SMARCC1 were set to 33077954
Mendeliome v0.5091 SMARCC1 Zornitza Stark changed review comment from: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort.
Sources: Literature; to: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort. Supportive mouse model.
Sources: Literature
Mendeliome v0.5091 SMARCC1 Zornitza Stark edited their review of gene: SMARCC1: Changed publications: 33077954, 24170322
Mendeliome v0.5091 SMARCC1 Zornitza Stark Marked gene: SMARCC1 as ready
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5091 SMARCC1 Zornitza Stark Classified gene: SMARCC1 as Green List (high evidence)
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5090 SMARCC1 Zornitza Stark gene: SMARCC1 was added
gene: SMARCC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 33077954
Phenotypes for gene: SMARCC1 were set to Congenital hydrocephalus
Review for gene: SMARCC1 was set to GREEN
Added comment: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort.
Sources: Literature
Mendeliome v0.5089 SLC18A3 Zornitza Stark Marked gene: SLC18A3 as ready
Mendeliome v0.5085 SYT2 Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in two families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.; to: Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.
Mendeliome v0.5085 SYT2 Zornitza Stark Marked gene: SYT2 as ready
Mendeliome v0.5082 CHAT Zornitza Stark Marked gene: CHAT as ready
Mendeliome v0.5079 ALG2 Zornitza Stark Marked gene: ALG2 as ready
Mendeliome v0.5079 ALG2 Zornitza Stark Phenotypes for gene: ALG2 were changed from to Myasthenic syndrome, congenital, 14, with tubular aggregates, MIM# 616228; Congenital disorder of glycosylation, type Ii, MIM# 607906
Mendeliome v0.5075 ALG2 Zornitza Stark reviewed gene: ALG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23404334, 24461433, 12684507; Phenotypes: Myasthenic syndrome, congenital, 14, with tubular aggregates, MIM# 616228, Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5075 AGRN Zornitza Stark Marked gene: AGRN as ready
Mendeliome v0.5072 DPH1 Zornitza Stark Marked gene: DPH1 as ready
Mendeliome v0.5072 DPH1 Zornitza Stark Phenotypes for gene: DPH1 were changed from to Developmental delay with short stature, dysmorphic facial features, and sparse hair, MIM# 616901
Mendeliome v0.5069 DPH1 Zornitza Stark reviewed gene: DPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29362492, 29410513, 25558065, 26220823]; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair, MIM# 616901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5068 LRP8 Bryony Thompson Marked gene: LRP8 as ready
Mendeliome v0.5067 LRP8 Bryony Thompson reviewed gene: LRP8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myocardial infarction, susceptibility to MIM#608446; Mode of inheritance: Unknown
Mendeliome v0.5067 TCF21 Bryony Thompson Marked gene: TCF21 as ready
Mendeliome v0.5066 TCF21 Bryony Thompson reviewed gene: TCF21: Rating: RED; Mode of pathogenicity: None; Publications: 16156022, 10769282, 24875298; Phenotypes: Sensorineural hearing loss, dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5066 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.
Mendeliome v0.5066 SETD1A Zornitza Stark Phenotypes for gene: SETD1A were changed from Epilepsy, early-onset, with or without developmental delay, MIM# 618832 to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5065 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5065 JARID2 Zornitza Stark Publications for gene: JARID2 were set to 23294540
Mendeliome v0.5064 JARID2 Zornitza Stark Classified gene: JARID2 as Green List (high evidence)
Mendeliome v0.5064 JARID2 Zornitza Stark Gene: jarid2 has been classified as Green List (High Evidence).
Mendeliome v0.5063 JARID2 Zornitza Stark edited their review of gene: JARID2: Added comment: 13 additional individuals reported, note CNVs common but LOF sequence variants identified too.; Changed rating: GREEN; Changed publications: 23294540, 33077894
Mendeliome v0.5063 NUDT2 Zornitza Stark Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy
Mendeliome v0.5060 NUDT2 Zornitza Stark edited their review of gene: NUDT2: Added comment: Three individuals from two additional families reported with a different homozygous variant and ID/polyneuropathy phenotype. Upgrade to Green.; Changed rating: GREEN; Changed publications: 27431290, 30059600, 33058507
Mendeliome v0.5060 AFF2 Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.
Mendeliome v0.5060 AFF2 Zornitza Stark Marked gene: AFF2 as ready
Mendeliome v0.5060 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from to Mental retardation, X-linked, FRAXE type 309548
Mendeliome v0.5057 AFF2 Zornitza Stark commented on gene: AFF2: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.
Mendeliome v0.5057 AFF2 Zornitza Stark reviewed gene: AFF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8334699, 21739600; Phenotypes: Mental retardation, X-linked, FRAXE type 309548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5057 AUTS2 Zornitza Stark Marked gene: AUTS2 as ready
Mendeliome v0.5057 AUTS2 Zornitza Stark Phenotypes for gene: AUTS2 were changed from to Mental retardation, autosomal dominant 26, MIM#615834
Mendeliome v0.5054 AUTS2 Zornitza Stark reviewed gene: AUTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23332918, 25205402, 31474318; Phenotypes: Mental retardation, autosomal dominant 26, MIM#615834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5051 ITSN2 Zornitza Stark Marked gene: ITSN2 as ready
Mendeliome v0.5050 ITSN2 Elena Savva gene: ITSN2 was added
gene: ITSN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITSN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITSN2 were set to PMID: 29773874
Phenotypes for gene: ITSN2 were set to Nephrotic syndrome
Review for gene: ITSN2 was set to GREEN
Added comment: PMID: 29773874: 2 families (3 patients) with homozygous missense or chet missense/PTC + null mice recapitulating the human phenotype.
Functional analysis of all variants shows an inability for Cdc42 activation as shown by wildtype overexpression
Sources: Literature
Mendeliome v0.5050 PI4K2A Zornitza Stark Marked gene: PI4K2A as ready
Mendeliome v0.5050 PI4K2A Zornitza Stark gene: PI4K2A was added
gene: PI4K2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 32418222
Phenotypes for gene: PI4K2A were set to Cutis laxa, intellectual disability, movement disorder
Review for gene: PI4K2A was set to RED
Added comment: Single individual reported with homozygous missense variant and functional data including mouse model.
Sources: Literature
Mendeliome v0.5049 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
Mendeliome v0.5049 NR5A1 Zornitza Stark Phenotypes for gene: NR5A1 were changed from to Adrenocortical insufficiency, (MIM#612964); 46, XX sex reversal 4, (MIM# 617480); Premature ovarian failure 7, (MIM#612964); Spermatogenic failure 8, (MIM#613957); 46XY sex reversal 3, (MIM#612965)
Mendeliome v0.5046 NR5A1 Zornitza Stark reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31513305; Phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5046 HECW2 Zornitza Stark Marked gene: HECW2 as ready
Mendeliome v0.5042 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5041 ARHGEF9 Zornitza Stark edited their review of gene: ARHGEF9: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5041 ZMYND10 Zornitza Stark Marked gene: ZMYND10 as ready
Mendeliome v0.5041 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from to Ciliary dyskinesia, primary, 22, MIM#615444
Mendeliome v0.5038 ZMYND10 Zornitza Stark reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23891471, 23891469; Phenotypes: Ciliary dyskinesia, primary, 22, MIM#615444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5038 SPAG1 Zornitza Stark Marked gene: SPAG1 as ready
Mendeliome v0.5038 SPAG1 Zornitza Stark Phenotypes for gene: SPAG1 were changed from to Ciliary dyskinesia, primary, 28 (MIM#615505)
Mendeliome v0.5035 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622824, 32502479, 24055112; Phenotypes: Ciliary dyskinesia, primary, 28 (MIM#615505); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5035 MMP21 Zornitza Stark Marked gene: MMP21 as ready
Mendeliome v0.5032 DNAAF1 Zornitza Stark Marked gene: DNAAF1 as ready
Mendeliome v0.5032 DNAAF1 Zornitza Stark Phenotypes for gene: DNAAF1 were changed from to Ciliary dyskinesia, primary, 13, MIM# 613193
Mendeliome v0.5029 DNAAF1 Zornitza Stark reviewed gene: DNAAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19944400, 19944405, 32502479, 29228333, 27261005; Phenotypes: Ciliary dyskinesia, primary, 13, MIM# 613193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5029 LRRC6 Zornitza Stark Marked gene: LRRC6 as ready
Mendeliome v0.5029 LRRC6 Zornitza Stark Phenotypes for gene: LRRC6 were changed from to Ciliary dyskinesia, primary, 19, MIM# 614935
Mendeliome v0.5026 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122589, 23891469, 32622824, 29511670; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5026 GAS8 Zornitza Stark Marked gene: GAS8 as ready
Mendeliome v0.5026 GAS8 Zornitza Stark Phenotypes for gene: GAS8 were changed from to Ciliary dyskinesia, primary, 33, MIM#616726
Mendeliome v0.5023 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387594, 27120127; Phenotypes: Ciliary dyskinesia, primary, 33, mIM# 616726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5023 DNAI2 Zornitza Stark Marked gene: DNAI2 as ready
Mendeliome v0.5023 DNAI2 Zornitza Stark Phenotypes for gene: DNAI2 were changed from to Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444
Mendeliome v0.5020 DNAI2 Zornitza Stark reviewed gene: DNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18950741, 23261302; Phenotypes: Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5020 DNAI1 Zornitza Stark Marked gene: DNAI1 as ready
Mendeliome v0.5020 DNAI1 Zornitza Stark Phenotypes for gene: DNAI1 were changed from to Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400
Mendeliome v0.5017 DNAI1 Zornitza Stark reviewed gene: DNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10577904, 11231901, 32502479, 31765523, 30622330; Phenotypes: Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAH11 Zornitza Stark reviewed gene: DNAH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 12142464, 18022865, 22102620, 32633470, 31879361, 31765523, 31040315; Phenotypes: Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM#611884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAAF5 Zornitza Stark Marked gene: DNAAF5 as ready
Mendeliome v0.5016 DNAAF5 Zornitza Stark Phenotypes for gene: DNAAF5 were changed from to Ciliary dyskinesia, primary, 18, MIM# 614874
Mendeliome v0.5013 DNAAF5 Zornitza Stark reviewed gene: DNAAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23040496, 29363216, 25232951; Phenotypes: Ciliary dyskinesia, primary, 18, MIM# 614874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5013 DNAAF3 Zornitza Stark Marked gene: DNAAF3 as ready
Mendeliome v0.5013 DNAAF3 Zornitza Stark Phenotypes for gene: DNAAF3 were changed from to Ciliary dyskinesia, primary, 2, MIM# 606763
Mendeliome v0.5010 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22387996, 32622824, 31186518; Phenotypes: Ciliary dyskinesia, primary, 2, MIM# 606763; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5010 RAB27A Zornitza Stark Marked gene: RAB27A as ready
Mendeliome v0.5007 DNAAF2 Zornitza Stark Marked gene: DNAAF2 as ready
Mendeliome v0.5007 DNAAF2 Zornitza Stark Phenotypes for gene: DNAAF2 were changed from to Ciliary dyskinesia, primary, 10, MIM# 612518
Mendeliome v0.5004 DNAAF2 Zornitza Stark reviewed gene: DNAAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19052621, 32638265, 31107948; Phenotypes: Ciliary dyskinesia, primary, 10, MIM# 612518; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5004 PPP1R13L Zornitza Stark Marked gene: PPP1R13L as ready
Mendeliome v0.5003 PPP1R13L Zornitza Stark gene: PPP1R13L was added
gene: PPP1R13L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R13L were set to 32666529; 28864777
Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy
Review for gene: PPP1R13L was set to GREEN
Added comment: Four families reported in PMID 28864777, but same homozygous variant, identity by descent. Five unrelated families reported in PMID 32666529. Severe progressive DCM with onset in infancy.
Sources: Expert list
Mendeliome v0.5002 CCNO Zornitza Stark Marked gene: CCNO as ready
Mendeliome v0.5002 CCNO Zornitza Stark Phenotypes for gene: CCNO were changed from to Ciliary dyskinesia, primary, 29, MIM# 615872
Mendeliome v0.4999 CCNO Zornitza Stark reviewed gene: CCNO: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747639, 31765523, 28801648; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Marked gene: CSNK1G1 as ready
Mendeliome v0.4998 CSNK1G1 Zornitza Stark gene: CSNK1G1 was added
gene: CSNK1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK1G1 were set to 33009664
Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures
Review for gene: CSNK1G1 was set to GREEN
Added comment: Borderline Green/Amber rating.

Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).
Sources: Literature
Mendeliome v0.4997 LMNB2 Zornitza Stark Marked gene: LMNB2 as ready
Mendeliome v0.4997 LMNB2 Zornitza Stark Phenotypes for gene: LMNB2 were changed from to {Lipodystrophy, partial, acquired, susceptibility to} 608709; Congenital microcephaly, Intellectual disability
Mendeliome v0.4994 LMNB2 Zornitza Stark reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826530, 22768673, 33033404; Phenotypes: {Lipodystrophy, partial, acquired, susceptibility to} 608709, Congenital microcephaly, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4993 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Added comment: Additional study PMID 33033404 reporting 7 individuals with recurrent missense variants in this gene and ID/microcephaly phenotype.; Changed publications: 32910914, 16951681, 19151023, 33033404
Mendeliome v0.4993 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 SREBF1 Zornitza Stark edited their review of gene: SREBF1: Added comment: HMD phenotype: 5 unrelated families reported with heterozygous variants at same residue (p.Arg557Cys and p.Arg557His) and a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Individuals developed cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses.; Changed publications: 32497488, 31790666, 32902915; Changed phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016, Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 CCDC40 Zornitza Stark Marked gene: CCDC40 as ready
Mendeliome v0.4991 CCDC40 Zornitza Stark Phenotypes for gene: CCDC40 were changed from to Ciliary dyskinesia, primary, 15, MIM#613808
Mendeliome v0.4988 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131974, 23255504, 31879361, 31765523, 31650533; Phenotypes: Ciliary dyskinesia, primary, 15, MIM#613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4988 CCDC39 Zornitza Stark Marked gene: CCDC39 as ready
Mendeliome v0.4988 CCDC39 Zornitza Stark Phenotypes for gene: CCDC39 were changed from to Ciliary dyskinesia, primary, 14, MIM# 613807
Mendeliome v0.4985 CCDC39 Zornitza Stark reviewed gene: CCDC39: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131972, 23255504; Phenotypes: Ciliary dyskinesia, primary, 14, MIM# 613807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4985 CCDC151 Zornitza Stark Marked gene: CCDC151 as ready
Mendeliome v0.4985 CCDC151 Zornitza Stark Phenotypes for gene: CCDC151 were changed from to Ciliary dyskinesia, primary, 30, MIM# 616037
Mendeliome v0.4982 CCDC151 Zornitza Stark reviewed gene: CCDC151: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192045, 25224326, 32490514, 32286033, 30504913; Phenotypes: Ciliary dyskinesia, primary, 30, MIM# 616037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4982 CCDC114 Zornitza Stark Marked gene: CCDC114 as ready
Mendeliome v0.4982 CCDC114 Zornitza Stark Phenotypes for gene: CCDC114 were changed from to Ciliary dyskinesia, primary, 20, MIM# 615067
Mendeliome v0.4979 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4979 CCDC103 Zornitza Stark Marked gene: CCDC103 as ready
Mendeliome v0.4979 CCDC103 Zornitza Stark Phenotypes for gene: CCDC103 were changed from to Ciliary dyskinesia, primary, 17, MIM# 614679
Mendeliome v0.4976 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581229, 32447765, 31858719, 28790179; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4976 GARS Zornitza Stark Marked gene: GARS as ready
Mendeliome v0.4976 GARS Zornitza Stark Gene: gars has been classified as Green List (High Evidence).
Mendeliome v0.4976 GARS Zornitza Stark Phenotypes for gene: GARS were changed from to Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder
Mendeliome v0.4975 GARS Zornitza Stark Publications for gene: GARS were set to
Mendeliome v0.4974 GARS Zornitza Stark Mode of inheritance for gene: GARS was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4973 GARS Zornitza Stark Tag new gene name tag was added to gene: GARS.
Mendeliome v0.4973 GARS Zornitza Stark reviewed gene: GARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 17101916, 22462675, 31985473, 32181591, 12690580, 25168514, 26503042, 29648643, 16982418, 24669931, 28594869; Phenotypes: Spinal muscular atrophy, infantile, James type, MIM# 619042, Charcot-Marie-Tooth disease, type 2D, MIM# 601472, Neuronopathy, distal hereditary motor, type VA, MIM# 600794, Multi-system mitochondrial disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4973 SELENON Zornitza Stark Marked gene: SELENON as ready
Mendeliome v0.4973 SELENON Zornitza Stark Phenotypes for gene: SELENON were changed from to Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Muscular dystrophy, rigid spine, 1, MIM# 602771
Mendeliome v0.4970 SELENON Zornitza Stark reviewed gene: SELENON: Rating: GREEN; Mode of pathogenicity: None; Publications: 11528383, 12192640, 16365872, 21131290, 21131290, 32154989, 32796131; Phenotypes: Myopathy, congenital, with fiber-type disproportion, MIM# 255310, Muscular dystrophy, rigid spine, 1, MIM# 602771; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4970 TNNT1 Zornitza Stark Marked gene: TNNT1 as ready
Mendeliome v0.4968 TNNT3 Zornitza Stark Marked gene: TNNT3 as ready
Mendeliome v0.4968 TNNT3 Zornitza Stark Phenotypes for gene: TNNT3 were changed from to Arthrogryposis, distal, type 2B2, MIM# 618435
Mendeliome v0.4964 TNNT3 Zornitza Stark reviewed gene: TNNT3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 12865991, 19142688, 21402185, 25337069, 17194691; Phenotypes: Arthrogryposis, distal, type 2B2, MIM# 618435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4964 STAC3 Zornitza Stark Marked gene: STAC3 as ready
Mendeliome v0.4961 SPEG Zornitza Stark Marked gene: SPEG as ready
Mendeliome v0.4961 SPEG Zornitza Stark Phenotypes for gene: SPEG were changed from to Centronuclear myopathy 5, MIM# 615959
Mendeliome v0.4958 SPEG Zornitza Stark reviewed gene: SPEG: Rating: GREEN; Mode of pathogenicity: None; Publications: 25087613, 31625632, 30412272, 30157964, 29614691, 29474540, 28624463, 26578207, 25087613; Phenotypes: Centronuclear myopathy 5, MIM# 615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4958 TPM3 Zornitza Stark Marked gene: TPM3 as ready
Mendeliome v0.4954 MICU1 Zornitza Stark Marked gene: MICU1 as ready
Mendeliome v0.4951 LMOD3 Zornitza Stark Marked gene: LMOD3 as ready
Mendeliome v0.4947 MYH2 Zornitza Stark Marked gene: MYH2 as ready
Mendeliome v0.4944 KLHL41 Zornitza Stark Marked gene: KLHL41 as ready
Mendeliome v0.4941 KLHL40 Zornitza Stark Marked gene: KLHL40 as ready
Mendeliome v0.4938 MYO18B Zornitza Stark Marked gene: MYO18B as ready
Mendeliome v0.4935 MEGF10 Zornitza Stark Marked gene: MEGF10 as ready
Mendeliome v0.4935 MEGF10 Zornitza Stark Phenotypes for gene: MEGF10 were changed from to Myopathy, areflexia, respiratory distress, and dysphagia, early-onset, MIM# 614399
Mendeliome v0.4932 MEGF10 Zornitza Stark reviewed gene: MEGF10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22101682, 22371254, 30802937; Phenotypes: Myopathy, areflexia, respiratory distress, and dysphagia, early-onset, MIM# 614399; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4930 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed rating: GREEN; Changed publications: 20671153, 25427950, 32055034, 29588463, 28289185; Changed phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD, Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4930 WDPCP Zornitza Stark Marked gene: WDPCP as ready
Mendeliome v0.4930 WDPCP Zornitza Stark Phenotypes for gene: WDPCP were changed from Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085 to Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4930 WDPCP Zornitza Stark Phenotypes for gene: WDPCP were changed from to Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Mendeliome v0.4926 WDPCP Zornitza Stark reviewed gene: WDPCP: Rating: AMBER; Mode of pathogenicity: None; Publications: 20671153, 25427950; Phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Marked gene: TUBGCP4 as ready
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Marked gene: DYNC2LI1 as ready
Mendeliome v0.4920 SLC20A2 Zornitza Stark Phenotypes for gene: SLC20A2 were changed from Basal ganglia calcification, idiopathic, 1, MIM# 213600 to Basal ganglia calcification, idiopathic, 1, MIM# 213600; ?hereditary multiple exostoses
Mendeliome v0.4917 SLC20A2 Elena Savva reviewed gene: SLC20A2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 24209445, 23437308, 32705272, 27943094; Phenotypes: Basal ganglia calcification, idiopathic, 1213600, ?hereditary multiple exostoses; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4916 FKBP14 Zornitza Stark Marked gene: FKBP14 as ready
Mendeliome v0.4913 EPG5 Zornitza Stark Marked gene: EPG5 as ready
Mendeliome v0.4910 EPG5 Zornitza Stark reviewed gene: EPG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222957, 26917586; Phenotypes: Vici syndrome, MIM# 242840, vacuolar myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4910 LMX1B Zornitza Stark Marked gene: LMX1B as ready
Mendeliome v0.4907 SEMA4A Zornitza Stark Marked gene: SEMA4A as ready
Mendeliome v0.4903 JPH2 Zornitza Stark Marked gene: JPH2 as ready
Mendeliome v0.4903 JPH2 Zornitza Stark Phenotypes for gene: JPH2 were changed from to Cardiomyopathy, hypertrophic, MIM#613873; dilated cardiomyopathy
Mendeliome v0.4899 JPH2 Zornitza Stark reviewed gene: JPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30681346, 17509612, 23973696, 26869393, 28393127, 30235249, 31227780; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873, dilated cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4899 RGR Zornitza Stark Marked gene: RGR as ready
Mendeliome v0.4895 RDH11 Zornitza Stark Marked gene: RDH11 as ready
Mendeliome v0.4895 RDH11 Zornitza Stark gene: RDH11 was added
gene: RDH11 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732
Phenotypes for gene: RDH11 were set to Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108
Review for gene: RDH11 was set to RED
Added comment: Single family reported with compound heterozygous LOF variants segregating with disease in three siblings. Some functional data, but note mouse KO did not have eye phenotype.
Sources: Expert list
Mendeliome v0.4894 CEP112 Zornitza Stark Marked gene: CEP112 as ready
Mendeliome v0.4893 SVIL Zornitza Stark Phenotypes for gene: SVIL were changed from myopathy to Myofibrillar myopathy, MIM#619040
Mendeliome v0.4892 SVIL Zornitza Stark edited their review of gene: SVIL: Changed rating: AMBER; Changed phenotypes: Myofibrillar myopathy, MIM#619040
Mendeliome v0.4892 GPC6 Zornitza Stark Marked gene: GPC6 as ready
Mendeliome v0.4892 GPC6 Zornitza Stark Phenotypes for gene: GPC6 were changed from to Omodysplasia 1 (MIM#258315), AR
Mendeliome v0.4889 GPC6 Kristin Rigbye reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19481194; Phenotypes: Omodysplasia 1 (MIM#258315), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4889 SPATA7 Zornitza Stark Marked gene: SPATA7 as ready
Mendeliome v0.4886 KIRREL3 Zornitza Stark Marked gene: KIRREL3 as ready
Mendeliome v0.4886 KIRREL3 Zornitza Stark gene: KIRREL3 was added
gene: KIRREL3 was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: KIRREL3.
Mode of inheritance for gene: KIRREL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIRREL3 were set to 19012874
Phenotypes for gene: KIRREL3 were set to Intellectual disability
Review for gene: KIRREL3 was set to RED
Added comment: Variants associated with ID have now been re-classified based on population frequency.
Sources: Expert list
Mendeliome v0.4885 NEUROD1 Zornitza Stark Marked gene: NEUROD1 as ready
Mendeliome v0.4882 DNAAF4 Zornitza Stark Marked gene: DNAAF4 as ready
Mendeliome v0.4882 DNAAF4 Zornitza Stark Phenotypes for gene: DNAAF4 were changed from to Ciliary dyskinesia, primary, 25, MIM# 615482
Mendeliome v0.4879 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23872636; Phenotypes: Ciliary dyskinesia, primary, 25, MIM# 615482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4879 MAG Zornitza Stark Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, MIM# 616680 to Spastic paraplegia 75, autosomal recessive, MIM# 616680; Cerebellar ataxia
Mendeliome v0.4878 MAG Zornitza Stark changed review comment from: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported.; to: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms.
Mendeliome v0.4878 GZF1 Zornitza Stark Marked gene: GZF1 as ready
Mendeliome v0.4878 GZF1 Zornitza Stark Phenotypes for gene: GZF1 were changed from to Joint laxity, short stature, and myopia, MIM# 617662; Larsen-like syndrome
Mendeliome v0.4875 GZF1 Zornitza Stark reviewed gene: GZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33009817, 28475863; Phenotypes: Joint laxity, short stature, and myopia, MIM# 617662, Larsen-like syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4875 ITFG2 Zornitza Stark Marked gene: ITFG2 as ready
Mendeliome v0.4874 ITFG2 Zornitza Stark gene: ITFG2 was added
gene: ITFG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51). Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS. Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)]. As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Rated Amber as Cheema et al report on diagnostic outcomes and multiple candidate genes as part of a heterogenous cohort and details are therefore limited.
Sources: Literature
Mendeliome v0.4873 SHMT2 Zornitza Stark Marked gene: SHMT2 as ready
Mendeliome v0.4872 SHMT2 Zornitza Stark gene: SHMT2 was added
gene: SHMT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Mendeliome v0.4871 DHX38 Zornitza Stark Marked gene: DHX38 as ready
Mendeliome v0.4867 CCT2 Zornitza Stark Marked gene: CCT2 as ready
Mendeliome v0.4867 CCT2 Zornitza Stark gene: CCT2 was added
gene: CCT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: CCT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCT2 were set to 27645772; 29450543
Phenotypes for gene: CCT2 were set to Leber's congenital amaurosis
Review for gene: CCT2 was set to RED
Added comment: Single family reported with compound het missense variants, functional data, including animal model.
Sources: NHS GMS
Mendeliome v0.4866 CA4 Zornitza Stark Marked gene: CA4 as ready
Mendeliome v0.4862 VPS41 Zornitza Stark Marked gene: VPS41 as ready
Mendeliome v0.4862 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Mendeliome v0.4861 VPS16 Zornitza Stark Marked gene: VPS16 as ready
Mendeliome v0.4860 VPS16 Zornitza Stark gene: VPS16 was added
gene: VPS16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: Literature
Mendeliome v0.4859 KRIT1 Zornitza Stark Marked gene: KRIT1 as ready
Mendeliome v0.4859 KRIT1 Zornitza Stark Phenotypes for gene: KRIT1 were changed from to Cavernous malformations of CNS and retina, 116860; Cerebral cavernous malformations-1, 116860; Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations, 116860
Mendeliome v0.4856 SH3TC2 Zornitza Stark Marked gene: SH3TC2 as ready
Mendeliome v0.4856 SH3TC2 Zornitza Stark Phenotypes for gene: SH3TC2 were changed from to Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353
Mendeliome v0.4853 ABCC6 Zornitza Stark Marked gene: ABCC6 as ready
Mendeliome v0.4853 ABCC6 Zornitza Stark Added comment: Comment when marking as ready: Evidence for mono-allelic variants causing disease is limited.
Mendeliome v0.4853 CAPN3 Zornitza Stark Marked gene: CAPN3 as ready
Mendeliome v0.4853 CAPN3 Zornitza Stark Phenotypes for gene: CAPN3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129; Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600
Mendeliome v0.4850 CAPN3 Zornitza Stark reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31937337, 28881388, 32342993, 32557990; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129, Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4850 SLC6A5 Zornitza Stark Marked gene: SLC6A5 as ready
Mendeliome v0.4849 KRIT1 Elena Savva reviewed gene: KRIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16571644, 29593473; Phenotypes: Cavernous malformations of CNS and retina, 116860, Cerebral cavernous malformations-1, 116860, Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations, 116860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4846 ARX Zornitza Stark Marked gene: ARX as ready
Mendeliome v0.4846 ARX Zornitza Stark Gene: arx has been classified as Green List (High Evidence).
Mendeliome v0.4846 ARX Zornitza Stark Phenotypes for gene: ARX were changed from to Epileptic encephalopathy, early infantile, 1 MIM#308350; Hydranencephaly with abnormal genitalia MIM#300215; Lissencephaly, X-linked 2 MIM#300215; Mental retardation, X-linked 29 and others MIM#300419; Partington syndrome MIM#309510; Proud syndrome MIM#300004
Mendeliome v0.4845 ARX Zornitza Stark Publications for gene: ARX were set to
Mendeliome v0.4844 ARX Zornitza Stark Mode of inheritance for gene: ARX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.4843 SH3TC2 Elena Savva reviewed gene: SH3TC2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19744956, 20220177, 19744956, 20028792; Phenotypes: Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4843 ABCC6 Kristin Rigbye changed review comment from: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).; to: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PXE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).

In addition to missense, PTCs and splice variants, deletions and duplications in this gene comprise a significant proportion of variants and are a recognised mechanism / cause of PXE.
Mendeliome v0.4843 ARX Elena Savva reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 14722918, 19738637, 32519823, 28150386, 21496008; Phenotypes: Epileptic encephalopathy, early infantile, 1 MIM#308350, Hydranencephaly with abnormal genitalia MIM#300215, Lissencephaly, X-linked 2 MIM#300215, Mental retardation, X-linked 29 and others MIM#300419, Partington syndrome MIM#309510, Proud syndrome MIM#300004; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.4843 TBL1Y Zornitza Stark Phenotypes for gene: TBL1Y were changed from Hearing loss to Deafness, Y-linked 2, MIM# 400047
Mendeliome v0.4842 MCM2 Zornitza Stark Marked gene: MCM2 as ready
Mendeliome v0.4841 ATP1A4 Zornitza Stark Marked gene: ATP1A4 as ready
Mendeliome v0.4841 ATP1A4 Zornitza Stark gene: ATP1A4 was added
gene: ATP1A4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP1A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A4 were set to 32549268
Phenotypes for gene: ATP1A4 were set to Hemiplegic migraine
Review for gene: ATP1A4 was set to RED
Added comment: Single family reported where missense variant segregated with hemiplegic migraine in four affected individuals.
Sources: Literature
Mendeliome v0.4840 BSND Zornitza Stark Marked gene: BSND as ready
Mendeliome v0.4840 BSND Zornitza Stark Phenotypes for gene: BSND were changed from to Bartter syndrome, type 4a, MIM#602522
Mendeliome v0.4837 BSND Zornitza Stark changed review comment from: Some individuals with severe Bartter syndrome have been described as having intellectual disability, whereas others with milder symptoms have normal intellect.
Sources: Expert list; to: Well established gene-disease association.
Sources: Expert list
Mendeliome v0.4837 LTBP2 Zornitza Stark Marked gene: LTBP2 as ready
Mendeliome v0.4837 LTBP2 Zornitza Stark Phenotypes for gene: LTBP2 were changed from to Glaucoma 3, primary congenital, D 613086; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750
Mendeliome v0.4834 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19656777, 19361779, 20617341, 32165823, 30380740, 30565850; Phenotypes: Glaucoma 3, primary congenital, D 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4833 CYP1B1 Zornitza Stark reviewed gene: CYP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9463332, 10655546, 12372064, 21081970; Phenotypes: Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, MIM# 231300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4832 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia to Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
Mendeliome v0.4829 NEK9 Zornitza Stark edited their review of gene: NEK9: Added comment: Another Saudi family described with which 2 sisters and a female cousin who had a similar disorder characterised by arthrogryposis apparent since early childhood, avascular necrosis of the hip (Perthes disease), and upward gaze palsy. Homozygous missense variant segregated with the phenotype. Given the small number of reports, it is unclear whether this represents a distinct association is part of a spectrum with includes the more severe phenotype described in the Irish traveller families.; Changed publications: 26908619, 21271645; Changed phenotypes: Lethal congenital contracture syndrome 10, MIM# 617022, Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262, Skeletal dysplasia
Mendeliome v0.4829 IL11RA Zornitza Stark Marked gene: IL11RA as ready
Mendeliome v0.4825 EFNB1 Zornitza Stark Marked gene: EFNB1 as ready
Mendeliome v0.4822 ABCC6 Kristin Rigbye reviewed gene: ABCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28102862; Phenotypes: Pseudoxanthoma elasticum (MIM#264800), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4822 AGAP1 Zornitza Stark Marked gene: AGAP1 as ready
Mendeliome v0.4821 AGAP1 Zornitza Stark gene: AGAP1 was added
gene: AGAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483
Phenotypes for gene: AGAP1 were set to Cerebral palsy
Review for gene: AGAP1 was set to AMBER
Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism.
Sources: Literature
Mendeliome v0.4820 SMN1 Zornitza Stark Marked gene: SMN1 as ready
Mendeliome v0.4820 SMN1 Zornitza Stark Phenotypes for gene: SMN1 were changed from to Spinal muscular atrophy-1, MIM# 253300
Mendeliome v0.4817 SMN1 Zornitza Stark reviewed gene: SMN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7813012; Phenotypes: Spinal muscular atrophy-1, MIM# 253300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4817 BUB1B Zornitza Stark Marked gene: BUB1B as ready
Mendeliome v0.4817 BUB1B Zornitza Stark Phenotypes for gene: BUB1B were changed from to Mosaic variegated aneuploidy syndrome 1, MIM# 257300; Premature ovarian failure
Mendeliome v0.4814 BUB1B Zornitza Stark reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32716490, 18548531; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM# 257300, Premature ovarian failure; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4814 ROM1 Zornitza Stark Marked gene: ROM1 as ready
Mendeliome v0.4811 FOXC1 Zornitza Stark Marked gene: FOXC1 as ready
Mendeliome v0.4808 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Mendeliome v0.4807 ALG14 Zornitza Stark changed review comment from: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation; to: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation. The three OMIM disorders may represent a spectrum of severity for CDG.
Mendeliome v0.4807 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036, Disorder of N-glycosylation
Mendeliome v0.4807 FOXC1 Eleanor Williams reviewed gene: FOXC1: Rating: ; Mode of pathogenicity: None; Publications: 32720677; Phenotypes: eye and vascular development; Mode of inheritance: None
Mendeliome v0.4807 BUB1B Eleanor Williams reviewed gene: BUB1B: Rating: ; Mode of pathogenicity: None; Publications: 32716490; Phenotypes: premature ovarian insufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4807 SMN1 Eleanor Williams reviewed gene: SMN1: Rating: ; Mode of pathogenicity: None; Publications: 32644125, 32644120; Phenotypes: Spinal muscular atrophy; Mode of inheritance: None
Mendeliome v0.4807 ACER3 Zornitza Stark Marked gene: ACER3 as ready
Mendeliome v0.4796 AP1S1 Zornitza Stark Marked gene: AP1S1 as ready
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AKNA Seb Lunke Marked gene: AKNA as ready
Mendeliome v0.4791 GOLGA3 Zornitza Stark Marked gene: GOLGA3 as ready
Mendeliome v0.4789 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the hypomorphic thoc1 in mouse induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4789 GOLGA3 Elena Savva gene: GOLGA3 was added
gene: GOLGA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GOLGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA3 were set to PMID: 23495255
Phenotypes for gene: GOLGA3 were set to Primary ciliary dyskinesia
Review for gene: GOLGA3 was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with a homozygous missense and PCD

PMID: 23495255; null mice have failed spermatogenesis
Sources: Literature
Mendeliome v0.4789 PRICKLE3 Seb Lunke Marked gene: PRICKLE3 as ready
Mendeliome v0.4789 PRICKLE3 Seb Lunke Added comment: Comment on list classification: Single variant only and questionable association due to uncertainty of role around ND4.
Mendeliome v0.4788 AKNA Elena Savva gene: AKNA was added
gene: AKNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AKNA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKNA were set to PMID: 21606955
Phenotypes for gene: AKNA were set to Primary ciliary dyskinesia
Review for gene: AKNA was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with homozygous PTCs with PCD. Carrier parents and mutation negative siblings (5) was normal.

PMID: 21606955: Null mice have neonatal death with systemic inflammation and alveolar loss
Sources: Literature
Mendeliome v0.4788 THOC1 Zornitza Stark Marked gene: THOC1 as ready
Mendeliome v0.4787 GBF1 Seb Lunke Marked gene: GBF1 as ready
Mendeliome v0.4786 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4785 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
Mendeliome v0.4784 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814
Phenotypes for gene: RNPC3 were set to Growth hormone deficiency
Review for gene: RNPC3 was set to AMBER
Added comment: Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Sources: Literature
Mendeliome v0.4783 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4783 PRICKLE3 Teresa Zhao gene: PRICKLE3 was added
gene: PRICKLE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRICKLE3 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: PRICKLE3 were set to 32516135
Phenotypes for gene: PRICKLE3 were set to Leber’s hereditary optic neuropathy MIM#535000
Review for gene: PRICKLE3 was set to AMBER
Added comment: Reported as X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision.

Defective assembly, stability, and function of ATP synthase observed using Lymphoblastoid cell lines from one of the families.

This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON.

Prickle3-deficient mice exhibited pronounced ATPase deficiencies.
Sources: Literature
Mendeliome v0.4783 NUAK2 Seb Lunke Marked gene: NUAK2 as ready
Mendeliome v0.4783 GBF1 Paul De Fazio changed review comment from: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature; to: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo).

Age of onset varied from childhood (nonsense variant) to 50s. Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature
Mendeliome v0.4783 NUAK2 Seb Lunke gene: NUAK2 was added
gene: NUAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NUAK2 were set to 32845958
Phenotypes for gene: NUAK2 were set to ANENCEPHALY (OMIM#206500)
Review for gene: NUAK2 was set to AMBER
Added comment: Novel gene described in single consanguineous family with three FDIU and extensive anencephaly. Hom inframe del affecting functional kinase domain, parents confirmed carriers. Good functional data showing loss of enzyme function and mouse model with 40% anencephaly after knock-out.
Sources: Literature
Mendeliome v0.4782 THOC1 Melanie Marty gene: THOC1 was added
gene: THOC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THOC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THOC1 were set to 32776944
Phenotypes for gene: THOC1 were set to Nonsyndromic hearing loss
Review for gene: THOC1 was set to AMBER
Added comment: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4782 MBTPS1 Zornitza Stark Marked gene: MBTPS1 as ready
Mendeliome v0.4781 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
Mendeliome v0.4780 GBF1 Paul De Fazio gene: GBF1 was added
gene: GBF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GBF1 were set to 32937143
Phenotypes for gene: GBF1 were set to Axonal Neuropathy
Review for gene: GBF1 was set to GREEN
gene: GBF1 was marked as current diagnostic
Added comment: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature
Mendeliome v0.4780 ALS2 Ain Roesley 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 32214227
Phenotypes for gene: ALS2 were set to Tetraparesis with affection of upper and lower motor neuron
Penetrance for gene: ALS2 were set to unknown
Review for gene: ALS2 was set to RED
Added comment: In a cohort of Palestinian and Israeli Arabs with neurological disorders, a family with 2 affecteds were homozygous for a nonsense variant. Authors classified as likely path by ACMG guidelines
Sources: Literature
Mendeliome v0.4780 QRICH1 Zornitza Stark Marked gene: QRICH1 as ready
Mendeliome v0.4777 GREB1L Zornitza Stark Marked gene: GREB1L as ready
Mendeliome v0.4774 IL1RAP Zornitza Stark Marked gene: IL1RAP as ready
Mendeliome v0.4774 IL1RAP Zornitza Stark gene: IL1RAP was added
gene: IL1RAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1RAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL1RAP were set to 31954058
Phenotypes for gene: IL1RAP were set to Steroid-sensitive nephrotic syndrome
Review for gene: IL1RAP was set to RED
Added comment: A pair of siblings with compound heterozygous variants in this gene and steroid-sensitive nephrotic syndrome. Functional effect of variants demonstrated but mouse model does not have proteinuria.
Sources: Literature
Mendeliome v0.4770 NEMF Zornitza Stark changed review comment from: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature; to: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.

Single individual with de novo variant reported, postulated dominant negative effect. Evidence for mono allelic variants causing disease is limited.
Sources: Literature
Mendeliome v0.4769 HOMER2 Zornitza Stark Marked gene: HOMER2 as ready
Mendeliome v0.4766 TPRN Zornitza Stark Marked gene: TPRN as ready
Mendeliome v0.4763 TMC1 Zornitza Stark Marked gene: TMC1 as ready
Mendeliome v0.4760 TMIE Zornitza Stark Marked gene: TMIE as ready
Mendeliome v0.4757 TRIOBP Zornitza Stark Marked gene: TRIOBP as ready
Mendeliome v0.4754 STRC Zornitza Stark Marked gene: STRC as ready
Mendeliome v0.4751 NUP188 Zornitza Stark Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804; microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Mendeliome v0.4750 NUP188 Zornitza Stark edited their review of gene: NUP188: Changed phenotypes: Sandestig-Stefanova syndrome, 618804, microcephaly, ID, cataract, structural brain abnormalities, hypoventilation
Mendeliome v0.4750 SETD1A Zornitza Stark Marked gene: SETD1A as ready
Mendeliome v0.4749 SETD1A Zornitza Stark gene: SETD1A was added
gene: SETD1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SETD1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD1A were set to 31197650; 32346159
Phenotypes for gene: SETD1A were set to Epilepsy, early-onset, with or without developmental delay, MIM# 618832
Review for gene: SETD1A was set to GREEN
Added comment: 19 unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype, primarily manifesting and ID and seizures. LOF mechanism supported by functional data. Three mouse models. SNPs in this gene have also been associated with risk of developing schizophrenia.
Sources: Literature
Mendeliome v0.4748 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome to Spastic paraplegia-83 (SPG83), MIM#619027; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4747 HPDL Zornitza Stark edited their review of gene: HPDL: Added comment: Although two distinct distinct disease associations have been assigned by OMIM, these clinical presentations likely represent a continuum of severity for an underlying mitochondrial disorder.; Changed phenotypes: Spastic paraplegia-83 (SPG83), MIM#619027, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026
Mendeliome v0.4747 HPDL Zornitza Stark commented on gene: HPDL: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Frequently observed clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Mendeliome v0.4745 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.4743 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Note we have reported the association with AMC previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.; Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.4743 PRKD1 Zornitza Stark changed review comment from: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; to: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.'

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.
Mendeliome v0.4742 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4742 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 32928894; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4742 SIX1 Zornitza Stark Marked gene: SIX1 as ready
Mendeliome v0.4739 PTPRQ Zornitza Stark Marked gene: PTPRQ as ready
Mendeliome v0.4736 POU4F3 Zornitza Stark Marked gene: POU4F3 as ready
Mendeliome v0.4733 KPTN Zornitza Stark Marked gene: KPTN as ready
Mendeliome v0.4733 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from to Mental retardation, autosomal recessive 41 (MIM#615637)
Mendeliome v0.4730 NPHS1 Zornitza Stark Marked gene: NPHS1 as ready
Mendeliome v0.4728 TTI2 Zornitza Stark Marked gene: TTI2 as ready
Mendeliome v0.4728 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from to Mental retardation, autosomal recessive 39, MIM#615541
Mendeliome v0.4725 TTI2 Zornitza Stark reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32061250, 23956177, 31737043; Phenotypes: Mental retardation, autosomal recessive 39, MIM#615541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4725 IGSF10 Bryony Thompson Marked gene: IGSF10 as ready
Mendeliome v0.4724 IGSF10 Bryony Thompson gene: IGSF10 was added
gene: IGSF10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IGSF10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IGSF10 were set to 27137492; 31042289
Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency
Review for gene: IGSF10 was set to AMBER
Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance.
Sources: Literature
Mendeliome v0.4723 KPTN Melanie Marty reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239382, 32358097, 32808430; Phenotypes: Mental retardation, autosomal recessive 41 (MIM#615637); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4723 PFN1 Zornitza Stark Marked gene: PFN1 as ready
Mendeliome v0.4720 PCDH15 Zornitza Stark Marked gene: PCDH15 as ready
Mendeliome v0.4717 WHRN Zornitza Stark Marked gene: WHRN as ready
Mendeliome v0.4714 OTOGL Zornitza Stark Marked gene: OTOGL as ready
Mendeliome v0.4711 RDX Zornitza Stark Marked gene: RDX as ready
Mendeliome v0.4708 OTOA Zornitza Stark Marked gene: OTOA as ready
Mendeliome v0.4705 MYO7A Zornitza Stark Marked gene: MYO7A as ready
Mendeliome v0.4702 SMPX Zornitza Stark Marked gene: SMPX as ready
Mendeliome v0.4699 MYO6 Zornitza Stark Marked gene: MYO6 as ready
Mendeliome v0.4696 MYO15A Zornitza Stark Marked gene: MYO15A as ready
Mendeliome v0.4693 MYH9 Zornitza Stark Marked gene: MYH9 as ready
Mendeliome v0.4693 MYH9 Zornitza Stark Phenotypes for gene: MYH9 were changed from to Deafness, autosomal dominant 17, MIM# 603622; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; MYH9-related disorders
Mendeliome v0.4690 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 9390828, 24890873, 17146397, 25505834, 16630581, 16162639, 23976996, 21908426; Phenotypes: Deafness, autosomal dominant 17, MIM# 603622, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100, MYH9-related disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4690 MARVELD2 Zornitza Stark Marked gene: MARVELD2 as ready
Mendeliome v0.4690 MARVELD2 Zornitza Stark Gene: marveld2 has been classified as Green List (High Evidence).
Mendeliome v0.4690 MARVELD2 Zornitza Stark Phenotypes for gene: MARVELD2 were changed from to Deafness, autosomal recessive 49, MIM# 610153
Mendeliome v0.4689 MARVELD2 Zornitza Stark Publications for gene: MARVELD2 were set to
Mendeliome v0.4688 MARVELD2 Zornitza Stark Mode of inheritance for gene: MARVELD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 MARVELD2 Zornitza Stark reviewed gene: MARVELD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186462, 18084694, 22903915, 27344577, 26677943, 23979167; Phenotypes: Deafness, autosomal recessive 49, MIM# 610153; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 RPL9 Zornitza Stark Marked gene: RPL9 as ready
Mendeliome v0.4687 RPL9 Zornitza Stark Added comment: Comment when marking as ready: Second individual reported with same c.-2+1G>C variant in the 5′UTR of RPL9, deleterious effect demonstrated, functional data, upgrade to Amber.
Mendeliome v0.4685 RPL9 Arina Puzriakova changed review comment from: PMID: 31799629 (2020) - One individual diagnosed with Diamond Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.; to: PMID: 31799629 (2020) - Female infant diagnosed with Diamond-Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Phenotypic overlap can be seen with the previously reported case with the same variant, including colitis, thumb anomaly, and microcephaly. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.
Mendeliome v0.4685 LRTOMT Zornitza Stark Marked gene: LRTOMT as ready
Mendeliome v0.4682 LHFPL5 Zornitza Stark Marked gene: LHFPL5 as ready
Mendeliome v0.4679 GYS1 Zornitza Stark Marked gene: GYS1 as ready
Mendeliome v0.4676 PIGT Zornitza Stark Marked gene: PIGT as ready
Mendeliome v0.4672 ALG13 Zornitza Stark Marked gene: ALG13 as ready
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Marked gene: BLOC1S5 as ready
Mendeliome v0.4668 BLOC1S5 Zornitza Stark gene: BLOC1S5 was added
gene: BLOC1S5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome
Review for gene: BLOC1S5 was set to GREEN
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2). Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Mendeliome v0.4667 FOXL2 Zornitza Stark Marked gene: FOXL2 as ready
Mendeliome v0.4667 FOXL2 Zornitza Stark Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100)
Mendeliome v0.4664 FOXL2 Ain Roesley changed review comment from: PMID: 31077882; 19x probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161); to: PMID: 31077882; >100 probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161)
Mendeliome v0.4664 FOXL2 Ain Roesley reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31077882, 18642388, 17089161; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4664 ILDR1 Zornitza Stark Marked gene: ILDR1 as ready
Mendeliome v0.4661 HOXA2 Zornitza Stark Marked gene: HOXA2 as ready
Mendeliome v0.4661 HOXA2 Zornitza Stark Phenotypes for gene: HOXA2 were changed from to Microtia with or without hearing impairment, MIM# 612290
Mendeliome v0.4658 HOXA2 Zornitza Stark reviewed gene: HOXA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18394579, 23775976, 27503514, 32649979, 31567444; Phenotypes: Microtia with or without hearing impairment, MIM# 612290; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4658 GRXCR1 Zornitza Stark Marked gene: GRXCR1 as ready
Mendeliome v0.4655 GPSM2 Zornitza Stark Marked gene: GPSM2 as ready
Mendeliome v0.4652 GIPC3 Zornitza Stark Marked gene: GIPC3 as ready
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Over 50 affected individuals from more than 10 families reported, mouse model. Single family with two siblings reported with bi-allelic variants in this gene and deafness (homozygous LOF) in PMID 29449721, evidence for bi-allelic disease is limited.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4644 COQ5 Zornitza Stark Phenotypes for gene: COQ5 were changed from Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability to Coenzyme Q10 deficiency, primary 9, MIM#619028; Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability
Mendeliome v0.4643 COQ5 Zornitza Stark edited their review of gene: COQ5: Changed phenotypes: Coenzyme Q10 deficiency, primary 9, MIM#619028, Cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, intellectual disability
Mendeliome v0.4643 GATA3 Zornitza Stark Marked gene: GATA3 as ready
Mendeliome v0.4643 GATA3 Zornitza Stark Phenotypes for gene: GATA3 were changed from to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255
Mendeliome v0.4640 GATA3 Zornitza Stark reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10935639, 11389161, 21120445, 26316437, 25771973, 27387476, 30396722; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4639 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21480479, 21306635, 18435799, 17236138, 21306635, 18701883, 8223243, 26995070, 29902227, 30504125; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM# 610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4639 EYA4 Zornitza Stark Phenotypes for gene: EYA4 were changed from to Deafness, autosomal dominant 10, MIM# 601316; Cardiomyopathy, dilated, 1J, MIM# 605362
Mendeliome v0.4636 EYA4 Zornitza Stark reviewed gene: EYA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11159937, ​17568404, 25681523, 25963406, 25242383, 26331839, 18219393, 27545760, 15735644, 10769282, 30155266; Phenotypes: Deafness, autosomal dominant 10, MIM# 601316, Cardiomyopathy, dilated, 1J, MIM# 605362; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4636 ESPN Zornitza Stark Marked gene: ESPN as ready
Mendeliome v0.4636 ESPN Zornitza Stark Phenotypes for gene: ESPN were changed from to Deafness, autosomal recessive 36, MIM# 609006; Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006
Mendeliome v0.4633 ESPN Zornitza Stark reviewed gene: ESPN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15286153, 18973245, 26445815, 28281779, 10975527, 15930085; Phenotypes: Deafness, autosomal recessive 36, MIM# 609006, Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4633 DFNB59 Zornitza Stark Marked gene: DFNB59 as ready
Mendeliome v0.4630 DFNA5 Zornitza Stark Marked gene: DFNA5 as ready
Mendeliome v0.4627 RIC3 Bryony Thompson Marked gene: RIC3 as ready
Mendeliome v0.4626 RIC3 Bryony Thompson reviewed gene: RIC3: Rating: RED; Mode of pathogenicity: None; Publications: 27055476, 28153381, 28606768, 32794657; Phenotypes: Parkinson disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4624 MRPS25 Zornitza Stark Phenotypes for gene: MRPS25 were changed from Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum to Combined oxidative phosphorylation deficiency 50, MIM# 619025; Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Mendeliome v0.4623 MRPS25 Zornitza Stark edited their review of gene: MRPS25: Changed phenotypes: Combined oxidative phosphorylation deficiency 50, MIM# 619025, Dyskinetic cerebral palsy, Mitochondrial myopathy, Partial agenesis of the corpus callosum
Mendeliome v0.4623 COL4A5 Zornitza Stark Marked gene: COL4A5 as ready
Mendeliome v0.4621 COCH Zornitza Stark Marked gene: COCH as ready
Mendeliome v0.4618 CLRN1 Zornitza Stark Marked gene: CLRN1 as ready
Mendeliome v0.4615 CLPP Zornitza Stark Marked gene: CLPP as ready
Mendeliome v0.4612 CLDN14 Zornitza Stark Marked gene: CLDN14 as ready
Mendeliome v0.4609 CIB2 Zornitza Stark Marked gene: CIB2 as ready
Mendeliome v0.4606 GCM2 Zornitza Stark Marked gene: GCM2 as ready
Mendeliome v0.4606 GCM2 Zornitza Stark Phenotypes for gene: GCM2 were changed from to Hyperparathyroidism 4, OMIM #617343
Mendeliome v0.4602 GCM2 Zornitza Stark reviewed gene: GCM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27745835; Phenotypes: Hyperparathyroidism 4, OMIM #617343; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4602 SECISBP2 Zornitza Stark Marked gene: SECISBP2 as ready
Mendeliome v0.4599 UBA1 Zornitza Stark Marked gene: UBA1 as ready
Mendeliome v0.4599 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830
Mendeliome v0.4596 UBA1 Zornitza Stark reviewed gene: UBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18179898, 32181232, 31932168, 29034082, 27699224, 26028276, 23518311; Phenotypes: Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4596 TRIP4 Zornitza Stark Marked gene: TRIP4 as ready
Mendeliome v0.4596 TRIP4 Zornitza Stark Phenotypes for gene: TRIP4 were changed from to Spinal muscular atrophy with congenital bone fractures 1, MIM# 616866; Muscular dystrophy, congenital, Davignon-Chauveau type 617066
Mendeliome v0.4593 TRIP4 Zornitza Stark reviewed gene: TRIP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26924529, 31794073; Phenotypes: Spinal muscular atrophy with congenital bone fractures 1, MIM# 616866, Muscular dystrophy, congenital, Davignon-Chauveau type 617066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4593 EXOSC9 Zornitza Stark Marked gene: EXOSC9 as ready
Mendeliome v0.4593 EXOSC9 Zornitza Stark Phenotypes for gene: EXOSC9 were changed from to Pontocerebellar hypoplasia, type 1D, MIM# 618065
Mendeliome v0.4590 EXOSC9 Zornitza Stark reviewed gene: EXOSC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30690203, 29727687; Phenotypes: Pontocerebellar hypoplasia, type 1D, MIM# 618065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4590 SLC7A14 Zornitza Stark Marked gene: SLC7A14 as ready
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Marked gene: ATP6V1B1 as ready
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300
Mendeliome v0.4583 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916796, 12414817, 16611712, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4583 C1orf194 Zornitza Stark Phenotypes for gene: C1orf194 were changed from Charcot-Marie-Tooth to Charcot-Marie-Tooth disease, intermediate or demyelinating
Mendeliome v0.4581 ALB Zornitza Stark Marked gene: ALB as ready
Mendeliome v0.4578 TREM2 Zornitza Stark Marked gene: TREM2 as ready
Mendeliome v0.4575 SPG21 Zornitza Stark Marked gene: SPG21 as ready
Mendeliome v0.4572 LMX1A Zornitza Stark Marked gene: LMX1A as ready
Mendeliome v0.4572 LMX1A Zornitza Stark Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 MIM#601412; non-syndromic hearing loss
Mendeliome v0.4569 LMX1A Zornitza Stark reviewed gene: LMX1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29754270, 32840933, 29971487; Phenotypes: Deafness, autosomal dominant 7 MIM#601412, non-syndromic hearing loss; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4569 RPS20 Bryony Thompson Marked gene: RPS20 as ready
Mendeliome v0.4568 RPS20 Bryony Thompson gene: RPS20 was added
gene: RPS20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS20 were set to 32790018
Phenotypes for gene: RPS20 were set to Diamond Blackfan anaemia
Mode of pathogenicity for gene: RPS20 was set to Other
Review for gene: RPS20 was set to AMBER
Added comment: Two unrelated cases where a de novo variant involving Ile84 (Ile84Ser and Ile84Asn), and reduce the RPS20 protein level in patient cells. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. Loss of function may not be the mechanism of disease, because loss of function variants appear to be exclusively associated with familial colorectal cancer without the DBA phenotype.
Sources: Literature
Mendeliome v0.4566 ABHD12 Zornitza Stark reviewed gene: ABHD12: Rating: GREEN; Mode of pathogenicity: None; Publications: 20797687, 24697911; Phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, MIM# 612674; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4566 SPAST Zornitza Stark Marked gene: SPAST as ready
Mendeliome v0.4566 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from to Spastic paraplegia 4, autosomal dominant (MIM#182601), AD
Mendeliome v0.4563 TRRAP Zornitza Stark Marked gene: TRRAP as ready
Mendeliome v0.4560 SPAST Chern Lim reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: None; Publications: 30476002, 30006150; Phenotypes: Spastic paraplegia 4, autosomal dominant (MIM#182601), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.4560 UPF3B Zornitza Stark Marked gene: UPF3B as ready
Mendeliome v0.4560 UPF3B Zornitza Stark Phenotypes for gene: UPF3B were changed from to Mental retardation, X-linked, syndromic 14, MIM# 300676
Mendeliome v0.4557 UPF3B Zornitza Stark reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 19377476, 17704778, 31737052, 28948974, 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, MIM# 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4557 C1orf194 Arina Puzriakova changed review comment from: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; to: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.
Mendeliome v0.4557 C1orf194 Arina Puzriakova reviewed gene: C1orf194: Rating: ; Mode of pathogenicity: None; Publications: 32592472; Phenotypes: Charcot-Marie-Tooth; Mode of inheritance: None
Mendeliome v0.4557 XPR1 Zornitza Stark Marked gene: XPR1 as ready
Mendeliome v0.4554 VPS13C Zornitza Stark Marked gene: VPS13C as ready
Mendeliome v0.4554 VPS13C Zornitza Stark Phenotypes for gene: VPS13C were changed from to Early-onset Parkinson disease-23, MIM# 616840
Mendeliome v0.4551 VPS13C Zornitza Stark reviewed gene: VPS13C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26942284 30452786 28862745; Phenotypes: Early-onset Parkinson disease-23, MIM# 616840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4551 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome to Basal ganglia calcification, idiopathic, 7, MIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.4548 KIAA1161 Zornitza Stark edited their review of gene: KIAA1161: Added comment: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.; Changed publications: 30656188, 30649222, 30460687, 29910000, 31951047; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4548 ALG14 Zornitza Stark Marked gene: ALG14 as ready
Mendeliome v0.4548 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation
Mendeliome v0.4545 ALG14 Zornitza Stark reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: 30221345, 23404334, 28733338; Phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Disorder of N-glycosylation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4545 TCF12 Zornitza Stark Marked gene: TCF12 as ready
Mendeliome v0.4542 RP1L1 Zornitza Stark Marked gene: RP1L1 as ready
Mendeliome v0.4542 RP1L1 Zornitza Stark Phenotypes for gene: RP1L1 were changed from to Occult macular dystrophy (MIM#613587) AD; Retinitis pigmentosa 88 (MIM#618826) AR
Mendeliome v0.4539 CYP11B2 Zornitza Stark Marked gene: CYP11B2 as ready
Mendeliome v0.4536 HPS5 Zornitza Stark Marked gene: HPS5 as ready
Mendeliome v0.4533 IBA57 Zornitza Stark Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, MIM#615330 to Multiple mitochondrial dysfunctions syndrome 3, MIM#615330; Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark changed review comment from: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.; to: MMDS3: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.

SPG74: Three families with spastic paraparesis as a feature of the condition.
Mendeliome v0.4531 IBA57 Zornitza Stark edited their review of gene: IBA57: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 3, MIM#615330, Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark Marked gene: IBA57 as ready
Mendeliome v0.4528 RP1L1 Teresa Zhao reviewed gene: RP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23281133, 30025130, 32360662; Phenotypes: Occult macular dystrophy (MIM#613587) AD, Retinitis pigmentosa 88 (MIM#618826) AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4526 NSUN3 Zornitza Stark edited their review of gene: NSUN3: Added comment: Second family reported with early-onset mitochondrial encephalomyopathy and seizures.; Changed publications: 27356879, 32488845; Changed phenotypes: Combined oxidative phosphorylation deficiency 48, MIM# 619012
Mendeliome v0.4525 LIFR Zornitza Stark edited their review of gene: LIFR: Added comment: Bi-allelic variants: At least 28 unique variants (nonsense, frameshift, splicing, missense, gross deletions) have been reported in individuals with Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, 22 of which are predicted to cause LOF, suggesting homozygous LOF is the mechanism of disease for this gene. Variants in this gene have been reported in at least 22 probands in four publications.

Mono-allelic variants: associated with CAKUT in 4 individuals, mouse model recapitulates phenotype.; Changed rating: GREEN; Changed publications: 14740318, 20447141, 24988918, 29620724, 28334964; Changed phenotypes: Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, MIM# 601559, CAKUT; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4525 PAX7 Zornitza Stark Marked gene: PAX7 as ready
Mendeliome v0.4520 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic :
DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift).

Biallelic :
DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects).

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Monoallelic SLC12A2 mutations :

► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below).

► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6).

Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested).

SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1).

The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients.

Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690).

Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder.

In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis.

► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx.

► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range.


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Biallelic SLC12A2 mutations:

► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G].

► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model.

► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4520 VPS37A Zornitza Stark Marked gene: VPS37A as ready
Mendeliome v0.4520 VPS37A Zornitza Stark Phenotypes for gene: VPS37A were changed from to Spastic paraplegia 53, autosomal recessive, MIM# 614898
Mendeliome v0.4516 VPS37A Zornitza Stark reviewed gene: VPS37A: Rating: AMBER; Mode of pathogenicity: None; Publications: 22717650; Phenotypes: Spastic paraplegia 53, autosomal recessive, MIM# 614898; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4516 TECPR2 Zornitza Stark Marked gene: TECPR2 as ready
Mendeliome v0.4516 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from to Spastic paraplegia 49, autosomal recessive, MIM# 615031; Autonomic-sensory neuropathy
Mendeliome v0.4513 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, MIM# 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4513 SMOC2 Zornitza Stark Marked gene: SMOC2 as ready
Mendeliome v0.4510 MAG Zornitza Stark Marked gene: MAG as ready
Mendeliome v0.4510 MAG Zornitza Stark Phenotypes for gene: MAG were changed from to Spastic paraplegia 75, autosomal recessive, MIM# 616680
Mendeliome v0.4507 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4507 DSTYK Zornitza Stark Marked gene: DSTYK as ready
Mendeliome v0.4507 DSTYK Zornitza Stark Phenotypes for gene: DSTYK were changed from to Congenital anomalies of kidney and urinary tract 1, MIM# 610805; Spastic paraplegia 23, MIM# 270750
Mendeliome v0.4504 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: GREEN; Mode of pathogenicity: None; Publications: 23862974, 23862974, 28618409, 28157540, 23862974; Phenotypes: Congenital anomalies of kidney and urinary tract 1, MIM# 610805, Spastic paraplegia 23, MIM# 270750; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4504 ZMYM2 Zornitza Stark Marked gene: ZMYM2 as ready
Mendeliome v0.4503 ZMYM2 Zornitza Stark gene: ZMYM2 was added
gene: ZMYM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Congenital anomalies of kidney and urinary tract; Neurodevelopmental disorder
Review for gene: ZMYM2 was set to GREEN
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants.

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Mendeliome v0.4502 MTX2 Zornitza Stark Marked gene: MTX2 as ready
Mendeliome v0.4501 MTX2 Zornitza Stark gene: MTX2 was added
gene: MTX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation.
Sources: Literature
Mendeliome v0.4500 RREB1 Zornitza Stark Marked gene: RREB1 as ready
Mendeliome v0.4500 RREB1 Zornitza Stark gene: RREB1 was added
gene: RREB1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: RREB1.
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to 32938917
Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder
Review for gene: RREB1 was set to RED
Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes.

In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature
Mendeliome v0.4499 FNIP1 Zornitza Stark Marked gene: FNIP1 as ready
Mendeliome v0.4498 NEMF Zornitza Stark Marked gene: NEMF as ready
Mendeliome v0.4497 NEMF Zornitza Stark gene: NEMF was added
gene: NEMF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Intellectual disability; neuropathy
Review for gene: NEMF was set to GREEN
Added comment: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature
Mendeliome v0.4496 FNIP1 Arina Puzriakova gene: FNIP1 was added
gene: FNIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FNIP1 were set to 32181500; 32905580
Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia
Review for gene: FNIP1 was set to GREEN
Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed.

- PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway.
Sources: Literature
Mendeliome v0.4496 TAOK1 Zornitza Stark Marked gene: TAOK1 as ready
Mendeliome v0.4493 TAOK1 Zornitza Stark changed review comment from: Monoallelic de novo variants reported in 8 individuals with nonspecific phenotype of intellectual disability and hypotonia. Most were LOF, 2 missense. 3 had macrocephaly.; to: Monoallelic de novo variants reported in 8 individuals with nonspecific phenotype of intellectual disability and hypotonia; 3 had macrocephaly.
Mendeliome v0.4493 CSF1R Zornitza Stark Marked gene: CSF1R as ready
Mendeliome v0.4493 CSF1R Zornitza Stark Phenotypes for gene: CSF1R were changed from to Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476); Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820)
Mendeliome v0.4489 L2HGDH Zornitza Stark Marked gene: L2HGDH as ready
Mendeliome v0.4489 L2HGDH Zornitza Stark Phenotypes for gene: L2HGDH were changed from to L-2-hydroxyglutaric aciduria, MIM#236792
Mendeliome v0.4486 L2HGDH Zornitza Stark reviewed gene: L2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 15385440; Phenotypes: L-2-hydroxyglutaric aciduria, MIM#236792; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4486 CSF1R Elena Savva reviewed gene: CSF1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31330095, 24336230; Phenotypes: Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476), Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4486 LMNB1 Zornitza Stark Marked gene: LMNB1 as ready
Mendeliome v0.4482 L2HGDH Elena Savva reviewed gene: L2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20052767; Phenotypes: L-2-hydroxyglutaric aciduria MIM#236792; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4482 MAPK8 Zornitza Stark Marked gene: MAPK8 as ready
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Marked gene: CTNNBL1 as ready
Mendeliome v0.4480 MAPK8 Arina Puzriakova gene: MAPK8 was added
gene: MAPK8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8 were set to 31784499
Phenotypes for gene: MAPK8 were set to Chronic mucocutaneous candidiasis; Connective tissue disorders
Added comment: PMID: 31784499 (2020) - Three cases in a single family with chronic mucocutaneous candidiasis and a connective tissue disorder that clinically overlaps with hEDS. WES revealed a splice-site variant (c.311+1G>A) in the MAPK8 gene that segregated with the disorder. Includes supportive functional data using patient-derived fibroblasts, showing that the variant impairs IL-17A/F immunity and the development of Th17 cells.
Sources: Literature
Mendeliome v0.4480 CTNNBL1 Arina Puzriakova gene: CTNNBL1 was added
gene: CTNNBL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTNNBL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNBL1 were set to 32484799
Phenotypes for gene: CTNNBL1 were set to Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency
Added comment: PMID: 32484799 (2020) - One patient with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC), associated with a homozygous missense M466V variant in the CTNNBL1 gene. Functional studies showed that the variant impaired interaction with AID, in turn disrupting AID-mediated antibody diversification in activated B-cells.
Sources: Literature
Mendeliome v0.4480 PDIA5 Zornitza Stark Marked gene: PDIA5 as ready
Mendeliome v0.4479 TNNI2 Zornitza Stark Marked gene: TNNI2 as ready
Mendeliome v0.4479 TNNI2 Zornitza Stark Phenotypes for gene: TNNI2 were changed from to Arthrogryposis, distal, type 2B1 (MIM#601680)
Mendeliome v0.4475 MEIS2 Michelle Torres reviewed gene: MEIS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25712757; Phenotypes: Cleft palate, cardiac defects, and mental retardation (MIM#600987); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4475 TNNI2 Michelle Torres changed review comment from: Only a handful of variants reported, with a cluster of pathogenic missense in the C-terminal (between p.165 and 175). Missense, nonsense (not NMD) and an inframe-deletion have been shown to result in gain of function.; to: Only a handful of variants reported, with a cluster of pathogenic missense in the C-terminal (between p.165 and 175). Missense, nonsense (not NMD) and an inframe-deletion have been shown to result in gain of function (PMIDs: 17194691, 25340332).
Mendeliome v0.4475 TNNI2 Michelle Torres reviewed gene: TNNI2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 17194691, 25340332; Phenotypes: Arthrogryposis, distal, type 2B1 (MIM#601680); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4475 MMP23A Bryony Thompson Marked gene: MMP23A as ready
Mendeliome v0.4473 TAF2 Zornitza Stark edited their review of gene: TAF2: Added comment: Evidence for gene-disease association is limited. Families reported as part of large cohorts with limited phenotypic data, and variants are homozygous missense without functional validation. Borderline Amber/Green.; Changed publications: 21937992, 22633631, 26350204, 24084144
Mendeliome v0.4473 TAF2 Elena Savva reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24084144, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4473 VPS11 Zornitza Stark Marked gene: VPS11 as ready
Mendeliome v0.4470 GGT1 Zornitza Stark Marked gene: GGT1 as ready
Mendeliome v0.4466 GGT1 Elena Savva edited their review of gene: GGT1: Added comment: PMID: 29483667 - 1 family (2 sibs) w/ a homozygous 16.9kb deletion spanning part of the gene and no others. Carrier parents were normal.

PMID: 23615310 - homozygous mutant mouse model have dwarfism, cataracts and coat colour abnormalities. Protein activity reduced to 4% of wildtype. Noted it was for use as a GGT deficiency model.

PMID: 31520399 - 2 families with AD inheritance showing GGT1 deficiency but NO clinical symptoms. Authors call GGTemia a benign condition.; Changed publications: PMID: 29483667, 23615310, 31520399
Mendeliome v0.4466 NAXE Zornitza Stark Marked gene: NAXE as ready
Mendeliome v0.4466 NAXE Zornitza Stark Phenotypes for gene: NAXE were changed from to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Mendeliome v0.4463 NAXE Zornitza Stark changed review comment from: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.; to: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.
Mendeliome v0.4463 NAXE Zornitza Stark reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27122014, 27616477, 31758406; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4463 NAXD Zornitza Stark Marked gene: NAXD as ready
Mendeliome v0.4463 NAXD Zornitza Stark Phenotypes for gene: NAXD were changed from to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Mendeliome v0.4460 NAXD Zornitza Stark reviewed gene: NAXD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30576410, 31755961, 32462209; Phenotypes: Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4460 ISCA2 Zornitza Stark Marked gene: ISCA2 as ready
Mendeliome v0.4457 PRIMPOL Zornitza Stark Marked gene: PRIMPOL as ready
Mendeliome v0.4453 KCNN4 Zornitza Stark Marked gene: KCNN4 as ready
Mendeliome v0.4452 KCNN4 Zornitza Stark gene: KCNN4 was added
gene: KCNN4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN4 were set to 26148990; 26198474; 26178367
Phenotypes for gene: KCNN4 were set to Dehydrated hereditary stomatocytosis 2, MIM# 616689
Review for gene: KCNN4 was set to GREEN
Added comment: At least three families reported.
Sources: Expert list
Mendeliome v0.4451 C15orf41 Zornitza Stark Marked gene: C15orf41 as ready
Mendeliome v0.4449 XRCC2 Zornitza Stark Marked gene: XRCC2 as ready
Mendeliome v0.4445 TSR2 Zornitza Stark Marked gene: TSR2 as ready
Mendeliome v0.4441 SRP72 Zornitza Stark Marked gene: SRP72 as ready
Mendeliome v0.4441 SRP72 Zornitza Stark Phenotypes for gene: SRP72 were changed from to Bone marrow failure syndrome 1, MIM# 614675
Mendeliome v0.4437 SRP72 Zornitza Stark reviewed gene: SRP72: Rating: AMBER; Mode of pathogenicity: None; Publications: 22541560, 31254415; Phenotypes: Bone marrow failure syndrome 1, MIM# 614675; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4437 SLC25A38 Zornitza Stark Marked gene: SLC25A38 as ready
Mendeliome v0.4434 SLC19A2 Zornitza Stark Marked gene: SLC19A2 as ready
Mendeliome v0.4431 SEC23B Zornitza Stark Marked gene: SEC23B as ready
Mendeliome v0.4428 RPS27 Zornitza Stark Marked gene: RPS27 as ready
Mendeliome v0.4424 RPS17 Zornitza Stark Marked gene: RPS17 as ready
Mendeliome v0.4421 RPL9 Zornitza Stark Marked gene: RPL9 as ready
Mendeliome v0.4421 RPL9 Zornitza Stark gene: RPL9 was added
gene: RPL9 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL9 were set to 29114930; 20116044
Phenotypes for gene: RPL9 were set to Diamond Blackfan anaemia
Review for gene: RPL9 was set to RED
Added comment: PMID: 29114930, de novo splice site variant, c.-2+1G>C, functional impact of this variant is likely deleterious but not proven. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad.
Sources: Expert list
Mendeliome v0.4420 RPL31 Zornitza Stark Marked gene: RPL31 as ready
Mendeliome v0.4416 PUS1 Zornitza Stark Marked gene: PUS1 as ready
Mendeliome v0.4413 OXSR1 Zornitza Stark Marked gene: OXSR1 as ready
Mendeliome v0.4412 NHP2 Zornitza Stark Marked gene: NHP2 as ready
Mendeliome v0.4409 LIG4 Zornitza Stark Marked gene: LIG4 as ready
Mendeliome v0.4406 HOXA11 Zornitza Stark Marked gene: HOXA11 as ready
Mendeliome v0.4406 HOXA11 Zornitza Stark Phenotypes for gene: HOXA11 were changed from to Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432
Mendeliome v0.4402 HOXA11 Zornitza Stark reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832, 16765069; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4402 TGM6 Zornitza Stark Marked gene: TGM6 as ready
Mendeliome v0.4402 TGM6 Zornitza Stark Phenotypes for gene: TGM6 were changed from to Spinocerebellar ataxia 35, MIM# 613908
Mendeliome v0.4398 TGM6 Zornitza Stark reviewed gene: TGM6: Rating: RED; Mode of pathogenicity: None; Publications: 30670339, 32426513; Phenotypes: Spinocerebellar ataxia 35, MIM# 613908; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4398 SVBP Zornitza Stark changed review comment from: 5 unrelated families with homozygous mutations in SVBP. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature; to: 5 unrelated families with homozygous mutations in SVBP. Some shared the same founder variant, p.Q28*. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature
Mendeliome v0.4398 SQSTM1 Zornitza Stark Marked gene: SQSTM1 as ready
Mendeliome v0.4395 SLC25A46 Zornitza Stark Marked gene: SLC25A46 as ready
Mendeliome v0.4395 SLC25A46 Zornitza Stark Phenotypes for gene: SLC25A46 were changed from to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Mendeliome v0.4392 SLC25A46 Zornitza Stark changed review comment from: Age of onset is variable, but childhood onset described. Ataxia is a feature.; 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.

At least 10 unrelated families reported, supportive functional data.
Mendeliome v0.4392 RORA Zornitza Stark Marked gene: RORA as ready
Mendeliome v0.4392 RORA Zornitza Stark Phenotypes for gene: RORA were changed from to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060
Mendeliome v0.4389 RORA Zornitza Stark reviewed gene: RORA: Rating: GREEN; Mode of pathogenicity: None; Publications: 29656859; Phenotypes: Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4389 MAPK8IP3 Zornitza Stark edited their review of gene: MAPK8IP3: Added comment: 18 unrelated individuals reported with de novo variants and a neurodevelopmental disorder characterised by global developmental delay, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and nonspecific dysmorphic facial features are described.; Changed publications: 30612693, 30945334
Mendeliome v0.4389 LARS2 Zornitza Stark Marked gene: LARS2 as ready
Mendeliome v0.4389 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Mendeliome v0.4389 LARS2 Zornitza Stark Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy
Mendeliome v0.4388 LARS2 Zornitza Stark Publications for gene: LARS2 were set to
Mendeliome v0.4387 LARS2 Zornitza Stark Mode of inheritance for gene: LARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4386 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4386 LAMA1 Zornitza Stark Marked gene: LAMA1 as ready
Mendeliome v0.4386 LAMA1 Zornitza Stark Phenotypes for gene: LAMA1 were changed from to Cerebellar ataxia, intellectual disability, oculomotor apraxia, cerebellar cysts; Poretti Boltshauser syndrome MIM#615960
Mendeliome v0.4383 LAMA1 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.
Sources: Expert list; to: Five unrelated families reported.
Sources: Expert list
Mendeliome v0.4383 KCNA2 Zornitza Stark Marked gene: KCNA2 as ready
Mendeliome v0.4383 KCNA2 Zornitza Stark Phenotypes for gene: KCNA2 were changed from to Early infantile encephalopathy 32, MIM#616366
Mendeliome v0.4380 KCNA2 Zornitza Stark commented on gene: KCNA2: Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations.
Mendeliome v0.4380 HARS2 Zornitza Stark Marked gene: HARS2 as ready
Mendeliome v0.4380 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Mendeliome v0.4380 HARS2 Zornitza Stark Phenotypes for gene: HARS2 were changed from to Perrault syndrome 2, MIM# 614926
Mendeliome v0.4379 HARS2 Zornitza Stark Publications for gene: HARS2 were set to
Mendeliome v0.4378 HARS2 Zornitza Stark Mode of inheritance for gene: HARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4377 HARS2 Zornitza Stark reviewed gene: HARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31827252; Phenotypes: Perrault syndrome 2, MIM# 614926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4377 ELOVL5 Zornitza Stark reviewed gene: ELOVL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25065913; Phenotypes: Spinocerebellar ataxia 38, MIM# 615957; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4377 EBF3 Zornitza Stark Marked gene: EBF3 as ready
Mendeliome v0.4374 DOCK3 Zornitza Stark Marked gene: DOCK3 as ready
Mendeliome v0.4371 ATP8A2 Zornitza Stark Marked gene: ATP8A2 as ready
Mendeliome v0.4371 ATP8A2 Zornitza Stark Phenotypes for gene: ATP8A2 were changed from to Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4, MIM#615268
Mendeliome v0.4368 ATP8A2 Zornitza Stark changed review comment from: Multiple individuals from unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list; to: 10 individuals from six unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list
Mendeliome v0.4368 ADPRHL2 Zornitza Stark Marked gene: ADPRHL2 as ready
Mendeliome v0.4368 ADPRHL2 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is ADPRS.
Mendeliome v0.4368 CNGB3 Zornitza Stark Marked gene: CNGB3 as ready
Mendeliome v0.4365 CNGA3 Zornitza Stark Marked gene: CNGA3 as ready
Mendeliome v0.4362 SPRED1 Zornitza Stark Marked gene: SPRED1 as ready
Mendeliome v0.4357 SOS2 Zornitza Stark Mode of pathogenicity for gene: SOS2 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4356 SOS2 Zornitza Stark reviewed gene: SOS2: 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: 25795793, 32788663; Phenotypes: Noonan syndrome 9, MIM# 616559; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4355 SOS1 Zornitza Stark edited their review of gene: SOS1: Added comment: Over 50 individuals reported with SOS1 variants and a Noonan syndrome phenotype. Pulmonic stenosis tends to be more frequent compared to those with PTPN11 mutations, and atrial septal defect is relatively rare. Ectodermal features including keratosis pilaris and curly hair are significantly more prevalent compared with the general Noonan population. Height below the third percentile and learning disability are observed in fewer individuals compared with Noonan syndrome in general. In contrast, macrocephaly is overrepresented among those with SOS1 mutations.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 17143285, 17143282, 28884940, 17586837; Changed phenotypes: Noonan syndrome 4, MIM# 610733; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4355 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Mendeliome v0.4353 SHOC2 Zornitza Stark Mode of pathogenicity for gene: SHOC2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4351 SHOC2 Zornitza Stark reviewed gene: SHOC2: 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: 19684605, 23918763, 20882035; Phenotypes: Noonan syndrome-like with loose anagen hair 1, MIM# 607721; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4351 RIT1 Zornitza Stark Marked gene: RIT1 as ready
Mendeliome v0.4349 RIT1 Zornitza Stark Mode of pathogenicity for gene: RIT1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4347 RIT1 Zornitza Stark reviewed gene: RIT1: 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: 23791108, 25124994, 24939608, 27101134; Phenotypes: Noonan syndrome 8, MIM# 615355; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4347 NRAS Zornitza Stark Marked gene: NRAS as ready
Mendeliome v0.4345 NRAS Zornitza Stark Mode of pathogenicity for gene: NRAS was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4343 NRAS Zornitza Stark reviewed gene: NRAS: 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: 19966803, 26467218, 28594414; Phenotypes: Noonan syndrome 6, MIM# 613224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4343 MAP2K2 Zornitza Stark Marked gene: MAP2K2 as ready
Mendeliome v0.4343 MAP2K2 Zornitza Stark Phenotypes for gene: MAP2K2 were changed from to Cardiofaciocutaneous syndrome 4, MIM# 615280
Mendeliome v0.4341 MAP2K2 Zornitza Stark Mode of pathogenicity for gene: MAP2K2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4339 MAP2K2 Zornitza Stark reviewed gene: MAP2K2: 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: 20358587, 16439621, 18042262; Phenotypes: Cardiofaciocutaneous syndrome 4, MIM# 615280; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4339 MAP2K1 Zornitza Stark Marked gene: MAP2K1 as ready
Mendeliome v0.4339 MAP2K1 Zornitza Stark Phenotypes for gene: MAP2K1 were changed from to Cardiofaciocutaneous syndrome 3, MIM# 615279
Mendeliome v0.4337 MAP2K1 Zornitza Stark Mode of pathogenicity for gene: MAP2K1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4335 MAP2K1 Zornitza Stark reviewed gene: MAP2K1: 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: 16439621, 17551924, 18042262, 20301365; Phenotypes: Cardiofaciocutaneous syndrome 3, MIM# 615279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4335 HRAS Zornitza Stark Marked gene: HRAS as ready
Mendeliome v0.4333 HRAS Zornitza Stark Mode of pathogenicity for gene: HRAS was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4331 HRAS Zornitza Stark reviewed gene: HRAS: 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: 16329078, 16372351, 16443854; Phenotypes: Costello syndrome, MIM# 218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4331 CBL Zornitza Stark Marked gene: CBL as ready
Mendeliome v0.4329 CBL Zornitza Stark Mode of pathogenicity for gene: CBL was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.4327 CBL Zornitza Stark reviewed gene: CBL: 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: 25358541, 20619386, 20543203, 20694012; Phenotypes: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia, MIM# 613563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4327 CSNK1D Zornitza Stark Marked gene: CSNK1D as ready
Mendeliome v0.4323 CACNA1E Zornitza Stark Marked gene: CACNA1E as ready
Mendeliome v0.4323 CACNA1E Zornitza Stark Phenotypes for gene: CACNA1E were changed from to Epileptic encephalopathy, early infantile, 69, MIM#618285
Mendeliome v0.4320 CACNA1E Zornitza Stark changed review comment from: At least 30 unrelated patients reported with heterozygous variants in this gene; primarily a seizure disorder, often with profound intellectual disability.; to: At least 30 unrelated patients reported with heterozygous variants in this gene; primarily a seizure disorder, often with profound intellectual disability. Additional common features included spastic quadriplegia, hyperreflexia, hyperkinetic movements, dystonia, myoclonus, clonus, poor or absent eye contact, nystagmus, cortical visual impairment, and loss of head control. Thirteen patients had congenital contractures and 13 had macrocephaly.
Mendeliome v0.4320 ATAD1 Zornitza Stark Marked gene: ATAD1 as ready
Mendeliome v0.4317 ATAD1 Zornitza Stark changed review comment from: Severe progressive neurological disorder, severe/profound intellectual disability is a feature; to: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Severe progressive neurological disorder, severe/profound intellectual disability is a feature.
Mendeliome v0.4316 ADAT1 Zornitza Stark Marked gene: ADAT1 as ready
Mendeliome v0.4315 ADAT1 Zornitza Stark gene: ADAT1 was added
gene: ADAT1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ADAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAT1 were set to 28180185; 29390050; 29659736
Phenotypes for gene: ADAT1 were set to Hyperekplexia 4, MIM#618011
Review for gene: ADAT1 was set to GREEN
Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures.
Sources: Expert list
Mendeliome v0.4312 OCA2 Zornitza Stark Marked gene: OCA2 as ready
Mendeliome v0.4309 OCA2 Elena Savva changed review comment from: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function; to: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function

2.7kb deletion is very common in sub-Saharan African populations (GeneReviews)
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X) identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671: recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016
Mendeliome v0.4308 SREBF1 Zornitza Stark reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4308 VPS13D Zornitza Stark Marked gene: VPS13D as ready
Mendeliome v0.4308 VPS13D Zornitza Stark Phenotypes for gene: VPS13D were changed from to Spinocerebellar ataxia, autosomal recessive 4, MIM# 607317
Mendeliome v0.4304 FARSA Zornitza Stark Marked gene: FARSA as ready
Mendeliome v0.4304 FARSA Zornitza Stark Gene: farsa has been classified as Red List (Low Evidence).
Mendeliome v0.4304 FARSA Zornitza Stark gene: FARSA was added
gene: FARSA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Review for gene: FARSA was set to RED
Added comment: Autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts. Single affected individual reported, but FARSA interacts with FARSB, which causes a similar disorder.
Sources: Expert list
Mendeliome v0.4303 SLC1A3 Zornitza Stark Marked gene: SLC1A3 as ready
Mendeliome v0.4300 ANGPT2 Zornitza Stark Marked gene: ANGPT2 as ready
Mendeliome v0.4299 ANGPT2 Zornitza Stark gene: ANGPT2 was added
gene: ANGPT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANGPT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT2 were set to https://stm.sciencemag.org/content/12/560/eaax8013
Phenotypes for gene: ANGPT2 were set to Primary lymphoedema
Review for gene: ANGPT2 was set to GREEN
Added comment: Five unrelated individuals reported with primary lymphedema and variants in this gene, together with functional data.
Sources: Literature
Mendeliome v0.4298 UBR4 Zornitza Stark changed review comment from: Episodic ataxia reported in two families, but another molecular diagnosis present in the second, so suggested as a modifier. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.; to: Episodic ataxia reported in four families, but another molecular diagnosis present in the some, so suggested as a modifier. Variants are missense, with no supportive segregation or functional data, some are present at a low level in population databases. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.
Mendeliome v0.4298 SLC20A2 Zornitza Stark Marked gene: SLC20A2 as ready
Mendeliome v0.4295 SLC16A2 Zornitza Stark Marked gene: SLC16A2 as ready
Mendeliome v0.4292 TRIP13 Zornitza Stark Phenotypes for gene: TRIP13 were changed from to Mosaic variegated aneuploidy syndrome 3, MIM# 617598; Oocyte maturation defect 9, MIM# 619011
Mendeliome v0.4289 TRIP13 Zornitza Stark reviewed gene: TRIP13: Rating: GREEN; Mode of pathogenicity: None; Publications: 28553959, 32473092; Phenotypes: Mosaic variegated aneuploidy syndrome 3, MIM# 617598, Oocyte maturation defect 9, MIM# 619011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4289 HSP90B2P Bryony Thompson Marked gene: HSP90B2P as ready
Mendeliome v0.4288 NOBOX Zornitza Stark Marked gene: NOBOX as ready
Mendeliome v0.4288 NOBOX Zornitza Stark Phenotypes for gene: NOBOX were changed from to Premature ovarian failure 5,MIM#611548
Mendeliome v0.4285 NOBOX Zornitza Stark reviewed gene: NOBOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 27836978, 21837770, 25514101, 17701902, 27798098, 29067606; Phenotypes: Premature ovarian failure 5,MIM#611548; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4281 TLR7 Zornitza Stark Marked gene: TLR7 as ready
Mendeliome v0.4278 EXOSC5 Zornitza Stark Marked gene: EXOSC5 as ready
Mendeliome v0.4278 EXOSC5 Zornitza Stark Phenotypes for gene: EXOSC5 were changed from to Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia
Mendeliome v0.4275 EXOSC5 Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Mendeliome v0.4275 EXOSC5 Arina Puzriakova reviewed gene: EXOSC5: Rating: ; Mode of pathogenicity: None; Publications: 32504085, 29302074; Phenotypes: Short stature, Motor developmental delays, Cerebellar hypoplasia, Ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4275 SLC20A1 Zornitza Stark Marked gene: SLC20A1 as ready
Mendeliome v0.4272 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Mendeliome v0.4272 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from to Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mendeliome v0.4269 NR2F1 Zornitza Stark Marked gene: NR2F1 as ready
Mendeliome v0.4266 RAD50 Zornitza Stark Marked gene: RAD50 as ready
Mendeliome v0.4262 KMT2D Zornitza Stark edited their review of gene: KMT2D: Added comment: Four further individuals with KMT2D-associated neurodevelopmental syndrome reported. Features include: athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. Two of the four individuals had severe interstitial lung disease.; Changed publications: 31949313, 32083401
Mendeliome v0.4261 CFAP58 Zornitza Stark Marked gene: CFAP58 as ready
Mendeliome v0.4260 WASHC4 Zornitza Stark Marked gene: WASHC4 as ready
Mendeliome v0.4259 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
Added comment: Three unrelated families reported.
Sources: Literature
Mendeliome v0.4258 DNAJC7 Seb Lunke Marked gene: DNAJC7 as ready
Mendeliome v0.4257 DNAJC7 Seb Lunke gene: DNAJC7 was added
gene: DNAJC7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC7 were set to 31768050
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. However gene described as risk factor, unclear why.

DOI: https://doi.org/10.1212/NXG.0000000000000503
Sources: Literature
Mendeliome v0.4256 SVIL Melanie Marty edited their review of gene: SVIL: Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.; Changed rating: AMBER
Mendeliome v0.4256 CFAP58 Crystle Lee edited their review of gene: CFAP58: Added comment: Biallelic variants reported in 5 unrelated males with nultiple morphological abnormalities of the sperm flagella (MMAF). Knockout mice were infertile.; Changed rating: GREEN; Changed publications: 32791035; Changed phenotypes: Multiple morphological abnormalities of the sperm flagella (MMAF) (PMID: 32791035); Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4256 HSPA9 Zornitza Stark Marked gene: HSPA9 as ready
Mendeliome v0.4256 HSPA9 Zornitza Stark Phenotypes for gene: HSPA9 were changed from to Anemia, sideroblastic, 4, MIM# 182170; Even-plus syndrome, MIM#616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Mendeliome v0.4252 SVIL Zornitza Stark Marked gene: SVIL as ready
Mendeliome v0.4252 SVIL Zornitza Stark Added comment: Comment when marking as ready: Two unrelated families only.
Mendeliome v0.4250 CFAP57 Zornitza Stark reviewed gene: CFAP57: Rating: AMBER; Mode of pathogenicity: None; Publications: 21574244, 32764743; Phenotypes: Van der Woude Syndrome, Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4250 HSPA9 Sue White reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26598328, 32869452; Phenotypes: https://www.omim.org/entry/616854, skeletal anomalies, congenital cardiac and renal anomalies: marked small nose; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4250 SVIL Melanie Marty gene: SVIL was added
gene: SVIL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to myopathy
Penetrance for gene: SVIL were set to unknown
Review for gene: SVIL was set to GREEN
Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.
Sources: Literature
Mendeliome v0.4250 CFAP58 Crystle Lee gene: CFAP58 was added
gene: CFAP58 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CFAP58 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP58 were set to 32791035
Phenotypes for gene: CFAP58 were set to Multiple morphological abnormalities of the sperm flagella (MMAF) (PMID: 32791035)
Review for gene: CFAP58 was set to AMBER
Added comment: 5 unrelated males reported with biallelic loss of function variants. Knockout mice were infertile (Abstract only)
Sources: Expert Review
Mendeliome v0.4249 MYT1L Zornitza Stark edited their review of gene: MYT1L: Added comment: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems.; Changed publications: 28859103, 32065501
Mendeliome v0.4249 ARID1A Zornitza Stark Marked gene: ARID1A as ready
Mendeliome v0.4249 ARID1A Zornitza Stark Gene: arid1a has been classified as Green List (High Evidence).
Mendeliome v0.4249 ARID1A Zornitza Stark Phenotypes for gene: ARID1A were changed from to Coffin-Siris syndrome 2 (MIM#614607)
Mendeliome v0.4248 ARID1A Zornitza Stark Publications for gene: ARID1A were set to
Mendeliome v0.4247 ARID1A Zornitza Stark Mode of inheritance for gene: ARID1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4246 PDE10A Zornitza Stark Marked gene: PDE10A as ready
Mendeliome v0.4242 MYSM1 Zornitza Stark changed review comment from: early-onset anaemia, leukopaenia, and decreased B cells, may have thrombocytopaenia or variable additional non-haematologic features, such as facial dysmorphism, skeletal anomalies, and mild developmental delay
Sources: Expert list; to: Early-onset anaemia, leukopaenia, and decreased B cells, may have thrombocytopaenia or variable additional non-haematologic features, such as facial dysmorphism, skeletal anomalies, and mild developmental delay. At least 4 unrelated families reported.
Sources: Expert list
Mendeliome v0.4242 PNPLA8 Kristin Rigbye reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29681094, 25512002; Phenotypes: Mitochondrial myopathy with lactic acidosis (MIM#251950), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4242 ARID1A Crystle Lee reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23929686, 22426308, 25168959; Phenotypes: Coffin-Siris syndrome 2 (MIM#614607); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4241 KIF1C Zornitza Stark Marked gene: KIF1C as ready
Mendeliome v0.4238 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Mendeliome v0.4235 GNB1 Zornitza Stark Marked gene: GNB1 as ready
Mendeliome v0.4235 GNB1 Zornitza Stark Phenotypes for gene: GNB1 were changed from to Mental retardation, autosomal dominant 42, MIM# 616973
Mendeliome v0.4232 GNB1 Zornitza Stark reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27108799, 30194818, 27668284, 31034681; Phenotypes: Mental retardation, autosomal dominant 42, MIM# 616973; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4232 NDUFB10 Zornitza Stark Phenotypes for gene: NDUFB10 were changed from fatal infantile lactic acidosis; cardiomyopathy to fatal infantile lactic acidosis; cardiomyopathy; Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4231 NDUFB10 Zornitza Stark edited their review of gene: NDUFB10: Changed phenotypes: fatal infantile lactic acidosis, cardiomyopathy, Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4231 SSBP1 Zornitza Stark Phenotypes for gene: SSBP1 were changed from Optic atrophy with or without extraocular phenotypes to Optic atrophy with or without extraocular phenotypes; Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510
Mendeliome v0.4230 MCM10 Zornitza Stark Marked gene: MCM10 as ready
Mendeliome v0.4230 MCM10 Zornitza Stark gene: MCM10 was added
gene: MCM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM10 were set to 32865517
Phenotypes for gene: MCM10 were set to Susceptibility to CMV
Review for gene: MCM10 was set to RED
Added comment: Compound heterozygous variants in minichromosomal maintenance complex member 10 (MCM10) reported as a cause of NK-cell deficiency in a child with fatal susceptibility to CMV.
Sources: Literature
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Mono-allelic variants: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: Association study (PMID 32330418) found enrichment of non-coding and LoF TET2 variants in cohort of individuals with early onset dementia, unclear if this is monogenic or polygenic contribution.; to: Mono-allelic variants: Association study (PMID 32330418) found enrichment of non-coding and LoF TET2 variants in cohort of individuals with early onset dementia, unclear if this is monogenic or polygenic contribution.
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2.; to: Bi-allelic variants PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2.
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 TET2 Zornitza Stark edited their review of gene: TET2: Added comment: PMID 32518946: 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin, and bi-allelic variants in TET2.; Changed rating: GREEN; Changed publications: 30890702, 31827242, 32330418, 32518946; Changed phenotypes: Dementia, Lymphoma/myeloid malignancy, Immunodeficiency; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4229 FDXR Zornitza Stark Marked gene: FDXR as ready
Mendeliome v0.4226 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Four families reported with bi-allelic variants in FDXR causing an autosomal recessive neurologic disorder characterised by onset of visual and hearing impairment in the first or second decades. Two individuals described with a more severe progressive neurological phenotype. Mouse model exhibits neurodegeneration.; Changed rating: GREEN; Changed publications: 30250212, 28965846
Mendeliome v0.4226 EXOC7 Zornitza Stark Marked gene: EXOC7 as ready
Mendeliome v0.4225 EIF2S3 Zornitza Stark Marked gene: EIF2S3 as ready
Mendeliome v0.4220 TRAPPC6B Zornitza Stark Marked gene: TRAPPC6B as ready
Mendeliome v0.4217 TRAPPC12 Zornitza Stark Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Mendeliome v0.4214 TRAPPC12 Zornitza Stark reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837, 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4214 TPRKB Zornitza Stark Marked gene: TPRKB as ready
Mendeliome v0.4211 TP53RK Zornitza Stark Marked gene: TP53RK as ready
Mendeliome v0.4208 TBC1D20 Zornitza Stark Marked gene: TBC1D20 as ready
Mendeliome v0.4208 TBC1D20 Zornitza Stark Phenotypes for gene: TBC1D20 were changed from to Warburg micro syndrome 4, MIM# 615663; Martsolf syndrome
Mendeliome v0.4205 TBC1D20 Zornitza Stark reviewed gene: TBC1D20: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239381, 32740904, 32162791; Phenotypes: Warburg micro syndrome 4, MIM# 615663, Martsolf syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4205 DHX34 Zornitza Stark Marked gene: DHX34 as ready
Mendeliome v0.4205 DHX34 Zornitza Stark gene: DHX34 was added
gene: DHX34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX34 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX34 were set to 31256877
Phenotypes for gene: DHX34 were set to Intellectual disability; congenital anomalies
Review for gene: DHX34 was set to RED
Added comment: Three families reported. Two with bi-allelic variants and ID/multiple congenital anomalies but another molecular diagnosis present in both (variants in established genes). Single de novo missense in another individual with ID and dysmorphism. No supporting functional data. Overall RED rating for both MOI.
Sources: Literature
Mendeliome v0.4204 DDX54 Zornitza Stark Marked gene: DDX54 as ready
Mendeliome v0.4204 DDX54 Zornitza Stark gene: DDX54 was added
gene: DDX54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX54 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DDX54 were set to 31256877
Phenotypes for gene: DDX54 were set to Intellectual disability; congenital anomalies
Review for gene: DDX54 was set to RED
Added comment: Three individuals reported with different MOIs and different phenotypes. One with de novo variant and ID, another with bi-allelic variants and ID, and a third with bi-allelic variants and CAKUT. All variants are missense, no functional data. Overall, Red rating given inconsistent phenotypes and modes of inheritance, each one is essentially treated separately for now until further cases identified.
Sources: Literature
Mendeliome v0.4203 DHX16 Zornitza Stark Marked gene: DHX16 as ready
Mendeliome v0.4202 DHX16 Zornitza Stark gene: DHX16 was added
gene: DHX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733
Review for gene: DHX16 was set to GREEN
Added comment: Four unrelated individuals reported with de novo missense variants in this gene. Three of the individuals died in infancy, so phenotypic spectrum difficult to discern. Two had seizures. Individual with long-term survival had a progressive course, evidence of myopathy, loss of hearing and vision, and normal IQ.
Sources: Literature
Mendeliome v0.4201 DHX37 Zornitza Stark Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Mendeliome v0.4198 DHX37 Zornitza Stark edited their review of gene: DHX37: Added comment: Bi-allelic disease: 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype, which also includes congenital anomalies particularly affecting the vertebrae and heart, but also some with microcephaly, brain anomalies.; Changed publications: 31337883, 31745530, 26539891, 31256877; Changed phenotypes: 46,XY gonadal dysgenesis, testicular regression syndrome (TRS), Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4198 CFL2 Zornitza Stark Marked gene: CFL2 as ready
Mendeliome v0.4195 TDRD7 Zornitza Stark Marked gene: TDRD7 as ready
Mendeliome v0.4195 TDRD7 Zornitza Stark Phenotypes for gene: TDRD7 were changed from Cataract 36 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis to Cataract 36, 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis
Mendeliome v0.4193 TDRD7 Zornitza Stark reviewed gene: TDRD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract 36, MIM# 613887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4193 PAK3 Zornitza Stark Marked gene: PAK3 as ready
Mendeliome v0.4193 PAK3 Zornitza Stark Phenotypes for gene: PAK3 were changed from to Mental retardation, X-linked 30/47, MIM# 300558; Intellectual disability
Mendeliome v0.4190 PAK3 Zornitza Stark reviewed gene: PAK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9731525, 10946356, 12884430, 17853471, 18523455, 32050918, 32005903, 31943058, 31843706, 31678216; Phenotypes: Mental retardation, X-linked 30/47, MIM# 300558; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4190 TDRD7 Arina Puzriakova reviewed gene: TDRD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32420594; Phenotypes: Congenital cataracts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4190 CLTC Zornitza Stark Marked gene: CLTC as ready
Mendeliome v0.4190 CLTC Zornitza Stark Phenotypes for gene: CLTC were changed from to Mental retardation, autosomal dominant 56, MIM# 617854
Mendeliome v0.4187 CLTC Zornitza Stark reviewed gene: CLTC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 26822784; Phenotypes: Mental retardation, autosomal dominant 56, MIM# 617854; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4187 RPL10 Zornitza Stark Marked gene: RPL10 as ready
Mendeliome v0.4187 RPL10 Zornitza Stark Phenotypes for gene: RPL10 were changed from to Mental retardation, X-linked, syndromic, 35, MIM# 300998
Mendeliome v0.4184 RPL10 Zornitza Stark reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: None; Publications: 25316788, 25846674, 26290468; Phenotypes: Mental retardation, X-linked, syndromic, 35, MIM# 300998; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4184 IFT122 Zornitza Stark Marked gene: IFT122 as ready
Mendeliome v0.4180 KIAA0319 Zornitza Stark Marked gene: KIAA0319 as ready
Mendeliome v0.4178 RARS2 Zornitza Stark Marked gene: RARS2 as ready
Mendeliome v0.4178 RARS2 Zornitza Stark Gene: rars2 has been classified as Green List (High Evidence).
Mendeliome v0.4178 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from Pontocerebellar hypoplasia, type 6, MIM# 611523 to Pontocerebellar hypoplasia, type 6, MIM# 611523; early onset cerebellar ataxia
Mendeliome v0.4177 RARS2 Zornitza Stark Publications for gene: RARS2 were set to 17847012; 25809939; 20635367
Mendeliome v0.4176 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6, MIM# 611523
Mendeliome v0.4175 RARS2 Zornitza Stark Publications for gene: RARS2 were set to
Mendeliome v0.4174 RARS2 Zornitza Stark Mode of inheritance for gene: RARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4173 RARS2 Zornitza Stark edited their review of gene: RARS2: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4172 RAB3GAP2 Zornitza Stark Marked gene: RAB3GAP2 as ready
Mendeliome v0.4172 RAB3GAP2 Zornitza Stark Phenotypes for gene: RAB3GAP2 were changed from to Warburg micro syndrome 2, MIM# 614225
Mendeliome v0.4169 RAB3GAP2 Zornitza Stark reviewed gene: RAB3GAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23420520, 20967465; Phenotypes: Warburg micro syndrome 2, MIM# 614225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4169 RAB3GAP1 Zornitza Stark Marked gene: RAB3GAP1 as ready
Mendeliome v0.4169 RAB3GAP1 Zornitza Stark Phenotypes for gene: RAB3GAP1 were changed from to Warburg micro syndrome 1, MIM# 600118
Mendeliome v0.4166 RAB3GAP1 Zornitza Stark reviewed gene: RAB3GAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15696165, 20512159, 23420520; Phenotypes: Warburg micro syndrome 1, MIM# 600118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4166 RAB18 Zornitza Stark Marked gene: RAB18 as ready
Mendeliome v0.4166 RAB18 Zornitza Stark Phenotypes for gene: RAB18 were changed from to Warburg micro syndrome 3, MIM# 614222
Mendeliome v0.4163 RAB18 Zornitza Stark reviewed gene: RAB18: Rating: GREEN; Mode of pathogenicity: None; Publications: 11237903, 23420520; Phenotypes: Warburg micro syndrome 3, MIM# 614222; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4163 PTPN23 Zornitza Stark Marked gene: PTPN23 as ready
Mendeliome v0.4160 PRUNE1 Zornitza Stark Marked gene: PRUNE1 as ready
Mendeliome v0.4160 PRUNE1 Zornitza Stark Phenotypes for gene: PRUNE1 were changed from to Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481
Mendeliome v0.4157 PRUNE1 Zornitza Stark reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 28334956; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4157 POGZ Zornitza Stark Marked gene: POGZ as ready
Mendeliome v0.4154 POC1A Zornitza Stark Marked gene: POC1A as ready
Mendeliome v0.4151 PLK4 Zornitza Stark Marked gene: PLK4 as ready
Mendeliome v0.4148 PIGH Zornitza Stark Marked gene: PIGH as ready
Mendeliome v0.4145 PCYT2 Zornitza Stark Marked gene: PCYT2 as ready
Mendeliome v0.4145 PCYT2 Zornitza Stark Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive 618770; global developmental delay; regression; spastic parapesis or tetraparesis; epilepsy; progressive cerebral and cerebellar atrophy
Mendeliome v0.4143 PCYT2 Zornitza Stark reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31637422; Phenotypes: Spastic paraplegia 82, autosomal recessive 618770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Marked gene: TRAPPC2L as ready
Mendeliome v0.4141 TIMM8A Zornitza Stark Marked gene: TIMM8A as ready
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Marked gene: TOGARAM1 as ready
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Red List (low evidence)
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4138 DPP6 Zornitza Stark Marked gene: DPP6 as ready
Mendeliome v0.4138 DPP6 Zornitza Stark Phenotypes for gene: DPP6 were changed from to Mental retardation, autosomal dominant 33 (MIM#616311)
Mendeliome v0.4134 DPP6 Zornitza Stark reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova changed review comment from: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature; to: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.

Sources: Literature
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Mendeliome v0.4134 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Mendeliome v0.4134 DPP6 Ain Roesley reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4134 PCGF2 Zornitza Stark Marked gene: PCGF2 as ready
Mendeliome v0.4131 TRIT1 Zornitza Stark Marked gene: TRIT1 as ready
Mendeliome v0.4128 CRIPT Zornitza Stark Marked gene: CRIPT as ready
Mendeliome v0.4125 CRIPT Ain Roesley gene: CRIPT was added
gene: CRIPT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to 24389050; 27250922
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789)
Penetrance for gene: CRIPT were set to unknown
Review for gene: CRIPT was set to AMBER
Added comment: PMID: 24389050
- 2 unrelated probands homozygous for PTVs. However 1 was deceased and DNA was unavailable therefore parents were sequenced

PMID: 27250922
- 1x proband
- het for a missense which was maternally inherited. Because the father was negative for SNVs, they did CMA and found a small heterozygous deletion 1.6kb in size encompassing exon 1 of CRIPT. This deletion was paternally inherited

*did not find new reports since
Sources: Literature
Mendeliome v0.4125 DIAPH1 Zornitza Stark Marked gene: DIAPH1 as ready
Mendeliome v0.4123 UFC1 Seb Lunke Marked gene: UFC1 as ready
Mendeliome v0.4121 UFC1 Paul De Fazio gene: UFC1 was added
gene: UFC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776; 30552426
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth (MIM#618076)
Review for gene: UFC1 was set to GREEN
gene: UFC1 was marked as current diagnostic
Added comment: PMID 29868776: 8 affected individuals from 4 families reported. 7 were described to be postnatally microcephalic (at or below 3rd percentile). One was -5.1SD and one was -3.6SD. SD values for the others weren't provided.

The following head circumference measurements were provided for 6 of the affecteds:

51cm at 16yo; 50cm at 19yo; 42.5cm at 12mo, 45cm at 28mo, 45.2cm at 7yo; 45cm at 4yo.

3 of the families were consanguineous Saudi families with the same homozygous missense variant.

In vitro functional expression studies showed that both mutations caused impaired thioester binding with UFM1. Patient cells also showed decreased UFC1 intermediate formation with UFM1. The decrease in function was consistent with a hypomorphic allele, and the authors suggested that complete loss of function would be embryonic lethal.

PMID 30552426: 1 more individual with epileptic encephalopathy reported with a different homozygous missense variant in UFC1. The patient had microcephaly <3rd percentile.
Sources: Literature
Mendeliome v0.4121 CENPE Seb Lunke Marked gene: CENPE as ready
Mendeliome v0.4121 CENPE Seb Lunke Phenotypes for gene: CENPE were changed from to Microcephaly 13, primary, autosomal recessive (MIM#616051)
Mendeliome v0.4117 CENPE Ain Roesley reviewed gene: CENPE: Rating: RED; Mode of pathogenicity: None; Publications: 24748105, 30086807; Phenotypes: Microcephaly 13, primary, autosomal recessive (MIM#616051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4117 CDC6 Seb Lunke Marked gene: CDC6 as ready
Mendeliome v0.4113 GMNN Zornitza Stark changed review comment from: Three unrelated individuals reported.; to: Three unrelated individuals reported, all variants in exon 2 (first coding exon).
Mendeliome v0.4113 CTNND1 Zornitza Stark Marked gene: CTNND1 as ready
Mendeliome v0.4112 CTNND1 Zornitza Stark reviewed gene: CTNND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28301459; Phenotypes: Blepharocheilodontic syndrome 2, MIM# 617681; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4112 CTNND1 Zornitza Stark Phenotypes for gene: CTNND1 were changed from to Blepharocheilodontic syndrome 2, MIM# 617681
Mendeliome v0.4108 RIPOR2 Zornitza Stark changed review comment from: Single family and animal model data.
Sources: Expert list; to: Single family with bi-allelic variants and animal model data.
Sources: Expert list
Mendeliome v0.4108 RIPOR2 Zornitza Stark Marked gene: RIPOR2 as ready
Mendeliome v0.4108 RIPOR2 Zornitza Stark Added comment: Comment when marking as ready: Insufficient evidence for Green rating for either MOI.
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Marked gene: ZFYVE19 as ready
Mendeliome v0.4101 TRPM7 Zornitza Stark Phenotypes for gene: TRPM7 were changed from {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500 to {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500; Cardiac arrhythmia, stillbirth
Mendeliome v0.4097 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Ion channel expressed in the nervous and cardiac systems. The variant associated with ALS/dementia in the Guam population, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.; Changed rating: AMBER; Changed publications: 32503408, 31423533; Changed phenotypes: {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4097 CHCHD10 Zornitza Stark Marked gene: CHCHD10 as ready
Mendeliome v0.4097 CHCHD10 Zornitza Stark Phenotypes for gene: CHCHD10 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911; Spinal muscular atrophy, Jokela type 615048; Myopathy, isolated mitochondrial, autosomal dominant 616209
Mendeliome v0.4093 CHCHD10 Zornitza Stark reviewed gene: CHCHD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24934289, 25428574, 25193783, 32042922, 31690696, 30877432, 30874923; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911, Spinal muscular atrophy, Jokela type 615048, Myopathy, isolated mitochondrial, autosomal dominant 616209; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4093 ADARB1 Zornitza Stark Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Intellectual disability; microcephaly; seizures
Mendeliome v0.4092 ADARB1 Zornitza Stark Publications for gene: ADARB1 were set to 32220291
Mendeliome v0.4091 CTNND1 Eleanor Williams changed review comment from: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).; to: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).
Mendeliome v0.4091 RIPOR2 Arina Puzriakova reviewed gene: RIPOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 32631815; Phenotypes: Sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.4091 NOTCH3 Eleanor Williams gene: NOTCH3 was added
gene: NOTCH3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NOTCH3 were set to 31960911
Phenotypes for gene: NOTCH3 were set to CADASIL
Review for gene: NOTCH3 was set to AMBER
Added comment: PMID: 31960911 - Gravesteijn et al 2020 - describe a family with a unique cysteine-altering NOTCH3 variant in exon 9 in 5 individuals, which is predicted to cause natural exon 9 skipping. This mimics the therapeutic NOTCH3 cysteine correction approach and allows the effect of cysteine corrective exon skipping on NOTCH3 protein aggregation and disease severity in humans to be studied. In this family the CADASIL phenotype was mild.

Note this gene is rated green on the Neurodegenerative disorders - adult onset panel in the Genomics England instance of PanelApp https://panelapp.genomicsengland.co.uk/panels/474/gene/NOTCH3/
Sources: Literature
Mendeliome v0.4091 TRPM7 Eleanor Williams commented on gene: TRPM7: PMID: 31423533 - Cartwright et al 2020 - functional studies on four heterozygous nonsynonymous variants that were observed in TRPM7 in four individual cases of unexplained still birth which were screened for variants in 35 candidate genes in PMID: 29874177 (Munroe et al 2018). TRPM7 is a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. They found two variants in TRPM7, p.G179V and p.T860M, reduce ion channel current expression, which in the case of p.T860M is likely due to rapid degradation mediated by the proteasome. In addition, the p.R494Q TRPM7 variant significantly increases TRPM7 ion channel current, in a cell-type specific manner. They believe that TRPM7 may play a key role in ensuring correct cardiac development of the fetus.
Mendeliome v0.4091 ZFYVE19 Arina Puzriakova gene: ZFYVE19 was added
gene: ZFYVE19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE19 were set to 32737136
Phenotypes for gene: ZFYVE19 were set to Cholestasis
Review for gene: ZFYVE19 was set to GREEN
Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis.

ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder.
Sources: Literature
Mendeliome v0.4091 TRPM7 Eleanor Williams reviewed gene: TRPM7: Rating: AMBER; Mode of pathogenicity: None; Publications: 31423533, 29874177; Phenotypes: still birth, cardiac development; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4091 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291, 32719099; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4091 IARS Zornitza Stark Tag new gene name tag was added to gene: IARS.
Mendeliome v0.4091 SRD5A3 Zornitza Stark Marked gene: SRD5A3 as ready
Mendeliome v0.4088 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Mendeliome v0.4088 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Microcephaly 20, primary, autosomal recessive, MIM# 617914; Meckel syndrome 12, MIM# 616258
Mendeliome v0.4085 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28892560, 29343805, 24128419; Phenotypes: Microcephaly 20, primary, autosomal recessive, MIM# 617914, Meckel syndrome 12, MIM# 616258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4085 KIF1BP Zornitza Stark Marked gene: KIF1BP as ready
Mendeliome v0.4082 TRIP11 Zornitza Stark Marked gene: TRIP11 as ready
Mendeliome v0.4079 PRF1 Zornitza Stark Marked gene: PRF1 as ready
Mendeliome v0.4079 PRF1 Zornitza Stark Added comment: Comment when marking as ready: Principal association is between bi-allelic variants and HLH.
Mendeliome v0.4076 HLCS Zornitza Stark Marked gene: HLCS as ready
Mendeliome v0.4076 HLCS Zornitza Stark Phenotypes for gene: HLCS were changed from to Holocarboxylase synthetase deficiency, MIM# 253270
Mendeliome v0.4073 HLCS Zornitza Stark reviewed gene: HLCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Holocarboxylase synthetase deficiency, MIM# 253270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4073 CA5A Zornitza Stark reviewed gene: CA5A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency, 615751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4073 CA5A Zornitza Stark Marked gene: CA5A as ready
Mendeliome v0.4073 CA5A Zornitza Stark Phenotypes for gene: CA5A were changed from to Hyperammonemia due to carbonic anhydrase VA deficiency, 615751
Mendeliome v0.4067 OSR1 Zornitza Stark Marked gene: OSR1 as ready
Mendeliome v0.4066 KDM1A Zornitza Stark reviewed gene: KDM1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26656649, 24838796, 27094131; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features 616728; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4066 KDM1A Zornitza Stark Marked gene: KDM1A as ready
Mendeliome v0.4066 KDM1A Zornitza Stark Phenotypes for gene: KDM1A were changed from to Cleft palate, psychomotor retardation, and distinctive facial features 616728; Multiple myeloma
Mendeliome v0.4063 COL11A1 Zornitza Stark Marked gene: COL11A1 as ready
Mendeliome v0.4063 COL11A1 Zornitza Stark Phenotypes for gene: COL11A1 were changed from to Fibrochondrogenesis 1 (MIM#228520); Marshall syndrome (MIM#154780); Stickler syndrome, type II (MIM#604841)
Mendeliome v0.4059 HLCS Elena Savva reviewed gene: HLCS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10190325; Phenotypes: Holocarboxylase synthetase deficiency, 253270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4059 CA5A Elena Savva reviewed gene: CA5A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26913920, 32381389; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency, 615751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4059 KDM1A Elena Savva reviewed gene: KDM1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29559475, 27094131; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features 616728, Multiple myeloma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4059 COL11A1 Elena Savva reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 25073711, 30245514, 32427345, 27081569, 21035103; Phenotypes: Fibrochondrogenesis 1 (MIM#228520), Marshall syndrome (MIM#154780), Stickler syndrome, type II (MIM#604841), {Lumbar disc herniation, susceptibility to}, (MIM#603932), ?Deafness, autosomal dominant 37, (MIM#618533); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4059 YRDC Zornitza Stark Marked gene: YRDC as ready
Mendeliome v0.4057 GON7 Zornitza Stark Marked gene: GON7 as ready
Mendeliome v0.4056 GON7 Zornitza Stark gene: GON7 was added
gene: GON7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON7 were set to 31481669
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome
Review for gene: GON7 was set to GREEN
Added comment: 11 individuals from 5 families. Four of the families had the same homozygous variant, shared haplotype suggestive of founder effect. Clinical features included proteinuria, microcephaly, brain malformations and developmental delay. Supportive functional data.
Sources: Literature
Mendeliome v0.4055 LAGE3 Zornitza Stark Marked gene: LAGE3 as ready
Mendeliome v0.4052 LINGO1 Zornitza Stark Marked gene: LINGO1 as ready
Mendeliome v0.4052 LINGO1 Zornitza Stark Phenotypes for gene: LINGO1 were changed from to Mental retardation, autosomal recessive 64, MIM# 618103
Mendeliome v0.4048 LINGO1 Zornitza Stark reviewed gene: LINGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31668702; Phenotypes: Mental retardation, autosomal recessive 64, MIM# 618103; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4048 OSGEP Zornitza Stark Marked gene: OSGEP as ready
Mendeliome v0.4045 NUP107 Zornitza Stark Marked gene: NUP107 as ready
Mendeliome v0.4042 NSD2 Zornitza Stark Marked gene: NSD2 as ready
Mendeliome v0.4039 NSD2 Zornitza Stark changed review comment from: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.; to: 7 individuals with LOF variants in this gene, gene thought to be responsible for key features of Wolf-Hirschorn syndrome.
Mendeliome v0.4039 NCAPH Zornitza Stark Marked gene: NCAPH as ready
Mendeliome v0.4039 NCAPH Zornitza Stark Phenotypes for gene: NCAPH were changed from to Microcephaly 23, primary, autosomal recessive 617985
Mendeliome v0.4035 NCAPH Zornitza Stark reviewed gene: NCAPH: Rating: RED; Mode of pathogenicity: None; Publications: 27737959; Phenotypes: Microcephaly 23, primary, autosomal recessive 617985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4035 ATRIP Zornitza Stark Marked gene: ATRIP as ready
Mendeliome v0.4034 AP4E1 Zornitza Stark Marked gene: AP4E1 as ready
Mendeliome v0.4034 AP4E1 Zornitza Stark Phenotypes for gene: AP4E1 were changed from to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Mendeliome v0.4031 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20972249, 21620353, 21937992; Phenotypes: Spastic paraplegia 51, autosomal recessive, MIM# 613744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4031 AP4B1 Zornitza Stark Marked gene: AP4B1 as ready
Mendeliome v0.4031 AP4B1 Zornitza Stark Phenotypes for gene: AP4B1 were changed from to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Mendeliome v0.4028 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 22290197, 24700674, 24781758; Phenotypes: Spastic paraplegia 47, autosomal recessive, MIM# 614066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 TSEN2 Zornitza Stark Marked gene: TSEN2 as ready
Mendeliome v0.4028 TSEN2 Zornitza Stark Phenotypes for gene: TSEN2 were changed from to Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 TSEN2 Zornitza Stark edited their review of gene: TSEN2: Added comment: At least 3 unrelated families reported.; Changed rating: GREEN; Changed publications: 23562994, 20952379; Changed phenotypes: Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 ZSWIM6 Zornitza Stark Marked gene: ZSWIM6 as ready
Mendeliome v0.4022 ABCB11 Zornitza Stark Marked gene: ABCB11 as ready
Mendeliome v0.4019 ABCB1 Zornitza Stark Marked gene: ABCB1 as ready
Mendeliome v0.4015 ABCA3 Zornitza Stark Marked gene: ABCA3 as ready
Mendeliome v0.4015 ABCA3 Zornitza Stark Phenotypes for gene: ABCA3 were changed from to Surfactant metabolism dysfunction, pulmonary, 3, MIM# 610921
Mendeliome v0.4012 ABCA3 Zornitza Stark reviewed gene: ABCA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15044640; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 3, MIM# 610921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4012 ABCA12 Zornitza Stark Marked gene: ABCA12 as ready
Mendeliome v0.4012 ABCA12 Zornitza Stark Phenotypes for gene: ABCA12 were changed from to Ichthyosis, congenital, autosomal recessive 4A (MIM#601277); Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500)
Mendeliome v0.4009 ABCA12 Zornitza Stark reviewed gene: ABCA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31168818, 19664001, 31489029; Phenotypes: Ichthyosis, congenital, autosomal recessive 4A (MIM#601277), Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4006 AASS Zornitza Stark Marked gene: AASS as ready
Mendeliome v0.4002 AASS Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. Hyperlysinemia is generally considered to be a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.
Mendeliome v0.4002 AARS2 Zornitza Stark Marked gene: AARS2 as ready
Mendeliome v0.4002 AARS2 Zornitza Stark Gene: aars2 has been classified as Green List (High Evidence).
Mendeliome v0.4002 AARS2 Zornitza Stark Phenotypes for gene: AARS2 were changed from to Combined oxidative phosphorylation deficiency 8 MIM#614096; Leukoencephalopathy, progressive, with ovarian failure MIM#615889; MONDO:0013570
Mendeliome v0.4001 AARS2 Zornitza Stark Publications for gene: AARS2 were set to
Mendeliome v0.4000 AARS2 Zornitza Stark Mode of inheritance for gene: AARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3999 AARS2 Zornitza Stark edited their review of gene: AARS2: Changed phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889, MONDO:0013570
Mendeliome v0.3999 AARS2 Zornitza Stark reviewed gene: AARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30706699, 27839525, 21549344, 25058219, 24808023; Phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3999 AARS Zornitza Stark Marked gene: AARS as ready
Mendeliome v0.3999 AARS Zornitza Stark Gene: aars has been classified as Green List (High Evidence).
Mendeliome v0.3999 AARS Zornitza Stark Phenotypes for gene: AARS were changed from to Epileptic encephalopathy, early infantile, 29, MIM# 616339; Charcot-Marie-Tooth disease, axonal, type 2N, MIM# 613287
Mendeliome v0.3998 AARS Zornitza Stark Publications for gene: AARS were set to
Mendeliome v0.3997 AARS Zornitza Stark Mode of inheritance for gene: AARS was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3996 AARS Zornitza Stark reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28493438, 25817015, 20045102, 22009580, 22206013, 30373780, 26032230; Phenotypes: Epileptic encephalopathy, early infantile, 29, MIM# 616339, Charcot-Marie-Tooth disease, axonal, type 2N, MIM# 613287; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3996 AAGAB Zornitza Stark Marked gene: AAGAB as ready
Mendeliome v0.3996 AAGAB Zornitza Stark Phenotypes for gene: AAGAB were changed from to Keratoderma, palmoplantar, punctate type IA (MIM#148600)
Mendeliome v0.3993 AAGAB Zornitza Stark reviewed gene: AAGAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30451279, 26608363; Phenotypes: Keratoderma, palmoplantar, punctate type IA (MIM#148600); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3993 A4GALT Zornitza Stark Marked gene: A4GALT as ready
Mendeliome v0.3991 PAFAH1B1 Zornitza Stark Marked gene: PAFAH1B1 as ready
Mendeliome v0.3991 PAFAH1B1 Zornitza Stark Phenotypes for gene: PAFAH1B1 were changed from to Lissencephaly 1, MIM# 607432; Subcortical laminar heterotopia, MIM# 607432; MONDO:0011830
Mendeliome v0.3988 PAFAH1B1 Zornitza Stark reviewed gene: PAFAH1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11754098, 18285425; Phenotypes: Lissencephaly 1, MIM# 607432, Subcortical laminar heterotopia, MIM# 607432, MONDO:0011830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3988 LAMB1 Zornitza Stark Marked gene: LAMB1 as ready
Mendeliome v0.3985 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Mendeliome v0.3985 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041
Mendeliome v0.3982 TMEM5 Zornitza Stark reviewed gene: TMEM5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23217329, 23519211; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3982 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Mendeliome v0.3979 KIF2A Zornitza Stark Marked gene: KIF2A as ready
Mendeliome v0.3976 ISPD Zornitza Stark Marked gene: ISPD as ready
Mendeliome v0.3976 ISPD Zornitza Stark Phenotypes for gene: ISPD were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, MIM# 614643; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7, MIM# 616052
Mendeliome v0.3973 ISPD Zornitza Stark reviewed gene: ISPD: Rating: GREEN; Mode of pathogenicity: None; Publications: 22522421, 23217329, 23390185, 30060766, 28688748, 26404900; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, MIM# 614643, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7, MIM# 616052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3973 DCX Zornitza Stark Marked gene: DCX as ready
Mendeliome v0.3970 ASPRV1 Zornitza Stark Phenotypes for gene: ASPRV1 were changed from palmoplantar keratoderma; lamellar ichthyosis to Ichthyosis, lamellar, autosomal dominant, MIM# 146750; palmoplantar keratoderma; lamellar ichthyosis
Mendeliome v0.3969 ASPRV1 Zornitza Stark reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, lamellar, autosomal dominant, MIM# 146750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3969 MRPL44 Zornitza Stark Marked gene: MRPL44 as ready
Mendeliome v0.3966 KBTBD13 Zornitza Stark Marked gene: KBTBD13 as ready
Mendeliome v0.3966 KBTBD13 Zornitza Stark Phenotypes for gene: KBTBD13 were changed from to Nemaline myopathy 6, autosomal dominant, MIM# 609273; Hereditary motor neuropathy; late-onset limb girdle muscular dystrophy
Mendeliome v0.3963 KBTBD13 Zornitza Stark reviewed gene: KBTBD13: Rating: ; Mode of pathogenicity: None; Publications: 11731279, 21104864; Phenotypes: Nemaline myopathy 6, autosomal dominant, MIM# 609273, Hereditary motor neuropathy, late-onset limb girdle muscular dystrophy; Mode of inheritance: None
Mendeliome v0.3961 KBTBD13 Elena Savva reviewed gene: KBTBD13: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 28403181, 31167812, 31671076, 30208948; Phenotypes: Nemaline myopathy 6, autosomal dominant, 609273, Hereditary motor neuropathy, late-onset limb girdle muscular dystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3961 LAMA2 Zornitza Stark Marked gene: LAMA2 as ready
Mendeliome v0.3961 LAMA2 Zornitza Stark Phenotypes for gene: LAMA2 were changed from to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855; Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138
Mendeliome v0.3958 LAMA2 Zornitza Stark reviewed gene: LAMA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055037; Phenotypes: Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855, Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3958 GRIN2B Zornitza Stark Marked gene: GRIN2B as ready
Mendeliome v0.3958 GRIN2B Zornitza Stark Phenotypes for gene: GRIN2B were changed from to Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139
Mendeliome v0.3955 GRIN2B Zornitza Stark reviewed gene: GRIN2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28377535; Phenotypes: Mental retardation, autosomal dominant 6, MIM# 613970, Epileptic encephalopathy, early infantile, 27, MIM# 616139; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3955 GRIN1 Zornitza Stark Marked gene: GRIN1 as ready
Mendeliome v0.3952 BCLAF1 Zornitza Stark Marked gene: BCLAF1 as ready
Mendeliome v0.3951 ALG12 Zornitza Stark Marked gene: ALG12 as ready
Mendeliome v0.3950 SEC61A1 Zornitza Stark Marked gene: SEC61A1 as ready
Mendeliome v0.3945 ALG11 Zornitza Stark Marked gene: ALG11 as ready
Mendeliome v0.3942 NPRL2 Zornitza Stark Marked gene: NPRL2 as ready
Mendeliome v0.3942 NPRL2 Zornitza Stark Phenotypes for gene: NPRL2 were changed from to Epilepsy, familial focal, with variable foci 2, MIM# 617116; focal seizures; frontal lobe epilepsy; nocturnal frontal lobe epilepsy; temporal lobe epilepsy; focal cortical dysplasia
Mendeliome v0.3939 PDE2A Zornitza Stark Marked gene: PDE2A as ready
Mendeliome v0.3938 PDE2A Zornitza Stark gene: PDE2A was added
gene: PDE2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE2A were set to 32467598; 32196122; 29392776
Phenotypes for gene: PDE2A were set to Paroxysmal dyskinesia
Review for gene: PDE2A was set to GREEN
Added comment: Four unrelated families reported with childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy. One of the reports characterises the disorder as 'Rett-like'.
Sources: Literature
Mendeliome v0.3937 OTULIN Zornitza Stark Marked gene: OTULIN as ready
Mendeliome v0.3933 RRAGC Zornitza Stark Marked gene: RRAGC as ready
Mendeliome v0.3933 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from to Dilated cardiomyopathy; cataract
Mendeliome v0.3930 RRAGC Zornitza Stark reviewed gene: RRAGC: Rating: RED; Mode of pathogenicity: None; Publications: 27234373; Phenotypes: Dilated cardiomyopathy, cataract; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3930 RANBP17 Zornitza Stark Marked gene: RANBP17 as ready
Mendeliome v0.3929 MICA Zornitza Stark Marked gene: MICA as ready
Mendeliome v0.3928 CRADD Zornitza Stark Marked gene: CRADD as ready
Mendeliome v0.3928 CRADD Zornitza Stark Phenotypes for gene: CRADD were changed from to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Mendeliome v0.3925 CRADD Zornitza Stark reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3925 TDGF1 Zornitza Stark Marked gene: TDGF1 as ready
Mendeliome v0.3921 GABRA6 Zornitza Stark Marked gene: GABRA6 as ready
Mendeliome v0.3920 TMTC3 Zornitza Stark Marked gene: TMTC3 as ready
Mendeliome v0.3917 ARFGEF2 Zornitza Stark Marked gene: ARFGEF2 as ready
Mendeliome v0.3917 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Mendeliome v0.3917 ARFGEF2 Zornitza Stark Phenotypes for gene: ARFGEF2 were changed from to Periventricular heterotopia with microcephaly (MIM#608097)
Mendeliome v0.3916 ARFGEF2 Zornitza Stark Publications for gene: ARFGEF2 were set to
Mendeliome v0.3915 ARFGEF2 Zornitza Stark Mode of inheritance for gene: ARFGEF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3914 ARFGEF2 Zornitza Stark reviewed gene: ARFGEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25160555, 26126837, 23812912; Phenotypes: Periventricular heterotopia with microcephaly (MIM#608097); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3914 SLC6A3 Zornitza Stark Marked gene: SLC6A3 as ready
Mendeliome v0.3914 SLC6A3 Zornitza Stark Phenotypes for gene: SLC6A3 were changed from to Parkinsonism-dystonia, infantile, 1, MIM# 613135
Mendeliome v0.3911 SLC6A3 Zornitza Stark reviewed gene: SLC6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21112253; Phenotypes: Parkinsonism-dystonia, infantile, 1, MIM# 613135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3911 MAOA Zornitza Stark Marked gene: MAOA as ready
Mendeliome v0.3905 GLRB Zornitza Stark Marked gene: GLRB as ready
Mendeliome v0.3901 GLRA1 Zornitza Stark Marked gene: GLRA1 as ready
Mendeliome v0.3898 GABRG2 Zornitza Stark Marked gene: GABRG2 as ready
Mendeliome v0.3898 GABRG2 Zornitza Stark Phenotypes for gene: GABRG2 were changed from to Epileptic encephalopathy, early infantile, 74 618396; Epilepsy, generalized, with febrile seizures plus, type 3 607681
Mendeliome v0.3895 GABRG2 Zornitza Stark reviewed gene: GABRG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11326274, 11326275, 27864268; Phenotypes: Epileptic encephalopathy, early infantile, 74 618396, Epilepsy, generalized, with febrile seizures plus, type 3 607681; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3895 GABRB3 Zornitza Stark Marked gene: GABRB3 as ready
Mendeliome v0.3895 GABRB3 Zornitza Stark Phenotypes for gene: GABRB3 were changed from to Epileptic encephalopathy, early infantile, 43, MIM# 617113
Mendeliome v0.3892 GABRB3 Zornitza Stark reviewed gene: GABRB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23934111, 27476654; Phenotypes: Epileptic encephalopathy, early infantile, 43, MIM# 617113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3892 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
Mendeliome v0.3889 DBH Zornitza Stark Marked gene: DBH as ready
Mendeliome v0.3886 ARHGEF9 Zornitza Stark Marked gene: ARHGEF9 as ready
Mendeliome v0.3886 ARHGEF9 Zornitza Stark Gene: arhgef9 has been classified as Green List (High Evidence).
Mendeliome v0.3886 ARHGEF9 Zornitza Stark Phenotypes for gene: ARHGEF9 were changed from to Epileptic encephalopathy, early infantile, 8, MIM# 300607
Mendeliome v0.3885 ARHGEF9 Zornitza Stark Publications for gene: ARHGEF9 were set to
Mendeliome v0.3884 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3883 ARHGEF9 Zornitza Stark reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942680, 30048823, 29130122, 28620718; Phenotypes: Epileptic encephalopathy, early infantile, 8, MIM# 300607; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3883 STAT5B Zornitza Stark Marked gene: STAT5B as ready
Mendeliome v0.3879 ALDH5A1 Zornitza Stark Marked gene: ALDH5A1 as ready
Mendeliome v0.3876 ABAT Zornitza Stark Marked gene: ABAT as ready
Mendeliome v0.3874 ABAT Zornitza Stark edited their review of gene: ABAT: Added comment: Bi-allelic variants in ABAT are associated with a neurotransmitter disorder. However, there are also reports of families with encephalomyopathic MDS caused by bi-allelic variants in ABAT resulting in elevated GABA in subjects' brains as well as decreased mtDNA levels in subjects' fibroblasts. Nucleoside rescue and co-IP experiments demonstrate that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Unclear whether this a distinct disorder or part of a continuum caused by the enzyme being part of two pathways.; Changed publications: 25738457, 27903293, 28411234, 27596361, 20052547, 10407778, 6148708; Changed phenotypes: GABA-transaminase deficiency, MIM# 613163, mtDNA depletion syndrome (MDS)
Mendeliome v0.3873 LMBRD2 Zornitza Stark Marked gene: LMBRD2 as ready
Mendeliome v0.3872 LMBRD2 Zornitza Stark gene: LMBRD2 was added
gene: LMBRD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to GREEN
Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies.

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Mendeliome v0.3869 KAT5 Zornitza Stark Mode of pathogenicity for gene: KAT5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.3866 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3866 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Mendeliome v0.3866 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from to Spastic ataxia 5, autosomal recessive (MIM#614487); Spinocerebellar ataxia 28 (MIM#610246); Optic atrophy 12, MIM# 618977
Mendeliome v0.3863 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403, 32219868, 32600459, 32548275; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246), Optic atrophy 12, MIM# 618977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3863 MYOD1 Zornitza Stark Marked gene: MYOD1 as ready
Mendeliome v0.3861 TMEM237 Zornitza Stark Marked gene: TMEM237 as ready
Mendeliome v0.3859 TMEM237 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.; to: Well established gene-disease association.
Mendeliome v0.3859 NOD2 Zornitza Stark Marked gene: NOD2 as ready
Mendeliome v0.3856 PAX3 Zornitza Stark Marked gene: PAX3 as ready
Mendeliome v0.3856 PAX3 Zornitza Stark Phenotypes for gene: PAX3 were changed from to Craniofacial-deafness-hand syndrome (MIM#122880), AD 2; Waardenburg syndrome, type 1 (MIM#193500), AD; Waardenburg syndrome, type 3 (MIM#148820), AD, AR
Mendeliome v0.3850 PAX3 Michelle Torres reviewed gene: PAX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301703, 30854529; Phenotypes: Craniofacial-deafness-hand syndrome (MIM#122880), AD 2, Rhabdomyosarcoma 2, alveolar (MIM#268220), SMu, Waardenburg syndrome, type 1 (MIM#193500), AD, Waardenburg syndrome, type 3 (MIM#148820), AD, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3850 ESRRB Zornitza Stark Marked gene: ESRRB as ready
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Marked gene: HNRNPA2B1 as ready
Mendeliome v0.3846 HNRNPA2B1 Zornitza Stark gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPA2B1 were set to 23455423; 30279180; 29358076; 26744327; 23635965
Phenotypes for gene: HNRNPA2B1 were set to Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Review for gene: HNRNPA2B1 was set to AMBER
Added comment: One family reported that segregates cognitive impairment as part of the phenotype, and extensive functional analysis of protein, including a drosophila model.
Sources: Literature
Mendeliome v0.3845 PSMC3 Zornitza Stark Marked gene: PSMC3 as ready
Mendeliome v0.3844 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness; cataract
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Animal model.
Sources: Literature
Mendeliome v0.3843 SOS2 Zornitza Stark Marked gene: SOS2 as ready
Mendeliome v0.3838 RAI1 Zornitza Stark Marked gene: RAI1 as ready
Mendeliome v0.3835 TAF1C Zornitza Stark Marked gene: TAF1C as ready
Mendeliome v0.3834 TAF1C Zornitza Stark gene: TAF1C was added
gene: TAF1C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).
Sources: Expert list
Mendeliome v0.3833 KALRN Zornitza Stark Marked gene: KALRN as ready
Mendeliome v0.3833 KALRN Zornitza Stark Phenotypes for gene: KALRN were changed from to Susceptibility to coronary heart disease; Intellectual disability
Mendeliome v0.3829 KALRN Zornitza Stark reviewed gene: KALRN: Rating: RED; Mode of pathogenicity: None; Publications: 17357071, 27421267, 30675382, 32580138; Phenotypes: Susceptibility to coronary heart disease, Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3829 KRT6C Zornitza Stark Marked gene: KRT6C as ready
Mendeliome v0.3829 KRT6C Zornitza Stark Phenotypes for gene: KRT6C were changed from to Palmoplantar keratoderma, nonepidermolytic, focal or diffuse (MIM#615735)
Mendeliome v0.3826 KRT6C Zornitza Stark reviewed gene: KRT6C: Rating: GREEN; Mode of pathogenicity: None; Publications: 31823354; Phenotypes: Palmoplantar keratoderma, nonepidermolytic, focal or diffuse (MIM#615735); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3826 KRT6B Zornitza Stark Marked gene: KRT6B as ready
Mendeliome v0.3823 KRT2 Zornitza Stark Marked gene: KRT2 as ready
Mendeliome v0.3820 KRT17 Zornitza Stark Marked gene: KRT17 as ready
Mendeliome v0.3817 KRT17 Zornitza Stark changed review comment from: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma; to: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma. Steatocystoma multiplex is an allelic disorder.
Mendeliome v0.3817 SERPINB7 Zornitza Stark Marked gene: SERPINB7 as ready
Mendeliome v0.3817 SERPINB7 Zornitza Stark Phenotypes for gene: SERPINB7 were changed from to Palmoplantar keratoderma, Nagashima type (MIM#615598)
Mendeliome v0.3814 SERPINB7 Zornitza Stark reviewed gene: SERPINB7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24773080, 24207119, 24514002, 31706940; Phenotypes: Palmoplantar keratoderma, Nagashima type (MIM#615598); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3814 SLURP1 Zornitza Stark Marked gene: SLURP1 as ready
Mendeliome v0.3811 SLURP1 Zornitza Stark changed review comment from: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities.; to: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities. Note single report of manifesting carriers.
Mendeliome v0.3811 ACTN4 Zornitza Stark Marked gene: ACTN4 as ready
Mendeliome v0.3806 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14765194, 21900891, 28198005; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, MIM# 607473, Warfarin resistance, MIM# 122700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3806 TPM4 Zornitza Stark Marked gene: TPM4 as ready
Mendeliome v0.3805 TPM4 Zornitza Stark gene: TPM4 was added
gene: TPM4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TPM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TPM4 were set to 28134622; 31249973; 21153663
Phenotypes for gene: TPM4 were set to Macrothrombocytopaenia
Review for gene: TPM4 was set to GREEN
Added comment: Three families reported in addition to genome-wide association studies in nearly 70,000 individuals which indicate that SNVs in TPM4 exert an effect on the count and volume of platelets.
Sources: Expert list
Mendeliome v0.3804 THPO Zornitza Stark Marked gene: THPO as ready
Mendeliome v0.3799 THBD Zornitza Stark edited their review of gene: THBD: Added comment: Variants in this gene have also been linked to thrombophilia. Two families reported with a bleeding disorder, both variants located in the transmembrane domain.; Changed publications: 29500241, 19625716, 25564403, 32634856; Changed phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 6}, MIM# 612926, Bleeding disorder
Mendeliome v0.3799 TBXAS1 Zornitza Stark Marked gene: TBXAS1 as ready
Mendeliome v0.3797 SRC Zornitza Stark Marked gene: SRC as ready
Mendeliome v0.3795 SLFN14 Zornitza Stark Marked gene: SLFN14 as ready
Mendeliome v0.3793 PTPRJ Zornitza Stark Marked gene: PTPRJ as ready
Mendeliome v0.3792 PTPRJ Zornitza Stark gene: PTPRJ was added
gene: PTPRJ was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTPRJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPRJ were set to 30591527
Phenotypes for gene: PTPRJ were set to Thrombocytopaenia
Review for gene: PTPRJ was set to AMBER
Added comment: Two siblings reported with nonsyndromic thrombocytopenia characterised by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Supportive zebrafish model.
Sources: Expert list
Mendeliome v0.3791 PTGS1 Zornitza Stark Marked gene: PTGS1 as ready
Mendeliome v0.3790 PTGS1 Zornitza Stark gene: PTGS1 was added
gene: PTGS1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTGS1 were set to 32299908; 11442478; 27629384; 8562397
Phenotypes for gene: PTGS1 were set to Platelet dysfunction; bleeding
Review for gene: PTGS1 was set to AMBER
Added comment: Single molecularly characterised family reported. However, note at least two previous older reports where deficiency was identified at protein rather than gene level.
Sources: Expert list
Mendeliome v0.3789 PRKACG Zornitza Stark Marked gene: PRKACG as ready
Mendeliome v0.3788 PLAU Zornitza Stark Marked gene: PLAU as ready
Mendeliome v0.3786 PLA2G4A Zornitza Stark Marked gene: PLA2G4A as ready
Mendeliome v0.3784 MPIG6B Zornitza Stark Marked gene: MPIG6B as ready
Mendeliome v0.3782 MAT2A Zornitza Stark Marked gene: MAT2A as ready
Mendeliome v0.3778 LOX Zornitza Stark Marked gene: LOX as ready
Mendeliome v0.3775 KDSR Zornitza Stark Marked gene: KDSR as ready
Mendeliome v0.3775 KDSR Zornitza Stark Phenotypes for gene: KDSR were changed from to Erythrokeratodermia variabilis et progressiva 4, MIM# 617526; severe thrombocytopaenia
Mendeliome v0.3772 KDSR Zornitza Stark reviewed gene: KDSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 28774589, 30467204, 28575652; Phenotypes: Erythrokeratodermia variabilis et progressiva 4, MIM# 617526, severe thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3772 GGCX Zornitza Stark Marked gene: GGCX as ready
Mendeliome v0.3768 GPI Zornitza Stark Marked gene: GPI as ready
Mendeliome v0.3766 KANK2 Zornitza Stark Marked gene: KANK2 as ready
Mendeliome v0.3766 KANK2 Zornitza Stark Phenotypes for gene: KANK2 were changed from to Palmoplantar keratoderma and woolly hair (MIM#616099); Nephrotic syndrome, type 16, MIM#617783
Mendeliome v0.3763 KANK2 Zornitza Stark reviewed gene: KANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25961457, 24671081; Phenotypes: Palmoplantar keratoderma and woolly hair (MIM#616099), Nephrotic syndrome, type 16, MIM#617783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3763 FAM83G Zornitza Stark Marked gene: FAM83G as ready
Mendeliome v0.3763 FAM83G Zornitza Stark gene: FAM83G was added
gene: FAM83G was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FAM83G was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM83G were set to 29138053
Phenotypes for gene: FAM83G were set to Palmoplantar keratoderma, curly scalp hair and toenail dystrophy
Review for gene: FAM83G was set to RED
Added comment: PMID: 29138053; - 2 siblings born of consanguineous family presented with palmoplantar keratoderma and exuberant curly scalp hair - progressive development of yellowish thickened scaly skin affecting the palms and soles since 2 years of age, and toenail dystrophy in their teenage years > homozygous for a missense p.(Ala34Glu)
Sources: Expert list
Mendeliome v0.3762 LONP2 Zornitza Stark Marked gene: LONP2 as ready
Mendeliome v0.3761 CAST Zornitza Stark Marked gene: CAST as ready
Mendeliome v0.3758 CARD14 Zornitza Stark Marked gene: CARD14 as ready
Mendeliome v0.3758 CARD14 Zornitza Stark Gene: card14 has been classified as Green List (High Evidence).
Mendeliome v0.3758 CARD14 Zornitza Stark Phenotypes for gene: CARD14 were changed from to Pityriasis rubra pilaris (MIM#173200)
Mendeliome v0.3757 CARD14 Zornitza Stark Publications for gene: CARD14 were set to
Mendeliome v0.3756 CARD14 Zornitza Stark Mode of inheritance for gene: CARD14 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3755 CARD14 Zornitza Stark reviewed gene: CARD14: Rating: GREEN; Mode of pathogenicity: None; Publications: 22703878, 27760266; Phenotypes: Pityriasis rubra pilaris (MIM#173200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3755 TRPV3 Zornitza Stark Marked gene: TRPV3 as ready
Mendeliome v0.3752 EPHB2 Zornitza Stark Marked gene: EPHB2 as ready
Mendeliome v0.3748 ACTN1 Zornitza Stark Marked gene: ACTN1 as ready
Mendeliome v0.3745 DSG3 Zornitza Stark Marked gene: DSG3 as ready
Mendeliome v0.3744 ITGA9 Zornitza Stark Marked gene: ITGA9 as ready
Mendeliome v0.3743 MADD Zornitza Stark Marked gene: MADD as ready
Mendeliome v0.3740 UNC45A Zornitza Stark Marked gene: UNC45A as ready
Mendeliome v0.3740 UNC45A Zornitza Stark Phenotypes for gene: UNC45A were changed from to Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Mendeliome v0.3737 UNC45A Zornitza Stark reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29429573; Phenotypes: Cholestasis, Diarrhoea, Bone fragility, Impaired hearing; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3736 SMO Zornitza Stark Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis; Curry-Jones syndrome, somatic mosaic 601707 to Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800; Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 SMO Zornitza Stark edited their review of gene: SMO: Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800, Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 HFE2 Zornitza Stark Marked gene: HFE2 as ready
Mendeliome v0.3733 FAM50A Zornitza Stark Marked gene: FAM50A as ready
Mendeliome v0.3732 FAM50A Zornitza Stark gene: FAM50A was added
gene: FAM50A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).
Sources: Literature
Mendeliome v0.3731 ADK Zornitza Stark Marked gene: ADK as ready
Mendeliome v0.3728 SGK3 Zornitza Stark gene: SGK3 was added
gene: SGK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SGK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGK3 were set to 31821448
Phenotypes for gene: SGK3 were set to Hypophosphatemic rickets
Review for gene: SGK3 was set to RED
Added comment: 5 individuals from one family where a splice site variant segregated with disease.
Sources: Literature
Mendeliome v0.3727 SEC24D Zornitza Stark Marked gene: SEC24D as ready
Mendeliome v0.3727 SEC24D Zornitza Stark Phenotypes for gene: SEC24D were changed from to Cole-Carpenter syndrome 2, MIM# 616294
Mendeliome v0.3724 SEC24D Zornitza Stark reviewed gene: SEC24D: Rating: GREEN; Mode of pathogenicity: None; Publications: 30462379, 27942778, 26467156, 25683121; Phenotypes: Cole-Carpenter syndrome 2, MIM# 616294; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3724 P4HB Zornitza Stark Marked gene: P4HB as ready
Mendeliome v0.3724 P4HB Zornitza Stark Phenotypes for gene: P4HB were changed from to Cole-Carpenter syndrome 1, MIM#112240
Mendeliome v0.3721 P4HB Zornitza Stark reviewed gene: P4HB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30063094, 29263160, 25683117, 29384951; Phenotypes: Cole-Carpenter syndrome 1, MIM#112240; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3721 MPDZ Zornitza Stark Marked gene: MPDZ as ready
Mendeliome v0.3718 MPDZ Zornitza Stark changed review comment from: Five Saudi families reported with same homozygous variant, p.Gln210Ter, founder effect. Additional 4 families report from different ethnic backgrounds and at least 4 different variants. Mouse model.; to: Five Saudi families reported with same homozygous variant, p.Gln210Ter, founder effect. Additional 4 families reported from different ethnic backgrounds and at least 4 different variants. Mouse model.
Mendeliome v0.3718 B3GNT2 Zornitza Stark Phenotypes for gene: B3GNT2 were changed from to Muscular dystrophy-dystroglycanopathy
Mendeliome v0.3714 B3GNT2 Zornitza Stark edited their review of gene: B3GNT2: Added comment: Gene previously known as B3GNT1. Two families reported.; Changed rating: AMBER; Changed publications: 23359570, 23877401; Changed phenotypes: Muscular dystrophy-dystroglycanopathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3713 HYLS1 Melanie Marty changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human cells have shown mislocalisation of the protein to the nucleus (PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.
Mendeliome v0.3713 CNTN2 Zornitza Stark Marked gene: CNTN2 as ready
Mendeliome v0.3711 DTNA Zornitza Stark Marked gene: DTNA as ready
Mendeliome v0.3711 DTNA Zornitza Stark Phenotypes for gene: DTNA were changed from to Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169
Mendeliome v0.3707 DTNA Zornitza Stark reviewed gene: DTNA: Rating: RED; Mode of pathogenicity: None; Publications: 29118297, 11238270, 16427346; Phenotypes: Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3707 HYLS1 Zornitza Stark Marked gene: HYLS1 as ready
Mendeliome v0.3707 HYLS1 Zornitza Stark Added comment: Comment when marking as ready: Borderline Amber/Green and mechanism unclear. However, given at least two variants reported with a ciliopathy phenotype and supporting functional data from multiple animal models all indicative of ciliopathy, keep Green.
Mendeliome v0.3703 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (MIM#618577), AD to Mental retardation, autosomal dominant 48, MIM# 617751
Mendeliome v0.3702 RAC1 Zornitza Stark Marked gene: RAC1 as ready
Mendeliome v0.3698 FANCD2 Zornitza Stark Marked gene: FANCD2 as ready
Mendeliome v0.3696 BCOR Zornitza Stark Marked gene: BCOR as ready
Mendeliome v0.3696 BCOR Zornitza Stark Phenotypes for gene: BCOR were changed from to Microphthalmia, syndromic 2, MIM# 300166; Oculofaciocardiodental syndrome; Lenz microphthalmia
Mendeliome v0.3693 BCOR Zornitza Stark reviewed gene: BCOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 29974297; Phenotypes: Microphthalmia, syndromic 2, MIM# 300166, Oculofaciocardiodental syndrome, Lenz microphthalmia; 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 v0.3692 ARSE Zornitza Stark Mode of inheritance for gene: ARSE was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3691 ARSE Zornitza Stark Marked gene: ARSE as ready
Mendeliome v0.3691 ARSE Zornitza Stark Gene: arse has been classified as Green List (High Evidence).
Mendeliome v0.3691 ARSE Zornitza Stark Phenotypes for gene: ARSE were changed from to Chondrodysplasia punctata, X-linked recessive, MIM# 302950
Mendeliome v0.3690 ARSE Zornitza Stark Tag new gene name tag was added to gene: ARSE.
Mendeliome v0.3690 ARSE Zornitza Stark reviewed gene: ARSE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3690 TPP1 Zornitza Stark Marked gene: TPP1 as ready
Mendeliome v0.3690 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270
Mendeliome v0.3687 PSAT1 Zornitza Stark Marked gene: PSAT1 as ready
Mendeliome v0.3684 TPP1 Michelle Torres reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2 204500, Spinocerebellar ataxia, autosomal recessive 7 609270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3684 FBXO11 Zornitza Stark Marked gene: FBXO11 as ready
Mendeliome v0.3681 FRMD7 Zornitza Stark Marked gene: FRMD7 as ready
Mendeliome v0.3678 AIFM1 Zornitza Stark Marked gene: AIFM1 as ready
Mendeliome v0.3675 PIGQ Zornitza Stark edited their review of gene: PIGQ: Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548).

Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362).

Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality.

PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis.

More than 10 variants have been reported to date (missense / pLoF).; Changed phenotypes: Epileptic encephalopathy, early infantile, 77, MIM# 618548
Mendeliome v0.3674 SEC61B Zornitza Stark Marked gene: SEC61B as ready
Mendeliome v0.3672 CHI3L1 Zornitza Stark Marked gene: CHI3L1 as ready
Mendeliome v0.3670 C3orf52 Zornitza Stark Marked gene: C3orf52 as ready
Mendeliome v0.3669 C3orf52 Zornitza Stark gene: C3orf52 was added
gene: C3orf52 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C3orf52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C3orf52 were set to 32336749
Phenotypes for gene: C3orf52 were set to Localized hypotrichosis
Review for gene: C3orf52 was set to AMBER
Added comment: 2 families with 4 individuals with localised hypotrichosis and homozygous variants in C3ORF52. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H–mediated 2-acyl-lysophosphatidic acid (LPA) biosynthesis. Same pathway as two other genes for localised hypotrichosis (LIPH and LPAR6)
Sources: Literature
Mendeliome v0.3668 NDUFA8 Zornitza Stark Marked gene: NDUFA8 as ready
Mendeliome v0.3668 NDUFA8 Zornitza Stark gene: NDUFA8 was added
gene: NDUFA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA8 were set to 32385911
Phenotypes for gene: NDUFA8 were set to NDUFA8-related mitochondrial disease; Developmental delay; microcehaly; seizures
Review for gene: NDUFA8 was set to RED
Added comment: Single individual reported with homozygous variant, fibroblasts showed apparent biochemical defects in mitochondrial complex I.
Sources: Literature
Mendeliome v0.3667 DLG5 Zornitza Stark Marked gene: DLG5 as ready
Mendeliome v0.3666 DLG5 Zornitza Stark gene: DLG5 was added
gene: DLG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLG5 were set to 32631816
Phenotypes for gene: DLG5 were set to Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations
Review for gene: DLG5 was set to GREEN
Added comment: Four unrelated families reported, supportive Xenopus animal model data.
Sources: Literature
Mendeliome v0.3665 AHR Zornitza Stark Marked gene: AHR as ready
Mendeliome v0.3664 M1AP Zornitza Stark Marked gene: M1AP as ready
Mendeliome v0.3663 MORC2 Zornitza Stark Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688; Intellectual disability to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688; Intellectual disability
Mendeliome v0.3662 RELN Zornitza Stark changed review comment from: Well established gene-disease association with bi-allelic variants and lissencephaly.; to: Well established gene-disease association with bi-allelic variants and lissencephaly. Mono-allelic variants linked to epilepsy.
Mendeliome v0.3662 RELN Zornitza Stark Marked gene: RELN as ready
Mendeliome v0.3658 CALCRL Zornitza Stark Marked gene: CALCRL as ready
Mendeliome v0.3657 CALCRL Hazel Phillimore gene: CALCRL was added
gene: CALCRL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CALCRL were set to PMID: 30115739
Phenotypes for gene: CALCRL were set to ?Lymphatic malformation 8 (MIM# 618773); hydrops fetalis
Review for gene: CALCRL was set to RED
Added comment: Homozygous in-frame deletion (Val205del) in the CALCRL gene (Val205del) in a 22 week-old fetus with hydrops details due to lymphatic malformation. Consanguineous parents.
Heterozygosity of the variant was also suggested to be associated with spontaneous miscarriage and subfertility. Consanguineous family with 8 total miscarriages from 3 carrier women, and 2 of these were confirmed to be due to hydrops fetalis.
Note: possible association of a variant in ASAH1 gene that is associated with Farber lipogranulomatosis which can sometimes present with antenatal hydrops fetalis. (Homozygosity in one of the fetuses, fetus and heterozygosity in some of the family members).
In vitro biochemical assays indicated that the variant causes misfolding of the protein and reduced association with its chaperone, RAMP2, and reduced translocation to the plasma membrane. (PMID: 30115739; Mackie, DI. et al., 2018).
Sources: Literature
Mendeliome v0.3657 MORC2 Dean Phelan reviewed gene: MORC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32693025; Phenotypes: Spinal muscular atrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3657 M1AP Ee Ming Wong gene: M1AP was added
gene: M1AP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: M1AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: M1AP were set to PMID: 32673564
Phenotypes for gene: M1AP were set to non-obstructive azoospermia (NOA); severe spermatogenic failure; male infertility
Review for gene: M1AP was set to GREEN
gene: M1AP was marked as current diagnostic
Added comment: - One frameshift variant identified in 9 infertile men either in homozygous or compound heterozygous form
- One missense variant segregated with infertility in five men from a consanguineous Turkish family
Sources: Literature
Mendeliome v0.3657 AHR Chern Lim gene: AHR was added
gene: AHR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHR were set to 29726989; 31896775
Phenotypes for gene: AHR were set to ?Retinitis pigmentosa 85 MIM#618345; foveal hypoplasia and infantile nystagmus
Review for gene: AHR was set to AMBER
Added comment: - One reported homozygous splice variant in a consanguineous family & a mouse model (PMID: 29726989)

- A homozygous nonsense variant in 1 consanguineous family with foveal hypoplasia and infantile nystagmus (PMID:31896775).
Sources: Literature
Mendeliome v0.3657 CRY1 Zornitza Stark Marked gene: CRY1 as ready
Mendeliome v0.3656 FBXL7 Zornitza Stark Marked gene: FBXL7 as ready
Mendeliome v0.3656 FBXL7 Zornitza Stark Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. to Hennekam lymphangiectasia-lymphedema syndrome
Mendeliome v0.3653 CRY1 Ee Ming Wong gene: CRY1 was added
gene: CRY1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRY1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRY1 were set to PMID: 28388406; PMID: 32538895
Phenotypes for gene: CRY1 were set to Attention deficit/hyperactivity disorder (ADHD); Delayed sleep phase disorder (DSPD),
Penetrance for gene: CRY1 were set to Incomplete
Review for gene: CRY1 was set to GREEN
gene: CRY1 was marked as current diagnostic
Added comment: - Splice variants identified in 7 families with ADHD and DSPD
- Gain of function suggested for CRY1Δ11 (PMID: 28388406)
- Loss of function suggested for CRY1Δ6 (HEK293T cells transfected with a Per1::Luc reporter plasmid showed reduced repressor activity compared to WT and CRY1Δ11)
Sources: Literature
Mendeliome v0.3653 HPDL Zornitza Stark Marked gene: HPDL as ready
Mendeliome v0.3651 NCKAP1L Zornitza Stark Marked gene: NCKAP1L as ready
Mendeliome v0.3649 MYLPF Zornitza Stark Marked gene: MYLPF as ready
Mendeliome v0.3649 MYLPF Zornitza Stark Added comment: Comment when marking as ready: Two variants each for the bi-allelic and the mono-allelic gene-disease associations.
Mendeliome v0.3648 FBXL7 Hazel Phillimore changed review comment from: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature; to: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3648 SCAF4 Zornitza Stark Marked gene: SCAF4 as ready
Mendeliome v0.3647 FBXL7 Hazel Phillimore gene: FBXL7 was added
gene: FBXL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL7 were set to PMID: 31633297
Phenotypes for gene: FBXL7 were set to Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Review for gene: FBXL7 was set to AMBER
Added comment: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3647 PJA1 Zornitza Stark Marked gene: PJA1 as ready
Mendeliome v0.3647 HPDL Crystle Lee gene: HPDL was added
gene: HPDL was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Neurological disorder
Review for gene: HPDL was set to GREEN
Added comment: Biallelic variants reported in 13 families with a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia
Sources: Expert Review
Mendeliome v0.3646 PJA1 Zornitza Stark gene: PJA1 was added
gene: PJA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Intellectual disability; trigonocephaly
Review for gene: PJA1 was set to AMBER
Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals, supportive mouse model. Individuals shared a common haplotype, suggestive of founder effect
Sources: Literature
Mendeliome v0.3645 MYLPF Crystle Lee gene: MYLPF was added
gene: MYLPF was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MYLPF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLPF were set to 32707087
Phenotypes for gene: MYLPF were set to Distal arthrogryoposis
Review for gene: MYLPF was set to GREEN
Added comment: 2 different homozygous variants reported in 6 consanguineous families with DA and an additional 2 different dominantly inherited variants in 2 families, with supporting animal model.
Sources: Expert Review
Mendeliome v0.3645 MCF2 Zornitza Stark Marked gene: MCF2 as ready
Mendeliome v0.3645 MCF2 Zornitza Stark gene: MCF2 was added
gene: MCF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCF2 were set to 31846234
Phenotypes for gene: MCF2 were set to Perisylvian polymicrogyria
Review for gene: MCF2 was set to RED
Added comment: Single individual reported, inherited missense variant from unaffected mother, some support from mouse model.
Sources: Literature
Mendeliome v0.3644 SCAF4 Crystle Lee gene: SCAF4 was added
gene: SCAF4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to Mild intellectual disability; seizures; behavioral abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: > 5 variants reported in individuals with variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies.
Sources: Expert Review
Mendeliome v0.3644 NARS Zornitza Stark Marked gene: NARS as ready
Mendeliome v0.3644 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Mendeliome v0.3644 NARS Zornitza Stark Classified gene: NARS as Green List (high evidence)
Mendeliome v0.3644 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Mendeliome v0.3643 NARS Zornitza Stark gene: NARS was added
gene: NARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).
Sources: Literature
Mendeliome v0.3642 ZNF407 Zornitza Stark Marked gene: ZNF407 as ready
Mendeliome v0.3638 DDX58 Zornitza Stark Marked gene: DDX58 as ready
Mendeliome v0.3635 DDX58 Zornitza Stark changed review comment from: Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies.; to: Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies. At least 3 families reported.
Mendeliome v0.3635 IVNS1ABP Zornitza Stark Marked gene: IVNS1ABP as ready
Mendeliome v0.3635 IVNS1ABP Zornitza Stark Phenotypes for gene: IVNS1ABP were changed from Primary immunodeficiency to Immunodeficiency 70, MIM#618969
Mendeliome v0.3632 MAPK1 Zornitza Stark Marked gene: MAPK1 as ready
Mendeliome v0.3631 MAPK1 Zornitza Stark gene: MAPK1 was added
gene: MAPK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Literature
Mendeliome v0.3630 ASPM Zornitza Stark Marked gene: ASPM as ready
Mendeliome v0.3630 ASPM Zornitza Stark Phenotypes for gene: ASPM were changed from to Microcephaly 5, primary, autosomal recessive, MIM#608716
Mendeliome v0.3627 ASPM Elena Savva reviewed gene: ASPM: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:29243349; Phenotypes: Microcephaly 5, primary, autosomal recessive, 608716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3627 AMBRA1 Bryony Thompson Marked gene: AMBRA1 as ready
Mendeliome v0.3626 AMBRA1 Bryony Thompson gene: AMBRA1 was added
gene: AMBRA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMBRA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMBRA1 were set to 17589504; 32333458
Phenotypes for gene: AMBRA1 were set to Neural tube defects
Review for gene: AMBRA1 was set to GREEN
Added comment: 5 rare missense variants were identified in 6 cases from a neural tube defect cohort, and 4 (p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) of them were functionally validated to affect autophagy regulation in vitro or zebrafish embryo development in vivo. There is also null mouse model with neural tube defects.
Sources: Literature
Mendeliome v0.3624 ERLEC1 Bryony Thompson gene: ERLEC1 was added
gene: ERLEC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERLEC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERLEC1 were set to 32442352
Phenotypes for gene: ERLEC1 were set to Class III malocclusion
Review for gene: ERLEC1 was set to GREEN
Added comment: A heterozygous missense variant was found to co-segregate with dentofacial deformity in a multi-generational Chinese pedigree (2 unaffected carriers & 11 affected carriers), and 3 additional missense variants were identified in 3 unrelated cases from a sporadic malocclusion cohort. Additional functional assays were conducted to demonstrate that the proper level of ERLEC1 expression is crucial for proper osteogenic differentiation. All identified missense variants were assessed using luciferase reporter assays, and altered activity.
Sources: Literature
Mendeliome v0.3622 WDR1 Zornitza Stark Marked gene: WDR1 as ready
Mendeliome v0.3619 KREMEN1 Bryony Thompson Marked gene: KREMEN1 as ready
Mendeliome v0.3618 KREMEN1 Bryony Thompson gene: KREMEN1 was added
gene: KREMEN1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KREMEN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KREMEN1 were set to 27049303; 27550540
Phenotypes for gene: KREMEN1 were set to Ectodermal dysplasia 13, hair/tooth type MIM#617392
Review for gene: KREMEN1 was set to AMBER
Added comment: 4 consanguineous Palestinian families segregating the same homozygous missense (Phe209Ser) with disease phenotype which includes hair abnormalities. Possible founder variant. There are also animal model functional assays that suggest the gene is involved in hair development.
Sources: Expert list
Mendeliome v0.3617 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Impaired intestinal peristalsis; dysmorphic features to Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features
Mendeliome v0.3616 ANO1 Zornitza Stark Marked gene: ANO1 as ready
Mendeliome v0.3614 TUBB2A Zornitza Stark Marked gene: TUBB2A as ready
Mendeliome v0.3611 PMP22 Zornitza Stark Marked gene: PMP22 as ready
Mendeliome v0.3611 PMP22 Zornitza Stark Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1A, MIM# 118220; Charcot-Marie-Tooth disease, type 1E, MIM# 118300; Dejerine-Sottas disease, MIM# 145900; Neuropathy, recurrent, with pressure palsies 162500; Roussy-Levy syndrome 180800
Mendeliome v0.3608 PMP22 Zornitza Stark reviewed gene: PMP22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 1A, MIM# 118220, Charcot-Marie-Tooth disease, type 1E, MIM# 118300, Dejerine-Sottas disease, MIM# 145900, Neuropathy, recurrent, with pressure palsies 162500, Roussy-Levy syndrome 180800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3608 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Mendeliome v0.3608 OTX2 Zornitza Stark Phenotypes for gene: OTX2 were changed from to Microphthalmia, syndromic 5, MIM# 610125; Pituitary hormone deficiency, combined, 6, MIM# 613986; Retinal dystrophy, early-onset, with or without pituitary dysfunction, MIM# 610125
Mendeliome v0.3606 OTX2 Zornitza Stark reviewed gene: OTX2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, syndromic 5, MIM# 610125, Pituitary hormone deficiency, combined, 6, MIM# 613986, Retinal dystrophy, early-onset, with or without pituitary dysfunction, MIM# 610125; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3606 CDAN1 Zornitza Stark Marked gene: CDAN1 as ready
Mendeliome v0.3603 NGLY1 Zornitza Stark Marked gene: NGLY1 as ready
Mendeliome v0.3600 IMPG2 Zornitza Stark Phenotypes for gene: IMPG2 were changed from Retinitis pigmentosa 56, MIM#613581 to Retinitis pigmentosa 56, MIM#613581; Macular dystrophy, vitelliform, 5, MIM# 616152
Mendeliome v0.3598 IMPG2 Zornitza Stark Marked gene: IMPG2 as ready
Mendeliome v0.3595 GNPNAT1 Zornitza Stark Marked gene: GNPNAT1 as ready
Mendeliome v0.3593 EEF1A2 Zornitza Stark Marked gene: EEF1A2 as ready
Mendeliome v0.3593 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from to Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393
Mendeliome v0.3591 EEF1A2 Zornitza Stark Mode of pathogenicity for gene: EEF1A2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.3590 ANO1 Arina Puzriakova changed review comment from: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature; to: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Mendeliome v0.3590 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Mendeliome v0.3590 GNPNAT1 Arina Puzriakova changed review comment from: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature
Mendeliome v0.3590 GNPNAT1 Arina Puzriakova gene: GNPNAT1 was added
gene: GNPNAT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 32591345
Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia
Review for gene: GNPNAT1 was set to RED
Added comment: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Mendeliome v0.3590 EEF1A2 Eleanor Williams reviewed gene: EEF1A2: Rating: ; 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: 32160274; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.3590 PKD1L1 Zornitza Stark Marked gene: PKD1L1 as ready
Mendeliome v0.3586 IVNS1ABP Bryony Thompson gene: IVNS1ABP was added
gene: IVNS1ABP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IVNS1ABP were set to 32499645
Phenotypes for gene: IVNS1ABP were set to Primary immunodeficiency
Review for gene: IVNS1ABP was set to GREEN
Added comment: 3 unrelated families with putative loss of function variants. Case features and immunophenotyping of patient cells is suggestive of a combined immune deficiency, based on the ESID definitions of PID subtypes.
Sources: Literature
Mendeliome v0.3585 PTPN2 Bryony Thompson Marked gene: PTPN2 as ready
Mendeliome v0.3584 PTPN2 Bryony Thompson gene: PTPN2 was added
gene: PTPN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN2 were set to 32499645; 27658548
Phenotypes for gene: PTPN2 were set to Lupus; arthritis; common variable immunodeficiency
Review for gene: PTPN2 was set to AMBER
Added comment: A single family with a proband diagnosed with CVID and arthiritis (among other features) with an intronic expression quantitative trait loci (eQTL) rs2847297-G in trans with a stopgain variant. The stopgain variant was also identified in the proband's mother, who was diagnosed with lupus. A Ptpn2 deficient mouse model also demonstrates an autoimmune phenotype.
Sources: Literature
Mendeliome v0.3583 SOCS1 Bryony Thompson Marked gene: SOCS1 as ready
Mendeliome v0.3582 SOCS1 Bryony Thompson gene: SOCS1 was added
gene: SOCS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SOCS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOCS1 were set to 32499645; 10490099; 10490100
Phenotypes for gene: SOCS1 were set to Common variable immunodeficiency
Review for gene: SOCS1 was set to GREEN
Added comment: 2 unrelated families with truncating variants with supportive immunophenotyping of patient cells, and supporting null mouse models.
Sources: Literature
Mendeliome v0.3581 MRPS23 Zornitza Stark Phenotypes for gene: MRPS23 were changed from Hepatic disease; Combined respiratory chain complex deficienciesHepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities to Hepatic disease; Combined respiratory chain complex deficiencies; Hepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities; Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3580 MRPS23 Zornitza Stark edited their review of gene: MRPS23: Changed phenotypes: Hepatic disease, Combined respiratory chain complex deficiencies, Cardiomyopathy, Tubulopathy, Lactic acidosis, Structural brain abnormalities, Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3580 MRPL12 Zornitza Stark Phenotypes for gene: MRPL12 were changed from Growth retardation; neurological deterioration; mitochondrial translation deficiency to Growth retardation; neurological deterioration; mitochondrial translation deficiency; Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3579 MRPL12 Zornitza Stark edited their review of gene: MRPL12: Changed phenotypes: Growth retardation, neurological deterioration, mitochondrial translation deficiency, Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3578 OXCT1 Zornitza Stark Marked gene: OXCT1 as ready
Mendeliome v0.3575 KCNJ1 Zornitza Stark Marked gene: KCNJ1 as ready
Mendeliome v0.3575 KCNJ1 Zornitza Stark Phenotypes for gene: KCNJ1 were changed from to Bartter syndrome, type 2, 241200
Mendeliome v0.3572 ZFYVE27 Zornitza Stark Marked gene: ZFYVE27 as ready
Mendeliome v0.3572 ZFYVE27 Zornitza Stark Phenotypes for gene: ZFYVE27 were changed from to Spastic paraplegia 33, autosomal dominant MIM#610244
Mendeliome v0.3569 KLF10 Zornitza Stark Marked gene: KLF10 as ready
Mendeliome v0.3568 MYOZ2 Zornitza Stark Marked gene: MYOZ2 as ready
Mendeliome v0.3568 MYOZ2 Zornitza Stark Phenotypes for gene: MYOZ2 were changed from to Cardiomyopathy, hypertrophic, 16 MIM#613838
Mendeliome v0.3564 TRIM63 Zornitza Stark Marked gene: TRIM63 as ready
Mendeliome v0.3564 TRIM63 Zornitza Stark Added comment: Comment when marking as ready: Large case series published subsequent to ClinGen assessment.
Mendeliome v0.3563 PDLIM3 Zornitza Stark Marked gene: PDLIM3 as ready
Mendeliome v0.3562 OBSCN Zornitza Stark Marked gene: OBSCN as ready
Mendeliome v0.3561 OBSCN Paul De Fazio gene: OBSCN was added
gene: OBSCN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OBSCN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: OBSCN were set to 30681346; 26573135; 17716621; 25173926; 28630914
Phenotypes for gene: OBSCN were set to Hypertrophic cardiomyopathy
Review for gene: OBSCN was set to RED
gene: OBSCN was marked as current diagnostic
Added comment: Limited evidence by ClinGen working group.

Via ClinGen: 8 probands in 3 publications but only 3 probands from 1 publication were though to have pathogenic variants (others were excluded based on population frequency and expert review).

No additional case reports were found. A mouse model lends some support to the association of this gene with heart disease although not HCM specifically.
Sources: Literature
Mendeliome v0.3561 PDLIM3 Ain Roesley gene: PDLIM3 was added
gene: PDLIM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDLIM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PDLIM3 were set to 30681346; 26455666; 20801532
Phenotypes for gene: PDLIM3 were set to Hypertrophic cardiomyopathy
Penetrance for gene: PDLIM3 were set to unknown
Added comment: PMID: 30681346;
LIMITED by ClinGen working group

PMID: 26455666;
1x proband with multi-exon deletion

PMID: 20801532;
1x proband het for a missense
Sources: Literature
Mendeliome v0.3561 TRIM63 Ain Roesley gene: TRIM63 was added
gene: TRIM63 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM63 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM63 were set to 30681346; 32451364
Phenotypes for gene: TRIM63 were set to Hypertrophic cardiomyopathy
Penetrance for gene: TRIM63 were set to unknown
Review for gene: TRIM63 was set to GREEN
Added comment: PMID: 30681346;
LIMITED by Clingen working group (last evaluated 2018)

PMID: 32451364
- 16 index cases with rare homozygous or compound heterozygous variants (15 HCM and one restrictive cardiomyopathy). None of these variants have homozygote counts in gnomAD.
- segregated in 3 families
- 1 index had another pathogenic truncating variant in MYBPC3
- 5 missense and 3 PTCs
- Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy
Sources: Literature
Mendeliome v0.3561 MYOZ2 Paul De Fazio reviewed gene: MYOZ2: Rating: RED; Mode of pathogenicity: None; Publications: 17347475, 18591919, 28296734, 30681346, 22987565; Phenotypes: Cardiomyopathy, hypertrophic, 16 MIM#613838; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.3561 KLF10 Paul De Fazio gene: KLF10 was added
gene: KLF10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLF10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KLF10 were set to 22234868
Phenotypes for gene: KLF10 were set to HCM
gene: KLF10 was marked as current diagnostic
Added comment: Curated by ClinGen and rated as limited evidence.

Misssense mutations reported in six unrelated individuals patients (two males/four females), with family history of HCM only reported for one individual (PMID: 22234868). No further reports in the literature.
Sources: Literature
Mendeliome v0.3561 KCNJ1 Elena Savva reviewed gene: KCNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28630040; Phenotypes: Bartter syndrome, type 2, 241200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3561 KRT71 Bryony Thompson Marked gene: KRT71 as ready
Mendeliome v0.3560 KRT71 Bryony Thompson gene: KRT71 was added
gene: KRT71 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KRT71 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT71 were set to 14632181; 22592156; 19713490
Phenotypes for gene: KRT71 were set to ?Hypotrichosis 13, 615896
Review for gene: KRT71 was set to AMBER
Added comment: A single family with 3 affected members of a 3-generation Japanese family segregating a missense variant (F141C) with autosomal dominant woolly hair/hypotrichosis, with supporting functional assays and animal models.
Sources: Literature
Mendeliome v0.3559 ACADL Zornitza Stark Marked gene: ACADL as ready
Mendeliome v0.3559 ACADL Zornitza Stark Phenotypes for gene: ACADL were changed from to Pulmonary surfactant dysfunction
Mendeliome v0.3555 ACADL Zornitza Stark reviewed gene: ACADL: Rating: RED; Mode of pathogenicity: None; Publications: 24591516, 31399326; Phenotypes: Pulmonary surfactant dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3555 TWNK Zornitza Stark Marked gene: TWNK as ready
Mendeliome v0.3550 P2RX2 Zornitza Stark Marked gene: P2RX2 as ready
Mendeliome v0.3547 KCNQ4 Zornitza Stark Marked gene: KCNQ4 as ready
Mendeliome v0.3544 FLCN Zornitza Stark Marked gene: FLCN as ready
Mendeliome v0.3544 FLCN Zornitza Stark Phenotypes for gene: FLCN were changed from to Birt-Hogg-Dube syndrome (MIM#135150); Pneumothorax, primary spontaneous (MIM#173600)
Mendeliome v0.3541 FLCN Crystle Lee reviewed gene: FLCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17124507, 30586397, 31625278; Phenotypes: Birt-Hogg-Dube syndrome (MIM#135150), Pneumothorax, primary spontaneous (MIM#173600); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3541 LARS Zornitza Stark Publications for gene: LARS were set to 28774368; 30349989; 22607940
Mendeliome v0.3540 LARS Zornitza Stark edited their review of gene: LARS: Changed publications: 28774368, 30349989, 22607940, 32699352
Mendeliome v0.3540 LARS Zornitza Stark Phenotypes for gene: LARS were changed from Infantile liver failure syndrome 1, MIM# 615438 to Infantile liver failure syndrome 1, MIM# 615438; Seizures; Intellectual disability; Encephalopathy
Mendeliome v0.3539 LARS Zornitza Stark Marked gene: LARS as ready
Mendeliome v0.3539 LARS Zornitza Stark Added comment: Comment when marking as ready: Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Mendeliome v0.3539 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.3539 LARS Zornitza Stark Tag new gene name tag was added to gene: LARS.
Mendeliome v0.3539 KERA Zornitza Stark Marked gene: KERA as ready
Mendeliome v0.3536 CTRC Zornitza Stark Marked gene: CTRC as ready
Mendeliome v0.3532 CPA1 Zornitza Stark Marked gene: CPA1 as ready
Mendeliome v0.3532 CPA1 Zornitza Stark Phenotypes for gene: CPA1 were changed from to Susceptibility to chronic pancreatitis; Hereditary pancreatitis
Mendeliome v0.3529 CPA1 Zornitza Stark reviewed gene: CPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23955596, 28497564, 28258133, 31005883; Phenotypes: Susceptibility to chronic pancreatitis, Hereditary pancreatitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3529 CLDN2 Zornitza Stark Marked gene: CLDN2 as ready
Mendeliome v0.3525 BMP10 Zornitza Stark Marked gene: BMP10 as ready
Mendeliome v0.3524 BMP10 Zornitza Stark gene: BMP10 was added
gene: BMP10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BMP10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP10 were set to 30578383
Phenotypes for gene: BMP10 were set to Pulmonary arterial hypertension
Review for gene: BMP10 was set to AMBER
Added comment: A truncating mutation and a predicted loss-of-function missense variant were identified in BMP10 in two severely affected sporadic PAH female patients.
Sources: Expert list
Mendeliome v0.3523 SMAD1 Zornitza Stark Marked gene: SMAD1 as ready
Mendeliome v0.3522 SMAD1 Zornitza Stark gene: SMAD1 was added
gene: SMAD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SMAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD1 were set to 21898662; 23478097
Phenotypes for gene: SMAD1 were set to Pulmonary arterial hypertension
Review for gene: SMAD1 was set to AMBER
Added comment: One missense variant identified in a PAH case. Mouse model is consistent with pulmonary hypertension.
Sources: Expert list
Mendeliome v0.3521 BRAP Zornitza Stark Marked gene: BRAP as ready
Mendeliome v0.3521 BRAP Zornitza Stark gene: BRAP was added
gene: BRAP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAP were set to 30703135
Phenotypes for gene: BRAP were set to Pulmonary arterial hypertension
Review for gene: BRAP was set to RED
Added comment: A single BRAP missense variant in a Japanese family with PAH, with in vitro functional assays suggesting a gain-of-function.
Sources: Expert list
Mendeliome v0.3520 KLF2 Zornitza Stark Marked gene: KLF2 as ready
Mendeliome v0.3520 KLF2 Zornitza Stark gene: KLF2 was added
gene: KLF2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KLF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLF2 were set to 28188237
Phenotypes for gene: KLF2 were set to Pulmonary arterial hypertension
Review for gene: KLF2 was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.3519 ATP13A3 Zornitza Stark Marked gene: ATP13A3 as ready
Mendeliome v0.3518 ATP13A3 Zornitza Stark gene: ATP13A3 was added
gene: ATP13A3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP13A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP13A3 were set to 31798832; 30679663; 29650961
Phenotypes for gene: ATP13A3 were set to Pulmonary arterial hypertension
Review for gene: ATP13A3 was set to GREEN
Added comment: Three heterozygous frameshift variants, three stop gained, two splice region variants in ATP13A3, which are predicted to lead to loss of ATPase catalytic activity identified in idiopathic/familial PAH cases. Also one case with putative recessive inheritance reported. ATP13A3 mRNA expression is confirmed in primary PASMCs and endothelial cells where its loss hindered proliferation and enhanced apoptosis of endothelial cells, which is known as the initiation event of PAH.
Sources: Expert list
Mendeliome v0.3517 SMARCA2 Zornitza Stark Marked gene: SMARCA2 as ready
Mendeliome v0.3517 SMARCA2 Zornitza Stark Gene: smarca2 has been classified as Green List (High Evidence).
Mendeliome v0.3517 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome
Mendeliome v0.3516 SMARCA2 Zornitza Stark Publications for gene: SMARCA2 were set to
Mendeliome v0.3515 SMARCA2 Zornitza Stark Mode of pathogenicity for gene: SMARCA2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.3514 SMARCA2 Zornitza Stark Mode of inheritance for gene: SMARCA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3513 SMARCA2 Zornitza Stark reviewed gene: SMARCA2: 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: 26468571, 32694869; Phenotypes: Nicolaides-Baraitser syndrome, MIM #601358, Blepharophimosis-intellectual disability syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3513 MORC2 Zornitza Stark Marked gene: MORC2 as ready
Mendeliome v0.3513 MORC2 Zornitza Stark Phenotypes for gene: MORC2 were changed from to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688; Intellectual disability
Mendeliome v0.3510 MORC2 Zornitza Stark reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025, 26497905, 26659848; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2Z, MIM# 616688, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3510 DBT Zornitza Stark Marked gene: DBT as ready
Mendeliome v0.3507 PLCB3 Zornitza Stark Marked gene: PLCB3 as ready
Mendeliome v0.3506 ACOX1 Zornitza Stark Marked gene: ACOX1 as ready
Mendeliome v0.3502 MPL Zornitza Stark Marked gene: MPL as ready
Mendeliome v0.3502 MPL Zornitza Stark Phenotypes for gene: MPL were changed from to Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR
Mendeliome v0.3499 SH2B3 Zornitza Stark Marked gene: SH2B3 as ready
Mendeliome v0.3496 SH2B3 Zornitza Stark changed review comment from: Germline variants reported in association with increased risk for haematological malignancies.; to: Germline variants reported in association with increased risk for haematological malignancies.
Mendeliome v0.3496 MPL Chern Lim reviewed gene: MPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28955303, 26423830; Phenotypes: Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503, Thrombocythemia 2, MIM#601977, AD, SMu, Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3496 HPD Zornitza Stark Marked gene: HPD as ready
Mendeliome v0.3496 HPD Zornitza Stark Phenotypes for gene: HPD were changed from to Hawkinsinuria (MIM#140350), AD; Tyrosinemia type III (MIM#276710), AR
Mendeliome v0.3493 HPD Zornitza Stark reviewed gene: HPD: Rating: GREEN; Mode of pathogenicity: None; Publications: 10942115, 17560158; Phenotypes: Hawkinsinuria (MIM#140350), AD, Tyrosinemia type III (MIM#276710), AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3493 FANCM Zornitza Stark Marked gene: FANCM as ready
Mendeliome v0.3489 HDAC8 Zornitza Stark Marked gene: HDAC8 as ready
Mendeliome v0.3486 RBM8A Zornitza Stark Marked gene: RBM8A as ready
Mendeliome v0.3484 RPL15 Zornitza Stark Marked gene: RPL15 as ready
Mendeliome v0.3481 RPS28 Zornitza Stark Marked gene: RPS28 as ready
Mendeliome v0.3477 RPS29 Zornitza Stark Marked gene: RPS29 as ready
Mendeliome v0.3472 REN Zornitza Stark Marked gene: REN as ready
Mendeliome v0.3472 REN Zornitza Stark Phenotypes for gene: REN were changed from to Renal tubular dysgenesis, MIM# 267430; Autosomal dominant tubulointerstitial disease
Mendeliome v0.3469 REN Zornitza Stark reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 31586593, 31406136, 28701203, 21473025; Phenotypes: Renal tubular dysgenesis, MIM# 267430, Autosomal dominant tubulointerstitial disease; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3469 MDH1 Zornitza Stark Phenotypes for gene: MDH1 were changed from epilepsy; microcephaly; intellectual disability to epilepsy; microcephaly; intellectual disability; Epileptic encephalopathy, early infantile, 88, MIM#618959Epileptic encephalopathy, early infantile, 88, MIM#618959
Mendeliome v0.3468 MDH1 Zornitza Stark edited their review of gene: MDH1: Changed phenotypes: epilepsy, microcephaly, intellectual disability, Epileptic encephalopathy, early infantile, 88, MIM#618959
Mendeliome v0.3467 UVSSA Zornitza Stark Marked gene: UVSSA as ready
Mendeliome v0.3464 SEC23A Zornitza Stark Marked gene: SEC23A as ready
Mendeliome v0.3460 DACT1 Zornitza Stark Marked gene: DACT1 as ready
Mendeliome v0.3458 VPS33A Zornitza Stark Marked gene: VPS33A as ready
Mendeliome v0.3458 VPS33A Zornitza Stark Phenotypes for gene: VPS33A were changed from to Mucopolysaccharidosis-plus syndrome (MIM#617303)
Mendeliome v0.3454 VPS33A Zornitza Stark reviewed gene: VPS33A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28013294, 27547915; Phenotypes: Mucopolysaccharidosis-plus syndrome (MIM#617303); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3454 COG2 Zornitza Stark Marked gene: COG2 as ready
Mendeliome v0.3450 DACT1 Natalie Tan gene: DACT1 was added
gene: DACT1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: DACT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DACT1 were set to PMID: 28054444; 22610794; 19701191
Phenotypes for gene: DACT1 were set to ?Townes-Brocks syndrome 2 (OMIM #617466)
Review for gene: DACT1 was set to RED
Added comment: Webb et al. (2017) reported 6 affected members of a 3-generation family with ?Townes-Brocks syndrome-2, identified heterozygosity for a nonsense mutation in the DACT1 gene that segregated with disease. Clinical features include imperforate anus, rectovaginal fistula, crossed fused renal ectopia, vesicoureteral reflux, unilateral microtia, overfolded helices and cupped ears. One family member (proband's mother) with scoliosis and spina bifida occulta. Neural tube defects reported in a study of human fetuses (PMID: 22610794) and a mouse model (PMID: 19701191). Listed in Decipher v10.0 for an individual with abnormalities of (i) head or neck (ii) nervous system (iii) skeletal system. Unlike the gene SALL1 that causes Townes-Brocks syndrome 1, there is no information specifically relating to DACT1 with radial dysplasia, as these were not observed in the family with ?Townes-Brocks syndrome 2 (PMID: 28054444).
Sources: NHS GMS
Mendeliome v0.3450 G6PC3 Zornitza Stark Marked gene: G6PC3 as ready
Mendeliome v0.3447 POGLUT1 Zornitza Stark Marked gene: POGLUT1 as ready
Mendeliome v0.3447 POGLUT1 Zornitza Stark Phenotypes for gene: POGLUT1 were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 21 (MIM# 617232), Dowling-Degos disease 4 (MIM# 615696)
Mendeliome v0.3444 POGLUT1 Ain Roesley reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807076, 24387993; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 21 (MIM# 617232), Dowling-Degos disease 4 (MIM# 615696); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3444 ARSG Zornitza Stark Marked gene: ARSG as ready
Mendeliome v0.3444 ARSG Zornitza Stark Added comment: Comment when marking as ready: Additional family reported with a different variant, upgrade to Amber.
Mendeliome v0.3444 ARSG Zornitza Stark Gene: arsg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3444 ARSG Zornitza Stark Publications for gene: ARSG were set to 29300381; 20679209; 25452429; 26975023
Mendeliome v0.3443 ARSG Zornitza Stark Classified gene: ARSG as Amber List (moderate evidence)
Mendeliome v0.3443 ARSG Zornitza Stark Gene: arsg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3442 ARSG Zornitza Stark Tag founder tag was added to gene: ARSG.
Mendeliome v0.3442 ARSG Elena Savva reviewed gene: ARSG: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29300381, 20679209, 25452429, 26975023, 32455177; Phenotypes: Usher syndrome, type IV, MIM# 618144; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3441 FAM92A Zornitza Stark Marked gene: FAM92A as ready
Mendeliome v0.3439 KIAA0825 Zornitza Stark Marked gene: KIAA0825 as ready
Mendeliome v0.3437 ZNF141 Zornitza Stark Marked gene: ZNF141 as ready
Mendeliome v0.3433 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Mendeliome v0.3433 NR0B1 Zornitza Stark Added comment: Comment when marking as ready: Note 46XY reversal disorder is only associated with duplications.
Mendeliome v0.3430 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Mendeliome v0.3427 NSDHL Zornitza Stark Marked gene: NSDHL as ready
Mendeliome v0.3423 TFR2 Zornitza Stark Marked gene: TFR2 as ready
Mendeliome v0.3419 ABCD3 Zornitza Stark Marked gene: ABCD3 as ready
Mendeliome v0.3413 TBC1D32 Zornitza Stark changed review comment from: Three families reported, but phenotypes are broad, some suggestive of ciliopathy.; to: Three families reported now, but phenotypes are broad, some suggestive of ciliopathy.
Mendeliome v0.3413 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: Three families reported, but phenotypes are broad, some suggestive of ciliopathy.; Changed rating: AMBER; Changed publications: 24285566, 32573025, 32060556; Changed phenotypes: Orofaciodigital syndrome type IX, syndromic hypopituitarism
Mendeliome v0.3413 ORMDL3 Zornitza Stark Marked gene: ORMDL3 as ready
Mendeliome v0.3412 NSMF Zornitza Stark Marked gene: NSMF as ready
Mendeliome v0.3408 SPRY4 Zornitza Stark Marked gene: SPRY4 as ready
Mendeliome v0.3404 KISS1 Zornitza Stark Marked gene: KISS1 as ready
Mendeliome v0.3400 INSL3 Zornitza Stark Marked gene: INSL3 as ready
Mendeliome v0.3396 IL17RD Zornitza Stark Marked gene: IL17RD as ready
Mendeliome v0.3391 HS6ST1 Zornitza Stark Marked gene: HS6ST1 as ready
Mendeliome v0.3387 GNRH1 Zornitza Stark Marked gene: GNRH1 as ready
Mendeliome v0.3383 CUX2 Zornitza Stark Marked gene: CUX2 as ready
Mendeliome v0.3383 CUX2 Zornitza Stark Added comment: Comment when marking as ready: At least 10 individuals reported with same recurrent de novo missense variant.
Mendeliome v0.3383 CUX2 Zornitza Stark Phenotypes for gene: CUX2 were changed from to Epileptic encephalopathy, early infantile, 67, MIM#618141
Mendeliome v0.3380 DPM1 Zornitza Stark Marked gene: DPM1 as ready
Mendeliome v0.3377 CUX2 Elena Savva reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 2963073, 29795476; Phenotypes: Epileptic encephalopathy, early infantile, 67, 618141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3377 GIPC1 Zornitza Stark Marked gene: GIPC1 as ready
Mendeliome v0.3376 GIPC1 Zornitza Stark gene: GIPC1 was added
gene: GIPC1 was added to Mendeliome. Sources: Literature
5'UTR, STR tags were added to gene: GIPC1.
Mode of inheritance for gene: GIPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIPC1 were set to 32413282
Phenotypes for gene: GIPC1 were set to Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940
Review for gene: GIPC1 was set to AMBER
Added comment: 19 families reported with heterozygous trinucleotide repeat expansion in the 5-prime untranslated region and onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. Note this is unlikely to be tractable currently by most NGS assays.
Sources: Literature
Mendeliome v0.3375 SMC3 Zornitza Stark Marked gene: SMC3 as ready
Mendeliome v0.3372 DEAF1 Zornitza Stark Marked gene: DEAF1 as ready
Mendeliome v0.3366 ABCC9 Zornitza Stark Marked gene: ABCC9 as ready
Mendeliome v0.3366 ABCC9 Zornitza Stark Phenotypes for gene: ABCC9 were changed from to Hypertrichotic osteochondrodysplasia, MIM# 239850; Cantu syndrome; mild ID, similar facies, myopathy, cerebral white matter hyperintensities; cardiac systolic dysfunction
Mendeliome v0.3363 ABCC9 Zornitza Stark reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31575858, 22610116, 22608503; Phenotypes: Hypertrichotic osteochondrodysplasia, MIM# 239850, Cantu syndrome, mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3363 TSPYL1 Zornitza Stark Marked gene: TSPYL1 as ready
Mendeliome v0.3359 PIGM Zornitza Stark Marked gene: PIGM as ready
Mendeliome v0.3359 PIGM Zornitza Stark Phenotypes for gene: PIGM were changed from to Glycosylphosphatidylinositol deficiency, MIM# 610293; portal vein thrombosis; persistent absence seizures; macrocephaly; infantile-onset cerebrovascular thrombotic events
Mendeliome v0.3355 LEP Zornitza Stark Marked gene: LEP as ready
Mendeliome v0.3352 LEPR Zornitza Stark Marked gene: LEPR as ready
Mendeliome v0.3349 FEZF1 Zornitza Stark Marked gene: FEZF1 as ready
Mendeliome v0.3345 ESR2 Zornitza Stark Marked gene: ESR2 as ready
Mendeliome v0.3345 ESR2 Zornitza Stark Phenotypes for gene: ESR2 were changed from to 46,XY disorder of sex development; Ovarian dysgenesis 8, MIM# 618187
Mendeliome v0.3342 ESR2 Zornitza Stark reviewed gene: ESR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29261182, 9861029, 30113650; Phenotypes: 46,XY disorder of sex development, Ovarian dysgenesis 8, MIM# 618187; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3342 PIGM Paul De Fazio reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: None; Publications: 31445883, 16767100; Phenotypes: portal vein thrombosis, persistent absence seizures, macrocephaly, infantile-onset cerebrovascular thrombotic events; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3342 DMRT1 Zornitza Stark Marked gene: DMRT1 as ready
Mendeliome v0.3338 CBX2 Zornitza Stark Marked gene: CBX2 as ready
Mendeliome v0.3334 MCM5 Zornitza Stark Marked gene: MCM5 as ready
Mendeliome v0.3332 ATF3 Zornitza Stark Marked gene: ATF3 as ready
Mendeliome v0.3331 MCM5 Crystle Lee gene: MCM5 was added
gene: MCM5 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MCM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM5 were set to 28198391
Phenotypes for gene: MCM5 were set to ?Meier-Gorlin syndrome 8 (MIM#617564)
Review for gene: MCM5 was set to RED
Added comment: Compound heterozgyous variants reported in one patient. Insufficient evidence supporting gene disease association
Sources: Expert Review
Mendeliome v0.3331 CNPY3 Zornitza Stark Marked gene: CNPY3 as ready
Mendeliome v0.3331 CNPY3 Zornitza Stark Phenotypes for gene: CNPY3 were changed from to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Mendeliome v0.3328 CNPY3 Zornitza Stark reviewed gene: CNPY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29394991, 30237576; Phenotypes: Epileptic encephalopathy, early infantile, 60 (MIM 617929); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3328 KIF21B Zornitza Stark Marked gene: KIF21B as ready
Mendeliome v0.3327 KIF21B Zornitza Stark gene: KIF21B was added
gene: KIF21B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Mode of pathogenicity for gene: KIF21B 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: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Expert Review
Mendeliome v0.3326 TBC1D2B Zornitza Stark Marked gene: TBC1D2B as ready
Mendeliome v0.3325 TBC1D2B Zornitza Stark gene: TBC1D2B was added
gene: TBC1D2B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Review for gene: TBC1D2B was set to GREEN
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants. Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations. All were born to non-consanguineous couples and additional investigations were performed in some. Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses. In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts. TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation. Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.
Sources: Expert Review
Mendeliome v0.3324 EXOC2 Zornitza Stark Marked gene: EXOC2 as ready
Mendeliome v0.3323 EXOC2 Zornitza Stark gene: EXOC2 was added
gene: EXOC2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC2 were set to 32639540
Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Review for gene: EXOC2 was set to AMBER
Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations. Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3). Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals. EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis. Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration. An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2. Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome). The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants).
Sources: Expert Review
Mendeliome v0.3322 CCDC174 Zornitza Stark Marked gene: CCDC174 as ready
Mendeliome v0.3321 CCDC174 Zornitza Stark gene: CCDC174 was added
gene: CCDC174 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816). Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype. Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Expert Review
Mendeliome v0.3319 ABCA2 Zornitza Stark Marked gene: ABCA2 as ready
Mendeliome v0.3318 ABCA2 Zornitza Stark gene: ABCA2 was added
gene: ABCA2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808). There are 3 relevant publications (01-07-2020) : - Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations. - Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures. - Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype. All subjects harbored biallelic pLoF variants. N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency. Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Expert Review
Mendeliome v0.3317 HERC2 Zornitza Stark Marked gene: HERC2 as ready
Mendeliome v0.3317 HERC2 Zornitza Stark Phenotypes for gene: HERC2 were changed from to Mental retardation, autosomal recessive 38 (MIM 615516)
Mendeliome v0.3314 HERC2 Zornitza Stark reviewed gene: HERC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030; Phenotypes: Mental retardation, autosomal recessive 38 (MIM 615516); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3314 ALOX12 Zornitza Stark Marked gene: ALOX12 as ready
Mendeliome v0.3313 ETF1 Zornitza Stark Marked gene: ETF1 as ready
Mendeliome v0.3309 SGMS2 Bryony Thompson Marked gene: SGMS2 as ready
Mendeliome v0.3308 SGMS2 Bryony Thompson gene: SGMS2 was added
gene: SGMS2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGMS2 were set to 30779713; 32028018
Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550
Review for gene: SGMS2 was set to GREEN
Added comment: 12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments. 2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum.
Sources: Expert list
Mendeliome v0.3307 AKR1C4 Zornitza Stark Marked gene: AKR1C4 as ready
Mendeliome v0.3303 PIP5K1C Zornitza Stark Marked gene: PIP5K1C as ready
Mendeliome v0.3299 ERBB3 Zornitza Stark Marked gene: ERBB3 as ready
Mendeliome v0.3295 DPM2 Zornitza Stark Marked gene: DPM2 as ready
Mendeliome v0.3290 DYSF Zornitza Stark Marked gene: DYSF as ready
Mendeliome v0.3290 DYSF Zornitza Stark Phenotypes for gene: DYSF were changed from to Miyoshi muscular dystrophy 1 254130; Muscular dystrophy, limb-girdle, autosomal recessive 2 253601; Myopathy, distal, with anterior tibial onset 606768
Mendeliome v0.3287 NEB Zornitza Stark Marked gene: NEB as ready
Mendeliome v0.3284 MRPS34 Zornitza Stark Marked gene: MRPS34 as ready
Mendeliome v0.3281 DYSF Elena Savva reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27602406; Phenotypes: Miyoshi muscular dystrophy 1 254130, Muscular dystrophy, limb-girdle, autosomal recessive 2 253601, Myopathy, distal, with anterior tibial onset 606768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3281 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412; Cataract
Mendeliome v0.3278 GLS Zornitza Stark edited their review of gene: GLS: Added comment: In addition, single individual also reported with de novo, GoF variant with profound ID, cataract.; Changed publications: 30575854, 30970188, 30239721
Mendeliome v0.3278 GLS Zornitza Stark edited their review of gene: GLS: Changed phenotypes: Epileptic encephalopathy, early infantile, 71, MIM# 618328, Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412, Catarct; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3278 PYCR1 Dean Phelan changed review comment from: Aortopathy/Connective tissue review

Variants in this gene are associated with Cutis Laxa:
Cutis laxa type 2 (ARCL2, [MIM 219200]) is an autosomal-recessive multisystem disorder with prominent connective-tissue features characterized by the appearance of premature aging, particularly wrinkled and lax skin with reduced elasticity.

GEL PanelApp: Green in EDS panel - clinical features overlapping EDS
Cutis laxa, autosomal recessive, type IIIB (ARCL3B) PMID: 19648921,4076251, 22052856
Cutis laxa, autosomal recessive, type IIB (ARCL2B) PMID: 19576563, 19648921, 9648921, 22052856, 28294978 AR

PMID: 27756598: a homozygous mutation in PYCR1 segregating in the family with the affected individuals with complex connective tissue disorder and severe intellectual disability.; to: Aortopathy/Connective tissue review

Variants in this gene are associated with Cutis Laxa:
Cutis laxa type 2 (ARCL2, [MIM 219200]) is an autosomal-recessive multisystem disorder with prominent connective-tissue features characterized by the appearance of premature aging, particularly wrinkled and lax skin with reduced elasticity.

GEL PanelApp: Green in EDS panel - clinical features overlapping EDS
Cutis laxa, autosomal recessive, type IIIB (ARCL3B) PMID: 19648921,4076251, 22052856
Cutis laxa, autosomal recessive, type IIB (ARCL2B) PMID: 19576563, 19648921, 9648921, 22052856, 28294978 AR

PMID: 27756598: a homozygous mutation in PYCR1 segregating in the family with the affected individuals with complex connective tissue disorder and severe intellectual disability.
Mendeliome v0.3278 PYCR1 Seb Lunke Marked gene: PYCR1 as ready
Mendeliome v0.3275 PIGY Zornitza Stark Marked gene: PIGY as ready
Mendeliome v0.3275 PIGY Zornitza Stark Phenotypes for gene: PIGY were changed from to Hyperphosphatasia with mental retardation syndrome 6, MIM# 616809
Mendeliome v0.3271 MTMR14 Zornitza Stark Marked gene: MTMR14 as ready
Mendeliome v0.3271 MTMR14 Zornitza Stark Added comment: Comment when marking as ready: Single family and animal models; postulated to be a modifier in the other family.
Mendeliome v0.3270 MTMR14 Zornitza Stark Marked gene: MTMR14 as ready
Mendeliome v0.3270 MTMR14 Zornitza Stark Added comment: Comment when marking as ready: Postulated to be a modifier.
Mendeliome v0.3268 P4HA1 Zornitza Stark Marked gene: P4HA1 as ready
Mendeliome v0.3267 PIGY Elena Savva reviewed gene: PIGY: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26293662; Phenotypes: Hyperphosphatasia with mental retardation syndrome 6, MIM# 616809; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3267 GGPS1 Zornitza Stark Marked gene: GGPS1 as ready
Mendeliome v0.3266 GGPS1 Zornitza Stark gene: GGPS1 was added
gene: GGPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy; Deafness; Ovarian insufficiency
Review for gene: GGPS1 was set to GREEN
Added comment: 11 individuals from 6 unrelated families reported. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. Knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality.
Sources: Literature
Mendeliome v0.3265 MTMR14 Elena Savva reviewed gene: MTMR14: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 20400459, 20817957, 19465920, 17008356; Phenotypes: {Centronuclear myopathy, autosomal, modifier of}, MIM# 160150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3265 DNMBP Seb Lunke Marked gene: DNMBP as ready
Mendeliome v0.3264 DNMBP Seb Lunke gene: DNMBP was added
gene: DNMBP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNMBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNMBP were set to 30290152
Phenotypes for gene: DNMBP were set to congenital cataract
Review for gene: DNMBP was set to GREEN
gene: DNMBP was marked as current diagnostic
Added comment: Multiple individuals from three independent large consanguineous families with bilateral infantile cataracts. Seperate hom nonsense variants.
Sources: Literature
Mendeliome v0.3263 CRYGA Zornitza Stark Marked gene: CRYGA as ready
Mendeliome v0.3263 CRYGA Zornitza Stark gene: CRYGA was added
gene: CRYGA was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: CRYGA.
Mode of inheritance for gene: CRYGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRYGA were set to 30450742; 28839118
Phenotypes for gene: CRYGA were set to Cataract
Review for gene: CRYGA was set to RED
Added comment: Reported as potentially disease causing in multiple individuals from two seperate families, but in both cases variant is present in the general population (20 Hets for one variant, >1000 hets and 9 homs in other variant)
Sources: Expert list
Mendeliome v0.3262 AKR1E2 Zornitza Stark Marked gene: AKR1E2 as ready
Mendeliome v0.3262 AKR1E2 Zornitza Stark gene: AKR1E2 was added
gene: AKR1E2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: AKR1E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKR1E2 were set to 26622071
Phenotypes for gene: AKR1E2 were set to congenital cataracts
Review for gene: AKR1E2 was set to RED
Added comment: Same family with homozygous canonical splice variants and 3 cases of congenital cataract described in 2012 (original) and 2015 (review). No other descriptions since.
Sources: Expert list
Mendeliome v0.3261 ADAMTSL4 Zornitza Stark Marked gene: ADAMTSL4 as ready
Mendeliome v0.3258 HIST1H4C Zornitza Stark Marked gene: HIST1H4C as ready
Mendeliome v0.3255 SFTPA1 Zornitza Stark Marked gene: SFTPA1 as ready
Mendeliome v0.3255 SFTPA1 Zornitza Stark Phenotypes for gene: SFTPA1 were changed from to Idiopathic pulmonary fibrosis
Mendeliome v0.3251 SFTPA1 Zornitza Stark reviewed gene: SFTPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31601679, 30854216, 28869238, 26792177; Phenotypes: Idiopathic pulmonary fibrosis; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3251 CFAP74 Zornitza Stark Marked gene: CFAP74 as ready
Mendeliome v0.3250 CFAP74 Zornitza Stark gene: CFAP74 was added
gene: CFAP74 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP74 were set to 32555313
Phenotypes for gene: CFAP74 were set to Primary ciliary dyskinesia; infertility
Review for gene: CFAP74 was set to AMBER
Added comment: Two unrelated individuals with compound het missense variants reported.
Sources: Literature
Mendeliome v0.3249 ASPRV1 Zornitza Stark Marked gene: ASPRV1 as ready
Mendeliome v0.3248 ASPRV1 Ee Ming Wong gene: ASPRV1 was added
gene: ASPRV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASPRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASPRV1 were set to PMID: 32516568
Phenotypes for gene: ASPRV1 were set to palmoplantar keratoderma; lamellar ichthyosis
Review for gene: ASPRV1 was set to GREEN
gene: ASPRV1 was marked as current diagnostic
Added comment: -3 heterozygous missense variants identified across 4 unrelated kindreds
-mutant ASPRV1 expressed in human keratinocytes suggests impaired filaggrin processing
Sources: Literature
Mendeliome v0.3248 LGR4 Zornitza Stark Marked gene: LGR4 as ready
Mendeliome v0.3246 SREBF1 Seb Lunke Marked gene: SREBF1 as ready
Mendeliome v0.3245 BTG4 Seb Lunke Marked gene: BTG4 as ready
Mendeliome v0.3244 TRIP13 Seb Lunke Marked gene: TRIP13 as ready
Mendeliome v0.3242 SREBF1 Paul De Fazio gene: SREBF1 was added
gene: SREBF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SREBF1 were set to 32497488
Phenotypes for gene: SREBF1 were set to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome
Review for gene: SREBF1 was set to GREEN
gene: SREBF1 was marked as current diagnostic
Added comment: 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. 3 different msisense variants identified affecting the same region (residues 527, 528, and 530). Functional studies support impaired function (impaired nuclear translocation of the transcriptionally active form of SREBP1 resulting in lower expression of the SREBP1 variants). Increased keratinocyte apoptosis was observed in patient scalp samples.
Sources: Literature
Mendeliome v0.3242 RAP1GDS1 Zornitza Stark Marked gene: RAP1GDS1 as ready
Mendeliome v0.3241 BTG4 Ain Roesley gene: BTG4 was added
gene: BTG4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BTG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BTG4 were set to PMID: 32502391
Phenotypes for gene: BTG4 were set to Zygotic cleavage failure (ZCF)
Penetrance for gene: BTG4 were set to unknown
Added comment: PMID: 32502391
- 4 affecteds from 4 families including 3 consanguineous families. 3 PTVs + 1 splice.
- in vitro assays in HELA cells showed all PTVs had complete loss of protein. The missense variant had abolished interaction with CNOT7
- In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF
Sources: Literature
Mendeliome v0.3241 KIAA1217 Zornitza Stark Marked gene: KIAA1217 as ready
Mendeliome v0.3240 KIAA1217 Zornitza Stark gene: KIAA1217 was added
gene: KIAA1217 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIAA1217 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIAA1217 were set to 32369272
Phenotypes for gene: KIAA1217 were set to Vertebral anomalies, syndromic and non-syndromic
Review for gene: KIAA1217 was set to AMBER
Added comment: 10 families reported, however note only 3 of the variants were absent from gnomad, inheritance not reported, most variants are missense.
Sources: Literature
Mendeliome v0.3239 RAP1GDS1 Zornitza Stark gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to 32431071
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features
Review for gene: RAP1GDS1 was set to AMBER
Added comment: Four individuals from two consanguineous families, same homozygous splice site variant detected.
Sources: Literature
Mendeliome v0.3238 HOXD10 Zornitza Stark Marked gene: HOXD10 as ready
Mendeliome v0.3238 HOXD10 Zornitza Stark Phenotypes for gene: HOXD10 were changed from to Charcot-Marie-Tooth disease, foot deformity of; Vertical talus, congenital (MIM#192950)
Mendeliome v0.3234 HOXD10 Crystle Lee reviewed gene: HOXD10: Rating: AMBER; Mode of pathogenicity: None; Publications: 15146389, 16450407; Phenotypes: Charcot-Marie-Tooth disease, foot deformity of, Vertical talus, congenital (MIM#192950); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3234 ADPRHL2 Zornitza Stark Marked gene: ADPRHL2 as ready
Mendeliome v0.3234 ADPRHL2 Zornitza Stark Phenotypes for gene: ADPRHL2 were changed from to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170
Mendeliome v0.3231 ADPRHL2 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.
Sources: Expert list; to: 14 families reported, onset is in the first years of life following normal early development. Patients have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy.
Sources: Expert list
Mendeliome v0.3231 GPR161 Zornitza Stark Marked gene: GPR161 as ready
Mendeliome v0.3230 GPR161 Zornitza Stark gene: GPR161 was added
gene: GPR161 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPR161 were set to 31609649
Phenotypes for gene: GPR161 were set to Predisposition to paediatric medulloblastoma
Review for gene: GPR161 was set to GREEN
Added comment: 6 unrelated individuals reported with germline variants, 5 with truncating, one missense. Somatic second hit in tumour tissue.
Sources: Literature
Mendeliome v0.3229 SETD1B Zornitza Stark Marked gene: SETD1B as ready
Mendeliome v0.3226 ARF1 Zornitza Stark Marked gene: ARF1 as ready
Mendeliome v0.3226 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Mendeliome v0.3226 ARF1 Zornitza Stark Classified gene: ARF1 as Green List (high evidence)
Mendeliome v0.3226 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Mendeliome v0.3225 ARF1 Zornitza Stark gene: ARF1 was added
gene: ARF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, MIM# 618185
Review for gene: ARF1 was set to GREEN
Added comment: Three unrelated individuals reported with de novo missense in this gene.
Sources: Expert list
Mendeliome v0.3224 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from Intellectual disability; seizures; PVNH; dysmorphic features to Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918
Mendeliome v0.3223 MAP1B Zornitza Stark edited their review of gene: MAP1B: Changed phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features, Periventricular nodular heterotopia 9, MIM# 618918
Mendeliome v0.3223 MRAS Zornitza Stark Marked gene: MRAS as ready
Mendeliome v0.3222 MRAS Zornitza Stark changed review comment from: Two unrelated individuals reported with de novo variants in this gene. Rated as LIMITED by ClinGen.
Sources: Expert list; to: Two unrelated individuals reported with de novo variants in this gene initially. Rated as LIMITED by ClinGen in 2018. Note 4 further individuals reported since.
Sources: Expert list
Mendeliome v0.3222 MRAS Zornitza Stark gene: MRAS was added
gene: MRAS was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAS were set to 28289718
Phenotypes for gene: MRAS were set to Noonan syndrome
Review for gene: MRAS was set to AMBER
Added comment: Two unrelated individuals reported with de novo variants in this gene. Rated as LIMITED by ClinGen.
Sources: Expert list
Mendeliome v0.3221 A2ML1 Zornitza Stark Marked gene: A2ML1 as ready
Mendeliome v0.3217 NRG1 Bryony Thompson Marked gene: NRG1 as ready
Mendeliome v0.3216 NRG1 Bryony Thompson gene: NRG1 was added
gene: NRG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NRG1 were set to 22574178; 21706185; 28190554
Phenotypes for gene: NRG1 were set to Hirschsprung disease
Review for gene: NRG1 was set to AMBER
Added comment: Has been reported as a Hirschsprung disease susceptibility loci, with common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. There are also two publications with rare variants reported in this gene (at least one de novo) and supporting in vitro functional assays. A null zebrafish model was also supportive of a role in Hirschsprung disease.
Sources: Expert list
Mendeliome v0.3215 FLRT3 Zornitza Stark Marked gene: FLRT3 as ready
Mendeliome v0.3211 CCDC32 Zornitza Stark Marked gene: CCDC32 as ready
Mendeliome v0.3211 CCDC32 Zornitza Stark Added comment: Comment when marking as ready: Three affected individuals from two unrelated families, supportive animal model and other functional data consistent with this being a ciliopathy.
Mendeliome v0.3210 CAPZA2 Zornitza Stark Marked gene: CAPZA2 as ready
Mendeliome v0.3209 PPP3R1 Zornitza Stark Marked gene: PPP3R1 as ready
Mendeliome v0.3209 PPP3R1 Zornitza Stark Added comment: Comment when marking as ready: Currently just a locus; note multiple mouse models implicating a role for this gene in cardiovascular, renal and brain development.
Mendeliome v0.3208 PLEK Zornitza Stark Marked gene: PLEK as ready
Mendeliome v0.3207 CNRIP1 Zornitza Stark Marked gene: CNRIP1 as ready
Mendeliome v0.3207 CNRIP1 Zornitza Stark Added comment: Comment when marking as ready: Currently just a locus, insufficient evidence for gene-disease association.
Mendeliome v0.3206 RAD21 Zornitza Stark Marked gene: RAD21 as ready
Mendeliome v0.3202 CAPZA2 Eleanor Williams gene: CAPZA2 was added
gene: CAPZA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAPZA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPZA2 were set to 32338762
Phenotypes for gene: CAPZA2 were set to intellectual disability
Review for gene: CAPZA2 was set to AMBER
Added comment: PMID: 32338762 - Huang et al 2020 - report 2 unrelated families (Chinese and European) in which a de novo heterozygous variant has been identified in CAPZA2 in paediatric probands that present with global motor development delay, speech delay, intellectual disability, hypotonia. One proband had seizures at 7 months but these were controlled with medication and did not repeat. The other proband at age one had an atypical febrile seizure that was controlled without medication. Functional studies in Drosophila suggest that these variants are mild loss of function mutations but that they can act as dominant negative variants in actin polymerization in bristles.
Sources: Literature
Mendeliome v0.3202 PPP3R1 Eleanor Williams gene: PPP3R1 was added
gene: PPP3R1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP3R1 were set to 32337552; 19159392
Phenotypes for gene: PPP3R1 were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: PPP3R1 was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 PLEK Eleanor Williams gene: PLEK was added
gene: PLEK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEK were set to 32337552; 19159392
Phenotypes for gene: PLEK were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: PLEK was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 CNRIP1 Eleanor Williams gene: CNRIP1 was added
gene: CNRIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNRIP1 were set to 32337552; 19159392
Phenotypes for gene: CNRIP1 were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: CNRIP1 was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 CCDC32 Eleanor Williams gene: CCDC32 was added
gene: CCDC32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC32 were set to 32307552
Phenotypes for gene: CCDC32 were set to craniofacial, cardiac and neurodevelopmental anomalies
Review for gene: CCDC32 was set to AMBER
Added comment: PMID: 32307552 - Harel et al 2020 - reports 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32. Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and shows a role for ccdc32 in craniofacial, brain and left/right axis development.
Sources: Literature
Mendeliome v0.3202 SKIV2L Zornitza Stark changed review comment from: Multiple families reported with trichohepatoenteric syndrome.; to: Multiple families reported with trichohepatoenteric syndrome, agree unclear if ID is an association.
Mendeliome v0.3202 SKIV2L Zornitza Stark Marked gene: SKIV2L as ready
Mendeliome v0.3199 NLRP5 Zornitza Stark Marked gene: NLRP5 as ready
Mendeliome v0.3198 NLRP5 Zornitza Stark gene: NLRP5 was added
gene: NLRP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NLRP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP5 were set to 32222962; 31829238; 30877238
Phenotypes for gene: NLRP5 were set to Early embryonic arrest
Review for gene: NLRP5 was set to AMBER
Added comment: At least two families reported.
Sources: Literature
Mendeliome v0.3197 EMILIN1 Zornitza Stark Marked gene: EMILIN1 as ready
Mendeliome v0.3196 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Mendeliome v0.3195 HNRNPH1 Zornitza Stark gene: HNRNPH1 was added
gene: HNRNPH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPH1 were set to 32335897; 29938792
Phenotypes for gene: HNRNPH1 were set to HNRNPH1‐related syndromic intellectual disability
Review for gene: HNRNPH1 was set to GREEN
Added comment: 1st patient reported in 2018 with intellectual disability and dysmorphic features and HNRNPH1 heterozygous missense variant. 2020 paper reports additional 7 cases with ID, short stature, microcephaly, distinctive dysmorphic facial features, and congenital anomalies (cranial, brain, genitourinary, palate, ophthalmologic). They all had HNRNPH1 heterozygous pathogenic variants (missense, frameshift, in‐frame deletion, entire gene duplication) and were identified using clinical networks and GeneMatcher. No comments in paper if all de novo.
Sources: Literature
Mendeliome v0.3194 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Microcephaly; intellectual disability
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Mendeliome v0.3193 NME5 Zornitza Stark Marked gene: NME5 as ready
Mendeliome v0.3192 NME5 Zornitza Stark gene: NME5 was added
gene: NME5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NME5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NME5 were set to 32185794
Phenotypes for gene: NME5 were set to Primary ciliary dyskinesia
Review for gene: NME5 was set to AMBER
Added comment: One patient with PCD with situs solitus, with radial spokes (RS) and central pair (CP) defects. Patient had a homozygous nonsense variant in NME5, with parents as carriers. Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy.
Sources: Literature
Mendeliome v0.3189 ADAMTS19 Zornitza Stark reviewed gene: ADAMTS19: Rating: GREEN; Mode of pathogenicity: None; Publications: 32323311, 31844321; Phenotypes: Heart valve disease (HVD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3189 EMILIN1 Naomi Baker changed review comment from: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature; to: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature
Mendeliome v0.3189 EMILIN1 Naomi Baker gene: EMILIN1 was added
gene: EMILIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMILIN1 were set to PMID: 31978608; 26462740.
Phenotypes for gene: EMILIN1 were set to peripheral neuropathy
Penetrance for gene: EMILIN1 were set to unknown
Review for gene: EMILIN1 was set to AMBER
Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature
Mendeliome v0.3189 ADAMTS3 Zornitza Stark Marked gene: ADAMTS3 as ready
Mendeliome v0.3186 SP6 Zornitza Stark Marked gene: SP6 as ready
Mendeliome v0.3185 MCM3AP Eleanor Williams changed review comment from: PMID: 32202298 - Woldegebriel et al - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The child from the Netherlands presented with severe hypotonia and intellectual disability. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.; to: PMID: 32202298 - Woldegebriel et al 2020 - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The child from the Netherlands presented with severe hypotonia and intellectual disability. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.
Mendeliome v0.3185 SP6 Eleanor Williams gene: SP6 was added
gene: SP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SP6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP6 were set to 32167558; 18156176; 18297738; 22676574
Phenotypes for gene: SP6 were set to hypoplastic amelogenesis imperfecta
Review for gene: SP6 was set to AMBER
Added comment: PMID: 32167558 - Smith et al 2020 - report a 2 bp variant c.817_818GC>AA in SP6 in a Caucasian family with autosomal dominant hypoplastic AI which results in a missense change. Report that mice and rat knockouts also show a dental phenotype (PMID: 18156176, 18297738, 22676574 )
Sources: Literature
Mendeliome v0.3185 MYH8 Zornitza Stark Marked gene: MYH8 as ready
Mendeliome v0.3185 MYH8 Zornitza Stark Added comment: Comment when marking as ready: Recurrent variant p.R674Q has occurred de novo in at least some families.
Mendeliome v0.3185 MYH8 Zornitza Stark Phenotypes for gene: MYH8 were changed from to Trismus-pseudocamptodactyly syndrome MIM# 158300; Carney complex variant MIM# 608837
Mendeliome v0.3182 MYH8 Teresa Zhao reviewed gene: MYH8: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28377322, 18049072, 17041932; Phenotypes: Trismus-pseudocamptodactyly syndrome MIM# 158300, Carney complex variant MIM# 608837; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3182 CACNB1 Zornitza Stark Marked gene: CACNB1 as ready
Mendeliome v0.3182 CACNB1 Zornitza Stark gene: CACNB1 was added
gene: CACNB1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CACNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNB1 were set to 27832566; 8943043; 29212769
Phenotypes for gene: CACNB1 were set to Malignant hyperthermia susceptibility
Added comment: A single heterozygous case with a positive IVCT muscle biopsy has been reported with p.Val156Ala. The European non-Finnish allele frequency in gnomAD v2.1 is 0.001146 (148/129,118 alleles), which is higher than the expected population frequency for dominantly inherited malignant hyperthermia (0.1%). Additionally, functional assays of this variant, suggest it would only significantly affect function in the homozygous state (suggesting a recessive condition).
Sources: Expert list
Mendeliome v0.3181 GATA6 Zornitza Stark Marked gene: GATA6 as ready
Mendeliome v0.3181 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from to Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095
Mendeliome v0.3177 GATA6 Elena Savva reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:20581743, 19666519; Phenotypes: Pancreatic agenesis and congenital heart defects, 600001, Atrial septal defect 9, 614475, Atrioventricular septal defect 5, 614474, Tetralogy of Fallot, 187500, Persistent truncus arteriosus, 217095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.3177 CDH2 Zornitza Stark Phenotypes for gene: CDH2 were changed from Intellectual disability; corpus callosum abnormalities; congenital abnormalities to Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929
Mendeliome v0.3176 CDH2 Zornitza Stark edited their review of gene: CDH2: Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929
Mendeliome v0.3175 CDK19 Zornitza Stark Phenotypes for gene: CDK19 were changed from Intellectual disability; epileptic encephalopathy to Intellectual disability; epileptic encephalopathy; Epileptic encephalopathy, early infantile, 87, MIM# 618916
Mendeliome v0.3174 CDK19 Zornitza Stark edited their review of gene: CDK19: Changed phenotypes: Intellectual disability, epileptic encephalopathy, Epileptic encephalopathy, early infantile, 87, MIM# 618916
Mendeliome v0.3174 TSHZ1 Zornitza Stark changed review comment from: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487).; to: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487). Also note original report contains four individuals with deletions of this gene, further supporting gene-disease association.
Mendeliome v0.3173 TSHZ1 Zornitza Stark Marked gene: TSHZ1 as ready
Mendeliome v0.3170 ZBTB18 Zornitza Stark Marked gene: ZBTB18 as ready
Mendeliome v0.3170 ZBTB18 Zornitza Stark Phenotypes for gene: ZBTB18 were changed from to Mental retardation, autosomal dominant 22, MIM# 612337
Mendeliome v0.3164 ZBTB18 Elena Savva reviewed gene: ZBTB18: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 27598823, 29573576; Phenotypes: Mental retardation, autosomal dominant 22 612337; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3164 MT-TP Bryony Thompson Marked gene: MT-TP as ready
Mendeliome v0.3163 SETD2 Zornitza Stark Marked gene: SETD2 as ready
Mendeliome v0.3160 UBE2A Zornitza Stark Marked gene: UBE2A as ready
Mendeliome v0.3160 UBE2A Zornitza Stark Phenotypes for gene: UBE2A were changed from to Mental retardation, X-linked syndromic, Nascimento-type (MIM#300860)
Mendeliome v0.3157 UBE2A Zornitza Stark reviewed gene: UBE2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24053514, 16909393; Phenotypes: Mental retardation, X-linked syndromic, Nascimento-type (MIM#300860); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3157 AXL Bryony Thompson Marked gene: AXL as ready
Mendeliome v0.3156 AXL Bryony Thompson gene: AXL was added
gene: AXL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXL were set to 18787040; 24476074
Phenotypes for gene: AXL were set to Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism
Review for gene: AXL was set to AMBER
Added comment: Axl null mice had delayed first oestrus and persistently abnormal oestrous cyclicality compared with wild-type controls. Only a single study reported screening human cases. In a screen of 104 probands with KS or nIHH, four heterozygous AXL mutations were identified in two KS and two nIHH unrelated subjects (two males and two females). Three of the variants appear to be too common in gnomAD v2.1 given the reported prevalence of KS reported in GeneReviews (1:30,000 in males and 1:125,000 in females): c.587-6C>T (normal splicing in RNA studies, NFE AF 0.0001472), p.Q361P (NFE 0.002560), p.L50F (AJ 0.004405). The other variant p.S202C (4 hets, 1 female in gnomAD v2.1) is rare enough in gnomAD for a dominant disorder. In vitro functional assays were conducted and p.S202C had an significant effect on function, but so did the more common variant p.Q361P.
Sources: Literature
Mendeliome v0.3155 GANAB Zornitza Stark Marked gene: GANAB as ready
Mendeliome v0.3152 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Nueromuscular disorder to Neuromuscular disorder
Mendeliome v0.3151 GOLGA2 Zornitza Stark Marked gene: GOLGA2 as ready
Mendeliome v0.3150 GOLGA2 Elena Savva gene: GOLGA2 was added
gene: GOLGA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GOLGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Phenotypes for gene: GOLGA2 were set to Nueromuscular disorder
Review for gene: GOLGA2 was set to GREEN
Added comment: PMID: 30237576 - One 11 year old patient with a homozygous PTC.
Patient had global dev delay, microcephaly, distal muscle weakness with joint contractures and elevated CK levels. Muscle biopsy showed dystrophin changes. MRI at 2 years old showed brain atrophy with thin corpus callosum and hypomyelination. No seizures or regression.

PMID: 26742501 - One infant with a homozygous PTC.
Patient had dev delay, seizures, microcephaly and muscular dystrophy. Zebrafish null model recapitulates the human phenotype with microcephaly and skeletal muscle disorganization.

Summary: 2 patients + animal model
Sources: Expert list
Mendeliome v0.3149 HTR3D Bryony Thompson Marked gene: HTR3D as ready
Mendeliome v0.3148 ALOX5AP Bryony Thompson Marked gene: ALOX5AP as ready
Mendeliome v0.3147 PHOX2A Zornitza Stark Marked gene: PHOX2A as ready
Mendeliome v0.3147 PHOX2A Zornitza Stark Phenotypes for gene: PHOX2A were changed from to Fibrosis of extraocular muscles, congenital, 2 602078
Mendeliome v0.3143 PHOX2A Elena Savva reviewed gene: PHOX2A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 11600883, 18323871; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3142 ABCC1 Zornitza Stark Phenotypes for gene: ABCC1 were changed from Nonsyndromic hearing loss to Deafness-77, autosomal dominant (DFNA77), MIM#618915
Mendeliome v0.3141 SORD Zornitza Stark Phenotypes for gene: SORD were changed from isolated hereditary neuropathy to isolated hereditary neuropathy; Sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDDPN), MIM#618912
Mendeliome v0.3140 ANKRD1 Zornitza Stark Marked gene: ANKRD1 as ready
Mendeliome v0.3140 ANKRD1 Zornitza Stark Phenotypes for gene: ANKRD1 were changed from to Hypertrophic cardiomyopathy; Dilated cardiomyopathy
Mendeliome v0.3136 ANKRD1 Zornitza Stark reviewed gene: ANKRD1: Rating: RED; Mode of pathogenicity: None; Publications: 19608030, 19525294, 30681346; Phenotypes: Hypertrophic cardiomyopathy, Dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3136 CALR3 Zornitza Stark Marked gene: CALR3 as ready
Mendeliome v0.3136 CALR3 Zornitza Stark Phenotypes for gene: CALR3 were changed from to Hypertrophic cardiomyopathy
Mendeliome v0.3132 CALR3 Zornitza Stark reviewed gene: CALR3: Rating: RED; Mode of pathogenicity: None; Publications: 29988065; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3132 ALPK3 Zornitza Stark Marked gene: ALPK3 as ready
Mendeliome v0.3132 ALPK3 Zornitza Stark Phenotypes for gene: ALPK3 were changed from to Cardiomyopathy, familial hypertrophic 27, MIM# 618052
Mendeliome v0.3129 ALPK3 Zornitza Stark reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26846950, 27106955, 32480058; Phenotypes: Cardiomyopathy, familial hypertrophic 27, MIM# 618052; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3129 HSF4 Zornitza Stark Marked gene: HSF4 as ready
Mendeliome v0.3129 HSF4 Zornitza Stark Phenotypes for gene: HSF4 were changed from to Cataract 5, multiple types, 116800
Mendeliome v0.3126 HSF4 Zornitza Stark reviewed gene: HSF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31815953, 29243736, 26490182; Phenotypes: Cataract 5, multiple types, 116800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3126 FITM2 Bryony Thompson Marked gene: FITM2 as ready
Mendeliome v0.3124 DALRD3 Zornitza Stark Phenotypes for gene: DALRD3 were changed from Epileptic encephalopathy to Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 86 618910
Mendeliome v0.3123 DALRD3 Zornitza Stark edited their review of gene: DALRD3: Changed phenotypes: Epileptic encephalopathy, Epileptic encephalopathy, early infantile, 86 618910
Mendeliome v0.3123 CHD1L Zornitza Stark Marked gene: CHD1L as ready
Mendeliome v0.3119 NEXMIF Zornitza Stark Marked gene: NEXMIF as ready
Mendeliome v0.3119 NEXMIF Zornitza Stark Phenotypes for gene: NEXMIF were changed from to Mental retardation, X-linked 98 300912
Mendeliome v0.3116 MEF2C Zornitza Stark Marked gene: MEF2C as ready
Mendeliome v0.3116 MEF2C Zornitza Stark Phenotypes for gene: MEF2C were changed from to Chromosome 5q14.3 deletion syndrome, 613443; Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, 613443
Mendeliome v0.3114 KDM6A Zornitza Stark Marked gene: KDM6A as ready
Mendeliome v0.3111 MEF2C Elena Savva reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chromosome 5q14.3 deletion syndrome, 613443, Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, 613443; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3111 NEXMIF Elena Savva reviewed gene: NEXMIF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27358180; Phenotypes: Mental retardation, X-linked 98 300912; 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 v0.3111 STAG3 Bryony Thompson Marked gene: STAG3 as ready
Mendeliome v0.3110 STAG3 Bryony Thompson gene: STAG3 was added
gene: STAG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: STAG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAG3 were set to 24597867; 26059840; 31803224; 31363903
Phenotypes for gene: STAG3 were set to Premature ovarian failure 8 MIM#615723
Review for gene: STAG3 was set to GREEN
Added comment: At least four unrelated families with ovarian failure and a supporting null mouse model.
Sources: Expert list
Mendeliome v0.3109 SOHLH1 Bryony Thompson Marked gene: SOHLH1 as ready
Mendeliome v0.3108 SOHLH1 Bryony Thompson gene: SOHLH1 was added
gene: SOHLH1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SOHLH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SOHLH1 were set to 25774885; 16690745; 31042289; 20506135; 28718531
Phenotypes for gene: SOHLH1 were set to Ovarian dysgenesis 5 MIM#617690; Spermatogenic failure 32 MIM#618115
Review for gene: SOHLH1 was set to GREEN
Added comment: Women in 3 unrelated families with ovarian dysgenesis and homozygous variants, and a supporting null mouse model.
At least 4 males with heterozygous variants and spermatogenic failure.
Sources: Expert list
Mendeliome v0.3107 HFM1 Bryony Thompson Marked gene: HFM1 as ready
Mendeliome v0.3106 HFM1 Bryony Thompson gene: HFM1 was added
gene: HFM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HFM1 were set to 23555294; 24597873; 31279343
Phenotypes for gene: HFM1 were set to Premature ovarian failure 9 MIM#615724
Review for gene: HFM1 was set to GREEN
Added comment: Three cases from 2 unrelated families with compound heterozygous variants, and a single family with a heterozygous variant have been reported with ovarian failure. There is also a supporting null mouse model.
Sources: Expert list
Mendeliome v0.3105 NEK9 Zornitza Stark Marked gene: NEK9 as ready
Mendeliome v0.3101 MSTN Zornitza Stark Marked gene: MSTN as ready
Mendeliome v0.3097 HSPB8 Zornitza Stark Marked gene: HSPB8 as ready
Mendeliome v0.3097 HSPB8 Zornitza Stark Phenotypes for gene: HSPB8 were changed from to Distal myopathy; Vacuolar myopathy; Neuropathy, distal hereditary motor type IIA, 158590; Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673
Mendeliome v0.3094 HSPB8 Zornitza Stark reviewed gene: HSPB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32165108, 31403083, 28780615, 15122253, 26718575; Phenotypes: Distal myopathy, Vacuolar myopathy, Neuropathy, distal hereditary motor type IIA, 158590, Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673; Mode of inheritance: None
Mendeliome v0.3094 AMPD1 Zornitza Stark Marked gene: AMPD1 as ready
Mendeliome v0.3088 DCAF8 Bryony Thompson gene: DCAF8 was added
gene: DCAF8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DCAF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DCAF8 were set to 24500646
Phenotypes for gene: DCAF8 were set to Giant axonal neuropathy 2, autosomal dominant MIM#610100
Review for gene: DCAF8 was set to AMBER
Added comment: A single large family segregating a missense variant and in vitro functional assays demonstrating the variant reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function
Sources: Expert list
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Marked gene: ARL6IP1 as ready
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Gene: arl6ip1 has been classified as Green List (High Evidence).
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Classified gene: ARL6IP1 as Green List (high evidence)
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Gene: arl6ip1 has been classified as Green List (High Evidence).
Mendeliome v0.3086 ARL6IP1 Bryony Thompson gene: ARL6IP1 was added
gene: ARL6IP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP1 were set to 24482476; 31272422; 30980493; 28471035
Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive MIM#615685
Review for gene: ARL6IP1 was set to GREEN
gene: ARL6IP1 was marked as current diagnostic
Added comment: At least 4 families reported with paediatric onset complicated spastic paraplegia and neuropathy. Supporting zebrafish model.
Sources: Expert list
Mendeliome v0.3085 PMP2 Bryony Thompson Marked gene: PMP2 as ready
Mendeliome v0.3084 PMP2 Bryony Thompson gene: PMP2 was added
gene: PMP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMP2 were set to 26257172; 26828946; 27009151
Phenotypes for gene: PMP2 were set to Charcot-Marie-Tooth disease, demyelinating, type 1G MIM#618279
Review for gene: PMP2 was set to GREEN
Added comment: 4 unrelated families reported with missense variants, with supporting transgenic mouse and null zebrafish models.
Sources: Expert list
Mendeliome v0.3078 SI Zornitza Stark Marked gene: SI as ready
Mendeliome v0.3075 SV2B Seb Lunke Marked gene: SV2B as ready
Mendeliome v0.3075 SV2B Seb Lunke gene: SV2B was added
gene: SV2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SV2B was set to Unknown
Publications for gene: SV2B were set to 23617838; 23937191
Phenotypes for gene: SV2B were set to seizures
Review for gene: SV2B was set to RED
Added comment: Multiply described in Epilepsy studies investigating role of SV2 gene family, however no patients directly attributed to variants in this gene and mouse models indicate viability without seizures. Sources: Literature
Sources: Literature
Mendeliome v0.3074 ADGRG1 Elena Savva reviewed gene: ADGRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24531968; Phenotypes: Polymicrogyria, bilateral frontoparietal 606854, Polymicrogyria, bilateral perisylvian 615752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3074 RYR3 Zornitza Stark Marked gene: RYR3 as ready
Mendeliome v0.3073 RYR3 Zornitza Stark gene: RYR3 was added
gene: RYR3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RYR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Phenotypes for gene: RYR3 were set to Nemaline myopathy; fetal akinesia; arthrogryposis
Review for gene: RYR3 was set to AMBER
Added comment: One family reported with nemaline myopathy and other cases reported as part of large fetal akinesia/arthrogryposis discovery cohorts reporting multiple novel gene candidates.
Sources: Expert list
Mendeliome v0.3072 SCN3A Zornitza Stark Marked gene: SCN3A as ready
Mendeliome v0.3072 SCN3A Zornitza Stark Phenotypes for gene: SCN3A were changed from to Epilepsy, familial focal, with variable foci 4, MIM# 617935; Epileptic encephalopathy, early infantile, 62, MIM# 617938; Intellectual disability; Malformations of cortical development
Mendeliome v0.3068 SCN3A Zornitza Stark reviewed gene: SCN3A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32515017; Phenotypes: Epilepsy, familial focal, with variable foci 4, MIM# 617935, Epileptic encephalopathy, early infantile, 62, MIM# 617938, Intellectual disability, Malformations of cortical development; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3065 PLAG1 Zornitza Stark Marked gene: PLAG1 as ready
Mendeliome v0.3061 NEFH Zornitza Stark Marked gene: NEFH as ready
Mendeliome v0.3061 NEFH Zornitza Stark Phenotypes for gene: NEFH were changed from to Charcot-Marie-Tooth disease, axonal, type 2CC, MIM#616924
Mendeliome v0.3057 SLC6A1 Zornitza Stark Marked gene: SLC6A1 as ready
Mendeliome v0.3054 GATM Zornitza Stark Marked gene: GATM as ready
Mendeliome v0.3054 GATM Zornitza Stark Phenotypes for gene: GATM were changed from to Cerebral creatine deficiency syndrome 3, MIM# 612718; Fanconi renotubular syndrome 1, MIM# 134600
Mendeliome v0.3051 GATM Zornitza Stark reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 12468279, 20682460, 22386973, 29654216; Phenotypes: Cerebral creatine deficiency syndrome 3, MIM# 612718, Fanconi renotubular syndrome 1, MIM# 134600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3051 TRIM69 Zornitza Stark Marked gene: TRIM69 as ready
Mendeliome v0.3051 TRIM69 Zornitza Stark gene: TRIM69 was added
gene: TRIM69 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TRIM69 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TRIM69 were set to 22105173
Phenotypes for gene: TRIM69 were set to Susceptibility to herpes simplex encephalitis
Review for gene: TRIM69 was set to RED
Added comment: One individual with bi-allelic and one individual with mono-allelic variants in this gene described.
Sources: Expert list
Mendeliome v0.3050 NEFH Chern Lim reviewed gene: NEFH: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30992180, 27040688, 28709447; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2CC, MIM#616924; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.3050 LIMS2 Zornitza Stark Marked gene: LIMS2 as ready
Mendeliome v0.3050 LIMS2 Zornitza Stark gene: LIMS2 was added
gene: LIMS2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: LIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIMS2 were set to 25589244; 16317048
Phenotypes for gene: LIMS2 were set to Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue MIM#616827
Review for gene: LIMS2 was set to RED
Added comment: Only one family reported and Pinch2 -/- mice were viable and fertile with no apparent phenotype.
Sources: Expert list
Mendeliome v0.3049 FAN1 Elena Savva reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22772369; Phenotypes: Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3049 PSMB1 Zornitza Stark Marked gene: PSMB1 as ready
Mendeliome v0.3048 PSMB1 Zornitza Stark gene: PSMB1 was added
gene: PSMB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMB1 were set to 32129449
Phenotypes for gene: PSMB1 were set to Intellectual disability; microcephaly
Review for gene: PSMB1 was set to AMBER
Added comment: Two siblings reported with a homozygous missense variant in this gene; supportive experimental evidence including zebrafish model.
Sources: Literature
Mendeliome v0.3047 SLC12A6 Zornitza Stark Marked gene: SLC12A6 as ready
Mendeliome v0.3047 SLC12A6 Zornitza Stark Phenotypes for gene: SLC12A6 were changed from to Andermann syndrome; Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum; Intermediate CMT
Mendeliome v0.3044 SLC12A6 Zornitza Stark reviewed gene: SLC12A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439721; Phenotypes: Andermann syndrome, Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum, Intermediate CMT; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3044 C16orf62 Zornitza Stark changed review comment from: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Sources: Expert list; to: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251).
Sources: Expert list
Mendeliome v0.3044 EWSR1 Seb Lunke Marked gene: EWSR1 as ready
Mendeliome v0.3040 TRPM7 Zornitza Stark Marked gene: TRPM7 as ready
Mendeliome v0.3040 TRPM7 Zornitza Stark Phenotypes for gene: TRPM7 were changed from to {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500
Mendeliome v0.3038 TRPM7 Zornitza Stark reviewed gene: TRPM7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500; Mode of inheritance: None
Mendeliome v0.3038 C16orf62 Zornitza Stark Marked gene: C16orf62 as ready
Mendeliome v0.3037 C16orf62 Zornitza Stark gene: C16orf62 was added
gene: C16orf62 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 25434475
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Sources: Expert list
Mendeliome v0.3036 RHOBTB2 Zornitza Stark Marked gene: RHOBTB2 as ready
Mendeliome v0.3036 RHOBTB2 Zornitza Stark Phenotypes for gene: RHOBTB2 were changed from to Epileptic encephalopathy, early infantile, 64, MIM#618004
Mendeliome v0.3032 RHOBTB2 Elena Savva reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:29276004, 29768694; Phenotypes: Epileptic encephalopathy, early infantile, 64, 618004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3032 PPP1CB Zornitza Stark Marked gene: PPP1CB as ready
Mendeliome v0.3029 NUP88 Zornitza Stark Marked gene: NUP88 as ready
Mendeliome v0.3028 NUP88 Zornitza Stark gene: NUP88 was added
gene: NUP88 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP88 were set to 30543681
Phenotypes for gene: NUP88 were set to Fetal akinesia deformation sequence 4, MIM# 618393
Review for gene: NUP88 was set to GREEN
Added comment: Two unrelated families, functional data on the variants support pathogenicity as does a zebrafish model.
Sources: Literature
Mendeliome v0.3027 SMO Zornitza Stark Marked gene: SMO as ready
Mendeliome v0.3027 SMO Zornitza Stark Phenotypes for gene: SMO were changed from to Microcephaly, congenital heart disease, polydactyly, aganglionosis; Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3024 SMO Zornitza Stark reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283, 27236920; Phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Curry-Jones syndrome, somatic mosaic 601707; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3024 RBL2 Zornitza Stark Marked gene: RBL2 as ready
Mendeliome v0.3023 GRM7 Zornitza Stark Marked gene: GRM7 as ready
Mendeliome v0.3022 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay
Review for gene: GRM7 was set to GREEN
Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model.
Sources: Literature
Mendeliome v0.3021 PYGM Zornitza Stark Marked gene: PYGM as ready
Mendeliome v0.3021 PYGM Zornitza Stark Phenotypes for gene: PYGM were changed from to McArdle disease, MIM# 232600; Glycogen storage disease, autosomal dominant
Mendeliome v0.3018 PYGM Zornitza Stark reviewed gene: PYGM: Rating: GREEN; Mode of pathogenicity: None; Publications: 32386344; Phenotypes: McArdle disease, MIM# 232600, Glycogen storage disease, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3018 PERP Zornitza Stark Marked gene: PERP as ready
Mendeliome v0.3017 PERP Zornitza Stark gene: PERP was added
gene: PERP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PERP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PERP were set to 31898316
Phenotypes for gene: PERP were set to Erythrokeratoderma, no OMIM # yet
Review for gene: PERP was set to AMBER
Added comment: One extended multiplex consanguineous family with Erythrokeratoderma (striking similarity to that observed in Perp −/− mice), and a novel homozygous variant (c.466G>A; p.Gly156Arg) in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible.
Sources: Literature
Mendeliome v0.3016 ADCY6 Zornitza Stark Marked gene: ADCY6 as ready
Mendeliome v0.3015 ADCY6 Zornitza Stark gene: ADCY6 was added
gene: ADCY6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADCY6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADCY6 were set to 24319099; 26257172; 31846058
Phenotypes for gene: ADCY6 were set to Lethal congenital contracture syndrome 8, OMIM # 616287
Review for gene: ADCY6 was set to GREEN
Added comment: 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 v0.3014 DSCR3 Zornitza Stark Marked gene: DSCR3 as ready
Mendeliome v0.3014 DSCR3 Zornitza Stark gene: DSCR3 was added
gene: DSCR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DSCR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DSCR3 were set to 31845315
Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet
Review for gene: DSCR3 was set to RED
Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals.
Sources: Literature
Mendeliome v0.3013 LEF1 Zornitza Stark Marked gene: LEF1 as ready
Mendeliome v0.3013 LEF1 Zornitza Stark gene: LEF1 was added
gene: LEF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEF1 were set to 32022899
Phenotypes for gene: LEF1 were set to Ectodermal dysplasia, no OMIM# yet
Review for gene: LEF1 was set to RED
Added comment: In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. One report of two unrelated patients with 4q25 de novo deletion encompassing LEF1 , associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human.
Sources: Literature
Mendeliome v0.3012 OTUD7A Zornitza Stark Marked gene: OTUD7A as ready
Mendeliome v0.3010 OTUD7A Zornitza Stark gene: OTUD7A was added
gene: OTUD7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies.
Sources: Literature
Mendeliome v0.3009 GATAD2B Zornitza Stark Marked gene: GATAD2B as ready
Mendeliome v0.3009 GATAD2B Zornitza Stark Phenotypes for gene: GATAD2B were changed from to Mental retardation, autosomal dominant 18, OMIM # 615074
Mendeliome v0.3006 GATAD2B Zornitza Stark reviewed gene: GATAD2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31949314; Phenotypes: Mental retardation, autosomal dominant 18, OMIM # 615074; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3005 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Mendeliome v0.3002 COG4 Zornitza Stark Marked gene: COG4 as ready
Mendeliome v0.2999 ARL13B Zornitza Stark Marked gene: ARL13B as ready
Mendeliome v0.2999 ARL13B Zornitza Stark Gene: arl13b has been classified as Green List (High Evidence).
Mendeliome v0.2999 ARL13B Zornitza Stark Phenotypes for gene: ARL13B were changed from to Joubert syndrome 8, MIM# 612291
Mendeliome v0.2998 ARL13B Zornitza Stark Publications for gene: ARL13B were set to
Mendeliome v0.2997 ARL13B Zornitza Stark Mode of inheritance for gene: ARL13B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2996 ARL13B Zornitza Stark edited their review of gene: ARL13B: Added comment: Eight families reported in the literature. Many are homozygous missense variants in consanguineous families with no further supporting evidence, but sufficient number have functional evidence at protein level. Gene has appropriate tissue expression. Zebrafish model: curved tails and cystic kidneys. Hennin mouse model discovered in ENU mutagenesis screen: has polydactyly, ciliary defect, and much more severe neurological phenotype (neural tube defect).; Changed publications: 18674751, 25138100, 26092869, 27894351, 29255182, 17488627
Mendeliome v0.2996 DNAL1 Zornitza Stark Marked gene: DNAL1 as ready
Mendeliome v0.2996 DNAL1 Zornitza Stark Phenotypes for gene: DNAL1 were changed from to Ciliary dyskinesia, primary, 16, MIM# 614017
Mendeliome v0.2992 DNAL1 Zornitza Stark reviewed gene: DNAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21496787; Phenotypes: Ciliary dyskinesia, primary, 16, MIM# 614017; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2992 DNAH8 Zornitza Stark Marked gene: DNAH8 as ready
Mendeliome v0.2992 DNAH8 Zornitza Stark Phenotypes for gene: DNAH8 were changed from to Asthenozoospermia; primary ciliary dyskinesia
Mendeliome v0.2988 DNAH8 Zornitza Stark reviewed gene: DNAH8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31178125, 24307375; Phenotypes: Asthenozoospermia, primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2988 TTC5 Zornitza Stark Marked gene: TTC5 as ready
Mendeliome v0.2987 TTC5 Zornitza Stark gene: TTC5 was added
gene: TTC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Review for gene: TTC5 was set to GREEN
Added comment: Eleven individuals from seven families reported.
Sources: Literature
Mendeliome v0.2986 ACAD11 Zornitza Stark Marked gene: ACAD11 as ready
Mendeliome v0.2985 DNAH6 Zornitza Stark Marked gene: DNAH6 as ready
Mendeliome v0.2984 DRC1 Zornitza Stark Marked gene: DRC1 as ready
Mendeliome v0.2984 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from to Ciliary dyskinesia, primary, 21, MIM# 615294
Mendeliome v0.2981 DRC1 Zornitza Stark reviewed gene: DRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31960620; Phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294; Mode of inheritance: None
Mendeliome v0.2978 HIST1H4J Zornitza Stark Marked gene: HIST1H4J as ready
Mendeliome v0.2977 HIST1H4J Zornitza Stark gene: HIST1H4J was added
gene: HIST1H4J was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4J were set to 31804630
Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features
Review for gene: HIST1H4J was set to AMBER
Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to other HIST1H4C phenotype
Sources: Literature
Mendeliome v0.2976 MCIDAS Zornitza Stark Marked gene: MCIDAS as ready
Mendeliome v0.2976 MCIDAS Zornitza Stark Phenotypes for gene: MCIDAS were changed from to Ciliary dyskinesia, primary, 42 (MIM#618695)
Mendeliome v0.2973 MCIDAS Zornitza Stark reviewed gene: MCIDAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 25048963; Phenotypes: Ciliary dyskinesia, primary, 42 (MIM#618695); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2973 VWA3B Zornitza Stark Marked gene: VWA3B as ready
Mendeliome v0.2973 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 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures
Mendeliome v0.2972 TOR1AIP1 Zornitza Stark Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness
Mendeliome v0.2971 TOR1AIP1 Zornitza Stark Marked gene: TOR1AIP1 as ready
Mendeliome v0.2971 TOR1AIP1 Zornitza Stark Added comment: Comment when marking as ready: Highly variable phenotype. Few of the features are consistently reported across affected individuals.
Mendeliome v0.2970 EFEMP1 Zornitza Stark Marked gene: EFEMP1 as ready
Mendeliome v0.2966 ZFYVE27 Bryony Thompson reviewed gene: ZFYVE27: Rating: RED; Mode of pathogenicity: None; Publications: 16826525, 29980238, 18606302; Phenotypes: Spastic paraplegia 33, autosomal dominant MIM#610244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2966 TOR1AIP1 Kristin Rigbye reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32055997; Phenotypes: TOR1AIP1-associated nuclear envelopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2965 USP8 Bryony Thompson gene: USP8 was added
gene: USP8 was added to Mendeliome. Sources: Expert list
somatic tags were added to gene: USP8.
Mode of inheritance for gene: USP8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: USP8 were set to 25675982; 24482476; 25485838; 25942478
Phenotypes for gene: USP8 were set to Pituitary adenoma 4, ACTH-secreting, somatic MIM#219090; hereditary spastic paraplegia
Review for gene: USP8 was set to GREEN
Added comment: Recurrent somatic gain of function missense variants in pituitary adenomas cause Cushing's disease.
A single family reported with spastic paraplegia with a homozygous variant, and a zebrafish model with a movement disorder.
Sources: Expert list
Mendeliome v0.2964 RIMS2 Zornitza Stark Marked gene: RIMS2 as ready
Mendeliome v0.2961 TRIM71 Seb Lunke Marked gene: TRIM71 as ready
Mendeliome v0.2960 SCYL2 Zornitza Stark Marked gene: SCYL2 as ready
Mendeliome v0.2959 SCYL2 Zornitza Stark gene: SCYL2 was added
gene: SCYL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL2 were set to 31960134; 26203146
Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita (AMC); Zain syndrome
Review for gene: SCYL2 was set to AMBER
Added comment: Two unrelated families reported with AMC, variable other features including microcephaly.
Sources: Literature
Mendeliome v0.2958 CNP Seb Lunke Marked gene: CNP as ready
Mendeliome v0.2956 RIMS2 Paul De Fazio changed review comment from: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature; to: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant. Several individuals had autism. One had night blindness.
Sources: Literature
Mendeliome v0.2955 VWA3B Bryony Thompson gene: VWA3B was added
gene: VWA3B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: VWA3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA3B were set to 26157035
Phenotypes for gene: VWA3B were set to Spinocerebellar ataxia, autosomal recessive 22 MIM#616948
Review for gene: VWA3B was set to AMBER
Added comment: A homozygous missense variant was identified in 3 brothers from a single consanguineous Japanese family with autosomal recessive cerebellar ataxia. Transfection of the mutant VWA3B protein into several different cultured cell lines resulted in decreased cell viability.
Sources: Expert list
Mendeliome v0.2954 SLC12A2 Zornitza Stark Phenotypes for gene: SLC12A2 were changed from Kilquist syndrome; deafness; intellectual disability; dysmorphic features; absent salivation to Kilquist syndrome: deafness, intellectual disability, dysmorphic features, absent salivation; Congenital, severe to profound hearing loss
Mendeliome v0.2953 SOX6 Paul De Fazio changed review comment from: 6 LoF, 4 missense, and 6 intragenic deletion variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me (paper says 19 individuals from 17 families). 12 were de novo.
Sources: Literature; to: 6 LoF, 4 missense, and 6 intragenic deletion variants identified in individuals with a neurodevelopmental syndrome. Paper says 19 individuals from 17 families. 12 were de novo.
Sources: Literature
Mendeliome v0.2952 SOX6 Paul De Fazio changed review comment from: 6 LoF, 4 missense, and 6 intragenic deletion variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me.
Sources: Literature; to: 6 LoF, 4 missense, and 6 intragenic deletion variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me (paper says 19 individuals from 17 families). 12 were de novo.
Sources: Literature
Mendeliome v0.2950 PLD3 Bryony Thompson gene: PLD3 was added
gene: PLD3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PLD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLD3 were set to 29053796; 30312375; 30312384
Phenotypes for gene: PLD3 were set to Spinocerebellar ataxia 46 MIM#617770
Review for gene: PLD3 was set to AMBER
Added comment: A heterozygous missense was identified in 8 affected members of a single family with spinocerebellar ataxia, and supporting in vitro functional assays.
Sources: Expert list
Mendeliome v0.2949 SOX6 Paul De Fazio changed review comment from: 6 LoF and 4 missense variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me.
Sources: Literature; to: 6 LoF, 4 missense, and 6 intragenic deletion variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me.
Sources: Literature
Mendeliome v0.2949 SPATA13 Zornitza Stark Marked gene: SPATA13 as ready
Mendeliome v0.2949 SPATA13 Zornitza Stark Added comment: Comment when marking as ready: Adult-onset.
Mendeliome v0.2948 SOX6 Seb Lunke Marked gene: SOX6 as ready
Mendeliome v0.2947 KIF3B Zornitza Stark Marked gene: KIF3B as ready
Mendeliome v0.2945 POC5 Bryony Thompson Marked gene: POC5 as ready
Mendeliome v0.2944 POC5 Bryony Thompson gene: POC5 was added
gene: POC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POC5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 25642776; 29272404
Phenotypes for gene: POC5 were set to Idiopathic scoliosis; retinitis pigmentosa; short stature; microcephaly; recurrent glomerulonephritis
Review for gene: POC5 was set to GREEN
Added comment: Three heterozygous missense variants identified in three families segregating with idiopathic scoliosis, and supporting zebrafish models for each of the missense variants.
Also, one case reported with retinitis pigmentosa, short stature, microcephaly, and recurrent glomerulonephritis with a homozygous truncating variant and a supporting zebrafish model.
Sources: Literature
Mendeliome v0.2943 KIF3B Paul De Fazio gene: KIF3B was added
gene: KIF3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF3B were set to hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly
Review for gene: KIF3B was set to AMBER
Added comment: 2 families reported with missense variants, one de novo and one segregating in a six-generation pedigree. Functional studies in zebrafish showed the variants result in impaired rhodopsin trafficking.
Sources: Literature
Mendeliome v0.2943 SPATA13 Ain Roesley gene: SPATA13 was added
gene: SPATA13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPATA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPATA13 were set to PMID: 32339198
Phenotypes for gene: SPATA13 were set to primary angle-closure glaucoma
Added comment: PMID: 32339198; 10 unrelated probands with missense except for 2 families with inframe del of 9bp.
Sources: Literature
Mendeliome v0.2943 SOX6 Paul De Fazio gene: SOX6 was added
gene: SOX6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX6 were set to 32442410
Phenotypes for gene: SOX6 were set to ADHD; Craniosynostosis; Osteochondromas
Added comment: 6 LoF and 4 missense variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me.
Sources: Literature
Mendeliome v0.2943 CNP Kristin Rigbye gene: CNP was added
gene: CNP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNP were set to 32128616; 12590258
Phenotypes for gene: CNP were set to Hypomyelinating leukodystrophy
Review for gene: CNP was set to AMBER
Added comment: Single consanguineous family described with homozygous missense in affected child (additional two affected deceased offspring unavailable for testing; healthy carrier parents and sibling).
Loss of protein by Western blot and defect in F-actin structure and organization observed in patient fibroblasts.
Deficiency of CNP in mouse has previously been shown to cause a lethal white matter neurodegenerative phenotype (PMID: 12590258), similar to the phenotype observed in this family.
Sources: Literature
Mendeliome v0.2943 SLC12A2 Ee Ming Wong reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32294086; Phenotypes: Congenital, severe to profound hearing loss, minor motor developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2943 RIMS2 Paul De Fazio changed review comment from: Segregates with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature; to: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature
Mendeliome v0.2943 TRIM71 Elena Savva gene: TRIM71 was added
gene: TRIM71 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM71 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRIM71 were set to PMID: 29983323; 32168371; 30975633
Phenotypes for gene: TRIM71 were set to Hydrocephalus, congenital communicating, 1 618667
Mode of pathogenicity for gene: TRIM71 was set to Other
Added comment: PMID: 29983323 - 3 unrelated patients with de novo missense and hydrocephalus with ventriculomegaly (p.Arg608His recurrent). One patient then transmitted the variant to an affected child.

PMID: 32168371 - refers to the gene as an established sources of neurodevelopmental disorder

PMID: 30975633 - identifies and proves by functional studies that TRIM71 is essential for neurodevelopment. Proposes a LOF mechanism.
Sources: Literature
Mendeliome v0.2943 RIMS2 Paul De Fazio gene: RIMS2 was added
gene: RIMS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIMS2 were set to 32470375
Review for gene: RIMS2 was set to GREEN
Added comment: Segregates with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature
Mendeliome v0.2942 RBM7 Bryony Thompson gene: RBM7 was added
gene: RBM7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RBM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBM7 were set to 27193168
Phenotypes for gene: RBM7 were set to SMA-like spinal motor neuropathy; dHMN/dSMA
Review for gene: RBM7 was set to AMBER
Added comment: Single case with a homozygote variant, with functional assays in patient fibroblasts. Also, supporting zebrafish model.
Sources: Expert list
Mendeliome v0.2941 SORD Seb Lunke Marked gene: SORD as ready
Mendeliome v0.2940 SORD Seb Lunke gene: SORD was added
gene: SORD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to 32367058
Phenotypes for gene: SORD were set to isolated hereditary neuropathy
Review for gene: SORD was set to GREEN
gene: SORD was marked as current diagnostic
Added comment: 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG
(p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state
Sources: Literature
Mendeliome v0.2940 KCNJ8 Zornitza Stark Marked gene: KCNJ8 as ready
Mendeliome v0.2936 KCNE3 Zornitza Stark Marked gene: KCNE3 as ready
Mendeliome v0.2932 DNAH6 Elena Savva gene: DNAH6 was added
gene: DNAH6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH6 were set to PMID: 26918822
Phenotypes for gene: DNAH6 were set to Heterotaxy, Azoospermia
Review for gene: DNAH6 was set to AMBER
Added comment: PMID: 26918822 - zebrafish model has disrupted motile cilia and cilia length, with some body axis defects within embryos. Transfected human cells also had defective motile cilia and cilia width.
Two patients with heterotaxy, one homozygous (missense), the other heterozygous (missense), but the heterozygous carrier has an additional known PCD mutation in DNA1.

Summary: 1 convincing patient with animal model
Sources: Literature
Mendeliome v0.2932 XIST Zornitza Stark Marked gene: XIST as ready
Mendeliome v0.2930 SYNE2 Zornitza Stark Marked gene: SYNE2 as ready
Mendeliome v0.2930 SYNE2 Zornitza Stark Phenotypes for gene: SYNE2 were changed from to Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999
Mendeliome v0.2927 SYNE2 Bryony Thompson reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 32184094, 17761684; Phenotypes: Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999; Mode of inheritance: None
Mendeliome v0.2926 PRKAG3 Bryony Thompson reviewed gene: PRKAG3: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 17878938, 10818001; Phenotypes: increased glycogen content in skeletal muscle; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2926 ANO5 Zornitza Stark Marked gene: ANO5 as ready
Mendeliome v0.2925 ANO5 Zornitza Stark Phenotypes for gene: ANO5 were changed from to Gnathodiaphyseal dysplasia MIM#166260; Miyoshi muscular dystrophy 3 MIM#613319; Muscular dystrophy, limb-girdle, autosomal recessive 12 MIM#611307
Mendeliome v0.2923 CPT1B Zornitza Stark Marked gene: CPT1B as ready
Mendeliome v0.2920 MYF6 Bryony Thompson reviewed gene: MYF6: Rating: RED; Mode of pathogenicity: None; Publications: 11053684; Phenotypes: Centronuclear myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2919 MTMR14 Bryony Thompson reviewed gene: MTMR14: Rating: RED; Mode of pathogenicity: None; Publications: 17008356; Phenotypes: {Centronuclear myopathy, autosomal, modifier of} MIM#160150; Mode of inheritance: Unknown
Mendeliome v0.2918 ANO5 Bryony Thompson reviewed gene: ANO5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32112655; Phenotypes: Gnathodiaphyseal dysplasia MIM#166260, Miyoshi muscular dystrophy 3 MIM#613319, Muscular dystrophy, limb-girdle, autosomal recessive 12 MIM#611307; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2918 DNAJB11 Zornitza Stark Marked gene: DNAJB11 as ready
Mendeliome v0.2915 GPR143 Zornitza Stark Marked gene: GPR143 as ready
Mendeliome v0.2915 GPR143 Zornitza Stark Phenotypes for gene: GPR143 were changed from to congenital nystagmus 6, MIM 300814; type I ocular albinism, Nettleship-Falls type, MIM 300500
Mendeliome v0.2912 ELP1 Zornitza Stark Marked gene: ELP1 as ready
Mendeliome v0.2909 GPR143 Teresa Zhao reviewed gene: GPR143: Rating: GREEN; Mode of pathogenicity: None; Publications: 30555098, 29761529; Phenotypes: congenital nystagmus 6, MIM 300814, ty[e I ocular albinism, Nettleship-Falls type, MIM 300500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.2909 SNRNP200 Zornitza Stark Marked gene: SNRNP200 as ready
Mendeliome v0.2906 SNRNP200 Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo
Mendeliome v0.2906 SNRNP200 Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo
Mendeliome v0.2906 ALOXE3 Zornitza Stark Marked gene: ALOXE3 as ready
Mendeliome v0.2903 ARMC1 Zornitza Stark Marked gene: ARMC1 as ready
Mendeliome v0.2903 ARMC1 Zornitza Stark Gene: armc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2903 ARMC1 Zornitza Stark Classified gene: ARMC1 as Red List (low evidence)
Mendeliome v0.2903 ARMC1 Zornitza Stark Gene: armc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2902 ARMC1 Zornitza Stark reviewed gene: ARMC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.2902 STK36 Zornitza Stark Marked gene: STK36 as ready
Mendeliome v0.2902 STK36 Zornitza Stark Phenotypes for gene: STK36 were changed from to Primary ciliary dyskinesia
Mendeliome v0.2898 STK36 Zornitza Stark reviewed gene: STK36: Rating: RED; Mode of pathogenicity: None; Publications: 28543983; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2898 NME8 Zornitza Stark Marked gene: NME8 as ready
Mendeliome v0.2898 NME8 Zornitza Stark Phenotypes for gene: NME8 were changed from to Ciliary dyskinesia, primary, 6, MIM# 610852
Mendeliome v0.2894 TFAP2A Zornitza Stark Marked gene: TFAP2A as ready
Mendeliome v0.2890 NME8 Elena Savva reviewed gene: NME8: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 17360648; Phenotypes: Ciliary dyskinesia, primary, 6 610852; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2890 ARL3 Bryony Thompson Marked gene: ARL3 as ready
Mendeliome v0.2890 ARL3 Bryony Thompson Gene: arl3 has been classified as Green List (High Evidence).
Mendeliome v0.2890 ARL3 Bryony Thompson Classified gene: ARL3 as Green List (high evidence)
Mendeliome v0.2890 ARL3 Bryony Thompson Gene: arl3 has been classified as Green List (High Evidence).
Mendeliome v0.2889 ARL3 Bryony Thompson gene: ARL3 was added
gene: ARL3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502; 26964041; 30932721
Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#618161; Retinitis pigmentosa 83 MIM#618173
Review for gene: ARL3 was set to GREEN
Added comment: 4 patients from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. All reported cases had rod-cone dystrophy. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Two unrelated families with retinitis pigmentosa segregating the same heterozygous missense variant (Y90C).
Sources: Expert list
Mendeliome v0.2888 RARA Zornitza Stark Marked gene: RARA as ready
Mendeliome v0.2888 RARA Zornitza Stark Gene: rara has been classified as Red List (Low Evidence).
Mendeliome v0.2888 RARA Zornitza Stark Classified gene: RARA as Red List (low evidence)
Mendeliome v0.2888 RARA Zornitza Stark Gene: rara has been classified as Red List (Low Evidence).
Mendeliome v0.2887 RARA Zornitza Stark reviewed gene: RARA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.2887 ERBB2 Zornitza Stark Marked gene: ERBB2 as ready
Mendeliome v0.2885 BCR Zornitza Stark Marked gene: BCR as ready
Mendeliome v0.2882 CEP19 Bryony Thompson gene: CEP19 was added
gene: CEP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP19 were set to 29127258; 24268657
Phenotypes for gene: CEP19 were set to Morbid obesity and spermatogenic failure MIM#615703
Review for gene: CEP19 was set to AMBER
Added comment: A consanguineous Arab family with morbid obesity and infertility with a homozygous predicted null variant, and a mouse model that recapitulates the phenotype. Another homozygous variant has been identified in a consanguineous Bardet Beidl syndrome.
Sources: Literature
Mendeliome v0.2881 DALRD3 Zornitza Stark Marked gene: DALRD3 as ready
Mendeliome v0.2880 DALRD3 Zornitza Stark gene: DALRD3 was added
gene: DALRD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to Epileptic encephalopathy
Review for gene: DALRD3 was set to AMBER
Added comment: Two individuals reported with same homozygous nonsense variant, functional data.
Sources: Literature
Mendeliome v0.2879 GDF3 Zornitza Stark Marked gene: GDF3 as ready
Mendeliome v0.2876 KRAS Zornitza Stark Marked gene: KRAS as ready
Mendeliome v0.2876 KRAS Zornitza Stark Phenotypes for gene: KRAS were changed from to Cardiofaciocutaneous syndrome 2 615278; Noonan syndrome 3 609942; RAS-associated autoimmune leukoproliferative disorder 614470; Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200
Mendeliome v0.2872 GAA Zornitza Stark Marked gene: GAA as ready
Mendeliome v0.2870 HEXA Zornitza Stark Marked gene: HEXA as ready
Mendeliome v0.2867 DHX30 Zornitza Stark Marked gene: DHX30 as ready
Mendeliome v0.2867 DHX30 Zornitza Stark Added comment: Comment when marking as ready: Twelve unrelated individuals reported with de novo missense variants, some recurrent.
Mendeliome v0.2864 FAT1 Zornitza Stark Marked gene: FAT1 as ready
Mendeliome v0.2861 KRAS Elena Savva reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23059812, 17056636; Phenotypes: Arteriovenous malformation of the brain, somatic 108010, Bladder cancer, somatic 109800, Breast cancer, somatic 114480, Cardiofaciocutaneous syndrome 2 615278, Gastric cancer, somatic 137215, Leukemia, acute myeloid 601626, . Lung cancer, somatic 211980, Noonan syndrome 3 609942, Pancreatic carcinoma, somatic 260350, RAS-associated autoimmune leukoproliferative disorder 614470, Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2861 FAT1 Ee Ming Wong changed review comment from: - 5 consanguineous families with homozygous frameshift mutations in FAN1
- FAN1 KO mice had microphthalmia, with fully penetrant coloboma which was not observed in heterozygous mice
- in human retinal pigment epithelium (RPE) cells, FAN1 knockdown resulted in compromised early cell-cell junction integrity and filament organisation; to: - 5 consanguineous families with homozygous frameshift mutations in FAN1
- FAN1 KO mice had microphthalmia, with fully penetrant coloboma which was not observed in heterozygous mice
- in human retinal pigment epithelium (RPE) cells, FAN1 knockdown resulted in compromised early cell-cell junction integrity and filament organisation
Mendeliome v0.2861 PITPNM3 Bryony Thompson Marked gene: PITPNM3 as ready
Mendeliome v0.2860 JARID2 Zornitza Stark Marked gene: JARID2 as ready
Mendeliome v0.2860 JARID2 Zornitza Stark Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2860 JARID2 Zornitza Stark Classified gene: JARID2 as Amber List (moderate evidence)
Mendeliome v0.2860 JARID2 Zornitza Stark Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2859 JARID2 Zornitza Stark gene: JARID2 was added
gene: JARID2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: JARID2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JARID2 were set to 23294540
Phenotypes for gene: JARID2 were set to Intellectual disability
Review for gene: JARID2 was set to AMBER
Added comment: Emerging evidence that haploinsufficiency causes neurodevelopmental phenotypes, mostly based on CNV data to date.
Sources: Expert Review
Mendeliome v0.2857 ADIPOR1 Zornitza Stark Marked gene: ADIPOR1 as ready
Mendeliome v0.2853 TRIP12 Zornitza Stark Marked gene: TRIP12 as ready
Mendeliome v0.2853 TRIP12 Zornitza Stark Phenotypes for gene: TRIP12 were changed from to Mental retardation autosomal dominant 49, Clark-Baraitser Syndrome, MIM#617752
Mendeliome v0.2850 TRIP12 Zornitza Stark reviewed gene: TRIP12: Rating: GREEN; Mode of pathogenicity: None; Publications: 27848077, 28251352; Phenotypes: Mental retardation autosomal dominant 49, Clark-Baraitser Syndrome, MIM#617752; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2850 CX3CR1 Zornitza Stark Marked gene: CX3CR1 as ready
Mendeliome v0.2850 CX3CR1 Zornitza Stark Phenotypes for gene: CX3CR1 were changed from to Coronary artery disease, resistance to}, MIM# 607339; {Macular degeneration, age-related, 12} 613784; {Rapid progression to AIDS from HIV1 infection} 609423
Mendeliome v0.2848 CX3CR1 Zornitza Stark reviewed gene: CX3CR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coronary artery disease, resistance to}, MIM# 607339, {Macular degeneration, age-related, 12} 613784, {Rapid progression to AIDS from HIV1 infection} 609423; Mode of inheritance: None
Mendeliome v0.2848 CLCC1 Zornitza Stark Marked gene: CLCC1 as ready
Mendeliome v0.2847 CLCC1 Bryony Thompson gene: CLCC1 was added
gene: CLCC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CLCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCC1 were set to 30157172
Phenotypes for gene: CLCC1 were set to Retinitis pigmentosa 32
Review for gene: CLCC1 was set to AMBER
Added comment: A presumptive Pakastani founder mutation (c.75C>A, p.D25E) was identified in 8 consanguineous arRP families. A knockout zebrafish model and a Clcc1 +/- mouse model had a supporting retinal phenotype.
Sources: Expert list
Mendeliome v0.2846 B9D1 Zornitza Stark Marked gene: B9D1 as ready
Mendeliome v0.2842 B9D1 Zornitza Stark changed review comment from: Two unrelated individuals with JS and bi-allelic variants in this gene, plus one individual with a more severe Meckel phenotype described. Intellectual disability is part of the phenotype.
Sources: Expert list; to: Two unrelated individuals with JS and bi-allelic variants in this gene, plus one individual with a more severe Meckel phenotype described. This latter individual had a splice site variant and a deletion. Splice variant proven to result in exon skipping -> PTC, but the deletion spans a large region including 18 other genes. Patient also had an additional variant in CEP290 called LP. Authors perform functional studies on patient cells but given the large deletion/CEP290 variant i dont see the results are usable PMID: 25920555 - another report of digenic inheritance - not usable, patient was only heterozygous for a single B9D1 variant.
Mendeliome v0.2842 BBIP1 Zornitza Stark Phenotypes for gene: BBIP1 were changed from to Bardet-Biedl syndrome 18, MIM#615995
Mendeliome v0.2838 PACS1 Zornitza Stark Marked gene: PACS1 as ready
Mendeliome v0.2835 SLC15A4 Zornitza Stark Marked gene: SLC15A4 as ready
Mendeliome v0.2833 STARD7 Zornitza Stark Marked gene: STARD7 as ready
Mendeliome v0.2833 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Mendeliome v0.2833 STARD7 Zornitza Stark Classified gene: STARD7 as Green List (high evidence)
Mendeliome v0.2833 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Mendeliome v0.2832 STARD7 Zornitza Stark gene: STARD7 was added
gene: STARD7 was added to Mendeliome. Sources: Expert list
STR tags were added to gene: STARD7.
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Mode of pathogenicity for gene: STARD7 was set to Other
Review for gene: STARD7 was set to GREEN
Added comment: 158 individuals from 22 families reported with heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene.
Sources: Expert list
Mendeliome v0.2831 ERC1 Zornitza Stark Marked gene: ERC1 as ready
Mendeliome v0.2830 DHCR7 Zornitza Stark Marked gene: DHCR7 as ready
Mendeliome v0.2827 PDXK Zornitza Stark Marked gene: PDXK as ready
Mendeliome v0.2825 PDXK Russell Gear gene: PDXK was added
gene: PDXK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to (PMID: 31187503)
Phenotypes for gene: PDXK were set to Axonal polyneuropathy; optic atrophy
Review for gene: PDXK was set to RED
Added comment: Currently two unrelated families with axonal polyneuropathy and optic atrophy described in the same paper, with bi-allelic PDXK pathogenic variants. Functional work in the same paper includes work on patient derived fibroblasts, measurement of an axonal damage biomarker (NFL protein), and response to PLP supplementation treatment.

Need one further unrelated family to upgrade to green?
Sources: Literature
Mendeliome v0.2825 NDP Zornitza Stark Marked gene: NDP as ready
Mendeliome v0.2822 TMEM107 Zornitza Stark Marked gene: TMEM107 as ready
Mendeliome v0.2819 ALPL Zornitza Stark Marked gene: ALPL as ready
Mendeliome v0.2819 ALPL Zornitza Stark Phenotypes for gene: ALPL were changed from to Hypophosphatasia, adult 146300 (AD, AR); Hypophosphatasia, childhood 241510 AR; Hypophosphatasia, infantile 241500 AR; Odontohypophosphatasia 146300 AD, AR
Mendeliome v0.2815 LRRC56 Zornitza Stark Marked gene: LRRC56 as ready
Mendeliome v0.2814 LRRC56 Zornitza Stark reviewed gene: LRRC56: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 39, MIM# 618254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2814 ALPL Melanie Marty reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19500388, 23688511; Phenotypes: Hypophosphatasia, adult 146300 (AD, AR), Hypophosphatasia, childhood 241510 AR, Hypophosphatasia, infantile 241500 AR, Odontohypophosphatasia 146300 AD, AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.2814 LRRC56 Elena Savva gene: LRRC56 was added
gene: LRRC56 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: LRRC56 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC56 were set to PMID: 30388400
Phenotypes for gene: LRRC56 were set to Ciliary dyskinesia, primary, 39 618254
Added comment: PMID: 30388400 - used protist null model to show abnormal ciliary beatings, replicated the phenotype when the protist was transfected with mutant allele observed in a patient.
3 unrelated families reported with either homozygous splice, missense or chet (nonsense/splice). Patients exhibited phenotypes including chronic respiratory/ear infections, situs inversus
Sources: Expert list
Mendeliome v0.2814 MOGS Zornitza Stark Marked gene: MOGS as ready
Mendeliome v0.2811 TCF7L1 Zornitza Stark Marked gene: TCF7L1 as ready
Mendeliome v0.2811 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from to Congenital hypopituitarism
Mendeliome v0.2807 TCF7L1 Naomi Baker reviewed gene: TCF7L1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 26764381; Phenotypes: Congenital hypopituitarism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2807 GFI1B Bryony Thompson Marked gene: GFI1B as ready
Mendeliome v0.2806 GFI1B Bryony Thompson gene: GFI1B was added
gene: GFI1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GFI1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GFI1B were set to 24325358; 23927492; 28041820; 11825872
Phenotypes for gene: GFI1B were set to Bleeding disorder, platelet-type, 17 MIM#187900
Review for gene: GFI1B was set to GREEN
Added comment: Three families with a heterozygous variant and one case with a homozygous variant, with supporting in vitro functional assays. A null mouse model contained erythroid and megakaryocytic precursors arrested in their development.
Sources: Literature
Mendeliome v0.2805 PRKD1 Zornitza Stark Marked gene: PRKD1 as ready
Mendeliome v0.2805 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from to Congenital heart defects and ectodermal dysplasia, 617364
Mendeliome v0.2802 NODAL Zornitza Stark Marked gene: NODAL as ready
Mendeliome v0.2798 PIH1D3 Zornitza Stark Marked gene: PIH1D3 as ready
Mendeliome v0.2798 PIH1D3 Zornitza Stark Phenotypes for gene: PIH1D3 were changed from to Ciliary dyskinesia, primary, 36, X-linked (MIM#300991)
Mendeliome v0.2795 PIH1D3 Zornitza Stark reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 24421334, 28176794; Phenotypes: Ciliary dyskinesia, primary, 36, X-linked (MIM#300991); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.2795 COL10A1 Zornitza Stark Marked gene: COL10A1 as ready
Mendeliome v0.2791 CEP112 Bryony Thompson gene: CEP112 was added
gene: CEP112 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP112 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP112 were set to 31654588
Phenotypes for gene: CEP112 were set to Acephalic spermatozoa; infertility
Review for gene: CEP112 was set to AMBER
Added comment: Two unrelated cases reported with acephalic spermatozoa, one case with a homozygous nonsense variant and the other case with biallelic missense variants. CEP112 expression was significantly reduced in one of the cases, suggesting loss of function as a mechanism of disease.
Sources: Literature
Mendeliome v0.2790 PRKD1 Kristin Rigbye changed review comment from: Only 3 pathogenic missense reported to date, although two of these are recurring in unrelated individuals (ClinVar, Decipher, PMID: 27479907). No functional studies performed.; to: Only 3 pathogenic missense reported to date in unrelated individuals (ClinVar, Decipher, PMID: 27479907). No functional studies performed.
Mendeliome v0.2790 PRKD1 Kristin Rigbye reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2790 KPNA7 Alison Yeung Marked gene: KPNA7 as ready
Mendeliome v0.2789 NR4A2 Zornitza Stark Marked gene: NR4A2 as ready
Mendeliome v0.2788 NR4A2 Zornitza Stark gene: NR4A2 was added
gene: NR4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR4A2 were set to 31428396; 30504930; 29770430; 12756136; 9092472
Phenotypes for gene: NR4A2 were set to Intellectual disability; epilepsy
Review for gene: NR4A2 was set to GREEN
Added comment: Over ten individuals reported with mono-allelic variants in this gene and neurodevelopmental phenotypes. Link with dementia/Parkinson's disease disputed.
Sources: Literature
Mendeliome v0.2787 TET2 Zornitza Stark edited their review of gene: TET2: Added comment: Association study (PMID 32330418) found enrichment of non-coding and LoF TET2 variants in cohort of individuals with early onset dementia, unclear if this is monogenic or polygenic contribution.; Changed publications: 30890702, 31827242, 32330418
Mendeliome v0.2787 TOMM70 Zornitza Stark Marked gene: TOMM70 as ready
Mendeliome v0.2786 TOMM70 Zornitza Stark gene: TOMM70 was added
gene: TOMM70 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder
Review for gene: TOMM70 was set to AMBER
Added comment: TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria.
Bi-allelic disease: one individual reported with compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)]. Clinical features included severe anaemia, lactic acidosis, and developmental delay. Some functional data: in vitro cell model compensatory experiments.
Monoallelic disease: de novo mono allelic variants in the C-terminal region of TOMM70 reported in two individuals. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset, with one experiencing episodes of regression. Some functional data.
Sources: Expert list
Mendeliome v0.2784 CUL3 Zornitza Stark Marked gene: CUL3 as ready
Mendeliome v0.2781 EGR2 Zornitza Stark Marked gene: EGR2 as ready
Mendeliome v0.2781 EGR2 Zornitza Stark Phenotypes for gene: EGR2 were changed from to Charcot-Marie-Tooth disease, type 1D 607678 AD; Dejerine-Sottas disease 145900 AD, AR; Hypomyelinating neuropathy, congenital, 1 605253 AD, AR
Mendeliome v0.2777 EGR2 Zornitza Stark reviewed gene: EGR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 11523566, 31852952; Phenotypes: Charcot-Marie-Tooth disease, type 1D 607678 AD, Dejerine-Sottas disease 145900 AD, AR, Hypomyelinating neuropathy, congenital, 1 605253 AD, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2777 GAS2L2 Zornitza Stark Marked gene: GAS2L2 as ready
Mendeliome v0.2777 GAS2L2 Zornitza Stark Phenotypes for gene: GAS2L2 were changed from to Ciliary dyskinesia, primary, 41 (MIM # 618449)
Mendeliome v0.2773 GAS2L2 Zornitza Stark reviewed gene: GAS2L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30665704; Phenotypes: Ciliary dyskinesia, primary, 41 (MIM # 618449); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2773 KLB Zornitza Stark Marked gene: KLB as ready
Mendeliome v0.2770 NDNF Zornitza Stark Marked gene: NDNF as ready
Mendeliome v0.2769 NDNF Zornitza Stark gene: NDNF was added
gene: NDNF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDNF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NDNF were set to 31883645
Phenotypes for gene: NDNF were set to Congenital hypogonadotropic hypogonadism (CHH)
Review for gene: NDNF was set to GREEN
Added comment: Three heterozygous protein-truncating variants and one heterozygous missense variant identified in a cohort of 240 unrelated IHH patients. The authors also provided supporting evidence from animal models.
Sources: Literature
Mendeliome v0.2768 UGDH Zornitza Stark Marked gene: UGDH as ready
Mendeliome v0.2767 UGDH Zornitza Stark gene: UGDH was added
gene: UGDH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Review for gene: UGDH was set to GREEN
Added comment: 36 individuals with biallelic UGDH pathogenic variants reported. The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate. Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ. Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors
Sources: Literature
Mendeliome v0.2766 TRIM33 Zornitza Stark Marked gene: TRIM33 as ready
Mendeliome v0.2765 YIF1B Zornitza Stark Marked gene: YIF1B as ready
Mendeliome v0.2764 YIF1B Zornitza Stark gene: YIF1B was added
gene: YIF1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098; 26077767
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
Added comment: 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.
Sources: Literature
Mendeliome v0.2759 TNRC6B Zornitza Stark edited their review of gene: TNRC6B: Added comment: 17 unrelated individuals with heterozygous TNRC6B variants reported. Features included hypotonia (10/17), DD/ID (17/17 - ID was not universal: average IQ of 12 individuals was 73 (range : 50-113) with 4 having below 70), ADHD (11/17), ASD or autistic traits (8/17 and 5/17). Some/few presented with abnormal OFC (micro- / macrocephaly in 3/17 and 2/17), abnormal vision or hearing, variable other congenital anomalies, echocardiographic, GI or renal abnormalities, etc. Epilepsy was reported in 1/17. There was no recognisable gestalt.Detected variants included 14 pLoF, 1 missense SNV and 2 intragenic deletions. Variants had occurred as de novo events in 10/13 subjects for whom testing of both parents was possible. 3/13 subjects had inherited the variant from a parent with milder phenotype. Based on the type of variants identified, the pLI score of 1 in gnomAD and the HI index of 5.61%, the authors suggest haploinsufficiency as the most likely mechanism. Individuals with de novo TNRC6B variants have also been reported in larger cohorts (e.g. DDD study - PMID: 28135719, Iossifov et al - PMID: 25363768, Lelieveld et al - PMID: 27479843, Jónsson et al - PMID: 28959963). A previous study provided details on 2 sibs harboring a translocation which disrupted both TNRC6B and TCF20 (also associated with ID)(Babbs et al - PMID: 25228304).; Changed rating: GREEN; Changed publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Changed phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2759 CDC42BPB Zornitza Stark Marked gene: CDC42BPB as ready
Mendeliome v0.2758 CDC42BPB Zornitza Stark gene: CDC42BPB was added
gene: CDC42BPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Review for gene: CDC42BPB was set to GREEN
Added comment: 14 individuals with missense and loss-of-function CDC42BPB variants reported. Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc. Most variants occurred as de novo events (11/14) while inheritance was not available for few (3/14).
Sources: Literature
Mendeliome v0.2757 DNAJB13 Zornitza Stark Marked gene: DNAJB13 as ready
Mendeliome v0.2757 DNAJB13 Zornitza Stark Phenotypes for gene: DNAJB13 were changed from to Ciliary dyskinesia, primary, 34, MIM# 617091
Mendeliome v0.2753 DNAJB13 Zornitza Stark reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486783; Phenotypes: Ciliary dyskinesia, primary, 34, MIM# 617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2753 CFC1 Zornitza Stark Marked gene: CFC1 as ready
Mendeliome v0.2750 CFAP53 Zornitza Stark Marked gene: CFAP53 as ready
Mendeliome v0.2747 TTC25 Zornitza Stark Marked gene: TTC25 as ready
Mendeliome v0.2747 TTC25 Zornitza Stark Phenotypes for gene: TTC25 were changed from to Ciliary dyskinesia, primary, 35 (MIM#617092)
Mendeliome v0.2743 TTC25 Zornitza Stark reviewed gene: TTC25: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486780; Phenotypes: Ciliary dyskinesia, primary, 35 (MIM#617092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2743 CFAP43 Zornitza Stark Marked gene: CFAP43 as ready
Mendeliome v0.2743 CFAP43 Zornitza Stark Added comment: Comment when marking as ready: Good evidence for bi-allelic disease, much less so for mono-allelic.
Mendeliome v0.2742 CFAP43 Elena Savva gene: CFAP43 was added
gene: CFAP43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP43 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CFAP43 were set to PMID: 31884020; 28552195; 31004071; 29449551
Phenotypes for gene: CFAP43 were set to Hydrocephalus, normal pressure, 1 236690; Spermatogenic failure 19 617592
Added comment: aka WDR96

PMID: 31884020 - animal models (mouse, frog) demonstrate the protein localizes in ciliary axoneme and is involved in MOTILE cilia movement. LOF CFAP43 caused mucus acucmulation in airways, impaired spermatogenesis and hydrocephalus.

PMID: 28552195 - 3x chet (bilallelic PTCs or chet PTC/missense) with abnormal sperm motility. Null mouse models were also infertile.

PMID: 31004071 - one family with a heterozygous nonsense and AD inheritance of late onset hydrocephaly (checked in Mutalyzer, variant is NMD predicted). Abnormal cilia observed from mucosa sample. Null mice also show abnormal sperm and dilation of brain ventricles.

PMID: 29449551 - reports an additional 10 patients with either homozygous PTCs or chet PTC/missense who were infertile with flagella defects

Summary: single report of AD hydrocephaly
Sources: Literature
Mendeliome v0.2742 MYLK2 Zornitza Stark Marked gene: MYLK2 as ready
Mendeliome v0.2742 MYLK2 Zornitza Stark Phenotypes for gene: MYLK2 were changed from to Cardiomyopathy, hypertrophic, 1, digenic, 192600
Mendeliome v0.2738 MYLK2 Zornitza Stark reviewed gene: MYLK2: Rating: RED; Mode of pathogenicity: None; Publications: 11733062, 24082139, 25825456, 20301725; Phenotypes: Cardiomyopathy, hypertrophic, 1, digenic, 192600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2738 CDX2 Zornitza Stark Marked gene: CDX2 as ready
Mendeliome v0.2734 TAPT1 Zornitza Stark Marked gene: TAPT1 as ready
Mendeliome v0.2734 TAPT1 Zornitza Stark Phenotypes for gene: TAPT1 were changed from to Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897)
Mendeliome v0.2730 TAPT1 Zornitza Stark reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2729 CCDC28B Zornitza Stark edited their review of gene: CCDC28B: Added comment: PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers. Knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia 430C-T variant is postulated to be a modifier of BBS.; Changed rating: AMBER; Changed publications: 32139166; Changed phenotypes: {Bardet-Biedl syndrome 1, modifier of}, MIM#209900, Joubert syndrome
Mendeliome v0.2729 C21orf59 Zornitza Stark Marked gene: C21orf59 as ready
Mendeliome v0.2729 C21orf59 Zornitza Stark Added comment: Comment when marking as ready: p.Tyr245* recurrent in the Ashkenazi Jewish population
Mendeliome v0.2729 C11orf70 Zornitza Stark Marked gene: C11orf70 as ready
Mendeliome v0.2729 C11orf70 Zornitza Stark Phenotypes for gene: C11orf70 were changed from to Ciliary dyskinesia, primary, 38, MIM# 618063
Mendeliome v0.2726 C11orf70 Zornitza Stark reviewed gene: C11orf70: Rating: GREEN; Mode of pathogenicity: None; Publications: 29727693, 29727692; Phenotypes: Ciliary dyskinesia, primary, 38, MIM# 618063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2726 ARMC9 Zornitza Stark Marked gene: ARMC9 as ready
Mendeliome v0.2726 ARMC9 Zornitza Stark Gene: armc9 has been classified as Green List (High Evidence).
Mendeliome v0.2726 ARMC9 Zornitza Stark Phenotypes for gene: ARMC9 were changed from to Joubert syndrome 30, MIM#617622
Mendeliome v0.2725 ARMC9 Zornitza Stark Publications for gene: ARMC9 were set to
Mendeliome v0.2724 ARMC9 Zornitza Stark Mode of inheritance for gene: ARMC9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2723 ARMC9 Zornitza Stark edited their review of gene: ARMC9: Added comment: ARMC9 localizes to the ciliary basal body and daughter centriole and is predicted to function in ciliogenesis PMID: 28625504 - 8 families with Joubert syndrome, all variant types detected. Functional studies show protein localizes at the basal body and upregulates during ciliogenesis. Zebrafish with frameshift mutation recapitulated the human phenotype including a curved body, coloboma, retinal dystrophy and less cilia.; Changed rating: GREEN; Changed publications: 28625504
Mendeliome v0.2723 ARMC8 Zornitza Stark Marked gene: ARMC8 as ready
Mendeliome v0.2723 ARMC8 Zornitza Stark Gene: armc8 has been classified as Red List (Low Evidence).
Mendeliome v0.2723 ARMC8 Zornitza Stark Classified gene: ARMC8 as Red List (low evidence)
Mendeliome v0.2723 ARMC8 Zornitza Stark Gene: armc8 has been classified as Red List (Low Evidence).
Mendeliome v0.2722 ARMC8 Zornitza Stark reviewed gene: ARMC8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.2722 ARMC4 Zornitza Stark Marked gene: ARMC4 as ready
Mendeliome v0.2722 ARMC4 Zornitza Stark Gene: armc4 has been classified as Green List (High Evidence).
Mendeliome v0.2722 ARMC4 Zornitza Stark Phenotypes for gene: ARMC4 were changed from to Ciliary dyskinesia, primary, 23, MIM# 615451
Mendeliome v0.2721 ARMC4 Zornitza Stark Publications for gene: ARMC4 were set to
Mendeliome v0.2720 ARMC4 Zornitza Stark Mode of inheritance for gene: ARMC4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2719 ARMC4 Zornitza Stark reviewed gene: ARMC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31765523, 23849778; Phenotypes: Ciliary dyskinesia, primary, 23, MIM# 615451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2719 ACVR2B Zornitza Stark Marked gene: ACVR2B as ready
Mendeliome v0.2715 ARMC8 Elena Savva reviewed gene: ARMC8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.2715 NID1 Zornitza Stark Marked gene: NID1 as ready
Mendeliome v0.2712 DARS Zornitza Stark Marked gene: DARS as ready
Mendeliome v0.2712 DARS Zornitza Stark Gene: dars has been classified as Green List (High Evidence).
Mendeliome v0.2712 DARS Zornitza Stark Phenotypes for gene: DARS were changed from to Hypomyelination with brainstem and spinal cord involvement and leg spasticity, MIM# 615281
Mendeliome v0.2711 DARS Zornitza Stark Publications for gene: DARS were set to
Mendeliome v0.2710 DARS Zornitza Stark Mode of inheritance for gene: DARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2709 DARS Zornitza Stark Tag new gene name tag was added to gene: DARS.
Mendeliome v0.2709 DARS Zornitza Stark reviewed gene: DARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 25527264, 23643384; Phenotypes: Hypomyelination with brainstem and spinal cord involvement and leg spasticity, MIM# 615281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2709 CCDC65 Zornitza Stark Marked gene: CCDC65 as ready
Mendeliome v0.2709 CCDC65 Zornitza Stark Phenotypes for gene: CCDC65 were changed from to Ciliary dyskinesia, primary, 27, MIM# 615504
Mendeliome v0.2706 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23991085, 24094744; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2706 C21orf59 Zornitza Stark Marked gene: C21orf59 as ready
Mendeliome v0.2706 C21orf59 Zornitza Stark Phenotypes for gene: C21orf59 were changed from to Ciliary dyskinesia, primary, 26, MIM# 615500
Mendeliome v0.2703 C21orf59 Zornitza Stark reviewed gene: C21orf59: Rating: GREEN; Mode of pathogenicity: None; Publications: 24094744; Phenotypes: Ciliary dyskinesia, primary, 26, MIM# 615500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2703 WISP3 Zornitza Stark Marked gene: WISP3 as ready
Mendeliome v0.2703 WISP3 Zornitza Stark Phenotypes for gene: WISP3 were changed from to Arthropathy, progressive pseudorheumatoid, of childhood, MIM# 208230; Spondyloepiphyseal dysplasia tarda with progressive arthropathy, MIM# 208230
Mendeliome v0.2700 WISP3 Zornitza Stark reviewed gene: WISP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10471507; Phenotypes: Arthropathy, progressive pseudorheumatoid, of childhood, MIM# 208230, Spondyloepiphyseal dysplasia tarda with progressive arthropathy, MIM# 208230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2700 ATP5E Zornitza Stark Marked gene: ATP5E as ready
Mendeliome v0.2700 ATP5E Zornitza Stark Phenotypes for gene: ATP5E were changed from to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 MIM#614053
Mendeliome v0.2696 ATP5E Zornitza Stark reviewed gene: ATP5E: Rating: AMBER; Mode of pathogenicity: None; Publications: 20566710, 27626380, 20026007; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 MIM#614053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2696 ATP5D Zornitza Stark Marked gene: ATP5D as ready
Mendeliome v0.2693 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Mendeliome v0.2693 ATP5A1 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: ATP5F1A
Mendeliome v0.2693 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from to Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Mendeliome v0.2689 ATP5A1 Zornitza Stark reviewed gene: ATP5A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23599390; Phenotypes: Combined oxidative phosphorylation deficiency 22 616045, Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2689 GLDC Zornitza Stark Marked gene: GLDC as ready
Mendeliome v0.2686 CD4 Zornitza Stark reviewed gene: CD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31781092; Phenotypes: Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2685 TNK2 Zornitza Stark Marked gene: TNK2 as ready
Mendeliome v0.2681 MAN2B2 Zornitza Stark Marked gene: MAN2B2 as ready
Mendeliome v0.2680 RIPK1 Zornitza Stark Marked gene: RIPK1 as ready
Mendeliome v0.2677 PIK3CG Zornitza Stark Marked gene: PIK3CG as ready
Mendeliome v0.2675 RC3H1 Zornitza Stark Marked gene: RC3H1 as ready
Mendeliome v0.2674 RC3H1 Zornitza Stark changed review comment from: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature; to: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data including mouse model.
Sources: Literature
Mendeliome v0.2674 RC3H1 Zornitza Stark gene: RC3H1 was added
gene: RC3H1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RC3H1 were set to 31636267
Phenotypes for gene: RC3H1 were set to Relapsing HLH
Review for gene: RC3H1 was set to RED
Added comment: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature
Mendeliome v0.2673 IFNG Zornitza Stark Marked gene: IFNG as ready
Mendeliome v0.2669 ITPKB Zornitza Stark gene: ITPKB was added
gene: ITPKB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITPKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITPKB were set to 31987846
Phenotypes for gene: ITPKB were set to Severe combined immunodeficiency, absent T cells, present B cells and NK cells
Review for gene: ITPKB was set to RED
Added comment: Single individual with homozygous bi-allelic LoF variant reported.
Sources: Literature
Mendeliome v0.2668 PSMB10 Zornitza Stark Marked gene: PSMB10 as ready
Mendeliome v0.2668 PSMB10 Zornitza Stark gene: PSMB10 was added
gene: PSMB10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMB10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMB10 were set to 31783057
Phenotypes for gene: PSMB10 were set to Autoinflammatory syndrome
Review for gene: PSMB10 was set to RED
Added comment: PSMB10 is part of the immunoproteasome, and other components cause auto inflammatory disorders. Single individual with homozygous missense variant reported.
Sources: Literature
Mendeliome v0.2667 ABHD12 Zornitza Stark Marked gene: ABHD12 as ready
Mendeliome v0.2667 ABHD12 Zornitza Stark Phenotypes for gene: ABHD12 were changed from to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674
Mendeliome v0.2665 ABCC6 Zornitza Stark Marked gene: ABCC6 as ready
Mendeliome v0.2665 AAAS Zornitza Stark Marked gene: AAAS as ready
Mendeliome v0.2663 NOS2 Zornitza Stark Marked gene: NOS2 as ready
Mendeliome v0.2663 NOS2 Zornitza Stark Phenotypes for gene: NOS2 were changed from to {Malaria, resistance to} 611162; Disseminated CMV disease
Mendeliome v0.2660 NOS2 Zornitza Stark reviewed gene: NOS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12433515, 31995689; Phenotypes: {Malaria, resistance to} 611162, Disseminated CMV disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2660 SNORA31 Zornitza Stark Marked gene: SNORA31 as ready
Mendeliome v0.2659 SNORA31 Zornitza Stark gene: SNORA31 was added
gene: SNORA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SNORA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNORA31 were set to 31806906
Phenotypes for gene: SNORA31 were set to Susceptibility to HSV1 encephalitis
Review for gene: SNORA31 was set to GREEN
Added comment: Five unrelated individuals reported with rare missense variants in this gene, functional data to support susceptibility to herpes simplex encephalitis.
Sources: Expert list
Mendeliome v0.2658 TCOF1 Zornitza Stark Marked gene: TCOF1 as ready
Mendeliome v0.2655 EMX2 Zornitza Stark Marked gene: EMX2 as ready
Mendeliome v0.2651 ATAD3A Zornitza Stark Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, MIM# 617183 to Harel-Yoon syndrome, MIM# 617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL SYNDROME) 618810
Mendeliome v0.2649 ATAD3A Zornitza Stark edited their review of gene: ATAD3A: Added comment: Mode of pathogenicity includes:
i) bi-allelic missense and nonsense variants and bi-allelic deletions that create an ATAD3B/ATAD3A fusion gene under the lowly expressed ATAD3B promoter
ii) monoallelic dominant-negative missense variants (either de novo or inherited) and de novo monoallelic duplications creating a dominant negative ATAD3A/ATAD3C fusion gene; Changed publications: 27640307, 32004445, 28549128; Changed phenotypes: Harel-Yoon syndrome, MIM# 617183, Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL SYNDROME) 618810
Mendeliome v0.2649 CTSA Zornitza Stark Marked gene: CTSA as ready
Mendeliome v0.2649 CTSA Zornitza Stark Phenotypes for gene: CTSA were changed from to Galactosialidosis, MIM# 256540; Cathepsin A-related arteriopathy with strokes and leukoencephalopathy
Mendeliome v0.2646 CTSA Zornitza Stark commented on gene: CTSA: Mono-allelic variants cause arteriopathy with strokes and leukodystrophy.
Mendeliome v0.2645 PI4KA Zornitza Stark Marked gene: PI4KA as ready
Mendeliome v0.2645 PI4KA Zornitza Stark Phenotypes for gene: PI4KA were changed from to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531
Mendeliome v0.2641 PI4KA Zornitza Stark reviewed gene: PI4KA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25855803; Phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2641 CDK5 Zornitza Stark Marked gene: CDK5 as ready
Mendeliome v0.2641 CDK5 Zornitza Stark Phenotypes for gene: CDK5 were changed from to Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342
Mendeliome v0.2637 CDK5 Zornitza Stark reviewed gene: CDK5: Rating: RED; Mode of pathogenicity: None; Publications: 25560765; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2637 VPS51 Zornitza Stark Marked gene: VPS51 as ready
Mendeliome v0.2636 VPS51 Zornitza Stark gene: VPS51 was added
gene: VPS51 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable.
Sources: Expert list
Mendeliome v0.2635 CTSA Zornitza Stark changed review comment from: Bi-allelic variants cause galactosialidosis, and mono-allelic variants cause CARASAL.; to: Bi-allelic variants associated with galactosialidosis, and mono-allelic variants associated with CARASAL.
Mendeliome v0.2635 CTSA Zornitza Stark reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31177426; Phenotypes: Galactosialidosis, MIM# 256540, Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2635 CDK19 Zornitza Stark Marked gene: CDK19 as ready
Mendeliome v0.2634 CDK19 Zornitza Stark gene: CDK19 was added
gene: CDK19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDK19 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK19 were set to 32330417
Phenotypes for gene: CDK19 were set to Intellectual disability; epileptic encephalopathy
Review for gene: CDK19 was set to GREEN
Added comment: Three unrelated individuals with de novo missense variants reported, and intellectual disability/epileptic encephalopathy. Supportive functional data.
Sources: Literature
Mendeliome v0.2633 MNS1 Zornitza Stark Marked gene: MNS1 as ready
Mendeliome v0.2632 MNS1 Zornitza Stark gene: MNS1 was added
gene: MNS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNS1 were set to 31534215; 30148830
Phenotypes for gene: MNS1 were set to Heterotaxy; male infertility
Review for gene: MNS1 was set to GREEN
Added comment: Eight families reported altogether, three LoF variants. Four Amish families share same homozygous founder variant, and some of the other reported families are consanguineous and share another founder variant. A reported female with a third variant, also had a homozygous variant in DNAH5 with a blended phenotype postulated.
Sources: Literature
Mendeliome v0.2631 DHX37 Zornitza Stark Marked gene: DHX37 as ready
Mendeliome v0.2630 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX37 were set to 31337883; 31745530
Phenotypes for gene: DHX37 were set to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS)
Review for gene: DHX37 was set to GREEN
Added comment: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature
Mendeliome v0.2629 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache
Mendeliome v0.2627 RAMP2 Zornitza Stark Marked gene: RAMP2 as ready
Mendeliome v0.2626 RAMP2 Zornitza Stark gene: RAMP2 was added
gene: RAMP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAMP2 were set to 31000793
Phenotypes for gene: RAMP2 were set to Primary open angle glaucoma
Review for gene: RAMP2 was set to AMBER
Added comment: Six variants identified in 16 of 4763 POAG patients from large cohorts; none identified in 10,953 control individuals. Some functional data.
Sources: Literature
Mendeliome v0.2625 ALPK1 Zornitza Stark changed review comment from: Three unrelated families reported. One of the variants segregated in four affected individuals in one family and another was found to be de novo. The third variant however was not segregated, and is also present in 18 individuals in gnomad. Hence the evidence for variant pathogenicity in this third case is not compelling.
Sources: Literature; to: Three unrelated families reported with PFAPA phenotype. One of the variants segregated in four affected individuals in one family and another was found to be de novo. The third variant however was not segregated, and is also present in 18 individuals in gnomad. Hence the evidence for variant pathogenicity in this third case is not compelling.
Sources: Literature
Mendeliome v0.2625 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Added comment: Six unrelated families reported with same recurrent missense variant c.710C>T, (p.Thr237Met) and ROSAH syndrome phenotype. Pancytopaenia and recurrent infections present in some.; Changed rating: GREEN; Changed publications: 31053777, 30967659, 31939038; Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, ROSAH syndrome, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache
Mendeliome v0.2624 MEPE Zornitza Stark gene: MEPE was added
gene: MEPE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MEPE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MEPE were set to 30287925
Phenotypes for gene: MEPE were set to hereditary congenital facial paresis; otosclerosis
Review for gene: MEPE was set to AMBER
Added comment: Single four-generation family reported with variant in this gene segregating nonprogressive HCFP and mixed hearing loss (HL). Damaging variants (truncating/frameshift) found to be enriched in otosclerosis cohort (p = 0.0006–0.0060).
Sources: Literature
Mendeliome v0.2623 PAICS Zornitza Stark Marked gene: PAICS as ready
Mendeliome v0.2623 PAICS Zornitza Stark gene: PAICS was added
gene: PAICS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAICS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAICS were set to 31600779
Phenotypes for gene: PAICS were set to Polyhydramnios; multiple congenital abnormalities
Review for gene: PAICS was set to RED
Added comment: Two sibs from single family reported with homozygous missense variant. Functional data to demonstrate effect on protein function.
Sources: Literature
Mendeliome v0.2622 GALM Zornitza Stark Marked gene: GALM as ready
Mendeliome v0.2621 POLR3GL Zornitza Stark Marked gene: POLR3GL as ready
Mendeliome v0.2621 POLR3GL Zornitza Stark Added comment: Comment when marking as ready: Three cases altogether but the phenotypes are very different -- may still represent a spectrum with the more severe phenotypes resulting from truncating variants but further cases needed.
Mendeliome v0.2620 GALM Hazel Phillimore gene: GALM was added
gene: GALM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to PMID: 30451973; 30910422
Phenotypes for gene: GALM were set to galactosaemia; type IV galactosaemia
Review for gene: GALM was set to GREEN
Added comment: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). This is therefore type IV galactosaemia.
In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. Loss-of-function mechanism. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973)
In vitro expression assay and an enzyme activity assay of 67 GALM variants, taken from ExAc database (missense, nonsense, frameshift and splice). 30 variants concluded to be pathogenic due to no protein expression or faint expression. 5 variants with mildly lower levels were determined as likely pathogenic. All concluded to be loss-of-function mechanism. Incidence of galactosaemia by GALM deficiency is comparable to that of other galactosaemias. Carrier frequency and incidence was estimated for different populations. (Iwasawa, S. et al. (2019); PMID: 30910422)
Sources: Literature
Mendeliome v0.2620 POLR3GL Paul De Fazio gene: POLR3GL was added
gene: POLR3GL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3GL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3GL were set to 31089205; 31695177
Phenotypes for gene: POLR3GL were set to endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Review for gene: POLR3GL was set to AMBER
gene: POLR3GL was marked as current diagnostic
Added comment: Biallelic canonical splice variants were identified in monozygotic twins and another individual with similar phenotypes from 2 unrelated families. Variants were inherited from carrier parents. RNA studies confirmed exon skipping occurs in all affected individuals.

A separate study identified a homozygous nonsense variant in an individual with features of Neonatal progeroid syndrome/Wiedemann–Rautenstrauch syndrome. Quantitative PCR showed reduction in mRNA suggestive of NMD.
Sources: Literature
Mendeliome v0.2620 TSPEAR Zornitza Stark Marked gene: TSPEAR as ready
Mendeliome v0.2620 TSPEAR Zornitza Stark Added comment: Comment when marking as ready: Association with isolated deafness is DISPUTED.
Mendeliome v0.2620 TSPEAR Zornitza Stark Gene: tspear has been classified as Green List (High Evidence).
Mendeliome v0.2620 TSPEAR Zornitza Stark Phenotypes for gene: TSPEAR were changed from to Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180
Mendeliome v0.2619 TSPEAR Zornitza Stark Publications for gene: TSPEAR were set to
Mendeliome v0.2618 TSPEAR Zornitza Stark Mode of inheritance for gene: TSPEAR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2617 PDGFRB Zornitza Stark Marked gene: PDGFRB as ready
Mendeliome v0.2613 TBL1Y Zornitza Stark Marked gene: TBL1Y as ready
Mendeliome v0.2613 TBL1Y Zornitza Stark Added comment: Comment when marking as ready: Single family, some functional data.
Mendeliome v0.2612 DGCR8 Zornitza Stark Marked gene: DGCR8 as ready
Mendeliome v0.2611 TSPEAR Chern Lim changed review comment from: Still a rare disease gene for ectodermal dysplasia but has been reported in at least 3 unrelated families. Functional study supported LoF. (PMIDs: 27736875, 30046887); to: Still a rare disease gene for ectodermal dysplasia but has been reported in at least 3 unrelated families in 2 papers. Functional study supported LoF. (PMIDs: 27736875, 30046887)
Mendeliome v0.2611 TSPEAR Chern Lim reviewed gene: TSPEAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27736875, 30046887; Phenotypes: Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2611 PDGFRB Ee Ming Wong changed review comment from: - > 3 unrelated families
- Functional studies on patient fibroblasts, HeLa and HEK293 cells harbouring mutant constructs demonstrate constitutive tyrosine kinase activation (gain of function) compared with WT constructs; to: - > 3 unrelated individuals diagnosed with Penttinen syndrome
- Functional studies on patient fibroblasts, HeLa and HEK293 cells harbouring mutant constructs demonstrate constitutive tyrosine kinase activation (gain of function) compared with WT constructs
Mendeliome v0.2611 TBL1Y Paul De Fazio changed review comment from: 9 affected males in a single 5-generation pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature; to: Y-linked inheritance pattern. Complete segregation of a missense variant demonstrated in 9 affected males in a 5-generation pedigree. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 TBL1Y Paul De Fazio changed review comment from: 9 affected males in a single pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature; to: 9 affected males in a single 5-generation pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 TBL1Y Paul De Fazio gene: TBL1Y was added
gene: TBL1Y was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBL1Y was set to Other
Publications for gene: TBL1Y were set to 30341416
Phenotypes for gene: TBL1Y were set to Hearing loss
Review for gene: TBL1Y was set to RED
gene: TBL1Y was marked as current diagnostic
Added comment: 9 affected males in a single pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 FOXF2 Zornitza Stark Marked gene: FOXF2 as ready
Mendeliome v0.2611 FOXF2 Zornitza Stark Added comment: Comment when marking as ready: Single family: variant has functional data to demonstrate effect on protein, plus mouse model supports gene-disease association.
Mendeliome v0.2610 DGCR8 Chern Lim gene: DGCR8 was added
gene: DGCR8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DGCR8 were set to 31805011
Phenotypes for gene: DGCR8 were set to Early-onset multinodular goiter and schwannomatosis
Review for gene: DGCR8 was set to RED
Added comment: A germline missense variant segregates in one family with autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter (MNG) with schwannomatosis. The missense is also a recurrent somatic missense variant in Wilms tumour. (PMID:31805011)
Sources: Literature
Mendeliome v0.2610 TDRD7 Zornitza Stark Phenotypes for gene: TDRD7 were changed from to Cataract 36 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis
Mendeliome v0.2607 TDRD7 Ee Ming Wong reviewed gene: TDRD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28837160, 21436445; Phenotypes: cataract, glaucoma, nonobstructive azoospermia, arrested spermatogenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2607 FOXF2 Hazel Phillimore changed review comment from: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Sources: Literature; to: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Previous names for FOXF2 include FKHL6 and FREAC2.
Sources: Literature
Mendeliome v0.2607 FOXF2 Hazel Phillimore gene: FOXF2 was added
gene: FOXF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOXF2 were set to PMID: 30561639; 22022403
Phenotypes for gene: FOXF2 were set to profound sensorineural hearing loss (SNHL); cochlea malformations; incomplete partition type I anomaly of the cochlea
Review for gene: FOXF2 was set to AMBER
Added comment: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Sources: Literature
Mendeliome v0.2607 COL13A1 Zornitza Stark Marked gene: COL13A1 as ready
Mendeliome v0.2604 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317 to Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.2602 KIAA1161 Hazel Phillimore reviewed gene: KIAA1161: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29910000, 31009047; Phenotypes: Basal ganglia calcification, idiopathic, 7, autosomal recessive (OMIM #618317), primary familial brain calcifications (PFBC), ataxia, dysarthria, cerebellar atrophy, akinetic-hypertonic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2602 CACNB4 Zornitza Stark edited their review of gene: CACNB4: Added comment: PMID 32176688: A homozygous missense variant (Leu126Pro) reported in two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. Some functional data.; Changed publications: 10762541, 9628818, 27003325, 32176688; Changed phenotypes: Episodic ataxia, type 5, MIM#613855, Intellectual disability, Epilepsy, Movement disorder
Mendeliome v0.2602 WDR83OS Zornitza Stark Marked gene: WDR83OS as ready
Mendeliome v0.2600 LSR Zornitza Stark Marked gene: LSR as ready
Mendeliome v0.2598 WDR83OS Ee Ming Wong gene: WDR83OS was added
gene: WDR83OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to PMID: 30250217
Phenotypes for gene: WDR83OS were set to Cholestasis
Review for gene: WDR83OS was set to RED
Added comment: - 1 consanguineous family with 3 affected individuals found to carry a homozygous splice site variant in WDR83OS
- The variant results in an aberrant truncated RNA transcript as demonstrated by RT-PCR
Sources: Literature
Mendeliome v0.2595 USP53 Zornitza Stark Marked gene: USP53 as ready
Mendeliome v0.2592 LSR Ee Ming Wong gene: LSR was added
gene: LSR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSR were set to PMID: 30250217
Phenotypes for gene: LSR were set to transient neonatal cholestasis; intellectual disability; short stature
Review for gene: LSR was set to RED
Added comment: 1 individual from 1 consanguineous family carrying a homozygous missense variant in LSR
Sources: Literature
Mendeliome v0.2592 PPM1F Zornitza Stark Marked gene: PPM1F as ready
Mendeliome v0.2591 USP53 Ee Ming Wong gene: USP53 was added
gene: USP53 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP53 were set to PMID: 30250217
Phenotypes for gene: USP53 were set to Deafness
Review for gene: USP53 was set to RED
Added comment: 1 consanguineous family carrying a homozygous truncating variant in USP53
Sources: Literature
Mendeliome v0.2591 PPM1F Ee Ming Wong gene: PPM1F was added
gene: PPM1F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPM1F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPM1F were set to PMID: 30250217
Phenotypes for gene: PPM1F were set to sclerosing cholangitis; short stature; hypothyroidism; abnormal tongue pigmentation
Review for gene: PPM1F was set to RED
Added comment: 1 consanguineous family found to carry a homozygous missense variant in PPM1F
Sources: Literature
Mendeliome v0.2591 SPEF2 Zornitza Stark Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, MIM#618751 to Spermatogenic failure 43, MIM#618751; Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype
Mendeliome v0.2589 SPEF2 Zornitza Stark reviewed gene: SPEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942643; Phenotypes: Spermatogenic failure 43, MIM#618751, Primary ciliary dyskinesia-like phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2589 KLC2 Zornitza Stark Marked gene: KLC2 as ready
Mendeliome v0.2588 KLC2 Zornitza Stark gene: KLC2 was added
gene: KLC2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC2 were set to 26385635
Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy MIM#609541
Review for gene: KLC2 was set to GREEN
Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Only reported cause of condition is the upstream large deletion, which is not detected by whole-exome sequencing.
Sources: Expert Review
Mendeliome v0.2586 KIF12 Zornitza Stark Marked gene: KIF12 as ready
Mendeliome v0.2584 ALPK1 Zornitza Stark Marked gene: ALPK1 as ready
Mendeliome v0.2583 ALPK1 Zornitza Stark gene: ALPK1 was added
gene: ALPK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to 31053777
Phenotypes for gene: ALPK1 were set to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome
Review for gene: ALPK1 was set to AMBER
Added comment: Three unrelated families reported. One of the variants segregated in four affected individuals in one family and another was found to be de novo. The third variant however was not segregated, and is also present in 18 individuals in gnomad. Hence the evidence for variant pathogenicity in this third case is not compelling.
Sources: Literature
Mendeliome v0.2582 LRRC32 Zornitza Stark Marked gene: LRRC32 as ready
Mendeliome v0.2581 LRRC32 Zornitza Stark gene: LRRC32 was added
gene: LRRC32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112
Phenotypes for gene: LRRC32 were set to Intellectual disability; cleft palate; proliferative retinopathy
Review for gene: LRRC32 was set to AMBER
Added comment: Three individuals from two consanguineous families segregated the same homozygous bi-allelic variant, c.1630C>T; p.(Arg544Ter), shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death.
Sources: Literature
Mendeliome v0.2580 KIF12 Ee Ming Wong gene: KIF12 was added
gene: KIF12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF12 were set to PMID: 30250217; 30976738
Phenotypes for gene: KIF12 were set to Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT)
Review for gene: KIF12 was set to AMBER
gene: KIF12 was marked as current diagnostic
Added comment: > 3 unrelated families,but they are all consanguineous families
Sources: Literature
Mendeliome v0.2579 UBAP1 Zornitza Stark Phenotypes for gene: UBAP1 were changed from Spastic paraplegia 80, autosomal dominant 618418 to Childhood-onset hereditary spastic paraplegia; Spastic paraplegia 80, autosomal dominant 618418
Mendeliome v0.2577 UBAP1 Zornitza Stark reviewed gene: UBAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31696996; Phenotypes: Childhood-onset hereditary spastic paraplegia, Spastic paraplegia 80, autosomal dominant 618418; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2577 RHOA Zornitza Stark Phenotypes for gene: RHOA were changed from normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia to normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia; dental anomalies; body asymmetry; limb length discrepancy
Mendeliome v0.2575 RHOA Zornitza Stark reviewed gene: RHOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31821646; Phenotypes: hypopigmented areas of the skin, dental anomalies, body asymmetry, limb length discrepancy, MRI abnormalities; Mode of inheritance: Other
Mendeliome v0.2575 IQCE Zornitza Stark Marked gene: IQCE as ready
Mendeliome v0.2574 IQCE Zornitza Stark gene: IQCE was added
gene: IQCE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQCE were set to 31549751; 28488682
Phenotypes for gene: IQCE were set to Postaxial polydactyly
Review for gene: IQCE was set to GREEN
Added comment: Four families reported with bi-allelic variants in this gene. The c.895_904del (p.Val301Serfs*8) was found in three of the families without sharing a common haplotype, suggesting a recurrent mechanism. RNA expression analysis on patients’ fibroblasts showed that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrated a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects.
Sources: Literature
Mendeliome v0.2573 NKX2-3 Zornitza Stark Marked gene: NKX2-3 as ready
Mendeliome v0.2573 NKX2-3 Zornitza Stark gene: NKX2-3 was added
gene: NKX2-3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NKX2-3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NKX2-3 were set to 31498527
Phenotypes for gene: NKX2-3 were set to Intestinal varicosities
Review for gene: NKX2-3 was set to RED
Added comment: Single multiplex family where truncating variant in this gene segregated with intestinal varicosities with a LOD score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice.
Sources: Literature
Mendeliome v0.2572 RPSA Zornitza Stark changed review comment from: Four families reported with mono allelic variants and idiopathic intestinal varies.; to: Four families reported with mono allelic variants and idiopathic intestinal varies, often in combination with asplenia.
Mendeliome v0.2572 RPSA Zornitza Stark Marked gene: RPSA as ready
Mendeliome v0.2572 RPSA Zornitza Stark Phenotypes for gene: RPSA were changed from to Asplenia, isolated congenital 271400; Idiopathic intestinal varices
Mendeliome v0.2569 RPSA Zornitza Stark reviewed gene: RPSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 23579497, 31498527; Phenotypes: Asplenia, isolated congenital 271400, Idiopathic intestinal varices; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2567 CRAT Zornitza Stark Marked gene: CRAT as ready
Mendeliome v0.2566 CRAT Zornitza Stark gene: CRAT was added
gene: CRAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRAT were set to 29395073; 31448845
Phenotypes for gene: CRAT were set to Neurodegeneration with brain iron accumulation 8, MIM# 617917; Leigh syndrome
Review for gene: CRAT was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants, one with NBIA and one with Leigh syndrome phenotype.
Sources: Literature
Mendeliome v0.2565 CWF19L1 Zornitza Stark Marked gene: CWF19L1 as ready
Mendeliome v0.2565 CWF19L1 Zornitza Stark Phenotypes for gene: CWF19L1 were changed from to Spinocerebellar ataxia, autosomal recessive 17, MIM#616127; intellectual disability, developmental delay
Mendeliome v0.2562 CWF19L1 Zornitza Stark reviewed gene: CWF19L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361784, 15981765, 26197978, 27016154, 30167849; Phenotypes: Spinocerebellar ataxia, autosomal recessive 17, MIM#616127, intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2561 B4GAT1 Zornitza Stark Marked gene: B4GAT1 as ready
Mendeliome v0.2561 B4GAT1 Zornitza Stark Phenotypes for gene: B4GAT1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13 MIM# 615287
Mendeliome v0.2557 B4GAT1 Zornitza Stark reviewed gene: B4GAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23359570, 23877401; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13 MIM# 615287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2556 THG1L Zornitza Stark changed review comment from: Five individuals from two Ashkenazi Jewish families with same homozygous missense variant, and another family ascertained through a large microcephaly cohort, also with SCA.
Sources: Literature; to: Four Ashkenazi Jewish families with same homozygous missense variant, and another family ascertained through a large microcephaly cohort, also with SCA. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes found in Exac or gnomAD.
Sources: Literature
Mendeliome v0.2556 THG1L Zornitza Stark edited their review of gene: THG1L: Changed rating: GREEN; Changed phenotypes: Spinocerebellar ataxia, autosomal recessive 28, MIM# 618800
Mendeliome v0.2556 THG1L Zornitza Stark Marked gene: THG1L as ready
Mendeliome v0.2554 THG1L Zornitza Stark gene: THG1L was added
gene: THG1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THG1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THG1L were set to 27307223; 31168944; 30214071
Phenotypes for gene: THG1L were set to Spinocerebellar ataxia, autosomal recessive 28, MIM# 618800
Review for gene: THG1L was set to AMBER
Added comment: Five individuals from two Ashkenazi Jewish families with same homozygous missense variant, and another family ascertained through a large microcephaly cohort, also with SCA.
Sources: Literature
Mendeliome v0.2553 TRPV1 Zornitza Stark Marked gene: TRPV1 as ready
Mendeliome v0.2553 TRPV1 Zornitza Stark gene: TRPV1 was added
gene: TRPV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPV1 were set to 29930394
Phenotypes for gene: TRPV1 were set to Susceptibility to malignant hyperthermia
Review for gene: TRPV1 was set to RED
Added comment: Two individuals reported with rare/novel missense variants in this gene, some functional data.
Sources: Literature
Mendeliome v0.2552 ZP2 Zornitza Stark Marked gene: ZP2 as ready
Mendeliome v0.2551 ZP2 Zornitza Stark gene: ZP2 was added
gene: ZP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZP2 were set to 30810869; 29895852
Phenotypes for gene: ZP2 were set to Female infertility
Review for gene: ZP2 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and thin zona pellucida.
Sources: Literature
Mendeliome v0.2549 GAD1 Zornitza Stark changed review comment from: Single family reported with bi-allelic variants. Association studies linking with neuropsychiatric issues.; to: Single family reported with bi-allelic variants and CP phenotype. Association studies linking with neuropsychiatric issues.
Mendeliome v0.2549 GAD1 Zornitza Stark edited their review of gene: GAD1: Added comment: 2020: 11 individuals from 6 consanguineous families reported with bi-allelic LOF variant and a developmental/epileptic encephalopathy. Seizure onset occurred in the first 2 months of life in all. All 10 individuals, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight individuals had joint contractures and/or pes equinovarus. Seven presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four individuals died before 4 years of age.; Changed rating: GREEN; Changed publications: 15571623, 32282878; Changed phenotypes: Cerebral palsy, spastic quadriplegic, 1, MIM#603513, Developmental and epileptic encephalopathy
Mendeliome v0.2548 GALNT2 Zornitza Stark gene: GALNT2 was added
gene: GALNT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation
Review for gene: GALNT2 was set to GREEN
Added comment: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities.
Sources: Literature
Mendeliome v0.2547 C7orf43 Zornitza Stark Marked gene: C7orf43 as ready
Mendeliome v0.2547 C7orf43 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: MAP11
Mendeliome v0.2546 C7orf43 Zornitza Stark gene: C7orf43 was added
gene: C7orf43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C7orf43 were set to 30715179
Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351
Review for gene: C7orf43 was set to AMBER
Added comment: Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model.
Sources: Literature
Mendeliome v0.2545 PLPBP Zornitza Stark Phenotypes for gene: PLPBP were changed from Epilepsy, early-onset, vitamin B6-dependent, 617290 to Epilepsy, early-onset, vitamin B6-dependent, MIM#617290
Mendeliome v0.2543 PLPBP Zornitza Stark reviewed gene: PLPBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 27912044, 31741821, 30668673; Phenotypes: Epilepsy, early-onset, vitamin B6-dependent, MIM# 617290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2543 GRIN2A Zornitza Stark Marked gene: GRIN2A as ready
Mendeliome v0.2543 GRIN2A Zornitza Stark Phenotypes for gene: GRIN2A were changed from to Epilepsy, focal, with speech disorder and with or without mental retardation, MIM# 245570
Mendeliome v0.2539 GRIN2A Zornitza Stark reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30544257; Phenotypes: Epilepsy, focal, with speech disorder and with or without mental retardation, MIM# 245570; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2539 TSEN34 Zornitza Stark Marked gene: TSEN34 as ready
Mendeliome v0.2539 TSEN34 Zornitza Stark Added comment: Comment when marking as ready: Reviewed ClinVar: all variants submitted are VOUS or LB, except for one LP, but no further details provided.
Mendeliome v0.2539 TSEN34 Zornitza Stark Phenotypes for gene: TSEN34 were changed from to Pontocerebellar hypoplasia type 2C, MIM# 612390
Mendeliome v0.2535 TSEN34 Zornitza Stark reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 18711368; Phenotypes: Pontocerebellar hypoplasia type 2C, MIM# 612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2535 TSEN54 Zornitza Stark Marked gene: TSEN54 as ready
Mendeliome v0.2535 TSEN54 Zornitza Stark Phenotypes for gene: TSEN54 were changed from to Pontocerebellar hypoplasia type 2A 277470; Pontocerebellar hypoplasia type 4 225753; Ataxia
Mendeliome v0.2532 TSEN54 Zornitza Stark reviewed gene: TSEN54: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 2A 277470, Pontocerebellar hypoplasia type 4 225753, Ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2530 TMPRSS9 Zornitza Stark Marked gene: TMPRSS9 as ready
Mendeliome v0.2530 SLC6A6 Zornitza Stark Marked gene: SLC6A6 as ready
Mendeliome v0.2530 GABRB2 Zornitza Stark Phenotypes for gene: GABRB2 were changed from Epileptic encephalopathy, infantile or early childhood, 2, MIM# 617829 to Epileptic encephalopathy, infantile or early childhood, 2, MIM# 617829
Mendeliome v0.2529 GABRB2 Zornitza Stark Phenotypes for gene: GABRB2 were changed from to Epileptic encephalopathy, infantile or early childhood, 2, MIM# 617829
Mendeliome v0.2526 NDE1 Zornitza Stark Marked gene: NDE1 as ready
Mendeliome v0.2526 NDE1 Zornitza Stark Added comment: Comment when marking as ready: The two OMIM phenotypes likely represent a spectrum of brain abnormalities associated with this gene.
Mendeliome v0.2523 CDC45 Zornitza Stark Marked gene: CDC45 as ready
Mendeliome v0.2520 CPSF1 Zornitza Stark Phenotypes for gene: CPSF1 were changed from Myopia 27, 618827; high myopia; early-onset high myopiaHigh myopia to Myopia 27, 618827; high myopia; early-onset high myopia
Mendeliome v0.2519 CPSF1 Zornitza Stark Marked gene: CPSF1 as ready
Mendeliome v0.2518 CHD4 Zornitza Stark Marked gene: CHD4 as ready
Mendeliome v0.2515 RASA1 Zornitza Stark Phenotypes for gene: RASA1 were changed from to Capillary malformation-arteriovenous malformation 1, MIM#608354
Mendeliome v0.2512 CFAP69 Zornitza Stark Marked gene: CFAP69 as ready
Mendeliome v0.2512 CFAP69 Zornitza Stark Phenotypes for gene: CFAP69 were changed from to Asthenoteratospermia (Impaired sperm motility; severe flagellar abnormalities (short, coiled, absent or irregular calibre))
Mendeliome v0.2509 ABCA4 Zornitza Stark Marked gene: ABCA4 as ready
Mendeliome v0.2509 ABCA4 Zornitza Stark Phenotypes for gene: ABCA4 were changed from to Cone-rod dystrophy 3, 604116; Fundus flavimaculatus, 248200; Retinal dystrophy, early-onset severe, 248200; Retinitis pigmentosa 19, 601718; Stargardt disease 1, 248200
Mendeliome v0.2506 TLK2 Zornitza Stark Marked gene: TLK2 as ready
Mendeliome v0.2503 DYRK1A Zornitza Stark Marked gene: DYRK1A as ready
Mendeliome v0.2503 DYRK1A Zornitza Stark Phenotypes for gene: DYRK1A were changed from to Mental retardation, autosomal dominant 7 (MIM#614104)
Mendeliome v0.2500 WARS Zornitza Stark Marked gene: WARS as ready
Mendeliome v0.2500 WARS Zornitza Stark Gene: wars has been classified as Green List (High Evidence).
Mendeliome v0.2500 WARS Zornitza Stark Classified gene: WARS as Green List (high evidence)
Mendeliome v0.2500 WARS Zornitza Stark Gene: wars has been classified as Green List (High Evidence).
Mendeliome v0.2498 POLR1B Zornitza Stark Marked gene: POLR1B as ready
Mendeliome v0.2498 POLR1B Zornitza Stark Phenotypes for gene: POLR1B were changed from bilateral malar and mandibular hypoplasia; microtia; coloboma; downslanting palpebral fissures; conductive deafness; cleft palate; heart malformations to Treacher-Collins syndrome
Mendeliome v0.2496 POLR1B Zornitza Stark changed review comment from: Five unrelated families and a zebrafish model.; to: Five unrelated families and a zebrafish model. Note four of the families had missense variants affecting same residue, p.Arg1003
Mendeliome v0.2496 SLC35D1 Zornitza Stark Marked gene: SLC35D1 as ready
Mendeliome v0.2493 C1orf194 Zornitza Stark Marked gene: C1orf194 as ready
Mendeliome v0.2493 C1orf194 Zornitza Stark Added comment: Comment when marking as ready: Two unrelated families with missense variants, one with intermediate CMT, the other with demyelinating CMT. Different phenotypic manifestations may relate to different mechanism, but this remains to be fully elucidated. Supportive mouse model.
Mendeliome v0.2491 REC114 Zornitza Stark Marked gene: REC114 as ready
Mendeliome v0.2490 UBA2 Zornitza Stark Marked gene: UBA2 as ready
Mendeliome v0.2489 GABRB2 Elena Savva reviewed gene: GABRB2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 27789573, 29100083; Phenotypes: Epileptic encephalopathy, infantile or early childhood, 2 617829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.2489 STIM1 Zornitza Stark Marked gene: STIM1 as ready
Mendeliome v0.2489 STIM1 Zornitza Stark Phenotypes for gene: STIM1 were changed from to Immunodeficiency 10 612783; Myopathy, tubular aggregate, 1 160565; Stormorken syndrome 185070
Mendeliome v0.2485 ORAI1 Zornitza Stark Marked gene: ORAI1 as ready
Mendeliome v0.2485 ORAI1 Zornitza Stark Phenotypes for gene: ORAI1 were changed from to Immunodeficiency 9, MIM# 612782; Myopathy, tubular aggregate, 2, MIM# 615883
Mendeliome v0.2481 RTTN Zornitza Stark Marked gene: RTTN as ready
Mendeliome v0.2481 RTTN Zornitza Stark Phenotypes for gene: RTTN were changed from to Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; Intellectual disability; cerebral polymicrogyria; primary microcephaly; growth defects; congenital anomalies
Mendeliome v0.2478 UBAP1 Zornitza Stark Marked gene: UBAP1 as ready
Mendeliome v0.2478 UBAP1 Zornitza Stark Phenotypes for gene: UBAP1 were changed from to Spastic paraplegia 80, autosomal dominant 618418
Mendeliome v0.2474 MRPS14 Zornitza Stark Phenotypes for gene: MRPS14 were changed from Combined oxidative phosphorylation deficiency 38, MIM# 618378 to Combined oxidative phosphorylation deficiency 38, MIM# 618378; perinatal hypertrophic cardiomyopathy, growth retardation, muscle hypotonia, elevated lactate, dysmorphy and intellectual disability
Mendeliome v0.2472 MCAT Zornitza Stark Marked gene: MCAT as ready
Mendeliome v0.2471 ABCC1 Zornitza Stark Marked gene: ABCC1 as ready
Mendeliome v0.2470 ABCC1 Zornitza Stark gene: ABCC1 was added
gene: ABCC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ABCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABCC1 were set to 31273342
Phenotypes for gene: ABCC1 were set to Nonsyndromic hearing loss
Review for gene: ABCC1 was set to AMBER
Added comment: Total of 3 variants reported in 3 families, including 1 which segregates in a large family (10 affected) PMID: 31273342; Li 2019: Reported 3 different het missense in 3 families with postlingual ADNSHL. 1 missense segregated in a large Chinese family. This variant is present in gnomAD (10 hets), but onset noted to be in 2nd or 3rd decade of life. Functional studies performed. Other 2 variants reported absent in gnomAD. Amber rating in light of gnomad frequency of one of the reported variants.
Sources: Literature
Mendeliome v0.2469 GABRA1 Zornitza Stark Marked gene: GABRA1 as ready
Mendeliome v0.2468 GABRA1 Zornitza Stark Phenotypes for gene: GABRA1 were changed from to Epileptic encephalopathy, early infantile, 19 615744; Rett syndrome; Rett-like phenotypes; idiopathic generalized Epilepsy; Dravet syndrome
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Marked gene: SIGMAR1 as ready
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Gene: sigmar1 has been classified as Green List (High Evidence).
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Phenotypes for gene: SIGMAR1 were changed from to Amyotrophic lateral sclerosis 16, juvenile 614373; ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726; distal hereditary motor neuropathy of Jerash type (HMNJ)
Mendeliome v0.2465 SIGMAR1 Zornitza Stark Publications for gene: SIGMAR1 were set to
Mendeliome v0.2464 SIGMAR1 Zornitza Stark Mode of inheritance for gene: SIGMAR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2463 ATOH7 Zornitza Stark Marked gene: ATOH7 as ready
Mendeliome v0.2463 ATOH7 Zornitza Stark Phenotypes for gene: ATOH7 were changed from to Persistent hyperplastic primary vitreous, autosomal recessive, MIM# 221900; microphthalmia; cataract; glaucoma; congenital retinal nonattachment
Mendeliome v0.2459 GNAI2 Zornitza Stark Marked gene: GNAI2 as ready
Mendeliome v0.2458 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy
Mendeliome v0.2455 KLHL24 Zornitza Stark reviewed gene: KLHL24: Rating: GREEN; Mode of pathogenicity: None; Publications: 30715372; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2455 FEM1B Zornitza Stark Marked gene: FEM1B as ready
Mendeliome v0.2455 FEM1B Zornitza Stark Added comment: Comment when marking as ready: Agree cannot be confident these represent three unrelated families.
Mendeliome v0.2452 SEC31A Zornitza Stark Marked gene: SEC31A as ready
Mendeliome v0.2452 SEC31A Zornitza Stark Phenotypes for gene: SEC31A were changed from congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MIM# 618651; congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive
Mendeliome v0.2450 SLC44A1 Zornitza Stark Marked gene: SLC44A1 as ready
Mendeliome v0.2450 SLC44A1 Zornitza Stark Added comment: Comment when marking as ready: Childhood onset neurodegeneration
Mendeliome v0.2449 SMCHD1 Zornitza Stark Marked gene: SMCHD1 as ready
Mendeliome v0.2449 SMCHD1 Zornitza Stark Added comment: Comment when marking as ready: Note association with FSHD2 is postulated to have digenic inheritance, caused by the combination of a heterozygous mutation in the SMCHD1 gene (614982) on chromosome 18p and presence of a haplotype on chromosome 4 that is permissive for DUX4 (606009) expression.
Mendeliome v0.2449 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from to Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.2446 CDKL5 Zornitza Stark Marked gene: CDKL5 as ready
Mendeliome v0.2446 CDKL5 Zornitza Stark Phenotypes for gene: CDKL5 were changed from to Epileptic encephalopathy, early infantile, 2, MIM 300672
Mendeliome v0.2443 AEBP1 Zornitza Stark Marked gene: AEBP1 as ready
Mendeliome v0.2440 SLC6A6 Chern Lim gene: SLC6A6 was added
gene: SLC6A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034
Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy
Review for gene: SLC6A6 was set to AMBER
Added comment: Different homozygous missense variants in 2 unrelated consanguineous families with early retinal degeneration, some functional studies. Patients in one of the families also had cardiomyopathy. (PMIDs: 31345061, 31903486)

One dilated cardiomyopathy patient with a homozygous deletion at a splice site (PMID: 29886034).
Sources: Literature
Mendeliome v0.2440 MRPS14 Dean Phelan reviewed gene: MRPS14: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30358850; Phenotypes: perinatal hypertrophic cardiomyopathy, growth retardation, muscle hypotonia, elevated lactate, dysmorphy and intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2440 TMPRSS9 Chern Lim gene: TMPRSS9 was added
gene: TMPRSS9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to autism spectrum disorder
Review for gene: TMPRSS9 was set to RED
Added comment: Association with Mendelian disease not established.

Is a candidate gene for autism spectrum disorder: single patient, compound heterozygous nonsense variants. Functional studies showed Tmprss9 gene is expressed in mouse brain, knockout mice had decreased social interest and social recognition. (PMID: 31943016)
Sources: Literature
Mendeliome v0.2440 MCAT Chern Lim gene: MCAT was added
gene: MCAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCAT were set to 31915829
Phenotypes for gene: MCAT were set to progressive autosomal recessive optic neuropathy
Review for gene: MCAT was set to RED
Added comment: One family reported - a consanguineous family, two homozygous missense variants in both affected siblings. Functional studies showed both missense together have synergic impact on MCAT protein misfolding; p.(L81R) had more impact on MCAT protein expression reduction than did the p.(R212W); some study in conditional knockout mice. (PMID:31915829)
Sources: Literature
Mendeliome v0.2440 CAP2 Melanie Marty edited their review of gene: CAP2: Added comment: 2 patients with dilated cardiomyopathy from 1 consanguineous family. The splice variant identified in this family was proven to cause exon skipping and functional studies showed protein level was reduced. A Cap2 knockout mouse model correlated with the clinical phenotype of DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development.; Changed rating: RED
Mendeliome v0.2440 WIPI2 Melanie Marty edited their review of gene: WIPI2: Added comment: Four homozygous patients from one consanguineous family with intellectual developmental, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function.; Changed rating: RED; Changed phenotypes: Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Mendeliome v0.2440 GFAP Paul De Fazio changed review comment from: Many (>20) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2440 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>20) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2440 UBAP1 Ain Roesley reviewed gene: UBAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31203368; Phenotypes: hereditary spastic paraplegia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2440 RTTN Ee Ming Wong reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 30879067; Phenotypes: Intellectual disability, cerebral polymicrogyria, primary microcephaly, growth defects, congenital anomalies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2440 PKDCC Paul De Fazio changed review comment from: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature; to: 2 apparently unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature
Mendeliome v0.2440 ORAI1 Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a slowly progressive myopathy (tubular aggregate myopathy/TAM)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy)
Mendeliome v0.2440 CDKL5 Teresa Zhao reviewed gene: CDKL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 2, MIM 300672; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.2440 UBA2 Elena Savva gene: UBA2 was added
gene: UBA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBA2 were set to PMID: 31332306; 31587267
Phenotypes for gene: UBA2 were set to Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly
Penetrance for gene: UBA2 were set to unknown
Review for gene: UBA2 was set to AMBER
Added comment: No OMIM phenotype

PMID: 31332306 - a single patient with a de novo PTC and split hand/foot malformation (SHFM). Additional two multigenic CNVs including this gene in patients with SHFM and ectrodactyly. Authors mention an additional de novo missense but the patient didnt have SHFM, argue low penetrance

PMID: 31587267 - a mother and son with aplasia cutis congenita (ACC), with a heterozygous PTC. Son also has ectrodactyly. Authors note an additional de novo missense in a patient with ACC.
Sources: Literature
Mendeliome v0.2440 ORAI1 Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy)
Mendeliome v0.2440 GSX2 Zornitza Stark Marked gene: GSX2 as ready
Mendeliome v0.2440 GSX2 Zornitza Stark Added comment: Comment when marking as ready: Intellectual disability, spastic tetraparesis, dystonia
Mendeliome v0.2440 REC114 Michelle Torres gene: REC114 was added
gene: REC114 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REC114 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REC114 were set to 30388401; 31704776
Phenotypes for gene: REC114 were set to Female infertility
Review for gene: REC114 was set to GREEN
Added comment: Three variants reported are either within or flanking exon 4.
- One hom patient (splice) had a miscarriage, 2 spontaneous complete hydatidiform moles, and 1 complete hydatidiform mole following intrauterine sperm injection (PMID: 30388401)
- Two hom unrelated patients from consanguineous families with abnormal pronuclear formation during fertilisation and subsequent early embrionic arrest resulting in female infertility. Both variants (1 missense and 1 splice) were shown to result in LoF (PMID: 31704776)
Sources: Literature
Mendeliome v0.2440 AGTPBP1 Kristin Rigbye reviewed gene: AGTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30420557; Phenotypes: Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy, Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2440 GSX2 Zornitza Stark Marked gene: GSX2 as ready
Mendeliome v0.2439 C1orf194 Ain Roesley gene: C1orf194 was added
gene: C1orf194 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C1orf194 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C1orf194 were set to PMID: 31199454
Phenotypes for gene: C1orf194 were set to Charcot-Marie-Tooth
Review for gene: C1orf194 was set to AMBER
Added comment: PMID: 31199454; 2 missense variants in 2 large families segregating in an AD pattern. Mouse models for one of the variants (p.(Ile121Asn) led to impairments in moto and neuromuscular functions
Sources: Literature
Mendeliome v0.2439 POLR1B Paul De Fazio changed review comment from: 6 individuals with Treacher-Collins syndrome described: 3 with de novo variants, one inherited from a mosaic father, and two inherited from affected mothers. Knockdown in zebrafish mimics the phenotype.
Sources: Literature; to: 6 individuals with Treacher-Collins syndrome described: 3 with de novo variants, one inherited from a mosaic father, and two inherited from affected mothers. Knockdown in zebrafish mimics the phenotype.
Sources: Literature
Mendeliome v0.2439 POLR1B Paul De Fazio gene: POLR1B was added
gene: POLR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR1B were set to 31649276
Phenotypes for gene: POLR1B were set to bilateral malar and mandibular hypoplasia; microtia; coloboma; downslanting palpebral fissures; conductive deafness; cleft palate; heart malformations
Review for gene: POLR1B was set to AMBER
gene: POLR1B was marked as current diagnostic
Added comment: 6 individuals with Treacher-Collins syndrome described: 3 with de novo variants, one inherited from a mosaic father, and two inherited from affected mothers. Knockdown in zebrafish mimics the phenotype.
Sources: Literature
Mendeliome v0.2439 CREB3L1 Zornitza Stark Marked gene: CREB3L1 as ready
Mendeliome v0.2436 WARS Naomi Baker gene: WARS was added
gene: WARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WARS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WARS were set to PMID: 28369220; 31321409; 31069783.
Phenotypes for gene: WARS were set to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); distal wasting; distal weakness; length-dependent motor axonal degeneration
Review for gene: WARS was set to GREEN
Added comment: 14 patients from five families were reported to have WARS-related neuropathy across three publications. Expression studies of mutant demonstrated decreased protein when compared to wild-type.
Sources: Literature
Mendeliome v0.2436 ACKR3 Zornitza Stark Marked gene: ACKR3 as ready
Mendeliome v0.2434 CYLD Zornitza Stark Marked gene: CYLD as ready
Mendeliome v0.2431 PCDH19 Zornitza Stark Marked gene: PCDH19 as ready
Mendeliome v0.2431 PCDH19 Zornitza Stark Phenotypes for gene: PCDH19 were changed from to Epileptic encephalopathy, early infantile, 9 300088; PCDH19-related epilepsy (early seizure onset, generalised or focused seizures); cognitive impairment
Mendeliome v0.2428 GFAP Zornitza Stark Marked gene: GFAP as ready
Mendeliome v0.2425 COPA Zornitza Stark Marked gene: COPA as ready
Mendeliome v0.2422 DYRK1A Crystle Lee reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25707398, 31263215; Phenotypes: Mental retardation, autosomal dominant 7 (MIM#614104); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.2421 PLOD3 Alison Yeung Marked gene: PLOD3 as ready
Mendeliome v0.2421 PLOD3 Alison Yeung Added comment: Comment when marking as ready: >3 unrelated families reported
Mendeliome v0.2421 FOXG1 Zornitza Stark Marked gene: FOXG1 as ready
Mendeliome v0.2421 FOXG1 Zornitza Stark Phenotypes for gene: FOXG1 were changed from to Rett syndrome, congenital variant, MIM# 613454
Mendeliome v0.2418 TBX6 Alison Yeung Marked gene: TBX6 as ready
Mendeliome v0.2418 TBX6 Alison Yeung Added comment: Comment when marking as ready: Biallelic variants associated with spondylocostal dysostosis in >3 unrelated individuals
Mouse model recapitulates phenotype
Mendeliome v0.2418 SAMD12 Zornitza Stark Marked gene: SAMD12 as ready
Mendeliome v0.2416 ABCA4 Kristin Rigbye reviewed gene: ABCA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 9054934, 30480703, 29847635, 29971439, 16103129, 30643219; Phenotypes: Cone-rod dystrophy 3, 604116, Fundus flavimaculatus, 248200, Retinal dystrophy, early-onset severe, 248200, Retinitis pigmentosa 19, 601718, Stargardt disease 1, 248200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2416 CFAP69 Ee Ming Wong reviewed gene: CFAP69: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29606301, 30415212; Phenotypes: Asthenoteratospermia (Impaired sperm motility, severe flagellar abnormalities (short, coiled, absent or irregular calibre)); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2416 UBE3A Alison Yeung Marked gene: UBE3A as ready
Mendeliome v0.2416 RASA1 Chern Lim reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14639529, 29891884, 24038909, 31300548; Phenotypes: Capillary malformation-arteriovenous malformation 1, MIM#608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.2416 ADAMTS19 Alison Yeung Marked gene: ADAMTS19 as ready
Mendeliome v0.2416 ADAMTS19 Alison Yeung Added comment: Comment on list classification: Two different homozygous variants in two consanguineous families. Animal model demonstrates cardiac phenotype
Await further reported families
Mendeliome v0.2415 YARS Zornitza Stark Marked gene: YARS as ready
Mendeliome v0.2415 YARS Zornitza Stark Gene: yars has been classified as Green List (High Evidence).
Mendeliome v0.2415 YARS Zornitza Stark Phenotypes for gene: YARS were changed from to Charcot-Marie-Tooth disease, dominant intermediate C 608323; Bi-allelic variants: ID, deafness, nystagmus
Mendeliome v0.2414 YARS Zornitza Stark Publications for gene: YARS were set to
Mendeliome v0.2413 YARS Zornitza Stark Mode of inheritance for gene: YARS was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2412 CFAP65 Zornitza Stark Marked gene: CFAP65 as ready
Mendeliome v0.2411 CAP2 Alison Yeung Marked gene: CAP2 as ready
Mendeliome v0.2411 CAP2 Alison Yeung Added comment: Comment on list classification: Currently only one consanguineous family reported.
Knockout mouse model shows cardiomyopathy but not other clinical features reported in this family
Mendeliome v0.2410 IGF1R Zornitza Stark Marked gene: IGF1R as ready
Mendeliome v0.2407 SHANK3 Zornitza Stark Marked gene: SHANK3 as ready
Mendeliome v0.2404 SCN1A Zornitza Stark Marked gene: SCN1A as ready
Mendeliome v0.2404 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208
Mendeliome v0.2401 CPSF1 Kristin Rigbye changed review comment from: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892).
Sources: Literature; to: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (PMID: 30689892).
Sources: Literature
Mendeliome v0.2401 CPSF1 Kristin Rigbye edited their review of gene: CPSF1: Changed phenotypes: Myopia 27, 618827, high myopia, early-onset high myopia, high myopia
Mendeliome v0.2401 CPSF1 Kristin Rigbye gene: CPSF1 was added
gene: CPSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CPSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CPSF1 were set to 30689892
Phenotypes for gene: CPSF1 were set to Myopia 27, 618827; high myopia; early-onset high myopiaHigh myopia
Review for gene: CPSF1 was set to GREEN
Added comment: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892).
Sources: Literature
Mendeliome v0.2401 STXBP1 Zornitza Stark Marked gene: STXBP1 as ready
Mendeliome v0.2401 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from to Epileptic encephalopathy, early infantile, 4 612164; Rett syndrome; Rett-like phenotypes
Mendeliome v0.2398 NAA10 Zornitza Stark Marked gene: NAA10 as ready
Mendeliome v0.2395 WDR45 Zornitza Stark Marked gene: WDR45 as ready
Mendeliome v0.2395 SIGMAR1 Michelle Torres changed review comment from: PMID: 31511340:
- N167I (1 het in gnomAD): in 7 consanguinous families from region of Jordan with a specific type of distal hereditary motor neuropathy of Jerash type (HMNJ). Experiments show loss of function effect.
- Lists recent publications with other variants (missense and truncating) in patients with distal hereditary motor neuropathy (dHMN) with mild pyramidal signs and jALS (juvenile ALS); to: PMID: 31511340:
- N167I (1 het in gnomAD): in 7 consanguinous families from region of Jordan with a specific type of distal hereditary motor neuropathy of Jerash type (HMNJ). Experiments show loss of function effect.
- Lists recent publications with other variants (missense and truncating) in patients with distal hereditary motor neuropathy (dHMN) with mild pyramidal signs and jALS (juvenile ALS)
Mendeliome v0.2392 SIGMAR1 Michelle Torres reviewed gene: SIGMAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31511340; Phenotypes: ?Amyotrophic lateral sclerosis 16, juvenile 614373, ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726, distal hereditary motor neuropathy of Jerash type (HMNJ); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2392 ATOH7 Paul De Fazio reviewed gene: ATOH7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22068589, 22645276, 31696227, 11493566, 11493566; Phenotypes: microphthalmia, cataract, glaucoma, congenital retinal nonattachment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2392 GNAI2 Elena Savva gene: GNAI2 was added
gene: GNAI2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNAI2 were set to PMID: 31036916
Phenotypes for gene: GNAI2 were set to Pituitary adenoma, ACTH-secreting, somatic; Ventricular tachycardia, idiopathic 192605; Syndromic developmental disorder
Review for gene: GNAI2 was set to AMBER
Added comment: Papers associating this gene to tachycardia are very old (pre 2000, OMIM).

PMID: 31036916 - a single de novo patient with syndromic developmental disorder

Summary: AMBER - one report, may be a coincidental de novo finding
Sources: Literature
Mendeliome v0.2392 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from {Microvascular complications of diabetes 6} 612634 to {Microvascular complications of diabetes 6} 612634; Lethal neonatal dilated cardiomyopathy
Mendeliome v0.2389 ASCC1 Zornitza Stark Marked gene: ASCC1 as ready
Mendeliome v0.2389 ASCC1 Zornitza Stark Phenotypes for gene: ASCC1 were changed from to Spinal muscular atrophy with congenital bone fractures 2, MIM#616867
Mendeliome v0.2386 FEM1B Elena Savva gene: FEM1B was added
gene: FEM1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEM1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1B were set to PMID: 31036916
Phenotypes for gene: FEM1B were set to Syndromic global developmental delay
Review for gene: FEM1B was set to AMBER
Added comment: No OMIM phenotype

PMID: 31036916 - a single de novo patient reported in a neurodevelopmental disorder cohort. Authors note another de novo case with the exact same variant (p.Arg126Gln) from the DDD study, and a 3rd patient from GeneMatcher with the same de novo missense again. Decipher shows this variant to be in a highly constrained region of the protein.

Have selected AMBER for now - not sure if GeneMatcher findings can be used as a 3rd case
Sources: Literature
Mendeliome v0.2386 SMAD2 Zornitza Stark Marked gene: SMAD2 as ready
Mendeliome v0.2386 SMAD2 Zornitza Stark Phenotypes for gene: SMAD2 were changed from to Aortic and arterial aneurysmal disease; connective tissue disease
Mendeliome v0.2384 RXFP2 Alison Yeung Added comment: Comment on list classification: Only single reported family with animal model reported. Both reviews to date are based on same publication. No new publications/reported cases since this one.
Mendeliome v0.2383 SMCHD1 Teresa Zhao changed review comment from: Seven probands with FSHD reported to have LP/P variants, which all predicted to disrupt the structure and conformation of SMCHD1.; to: Seven probands with FSHD reported to have LP/P variants, which all predicted to disrupt the structure and conformation of SMCHD1.

No particular geno-pheno correlation, but location of missense variants within the ATPase domain of MSCHD1 may contribute to the differences in phenotypic outcome (PMID: 31243061)
Mendeliome v0.2383 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2383 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2382 RXFP2 Zornitza Stark Marked gene: RXFP2 as ready
Mendeliome v0.2378 WIPI2 Melanie Marty gene: WIPI2 was added
gene: WIPI2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPI2 were set to 30968111
Phenotypes for gene: WIPI2 were set to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Review for gene: WIPI2 was set to AMBER
Added comment: Four homozygous patients from one consanguineous family with intellectual developmental, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function.
Sources: Literature
Mendeliome v0.2378 SEC31A Hazel Phillimore gene: SEC31A was added
gene: SEC31A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to PMID: 30464055
Phenotypes for gene: SEC31A were set to congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive
Review for gene: SEC31A was set to AMBER
Added comment: Frameshift. c.2776_2777, TA duplication, causing predicted p.A927fs*61 truncation and predicted NMD in 2 affected siblings in consanguineous Bedouin family with severe congenital neurological syndrome with spastic paraplegia, multiple contractures, profound developmental delay and convulsions. Failure to thrive. Lethal by age 4 years. Also had hearing defect, bilateral congenital cataract, horizontal nystagmus, with flat retina and optic atrophy. Supporting functional assays from knockout drosophila.
Sources: Literature
Mendeliome v0.2378 SLC44A1 Sebastian Lunke gene: SLC44A1 was added
gene: SLC44A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC44A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC44A1 were set to 31855247
Phenotypes for gene: SLC44A1 were set to progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria
Review for gene: SLC44A1 was set to GREEN
Added comment: Four affected individuals from three families with homozygous frameshift variants. Functional evidence points to impaired choline transporter function yet unchanged membrane phosphatidylcholine content. Choline treatments may be beneficial.
Sources: Literature
Mendeliome v0.2377 SMCHD1 Teresa Zhao reviewed gene: SMCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31600781; Phenotypes: Bosma arhinia microphthalmia syndrome, MIM 603457, Fascioscapulohumeral muscular dystrophy 2, digenic; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2377 GSX2 Elena Savva gene: GSX2 was added
gene: GSX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSX2 were set to PMID: 31412107
Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646
Review for gene: GSX2 was set to GREEN
Added comment: PMID: 31412107 - 2 unrelated patients with homozygous mutations (nonsense, missense). Functional analysis of the missense in transfected HeLa cells demonstrated protein mislocalization and protein expression. Downstream gene expression was also reduced by both mutations.

Summary: GREEN - 2 patients and functional evidence
Sources: Literature
Mendeliome v0.2377 SPEF2 Zornitza Stark Marked gene: SPEF2 as ready
Mendeliome v0.2376 PKDCC Alison Yeung Marked gene: PKDCC as ready
Mendeliome v0.2376 PKDCC Alison Yeung Added comment: Comment on list classification: Two unrelated consanguineous families reported with different homozygous variants
Pre-existing mouse model has similar phenotype
Needs more functional evidence or further reported families
Mendeliome v0.2375 SPEF2 Chern Lim gene: SPEF2 was added
gene: SPEF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344
Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751
Review for gene: SPEF2 was set to GREEN
gene: SPEF2 was marked as current diagnostic
Added comment: More than 3 unrelated families reported, all PTVs or splice variant. Functional studies showed SPEF2 protein levels were reduced in patients’ spermatozoa. (PMIDs: 31151990, 31278745, 31048344).
Sources: Literature
Mendeliome v0.2375 DHH Zornitza Stark Phenotypes for gene: DHH were changed from to 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080
Mendeliome v0.2372 MYCN Zornitza Stark Marked gene: MYCN as ready
Mendeliome v0.2371 CNNM4 Zornitza Stark Marked gene: CNNM4 as ready
Mendeliome v0.2371 PCDH19 Ee Ming Wong reviewed gene: PCDH19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18469813, 30287595; Phenotypes: PCDH19-related epilepsy (early seizure onset, generalised or focused seizures), cognitive impairment; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v0.2368 ATM Zornitza Stark Marked gene: ATM as ready
Mendeliome v0.2365 ADAMTS19 Crystle Lee changed review comment from: PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Expert Review; to: Borderline amber/green
PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Expert Review
Mendeliome v0.2365 ADAMTS19 Crystle Lee changed review comment from: PMID: 31844321; Wünnemann 2020: 4 affected in unrelated 2 consanguineous family with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Expert Review; to: PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Expert Review
Mendeliome v0.2365 FUS Elena Savva gene: FUS was added
gene: FUS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FUS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FUS were set to PMID: 32281455; 20668259; 20385912
Phenotypes for gene: FUS were set to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia 608030; Essential tremor, hereditary, 4 614782
Mode of pathogenicity for gene: FUS was set to Other
Review for gene: FUS was set to GREEN
Added comment: PMID: 32281455 - Reports a case of Pediatric Amyotrophic Lateral Sclerosis. Reviews and shows multiple other reports of ALS casued by FUS

PMID: 20668259 - additional reports of ALS

PMID: 20385912 - postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function.
Sources: Literature
Mendeliome v0.2365 ADAMTS19 Crystle Lee gene: ADAMTS19 was added
gene: ADAMTS19 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 31844321
Phenotypes for gene: ADAMTS19 were set to Non-syndromic heart valve disease
Review for gene: ADAMTS19 was set to GREEN
Added comment: PMID: 31844321; Wünnemann 2020: 4 affected in unrelated 2 consanguineous family with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Expert Review
Mendeliome v0.2365 ELOVL1 Hazel Phillimore changed review comment from: De novo in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features.; to: De novo missense (S165F) in 2 unrelated patients. Decrease in ELOVL1 enzyme activity. The same 2 patients are in PMIDs: 30487246 and 29496980 but with different clinical findings. Deafness and optic atrophy are the additional features.
Mendeliome v0.2365 ELOVL1 Hazel Phillimore reviewed gene: ELOVL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30487246, 29496980; Phenotypes: ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness, optic atrophy, nystagmus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2365 TNFRSF21 Alison Yeung Marked gene: TNFRSF21 as ready
Mendeliome v0.2364 YARS Dean Phelan reviewed gene: YARS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 30304524, 29232904, 27633801, 19561293; Phenotypes: peripheral neuropathy, multisystem disease, CMT; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2364 CFAP65 Daniel Flanagan gene: CFAP65 was added
gene: CFAP65 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP65 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP65 were set to 31501240; 31413122
Phenotypes for gene: CFAP65 were set to Spermatogenic failure 40 618664
Penetrance for gene: CFAP65 were set to unknown
Review for gene: CFAP65 was set to GREEN
gene: CFAP65 was marked as current diagnostic
Added comment: 9 patients with multiple morphological abnormalities of the sperm flagella (MMAF) or completely immotile spermatozoa, in which, homozygous or compound heterozygous truncating CFAP65 variants were identified. Cfap65-mutated male mice displayed typical MMAF phenotypes with severe morphological abnormalities of the sperm flagella (PMID: 31501240, 31413122).
Sources: Literature
Mendeliome v0.2364 CAP2 Melanie Marty gene: CAP2 was added
gene: CAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAP2 were set to 30518548
Phenotypes for gene: CAP2 were set to Dilated cardiomyopathy
Review for gene: CAP2 was set to AMBER
Added comment: 2 patients with dilated cardiomyopathy from 1 consanguineous family. The splice variant identified in this family was proven to cause exon skipping and functional studies showed protein level was reduced. A Cap2 knockout mouse model correlated with the clinical phenotype of DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development.
Sources: Literature
Mendeliome v0.2364 USP45 Alison Yeung Marked gene: USP45 as ready
Mendeliome v0.2363 SYCP2 Zornitza Stark Marked gene: SYCP2 as ready
Mendeliome v0.2361 SOD2 Chern Lim reviewed gene: SOD2: Rating: RED; Mode of pathogenicity: None; Publications: 31494578; Phenotypes: Lethal neonatal dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2361 ASCC1 Sarah Pantaleo reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327447, 12077347, 26924529, 31880396, 26503956; Phenotypes: Arthrogryposis, congenital bone fractures, spinal muscular atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2361 SMAD2 Melanie Marty reviewed gene: SMAD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29967133; Phenotypes: Aortic and arterial aneurysmal disease, connective tissue disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2361 PKDCC Paul De Fazio gene: PKDCC was added
gene: PKDCC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to PMID:30478137; 19097194
Phenotypes for gene: PKDCC were set to Dysmorphism; shortening of extremities
Review for gene: PKDCC was set to AMBER
gene: PKDCC was marked as current diagnostic
Added comment: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature
Mendeliome v0.2361 DHH Naomi Baker reviewed gene: DHH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31018998, 29471294, 11017805; Phenotypes: gonadal dysgenesis, minifascicular neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2361 TNFRSF21 Shannon Cowie gene: TNFRSF21 was added
gene: TNFRSF21 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TNFRSF21 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNFRSF21 were set to PMID: 31189563
Phenotypes for gene: TNFRSF21 were set to high myopia
Review for gene: TNFRSF21 was set to RED
gene: TNFRSF21 was marked as current diagnostic
Added comment: Source: JMG review Oct 2019
Large Chinese family, including 12 patients with non-syndromic HM
Immunofluorescence assay indicated that it is strongly expressed in the mouse eye.
Sources: Other
Mendeliome v0.2361 USP45 Kristin Rigbye gene: USP45 was added
gene: USP45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP45 were set to 30573563
Phenotypes for gene: USP45 were set to Leber congenital amaurosis; retinal dystrophy
Review for gene: USP45 was set to GREEN
Added comment: 2 unrelated Chinese families reported with rare homozygous variants (one missense, one nonsense) and Leber congenital amaurosis. Animal knockout functional studies supported gene-disease association.

PMID: 30573563 "By analysing WES data based on allele frequencies of in-house controls, population allele frequencies and in silico prediction tools, two rare homozygous mutations in USP45 were identified in two unrelated families. Immunohistochemistry of USP45 in the human and zebrafish retinal sections revealed enriched expression in the inner segments of photoreceptors. The knockdown of usp45 transcript in zebrafish led to abnormal retinal development with effects on photoreceptors, which could be successfully rescued by wild-type usp45 mRNA. Moreover, targeted knockout of Usp45 in mice caused abnormal electroretinography responses, similar to that seen in patients with LCA."
Sources: Literature
Mendeliome v0.2361 BAZ2B Zornitza Stark Marked gene: BAZ2B as ready
Mendeliome v0.2360 BAZ2B Zornitza Stark gene: BAZ2B was added
gene: BAZ2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BAZ2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAZ2B were set to 31999386; 28135719; 25363768
Phenotypes for gene: BAZ2B were set to Intellectual disability; autism
Review for gene: BAZ2B was set to GREEN
Added comment: Postulated as a candidate gene for ID/ASD by large-scale studies. Case series reports two individuals with small CNVs and and six with SNVs, mostly LoF type variants. Although the gene is generally intolerant of LoF, some LoF variants present in gnomad ?incomplete penetrance. Additional reported features were inconsistent
Sources: Literature
Mendeliome v0.2359 TPI1 Zornitza Stark Marked gene: TPI1 as ready
Mendeliome v0.2357 EMG1 Zornitza Stark Marked gene: EMG1 as ready
Mendeliome v0.2355 EIF2AK4 Zornitza Stark Marked gene: EIF2AK4 as ready
Mendeliome v0.2354 EIF2AK4 Zornitza Stark gene: EIF2AK4 was added
gene: EIF2AK4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: EIF2AK4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: EIF2AK4 were set to Pulmonary venoocclusive disease 2, MIM#234810
Review for gene: EIF2AK4 was set to GREEN
Added comment: Sources: Expert list
Mendeliome v0.2353 AGBL5 Zornitza Stark Marked gene: AGBL5 as ready
Mendeliome v0.2351 CPT1C Bryony Thompson Marked gene: CPT1C as ready
Mendeliome v0.2350 CPT1C Bryony Thompson gene: CPT1C was added
gene: CPT1C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CPT1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CPT1C were set to 25751282; 23973755
Phenotypes for gene: CPT1C were set to Spastic paraplegia 73, autosomal dominant MIM#616282
Review for gene: CPT1C was set to GREEN
Added comment: Two unrelated families dominant HSP and a supportive mouse model.
Sources: Expert list
Mendeliome v0.2349 ATP2B4 Bryony Thompson Marked gene: ATP2B4 as ready
Mendeliome v0.2348 ATP2B4 Bryony Thompson gene: ATP2B4 was added
gene: ATP2B4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP2B4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2B4 were set to 25119969; 25798335; 29691679
Phenotypes for gene: ATP2B4 were set to Hereditary spastic paraplegia
Review for gene: ATP2B4 was set to AMBER
Added comment: One Chinese family segregating a missense variant with HSP and one HSP case with a assumed de novo nonsense variant. Supporting in vitro functional assays for the missense variant.
Sources: Expert list
Mendeliome v0.2345 SEC63 Zornitza Stark Marked gene: SEC63 as ready
Mendeliome v0.2342 CYP1B1 Zornitza Stark Marked gene: CYP1B1 as ready
Mendeliome v0.2342 CYP1B1 Zornitza Stark Phenotypes for gene: CYP1B1 were changed from to Anterior segment dysgenesis 6, multiple subtypes, 617315; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, 231300
Mendeliome v0.2339 DAG1 Zornitza Stark Marked gene: DAG1 as ready
Mendeliome v0.2339 DAG1 Zornitza Stark Phenotypes for gene: DAG1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818; Walker-Warburg syndrome and tectocerebellar dysgraphia
Mendeliome v0.2336 DPYD Zornitza Stark Marked gene: DPYD as ready
Mendeliome v0.2333 MFSD8 Zornitza Stark Marked gene: MFSD8 as ready
Mendeliome v0.2333 MFSD8 Zornitza Stark Phenotypes for gene: MFSD8 were changed from to Ceroid lipofuscinosis, neuronal, 7 610951; Macular dystrophy with central cone involvement 616170
Mendeliome v0.2330 NF1 Zornitza Stark Marked gene: NF1 as ready
Mendeliome v0.2328 TECTA Zornitza Stark Marked gene: TECTA as ready
Mendeliome v0.2328 TECTA Zornitza Stark Added comment: Comment when marking as ready: Both recessive and dominant deafness associations assessed as DEFINITIVE by ClinGen.
Mendeliome v0.2323 TRAPPC9 Zornitza Stark Marked gene: TRAPPC9 as ready
Mendeliome v0.2323 TRAPPC9 Zornitza Stark Phenotypes for gene: TRAPPC9 were changed from to Mental retardation, autosomal recessive 13, MIM# 613192
Mendeliome v0.2320 TRAPPC9 Zornitza Stark reviewed gene: TRAPPC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 22549410, 20004765, 20004763; Phenotypes: Mental retardation, autosomal recessive 13, MIM# 613192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2320 SOS1 Zornitza Stark Marked gene: SOS1 as ready
Mendeliome v0.2320 SOS1 Zornitza Stark Added comment: Comment when marking as ready: The association with Noonan syndrome is well established; the association with gingival fibromatosis is questionable.
Mendeliome v0.2318 SOS1 Zornitza Stark Mode of pathogenicity for gene: SOS1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.2316 F11 Zornitza Stark Marked gene: F11 as ready
Mendeliome v0.2313 MED13L Zornitza Stark Marked gene: MED13L as ready
Mendeliome v0.2313 MED13L Zornitza Stark Added comment: Comment when marking as ready: The evidence for isolated CHD much less compelling than the association with a neurodevelopmental syndrome.
Mendeliome v0.2313 MED13L Zornitza Stark Phenotypes for gene: MED13L were changed from to Mental retardation and distinctive facial features with or without cardiac defects 616789; Transposition of the great arteries, dextro-looped 1 608808
Mendeliome v0.2310 PROKR2 Zornitza Stark Marked gene: PROKR2 as ready
Mendeliome v0.2309 CCT5 Bryony Thompson reviewed gene: CCT5: Rating: AMBER; Mode of pathogenicity: None; Publications: 16399879, 25124038, 25345891; Phenotypes: Neuropathy, hereditary sensory, with spastic paraplegia MIM#256840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2305 MED13L Elena Savva reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 29511999; Phenotypes: Mental retardation and distinctive facial features with or without cardiac defects 616789, Transposition of the great arteries, dextro-looped 1 608808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2305 SOS1 Elena Savva reviewed gene: SOS1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 25062969, 17143285, 17143282; Phenotypes: ?Fibromatosis, gingival, 1, 135300, Noonan syndrome 4, 610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.2305 XRCC1 Bryony Thompson Marked gene: XRCC1 as ready
Mendeliome v0.2304 XRCC1 Bryony Thompson gene: XRCC1 was added
gene: XRCC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: XRCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XRCC1 were set to 28002403; 29472272
Phenotypes for gene: XRCC1 were set to Spinocerebellar ataxia, autosomal recessive 26 MIM#617633
Review for gene: XRCC1 was set to GREEN
Added comment: Three South Asian cases (one with early adult onset and the other two with onset in childhood) reported with slowly progressive cerebellar ataxia accompanied by sensorimotor neuropathy. All with the recurrent splice variant (c.1293G>C, 2 homozygotes and a compound heterozygote). Mice with conditional deletion of the Xrcc1 gene in the brain showed cerebellar ataxia.
Sources: Expert list
Mendeliome v0.2303 TRAPPC9 Elena Savva reviewed gene: TRAPPC9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 13, 613192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2303 TRPC3 Bryony Thompson Marked gene: TRPC3 as ready
Mendeliome v0.2302 TRPC3 Bryony Thompson gene: TRPC3 was added
gene: TRPC3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TRPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC3 were set to 25477146; 19351902
Phenotypes for gene: TRPC3 were set to Spinocerebellar ataxia 41 MIM#616410
Mode of pathogenicity for gene: TRPC3 was set to Other
Review for gene: TRPC3 was set to AMBER
Added comment: A heterozygous gain-of function missense has been identified in a 40-year-old man with adult-onset spinocerebellar ataxia. A mouse model of dominant cerebellar ataxia, termed 'moonwalker', contains a gain-of-function variant in this gene.
Sources: Expert list
Mendeliome v0.2301 MFSD8 Elena Savva reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:31006324; Phenotypes: Ceroid lipofuscinosis, neuronal, 7 610951, Macular dystrophy with central cone involvement 616170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2301 DAG1 Elena Savva reviewed gene: DAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29337005, 25503980; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818, Walker-Warburg syndrome and tectocerebellar dysgraphia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2301 CYP1B1 Elena Savva reviewed gene: CYP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:21730847, 27243976; Phenotypes: Anterior segment dysgenesis 6, multiple subtypes, 617315, Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, 231300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2301 SLC9A1 Zornitza Stark Marked gene: SLC9A1 as ready
Mendeliome v0.2300 SLC9A1 Zornitza Stark gene: SLC9A1 was added
gene: SLC9A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC9A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC9A1 were set to 25205112; 30018422; 25760855
Phenotypes for gene: SLC9A1 were set to Lichtenstein-Knorr syndrome, MIM# 616291
Review for gene: SLC9A1 was set to AMBER
Added comment: Two families with bi-allelic variants in this gene reported and combination of deafness and ataxia.
Sources: Expert list
Mendeliome v0.2299 MTCL1 Bryony Thompson Marked gene: MTCL1 as ready
Mendeliome v0.2298 MTCL1 Bryony Thompson gene: MTCL1 was added
gene: MTCL1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MTCL1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MTCL1 were set to 30548255; 28283581
Phenotypes for gene: MTCL1 were set to slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia
Review for gene: MTCL1 was set to AMBER
Added comment: Single case with a homozygous loss of function variant in a Polish study of early-onset cerebellar ataxia, and a single family with a single heterozygous missense (p.Val1435Met) identified in two family members with adult-onset spinocerebellar ataxia. Mtcl1 gene disruption in mice results in abnormal motor coordination with Purkinje cell degeneration
Sources: Expert list
Mendeliome v0.2296 ATG5 Bryony Thompson gene: ATG5 was added
gene: ATG5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG5 were set to 16625204; 26812546
Phenotypes for gene: ATG5 were set to Spinocerebellar ataxia, autosomal recessive 25 MIM#617584
Review for gene: ATG5 was set to AMBER
Added comment: A homozgyous variant was identified in a single family with two affected siblings. Mice deficient for Atg5 specifically in neural cells and Atg5 null Drosophila develop progressive deficits in motor function.
Sources: Expert list
Mendeliome v0.2294 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724
Mendeliome v0.2290 IRF4 Zornitza Stark reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: None; Publications: 29537367; Phenotypes: Whipple's disease, [Skin/hair/eye pigmentation, variation in, 8] 611724; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2290 ACOX2 Zornitza Stark Marked gene: ACOX2 as ready
Mendeliome v0.2290 ACOX2 Zornitza Stark Added comment: Comment when marking as ready: The ACOX2 gene encodes a peroxisomal branched-chain acyl-CoA oxidase involved in bile acid synthesis.
Mendeliome v0.2288 LARS Zornitza Stark Marked gene: LARS as ready
Mendeliome v0.2288 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.2288 LARS Zornitza Stark Classified gene: LARS as Green List (high evidence)
Mendeliome v0.2288 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.2287 LARS Zornitza Stark gene: LARS was added
gene: LARS was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 28774368; 30349989; 22607940
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Review for gene: LARS was set to GREEN
gene: LARS was marked as current diagnostic
Added comment: Six unrelated families reported in the literature, reviewed in PMID: 30349989.
Sources: NHS GMS
Mendeliome v0.2286 KCNJ11 Zornitza Stark Marked gene: KCNJ11 as ready
Mendeliome v0.2282 SIPA1L3 Bryony Thompson Marked gene: SIPA1L3 as ready
Mendeliome v0.2281 SIPA1L3 Bryony Thompson gene: SIPA1L3 was added
gene: SIPA1L3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SIPA1L3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SIPA1L3 were set to 28951961; 27993984; 25804400
Phenotypes for gene: SIPA1L3 were set to Cataract 45 MIM#616851
Review for gene: SIPA1L3 was set to AMBER
Added comment: A consanguineous German family segregating a homozygous nonsense mutation in two sisters with congenital cataracts (PMID: 25804400). Null Zebrafish, Xenopus and mouse models recapitulate the human cataract phenotype. A case with congenital cataracts as a feature of their condition harboured a de novo balanced chromosomal translocation, 46,XY,t(2;19)(q37.3;q13.1), where breakpoint mapping and sequencing showed a physical disruption of the 5′UTR of SIPA1L3 (PMID: 26231217). In a case with bilateral congenital cataracts a heterozygous missense (D148Y) was identified and in vitro functional assays of the variant resulted in abnormal actin morphology (PMID: 26231217).
Sources: Expert list
Mendeliome v0.2280 KCNJ11 Elena Savva edited their review of gene: KCNJ11: Added comment: Congenital hyperinsulinism (HI) variants are generally reported in heterozygous patients where they also carry a somatic 2nd hit, or have isodisomy of the paternal allele (focal HI), or in bilallelic patients (diffuse HI). This condition can be dominant (but rarely), where patients with these missense are diazoxide-responsive. Patients with recessively inherited variants are diazoxide-unresponsive (OMIM, PMID:11395395, PMID: 23275527, PMID: 23345197).

Genotype-phenotype correlation:
Permanent neonatal diabetes – GOF (OMIM)
Permanent neonatal diabetes + other features – GOF (OMIM)
Congenital hyperinsulinism – LOF (PMID:18250167).

PTCs - LOF
Missense - Loss and gain of function
LOF – cause reduce channel expression, channel activity and increase current decay (PMID:18250167)
GOF - impair ATP-based sensitivity, more open state channel (OMIM)

Mutations generally occur on the paternal allele (PMID: 23345197).; Changed publications: PMID:18250167, 11395395, 23275527, 23345197
Mendeliome v0.2280 SLC18A2 Zornitza Stark Marked gene: SLC18A2 as ready
Mendeliome v0.2279 SLC18A2 Zornitza Stark gene: SLC18A2 was added
gene: SLC18A2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC18A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC18A2 were set to 23363473; 31240161; 26497564
Phenotypes for gene: SLC18A2 were set to Parkinsonism-dystonia, infantile, 2, MIM# 618049
Review for gene: SLC18A2 was set to GREEN
Added comment: At least three unrelated families reported, potential treatment implications
Sources: Expert Review
Mendeliome v0.2278 RNU4ATAC Zornitza Stark Marked gene: RNU4ATAC as ready
Mendeliome v0.2278 RNU4ATAC Zornitza Stark Added comment: Comment when marking as ready: Note gene is not protein coding.
Mendeliome v0.2278 RNU4ATAC Zornitza Stark Phenotypes for gene: RNU4ATAC were changed from to Microcephalic osteodysplastic primordial dwarfism, type I (MIM# 210710); Roifman syndrome (MIM# 616651)
Mendeliome v0.2275 RNU4ATAC Ain Roesley reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23794361, 26522830, 30455926; Phenotypes: Microcephalic osteodysplastic primordial dwarfism, type I (MIM# 210710), Roifman syndrome (MIM# 616651); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2275 IFT172 Zornitza Stark Marked gene: IFT172 as ready
Mendeliome v0.2275 IFT172 Zornitza Stark Added comment: Comment when marking as ready: Established ciliopathy gene.
Mendeliome v0.2275 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from to Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome
Mendeliome v0.2272 KMT2E Zornitza Stark Marked gene: KMT2E as ready
Mendeliome v0.2269 MACF1 Zornitza Stark Marked gene: MACF1 as ready
Mendeliome v0.2269 MAP1B Zornitza Stark Marked gene: MAP1B as ready
Mendeliome v0.2266 MAP3K20 Zornitza Stark Marked gene: MAP3K20 as ready
Mendeliome v0.2266 MAP3K7 Zornitza Stark Marked gene: MAP3K7 as ready
Mendeliome v0.2266 MAP3K7 Zornitza Stark Phenotypes for gene: MAP3K7 were changed from to Cardiospondylocarpofacial syndrome 157800 AD; Frontometaphyseal dysplasia 2 617137 AD
Mendeliome v0.2262 MARS2 Zornitza Stark Marked gene: MARS2 as ready
Mendeliome v0.2262 MARS2 Zornitza Stark Gene: mars2 has been classified as Green List (High Evidence).
Mendeliome v0.2262 MARS2 Zornitza Stark Phenotypes for gene: MARS2 were changed from to Combined oxidative phosphorylation deficiency 25, OMIM #616430; Spastic ataxia 3, autosomal recessive, OMIM #611390
Mendeliome v0.2261 MARS2 Zornitza Stark Publications for gene: MARS2 were set to
Mendeliome v0.2260 MARS2 Zornitza Stark Mode of inheritance for gene: MARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2259 MARS2 Zornitza Stark edited their review of gene: MARS2: Changed rating: GREEN; Changed publications: 25754315, 16672289
Mendeliome v0.2259 MARS2 Zornitza Stark changed review comment from: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV.; to: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV. Spastic ataxia association: note complex chromosomal rearrangements rather than SNVs reported in group of 54 French Canadians.
Mendeliome v0.2259 MECOM Zornitza Stark Marked gene: MECOM as ready
Mendeliome v0.2259 MECOM Zornitza Stark Phenotypes for gene: MECOM were changed from to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, MIM#616738
Mendeliome v0.2256 MED17 Zornitza Stark Marked gene: MED17 as ready
Mendeliome v0.2253 MTHFS Zornitza Stark Marked gene: MTHFS as ready
Mendeliome v0.2253 NEBL Zornitza Stark Marked gene: NEBL as ready
Mendeliome v0.2253 NEBL Zornitza Stark Phenotypes for gene: NEBL were changed from to Hypertrophic cardiomyopathy; dilated cardiomyopathy
Mendeliome v0.2250 NPHP3 Zornitza Stark Marked gene: NPHP3 as ready
Mendeliome v0.2248 NR2E1 Zornitza Stark Marked gene: NR2E1 as ready
Mendeliome v0.2247 NRROS Zornitza Stark Marked gene: NRROS as ready
Mendeliome v0.2247 NUP214 Zornitza Stark Marked gene: NUP214 as ready
Mendeliome v0.2246 NXN Zornitza Stark Marked gene: NXN as ready
Mendeliome v0.2246 PAX1 Zornitza Stark Marked gene: PAX1 as ready
Mendeliome v0.2242 PDE8B Zornitza Stark Marked gene: PDE8B as ready
Mendeliome v0.2239 ANLN Zornitza Stark Marked gene: ANLN as ready
Mendeliome v0.2237 PIGG Zornitza Stark Marked gene: PIGG as ready
Mendeliome v0.2237 PIGG Zornitza Stark Phenotypes for gene: PIGG were changed from to Mental retardation, autosomal recessive 53, MIM#616917
Mendeliome v0.2234 PIGU Zornitza Stark Marked gene: PIGU as ready
Mendeliome v0.2231 PUS3 Zornitza Stark Marked gene: PUS3 as ready
Mendeliome v0.2231 PUS3 Zornitza Stark Phenotypes for gene: PUS3 were changed from to Mental retardation, autosomal recessive 55, MIM# 617051
Mendeliome v0.2228 RUBCN Zornitza Stark Marked gene: RUBCN as ready
Mendeliome v0.2228 RUBCN Zornitza Stark Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, MIM#615705
Mendeliome v0.2225 SHANK2 Zornitza Stark Marked gene: SHANK2 as ready
Mendeliome v0.2225 SHANK2 Zornitza Stark Added comment: Comment when marking as ready: Reports of CNVs, LoF variants, and missense variants in this gene, generally ascertained in autism cohorts. Some de novo and others inherited from parents with a range of neuropsychiatric phenotypes.
Mendeliome v0.2222 SLC26A4 Zornitza Stark Marked gene: SLC26A4 as ready
Mendeliome v0.2222 SLC26A4 Zornitza Stark Phenotypes for gene: SLC26A4 were changed from to Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 600791; Pendred syndrome 274600
Mendeliome v0.2219 SMPD4 Zornitza Stark Marked gene: SMPD4 as ready
Mendeliome v0.2219 SMPD4 Zornitza Stark Phenotypes for gene: SMPD4 were changed from to Severe neurodevelopmental delay, microcephaly, arthrogryposis
Mendeliome v0.2216 SOX11 Zornitza Stark Marked gene: SOX11 as ready
Mendeliome v0.2216 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from to Coffin-Siris syndrome 9, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.2213 SOX11 Zornitza Stark changed review comment from: Heterozygous variant in a patient with Coffin-Siris like syndrome and small kidney; but also rare variants identified in a non-syndromic CAKUT cohort with some functional data.
Sources: Expert list; to: Coffin-Siris syndrome: two individuals with de novo mono-allelic missense variants in this gene, mouse model.
CAKUT: Heterozygous variant in a patient with Coffin-Siris like syndrome and small kidney; but also rare variants identified in a non-syndromic CAKUT cohort with some functional data.
Sources: Expert list
Mendeliome v0.2213 SOX11 Zornitza Stark edited their review of gene: SOX11: Changed rating: GREEN; Changed phenotypes: Coffin-Siris syndrome 9, MIM# 615866, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.2213 ADAM22 Zornitza Stark Marked gene: ADAM22 as ready
Mendeliome v0.2212 NDUFA12 Zornitza Stark Marked gene: NDUFA12 as ready
Mendeliome v0.2211 QRSL1 Zornitza Stark Marked gene: QRSL1 as ready
Mendeliome v0.2208 PPCS Zornitza Stark Marked gene: PPCS as ready
Mendeliome v0.2208 PPCS Zornitza Stark Phenotypes for gene: PPCS were changed from to Cardiomyopathy, dilated, 2C, MIM# 618189
Mendeliome v0.2204 PPCS Zornitza Stark changed review comment from: Five individuals from two unrelated families reported with missense variants. Functional studies in yeast to demonstrate impact of the variants on protein but not aimed at establishing gene-disease causation.; to: Five individuals from two unrelated families reported with missense variants. Functional studies in yeast to demonstrate impact of the variants on protein and cardiac dysfunction observed in Drosophila model.
Mendeliome v0.2204 PPCS Zornitza Stark reviewed gene: PPCS: Rating: AMBER; Mode of pathogenicity: None; Publications: 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2204 PET117 Zornitza Stark Marked gene: PET117 as ready
Mendeliome v0.2203 NUP188 Zornitza Stark Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract to microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Mendeliome v0.2200 NUP188 Zornitza Stark edited their review of gene: NUP188: Added comment: Additional 6 unrelated individuals with bi-allelic LoF variants reported, promoted to Green.; Changed rating: GREEN; Changed publications: 32021605, 28726809, 32275884; Changed phenotypes: microcephaly, ID, cataract, structural brain abnormalities, hypoventilation
Mendeliome v0.2200 TMTC2 Zornitza Stark Marked gene: TMTC2 as ready
Mendeliome v0.2198 TBCD Zornitza Stark Marked gene: TBCD as ready
Mendeliome v0.2198 TBCD Zornitza Stark Phenotypes for gene: TBCD were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, MIM#617193
Mendeliome v0.2193 UMOD Zornitza Stark Marked gene: UMOD as ready
Mendeliome v0.2193 TOR1AIP1 Zornitza Stark Marked gene: TOR1AIP1 as ready
Mendeliome v0.2193 UPK3A Zornitza Stark Marked gene: UPK3A as ready
Mendeliome v0.2193 UMOD Zornitza Stark Phenotypes for gene: UMOD were changed from to Glomerulocystic kidney disease with hyperuricemia and isosthenuria 609886; Hyperuricemic nephropathy, familial juvenile 1 162000; Medullary cystic kidney disease 2 603860
Mendeliome v0.2192 UMOD Zornitza Stark reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glomerulocystic kidney disease with hyperuricemia and isosthenuria 609886, Hyperuricemic nephropathy, familial juvenile 1 162000, Medullary cystic kidney disease 2 603860; Mode of inheritance: None
Mendeliome v0.2189 VARS Zornitza Stark Marked gene: VARS as ready
Mendeliome v0.2189 VARS Zornitza Stark Gene: vars has been classified as Green List (High Evidence).
Mendeliome v0.2189 VARS Zornitza Stark Phenotypes for gene: VARS were changed from to Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy; OMIM #617802
Mendeliome v0.2188 WNT10A Zornitza Stark Marked gene: WNT10A as ready
Mendeliome v0.2188 WNT10A Zornitza Stark Phenotypes for gene: WNT10A were changed from to Odontoonychodermal dysplasia; Schopf-Schulz-Passarge syndrome; Tooth agenesis, selective, 4
Mendeliome v0.2185 ZNF592 Zornitza Stark Marked gene: ZNF592 as ready
Mendeliome v0.2185 ZNF592 Zornitza Stark Phenotypes for gene: ZNF592 were changed from to SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 5
Mendeliome v0.2181 CLIC5 Zornitza Stark Marked gene: CLIC5 as ready
Mendeliome v0.2181 GNB2 Zornitza Stark Marked gene: GNB2 as ready
Mendeliome v0.2181 MIR96 Zornitza Stark Marked gene: MIR96 as ready
Mendeliome v0.2181 MYL1 Zornitza Stark Marked gene: MYL1 as ready
Mendeliome v0.2181 APOL1 Zornitza Stark Marked gene: APOL1 as ready
Mendeliome v0.2181 ARHGEF6 Zornitza Stark Marked gene: ARHGEF6 as ready
Mendeliome v0.2181 ARHGEF6 Zornitza Stark Gene: arhgef6 has been classified as Red List (Low Evidence).
Mendeliome v0.2181 CEP85L Zornitza Stark Marked gene: CEP85L as ready
Mendeliome v0.2180 MIEF2 Zornitza Stark Marked gene: MIEF2 as ready
Mendeliome v0.2180 POLE2 Zornitza Stark Marked gene: POLE2 as ready
Mendeliome v0.2180 PTCD1 Zornitza Stark Marked gene: PTCD1 as ready
Mendeliome v0.2180 TFAM Zornitza Stark Marked gene: TFAM as ready
Mendeliome v0.2179 NME3 Zornitza Stark Marked gene: NME3 as ready
Mendeliome v0.2178 MRPS28 Zornitza Stark Marked gene: MRPS28 as ready
Mendeliome v0.2178 MRPS28 Zornitza Stark gene: MRPS28 was added
gene: MRPS28 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MRPS28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS28 were set to 30566640
Phenotypes for gene: MRPS28 were set to Intrauterine growth retardation; developmental delay; dysmorphism
Review for gene: MRPS28 was set to RED
Added comment: Single individual reported.
Sources: Expert list
Mendeliome v0.2177 MRPS25 Zornitza Stark Marked gene: MRPS25 as ready
Mendeliome v0.2177 MRPS25 Zornitza Stark gene: MRPS25 was added
gene: MRPS25 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MRPS25 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS25 were set to 31039582
Phenotypes for gene: MRPS25 were set to Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Review for gene: MRPS25 was set to RED
Added comment: Single individual reported.
Sources: Expert list
Mendeliome v0.2176 MRPS23 Zornitza Stark Phenotypes for gene: MRPS23 were changed from Hepatic disease; Combined respiratory chain complex deficiencies to Hepatic disease; Combined respiratory chain complex deficienciesHepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities
Mendeliome v0.2173 MRPS23 Zornitza Stark edited their review of gene: MRPS23: Added comment: Four families reported.; Changed rating: GREEN; Changed publications: 26741492, 17873122, 25663021, 28752220; Changed phenotypes: Hepatic disease, Combined respiratory chain complex deficiencies, Cardiomyopathy, Tubulopathy, Lactic acidosis, Structural brain abnormalities
Mendeliome v0.2172 ERAL1 Zornitza Stark Marked gene: ERAL1 as ready
Mendeliome v0.2171 ERAL1 Zornitza Stark gene: ERAL1 was added
gene: ERAL1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ERAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERAL1 were set to 28449065
Phenotypes for gene: ERAL1 were set to Perrault syndrome 6, MIM# 617565
Review for gene: ERAL1 was set to AMBER
Added comment: Three individuals from same small geographical location with homozygous missense variant in this gene, functional data.
Sources: Expert list
Mendeliome v0.2170 COX5A Zornitza Stark Marked gene: COX5A as ready
Mendeliome v0.2170 COX5A Zornitza Stark gene: COX5A was added
gene: COX5A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COX5A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX5A were set to 2824752
Phenotypes for gene: COX5A were set to pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Review for gene: COX5A was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.2169 TRAF3IP2 Zornitza Stark Marked gene: TRAF3IP2 as ready
Mendeliome v0.2165 TRAF3 Zornitza Stark Marked gene: TRAF3 as ready
Mendeliome v0.2161 TNFSF12 Zornitza Stark Marked gene: TNFSF12 as ready
Mendeliome v0.2157 TNFRSF4 Zornitza Stark Marked gene: TNFRSF4 as ready
Mendeliome v0.2153 TNFRSF13C Zornitza Stark Marked gene: TNFRSF13C as ready
Mendeliome v0.2153 TNFRSF13C Zornitza Stark Phenotypes for gene: TNFRSF13C were changed from to Immunodeficiency, common variable, 4, MIM# 613494
Mendeliome v0.2149 TNFRSF13C Zornitza Stark reviewed gene: TNFRSF13C: Rating: AMBER; Mode of pathogenicity: None; Publications: 19666484, 26613719; Phenotypes: Immunodeficiency, common variable, 4, MIM# 613494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2149 TNFRSF13B Zornitza Stark Marked gene: TNFRSF13B as ready
Mendeliome v0.2149 TNFRSF13B Zornitza Stark Phenotypes for gene: TNFRSF13B were changed from to Immunodeficiency, common variable, 2, MIM# 240500
Mendeliome v0.2146 TNFRSF13B Zornitza Stark reviewed gene: TNFRSF13B: Rating: GREEN; Mode of pathogenicity: None; Publications: 17392798, 16007086, 18981294, 16007087; Phenotypes: Immunodeficiency, common variable, 2, MIM# 240500; Mode of inheritance: Other
Mendeliome v0.2146 THBD Zornitza Stark Marked gene: THBD as ready
Mendeliome v0.2142 TAPBP Zornitza Stark Marked gene: TAPBP as ready
Mendeliome v0.2142 TAPBP Zornitza Stark Phenotypes for gene: TAPBP were changed from to Bare lymphocyte syndrome, type I, MIM# 604571
Mendeliome v0.2135 TAPBP Zornitza Stark reviewed gene: TAPBP: Rating: RED; Mode of pathogenicity: None; Publications: 12149238; Phenotypes: Bare lymphocyte syndrome, type I, MIM# 604571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2135 SEMA3E Zornitza Stark Marked gene: SEMA3E as ready
Mendeliome v0.2135 SEMA3E Zornitza Stark Phenotypes for gene: SEMA3E were changed from to CHARGE syndrome, MIM#214800
Mendeliome v0.2132 SEMA3E Zornitza Stark reviewed gene: SEMA3E: Rating: AMBER; Mode of pathogenicity: None; Publications: 15235037, 31691538, 31464029; Phenotypes: CHARGE syndrome, MIM#214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2132 RNF31 Zornitza Stark Marked gene: RNF31 as ready
Mendeliome v0.2128 RHOH Zornitza Stark Marked gene: RHOH as ready
Mendeliome v0.2124 PSMB9 Zornitza Stark Marked gene: PSMB9 as ready
Mendeliome v0.2120 PSMB4 Zornitza Stark Marked gene: PSMB4 as ready
Mendeliome v0.2116 PSMA3 Zornitza Stark Marked gene: PSMA3 as ready
Mendeliome v0.2112 NFKBID Zornitza Stark Marked gene: NFKBID as ready
Mendeliome v0.2110 NFAT5 Zornitza Stark Marked gene: NFAT5 as ready
Mendeliome v0.2106 MS4A1 Zornitza Stark Marked gene: MS4A1 as ready
Mendeliome v0.2106 MS4A1 Zornitza Stark Phenotypes for gene: MS4A1 were changed from to Immunodeficiency, common variable, 5, MIM# 613495
Mendeliome v0.2102 MS4A1 Zornitza Stark reviewed gene: MS4A1: Rating: RED; Mode of pathogenicity: None; Publications: 20038800; Phenotypes: Immunodeficiency, common variable, 5, MIM# 613495; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2102 MASP2 Zornitza Stark Marked gene: MASP2 as ready
Mendeliome v0.2099 ITGAM Zornitza Stark Marked gene: ITGAM as ready
Mendeliome v0.2098 IRF7 Zornitza Stark Marked gene: IRF7 as ready
Mendeliome v0.2094 IL21 Zornitza Stark Marked gene: IL21 as ready
Mendeliome v0.2094 IL21 Zornitza Stark Phenotypes for gene: IL21 were changed from to Immunodeficiency, common variable, 11, MIM# 615767
Mendeliome v0.2090 IL21 Zornitza Stark reviewed gene: IL21: Rating: RED; Mode of pathogenicity: None; Publications: 24746753; Phenotypes: Immunodeficiency, common variable, 11, MIM# 615767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2090 IL17F Zornitza Stark Marked gene: IL17F as ready
Mendeliome v0.2086 FPR1 Zornitza Stark Marked gene: FPR1 as ready
Mendeliome v0.2083 FCN3 Zornitza Stark Marked gene: FCN3 as ready
Mendeliome v0.2079 FCGR3A Zornitza Stark Marked gene: FCGR3A as ready
Mendeliome v0.2075 CR2 Zornitza Stark Marked gene: CR2 as ready
Mendeliome v0.2074 CR2 Zornitza Stark Phenotypes for gene: CR2 were changed from to Immunodeficiency, common variable, 7, MIM# 614699
Mendeliome v0.2071 CR2 Zornitza Stark reviewed gene: CR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 22035880, 26325596; Phenotypes: Immunodeficiency, common variable, 7, MIM# 614699; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2071 CFHR4 Zornitza Stark Marked gene: CFHR4 as ready
Mendeliome v0.2070 CFHR2 Zornitza Stark Marked gene: CFHR2 as ready
Mendeliome v0.2063 CFB Zornitza Stark changed review comment from: Single individual reported, supportive immunophenotyping data.; to: Single individual reported with bi-allelic variants and complement deficiency, supportive immunophenotyping data. Mono-allelic variants linked to susceptibility to aHUS.
Mendeliome v0.2063 CFB Zornitza Stark Marked gene: CFB as ready
Mendeliome v0.2059 CD8A Zornitza Stark Marked gene: CD8A as ready
Mendeliome v0.2055 CD81 Zornitza Stark Marked gene: CD81 as ready
Mendeliome v0.2055 CD81 Zornitza Stark Phenotypes for gene: CD81 were changed from to Immunodeficiency, common variable, 6, MIM# 613496
Mendeliome v0.2051 CD81 Zornitza Stark reviewed gene: CD81: Rating: AMBER; Mode of pathogenicity: None; Publications: 20237408; Phenotypes: Immunodeficiency, common variable, 6, MIM# 613496; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2050 CD247 Zornitza Stark changed review comment from: Also known as CD3Z. Single individual reported with homozygous germline nonsense variant, which was present in some T cells, but others had the nonsense variant in combination with one of three different missense somatic variants.; to: Also known as CD3Z. Note one individual reported with homozygous germline nonsense variant, which was present in some T cells, but others had the nonsense variant in combination with one of three different missense somatic variants.
Mendeliome v0.2050 CD247 Zornitza Stark edited their review of gene: CD247: Added comment: Two reports in the literature, note additional two reports in ClinVar; functional data.; Changed rating: GREEN; Changed publications: 16672702, 17170122
Mendeliome v0.2050 C8G Zornitza Stark Marked gene: C8G as ready
Mendeliome v0.2049 BLOC1S6 Zornitza Stark Marked gene: BLOC1S6 as ready
Mendeliome v0.2045 MIR140 Zornitza Stark Marked gene: MIR140 as ready
Mendeliome v0.2044 MIR140 Zornitza Stark gene: MIR140 was added
gene: MIR140 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MIR140 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR140 were set to 30804514; 31633310
Phenotypes for gene: MIR140 were set to Spondyloepiphyseal dysplasia, Nishimura type, MIM# 618618
Review for gene: MIR140 was set to GREEN
Added comment: Single clinical paper (30804514) reports variant in affected mother and child (de novo in mother) and in a separate unrelated female (de novo) with spondylo-epiphyseal dysplasia. Mouse model (21576357) deletion of gene causes impaired longitudinal bone growth. Separate mouse model studies by same authors as clinical paper above (30804514) showed phenotype of mice with same mutation in this gene consistent with the skeletal dysplasia features of patients with the n.24A-G mutation, suggestive of neomorphic effects (mutation produces both loss-of-function and gain-of-function effects.)
Sources: Expert Review
Mendeliome v0.2039 AP1S3 Zornitza Stark Marked gene: AP1S3 as ready
Mendeliome v0.2039 AP1S3 Zornitza Stark Phenotypes for gene: AP1S3 were changed from to {Psoriasis 15, pustular, susceptibility to} 616106
Mendeliome v0.2035 AP1S3 Zornitza Stark reviewed gene: AP1S3: Rating: AMBER; Mode of pathogenicity: None; Publications: 24791904, 27388993; Phenotypes: {Psoriasis 15, pustular, susceptibility to} 616106; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2035 KCNT2 Zornitza Stark Phenotypes for gene: KCNT2 were changed from Epileptic encephalopathy, early infantile, 57, MIM#617771; Developmental and epileptic encephalopathy to Epileptic encephalopathy, early infantile, 57, MIM#617771; Developmental and epileptic encephalopathy; Epilepsy of infancy with migrating focal seizures (EIMFS)
Mendeliome v0.2033 KCNT2 Kristin Rigbye reviewed gene: KCNT2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29069600, 29740868, 32038177; Phenotypes: Epileptic encephalopathy, early infantile, 57, 617771, Epilepsy of infancy with migrating focal seizures (EIMFS); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2033 PIEZO1 Zornitza Stark Marked gene: PIEZO1 as ready
Mendeliome v0.2032 PIEZO1 Zornitza Stark Phenotypes for gene: PIEZO1 were changed from to Lymphatic malformation 6, 616843; Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, 194380
Mendeliome v0.2029 TBX19 Zornitza Stark Marked gene: TBX19 as ready
Mendeliome v0.2026 TCF20 Zornitza Stark Marked gene: TCF20 as ready
Mendeliome v0.2026 TCF20 Zornitza Stark Phenotypes for gene: TCF20 were changed from to Developmental delay with variable intellectual impairment and behavioral abnormalities, AD, MIM#618430
Mendeliome v0.2023 TFE3 Zornitza Stark Marked gene: TFE3 as ready
Mendeliome v0.2023 TFE3 Zornitza Stark Phenotypes for gene: TFE3 were changed from to TFE3-associated neurodevelopmental disorder; Intellectual disability; Epilepsy; Coarse facial features
Mendeliome v0.2020 TFE3 Zornitza Stark reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595499, 31833172; Phenotypes: TFE3-associated neurodevelopmental disorder, Intellectual disability, Epilepsy, Coarse facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2020 ICOSLG Zornitza Stark Marked gene: ICOSLG as ready
Mendeliome v0.2016 TCF20 Chern Lim reviewed gene: TCF20: Rating: GREEN; Mode of pathogenicity: None; Publications: 30739909, 30819258, 25228304; Phenotypes: Developmental delay with variable intellectual impairment and behavioral abnormalities, AD, MIM#618430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2013 IL6ST Zornitza Stark changed review comment from: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association.
Sources: Expert list; to: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association.
2020: 12 individuals from 8 unrelated families with seven different mono-allelic truncating variants, dominant negative effect proposed.
Sources: Expert list
Mendeliome v0.2013 PIEZO1 Kristin Rigbye reviewed gene: PIEZO1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23695678, 26333996; Phenotypes: Lymphatic malformation 6, 616843, Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, 194380; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2013 SAMD9L Zornitza Stark Marked gene: SAMD9L as ready
Mendeliome v0.2009 RFWD3 Zornitza Stark Marked gene: RFWD3 as ready
Mendeliome v0.2005 MAD2L2 Zornitza Stark Marked gene: MAD2L2 as ready
Mendeliome v0.2004 UBE2T Zornitza Stark Marked gene: UBE2T as ready
Mendeliome v0.2000 HAVCR2 Zornitza Stark Marked gene: HAVCR2 as ready
Mendeliome v0.1999 HAVCR2 Zornitza Stark gene: HAVCR2 was added
gene: HAVCR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HAVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HAVCR2 were set to 30374066; 30792187
Phenotypes for gene: HAVCR2 were set to T-cell lymphoma, subcutaneous panniculitis-like, MIM# 618398
Review for gene: HAVCR2 was set to GREEN
Added comment: Over 20 unrelated individuals reported, note germline confirmation in only a few. Some variants are recurrent: c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met).
Sources: Expert list
Mendeliome v0.1998 TRIM22 Zornitza Stark Marked gene: TRIM22 as ready
Mendeliome v0.1997 TRIM22 Zornitza Stark gene: TRIM22 was added
gene: TRIM22 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM22 were set to 26836588
Phenotypes for gene: TRIM22 were set to Inflammatory bowel disease
Review for gene: TRIM22 was set to GREEN
Added comment: Three unrelated families reported with bi-allelic variants in this gene, and very early onset IBD, some functional data.
Sources: Expert list
Mendeliome v0.1996 ALPI Zornitza Stark Marked gene: ALPI as ready
Mendeliome v0.1994 PSMG2 Zornitza Stark Marked gene: PSMG2 as ready
Mendeliome v0.1993 NLRP1 Zornitza Stark Marked gene: NLRP1 as ready
Mendeliome v0.1993 NLRP1 Zornitza Stark Phenotypes for gene: NLRP1 were changed from to Autoinflammation with arthritis and dyskeratosis, MIM# 617388; Palmoplantar carcinoma, multiple self-healing, MIM# 615225; Recurrent respiratory papillomatosis
Mendeliome v0.1990 NLRP1 Zornitza Stark reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27965258, 31484767, 27662089; Phenotypes: Autoinflammation with arthritis and dyskeratosis, MIM# 617388, Palmoplantar carcinoma, multiple self-healing 615225, Recurrent respiratory papillomatosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.1990 POLA1 Zornitza Stark Marked gene: POLA1 as ready
Mendeliome v0.1990 POLA1 Zornitza Stark Phenotypes for gene: POLA1 were changed from to Pigmentary disorder, reticulate, with systemic manifestations, X-linked, MIM# 301220; Van Esch-O'Driscoll syndrome OMIM# 301030
Mendeliome v0.1987 POLA1 Zornitza Stark reviewed gene: POLA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27019227, 31006512; Phenotypes: Pigmentary disorder, reticulate, with systemic manifestations, X-linked, MIM# 301220, Van Esch-O'Driscoll syndrome OMIM# 301030; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.1987 TIRAP Zornitza Stark changed review comment from: No evidence currently for Mendelian disease association. Some evidence for polymorphisms in this gene influencing susceptibility/protection from infectious disease.; to: No evidence currently for Mendelian disease association. Some evidence for polymorphisms in this gene influencing susceptibility/protection from infectious disease. One family with 8 individuals and bi-allelic variants and susceptibility to staphylococcal disease reported.
Mendeliome v0.1987 IRAK1 Zornitza Stark Marked gene: IRAK1 as ready
Mendeliome v0.1986 DBR1 Zornitza Stark Marked gene: DBR1 as ready
Mendeliome v0.1985 DBR1 Zornitza Stark gene: DBR1 was added
gene: DBR1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DBR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBR1 were set to 29474921
Phenotypes for gene: DBR1 were set to Viral infections of the brainstem
Review for gene: DBR1 was set to GREEN
Added comment: Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants.
Sources: Expert list
Mendeliome v0.1984 POLR3F Zornitza Stark Marked gene: POLR3F as ready
Mendeliome v0.1984 POLR3F Zornitza Stark gene: POLR3F was added
gene: POLR3F was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POLR3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3F were set to 30211253
Phenotypes for gene: POLR3F were set to Severe VZV infection
Review for gene: POLR3F was set to RED
Added comment: Missense variant identified in a pair of monozygotic twins. Variant was paternally inherited.
Sources: Expert list
Mendeliome v0.1983 POLR3C Zornitza Stark Marked gene: POLR3C as ready
Mendeliome v0.1982 POLR3C Zornitza Stark gene: POLR3C was added
gene: POLR3C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POLR3C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3C were set to 28783042
Phenotypes for gene: POLR3C were set to Severe VZV infection
Review for gene: POLR3C was set to AMBER
Added comment: One individual with POLR3C variant and another individual with both POL3RA and POL3RC variants.
Sources: Expert list
Mendeliome v0.1981 POLR3A Zornitza Stark Marked gene: POLR3A as ready
Mendeliome v0.1979 IFNAR2 Zornitza Stark Marked gene: IFNAR2 as ready
Mendeliome v0.1979 IFNAR2 Zornitza Stark Gene: ifnar2 has been classified as Red List (Low Evidence).
Mendeliome v0.1979 IFNAR2 Zornitza Stark Phenotypes for gene: IFNAR2 were changed from to Immunodeficiency 45, MIM# 616669
Mendeliome v0.1978 IFNAR2 Zornitza Stark Publications for gene: IFNAR2 were set to
Mendeliome v0.1977 IFNAR2 Zornitza Stark Mode of inheritance for gene: IFNAR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1976 IFNAR2 Zornitza Stark Classified gene: IFNAR2 as Red List (low evidence)
Mendeliome v0.1976 IFNAR2 Zornitza Stark Gene: ifnar2 has been classified as Red List (Low Evidence).
Mendeliome v0.1975 IFNAR2 Zornitza Stark reviewed gene: IFNAR2: Rating: RED; Mode of pathogenicity: None; Publications: 26424569; Phenotypes: Immunodeficiency 45, MIM# 616669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1975 IFNAR1 Zornitza Stark Marked gene: IFNAR1 as ready
Mendeliome v0.1975 IFNAR1 Zornitza Stark Gene: ifnar1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1975 IFNAR1 Zornitza Stark Classified gene: IFNAR1 as Amber List (moderate evidence)
Mendeliome v0.1975 IFNAR1 Zornitza Stark Gene: ifnar1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1974 IFNAR1 Zornitza Stark gene: IFNAR1 was added
gene: IFNAR1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IFNAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFNAR1 were set to 31270247
Phenotypes for gene: IFNAR1 were set to Severe disease caused by Yellow Fever vaccine and Measles vaccine
Review for gene: IFNAR1 was set to AMBER
Added comment: Two unrelated individuals reported with bi-allelic LoF variants, some functional data.
Sources: Expert list
Mendeliome v0.1973 IRF9 Zornitza Stark Marked gene: IRF9 as ready
Mendeliome v0.1971 CIB1 Zornitza Stark Marked gene: CIB1 as ready
Mendeliome v0.1965 JAK1 Zornitza Stark changed review comment from: Single family reported (mother and two children) with GoF variant.
Sources: Expert list; to: Single family reported (mother and two children) with GoF variant and immune dysregulation phenotype. Another individual reported with bi-allelic LoF and susceptibility to mycobacterial infections. Mouse model with NK defect.
Sources: Expert list
Mendeliome v0.1965 SPPL2A Zornitza Stark Marked gene: SPPL2A as ready
Mendeliome v0.1964 SPPL2A Zornitza Stark gene: SPPL2A was added
gene: SPPL2A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SPPL2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPPL2A were set to 30127434
Phenotypes for gene: SPPL2A were set to Susceptibility to mycobacteria and Salmonella
Review for gene: SPPL2A was set to AMBER
Added comment: Three individuals from two unrelated consanguineous family with two different homozygous splice site variants, functional data.
Sources: Expert list
Mendeliome v0.1963 IL23R Zornitza Stark Marked gene: IL23R as ready
Mendeliome v0.1959 IL12RB2 Zornitza Stark Marked gene: IL12RB2 as ready
Mendeliome v0.1958 C17orf62 Zornitza Stark Marked gene: C17orf62 as ready
Mendeliome v0.1957 C17orf62 Zornitza Stark gene: C17orf62 was added
gene: C17orf62 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984
Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease
Review for gene: C17orf62 was set to GREEN
Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name)
Sources: Expert list
Mendeliome v0.1956 MKL1 Zornitza Stark Marked gene: MKL1 as ready
Mendeliome v0.1954 HYOU1 Zornitza Stark Marked gene: HYOU1 as ready
Mendeliome v0.1953 SMARCD2 Zornitza Stark Marked gene: SMARCD2 as ready
Mendeliome v0.1953 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
Mendeliome v0.1953 SMARCD2 Zornitza Stark Classified gene: SMARCD2 as Green List (high evidence)
Mendeliome v0.1953 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
Mendeliome v0.1952 SMARCD2 Zornitza Stark gene: SMARCD2 was added
gene: SMARCD2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCD2 were set to 28369036; 28369034
Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2, MIM# 617475; Neutropaenia; Neurodevelopmental abnormalities in some; Myelodysplasia
Review for gene: SMARCD2 was set to GREEN
Added comment: Three unrelated families and functional data.
Sources: Expert list
Mendeliome v0.1951 TNFRSF9 Zornitza Stark Marked gene: TNFRSF9 as ready
Mendeliome v0.1950 TNFRSF9 Zornitza Stark gene: TNFRSF9 was added
gene: TNFRSF9 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TNFRSF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFRSF9 were set to 30872117; 31501153
Phenotypes for gene: TNFRSF9 were set to EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Review for gene: TNFRSF9 was set to GREEN
Added comment: Six unrelated individuals, two with same homozygous G109S missense variant, functional data.
Sources: Expert list
Mendeliome v0.1949 CTPS1 Zornitza Stark Marked gene: CTPS1 as ready
Mendeliome v0.1946 JAK1 Zornitza Stark Marked gene: JAK1 as ready
Mendeliome v0.1946 JAK1 Zornitza Stark gene: JAK1 was added
gene: JAK1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: JAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAK1 were set to 28111307
Phenotypes for gene: JAK1 were set to Eosinophilia; Eosinophilic enteritis; Thyroid disease; Poor growth; Viral infections
Review for gene: JAK1 was set to RED
Added comment: Single family reported (mother and two children) with GoF variant.
Sources: Expert list
Mendeliome v0.1945 IL2RB Zornitza Stark Marked gene: IL2RB as ready
Mendeliome v0.1943 AP3D1 Zornitza Stark Marked gene: AP3D1 as ready
Mendeliome v0.1943 AP3D1 Zornitza Stark gene: AP3D1 was added
gene: AP3D1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: AP3D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP3D1 were set to 26744459; 9697856
Phenotypes for gene: AP3D1 were set to Hermansky-Pudlak syndrome 10, MIM# 617050; Oculocutaneous albinism; Severe neutropaenia; Recurrent infections; Seizures; Hearing loss; Neurodevelopmental delay
Review for gene: AP3D1 was set to RED
Added comment: Single family and a mouse model.
Sources: Expert list
Mendeliome v0.1942 FAAP24 Zornitza Stark Marked gene: FAAP24 as ready
Mendeliome v0.1942 FAAP24 Zornitza Stark gene: FAAP24 was added
gene: FAAP24 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FAAP24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAAP24 were set to 27473539
Phenotypes for gene: FAAP24 were set to EBV infection-driven lymphoproliferative disease
Review for gene: FAAP24 was set to RED
Added comment: Single sib pair with homozygous missense variant, some functional data.
Sources: Expert list
Mendeliome v0.1941 SH3KBP1 Zornitza Stark Marked gene: SH3KBP1 as ready
Mendeliome v0.1941 SH3KBP1 Zornitza Stark gene: SH3KBP1 was added
gene: SH3KBP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SH3KBP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SH3KBP1 were set to 29636373; 21708930
Phenotypes for gene: SH3KBP1 were set to Immunodeficiency 61, MIM# 300310
Review for gene: SH3KBP1 was set to RED
Added comment: Single family reported, 247.5-kb intragenic deletion detected by array.
Sources: Expert list
Mendeliome v0.1940 ARHGEF1 Zornitza Stark Marked gene: ARHGEF1 as ready
Mendeliome v0.1940 ARHGEF1 Zornitza Stark Gene: arhgef1 has been classified as Red List (Low Evidence).
Mendeliome v0.1940 ARHGEF1 Zornitza Stark gene: ARHGEF1 was added
gene: ARHGEF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARHGEF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGEF1 were set to 30521495
Phenotypes for gene: ARHGEF1 were set to Immunodeficiency 62, MIM#618459
Review for gene: ARHGEF1 was set to RED
Added comment: Single family, functional data.
Sources: Expert list
Mendeliome v0.1939 ATP6AP1 Zornitza Stark Marked gene: ATP6AP1 as ready
Mendeliome v0.1936 IRF2BP2 Zornitza Stark Marked gene: IRF2BP2 as ready
Mendeliome v0.1936 IRF2BP2 Zornitza Stark gene: IRF2BP2 was added
gene: IRF2BP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IRF2BP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF2BP2 were set to 27016798
Phenotypes for gene: IRF2BP2 were set to Immunodeficiency, common variable, 14, MIM# 617765
Review for gene: IRF2BP2 was set to RED
Added comment: Single family reported only.
Sources: Expert list
Mendeliome v0.1933 TOP2B Zornitza Stark changed review comment from: Association with deafness: One multigenerational family where variant in this gene segregated; two additional variants identified in a cohort; supportive animal model data.
Association with immunological phenotypes: Four individuals from three unrelated families reported, all the variants affected the TOPRIM domain, functional data including mouse model.
Sources: Literature; to: Association with deafness: One multigenerational family where variant in this gene segregated; two additional variants identified in a cohort; supportive animal model data.
Association with immunological phenotypes: Four individuals from three unrelated families reported, all the variants affected the TOPRIM domain, functional data including mouse model.
Intellectual disability: two unrelated individuals reported with same de novo variant, c.187C > T, p.(His63Tyr) and also supportive mouse model data.
Sources: Literature
Mendeliome v0.1932 TOP2B Zornitza Stark changed review comment from: One multigenerational family where variant in this gene segregated; two additional variants identified in a cohort; supportive animal model data.
Sources: Literature; to: Association with deafness: One multigenerational family where variant in this gene segregated; two additional variants identified in a cohort; supportive animal model data.
Association with immunological phenotypes: Four individuals from three unrelated families reported, all the variants affected the TOPRIM domain, functional data including mouse model.
Sources: Literature
Mendeliome v0.1932 SLC39A7 Zornitza Stark Marked gene: SLC39A7 as ready
Mendeliome v0.1931 SLC39A7 Zornitza Stark gene: SLC39A7 was added
gene: SLC39A7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC39A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A7 were set to 30718914
Phenotypes for gene: SLC39A7 were set to Antibody deficiency; early onset infections; blistering dermatosis; failure to thrive; thrombocytopaenia
Review for gene: SLC39A7 was set to GREEN
Added comment: Five unrelated families with hypomorphic variants and a mouse model recapitulating phenotype.
Sources: Expert list
Mendeliome v0.1930 NFE2L2 Zornitza Stark Marked gene: NFE2L2 as ready
Mendeliome v0.1929 NFE2L2 Zornitza Stark gene: NFE2L2 was added
gene: NFE2L2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NFE2L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFE2L2 were set to 29018201
Phenotypes for gene: NFE2L2 were set to Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744; Recurrent respiratory and skin infection; Growth retardation; Developmental delay, borderline ID; White matter cerebral lesions
Review for gene: NFE2L2 was set to GREEN
Added comment: Four unrelated individuals reported.
Sources: Expert list
Mendeliome v0.1928 ERBIN Zornitza Stark Marked gene: ERBIN as ready
Mendeliome v0.1927 ERBIN Zornitza Stark gene: ERBIN was added
gene: ERBIN was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ERBIN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERBIN were set to 28126831
Phenotypes for gene: ERBIN were set to Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some
Review for gene: ERBIN was set to AMBER
Added comment: Single family and functional data.
Sources: Expert list
Mendeliome v0.1926 ZNF341 Zornitza Stark Marked gene: ZNF341 as ready
Mendeliome v0.1925 ZNF341 Zornitza Stark gene: ZNF341 was added
gene: ZNF341 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZNF341 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF341 were set to 29907691; 29907690
Phenotypes for gene: ZNF341 were set to Hyper-IgE recurrent infection syndrome 3, autosomal recessive, MIM# 618282; Mild facial dysmorphism; Early onset eczema; Recurrent bacterial skin infections, abscesses; Recurrent respiratory infections, lung abscesses and pneumothoraces; Hyperextensible joints, bone fractures, retention of primary teeth
Review for gene: ZNF341 was set to GREEN
Added comment: 19 individuals from 10 families reported, some sharing the same homozygous variants (at least 4 different LoF variants reported).
Sources: Expert list
Mendeliome v0.1924 IL6ST Zornitza Stark Marked gene: IL6ST as ready
Mendeliome v0.1923 IL6ST Zornitza Stark gene: IL6ST was added
gene: IL6ST was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL6ST were set to 28747427; 30309848; 12370259; 16041381; 31914175
Phenotypes for gene: IL6ST were set to Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response.
Review for gene: IL6ST was set to GREEN
Added comment: Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association.
Sources: Expert list
Mendeliome v0.1922 IL6R Zornitza Stark Marked gene: IL6R as ready
Mendeliome v0.1918 NSMCE2 Zornitza Stark Marked gene: NSMCE2 as ready
Mendeliome v0.1918 LIG1 Zornitza Stark Marked gene: LIG1 as ready
Mendeliome v0.1917 LIG1 Zornitza Stark gene: LIG1 was added
gene: LIG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG1 were set to 30395541
Phenotypes for gene: LIG1 were set to Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis
Review for gene: LIG1 was set to GREEN
Added comment: Five individuals from three families.
Sources: Expert list
Mendeliome v0.1916 POLE2 Zornitza Stark gene: POLE2 was added
gene: POLE2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POLE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLE2 were set to 26365386
Phenotypes for gene: POLE2 were set to Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism
Review for gene: POLE2 was set to RED
Added comment: Single family reported with homozygous splice site variant.
Sources: Expert list
Mendeliome v0.1915 FCHO1 Zornitza Stark Marked gene: FCHO1 as ready
Mendeliome v0.1914 FCHO1 Zornitza Stark gene: FCHO1 was added
gene: FCHO1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FCHO1 were set to 32098969; 30822429
Phenotypes for gene: FCHO1 were set to 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
Review for gene: FCHO1 was set to GREEN
Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data.
Sources: Expert list
Mendeliome v0.1913 REL Zornitza Stark Marked gene: REL as ready
Mendeliome v0.1913 REL Zornitza Stark gene: REL was added
gene: REL was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: REL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REL were set to 31103457
Phenotypes for gene: REL were set to Combined immunodeficiency; T cells: normal, decreased memory CD4, poor proliferation; B cells: low, mostly naive, few switched memory B cells, impaired proliferation; Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms; Defective innate immunity
Review for gene: REL was set to RED
Added comment: Single individual from consanguineous family reported with homozygous canonical splice site variant, no functional data.
Sources: Expert list
Mendeliome v0.1912 TFRC Zornitza Stark Marked gene: TFRC as ready
Mendeliome v0.1908 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma.; to: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.1908 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers.; to: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma.
Mendeliome v0.1908 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association.; to: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers.
Mendeliome v0.1908 RELA Zornitza Stark Marked gene: RELA as ready
Mendeliome v0.1906 RELB Zornitza Stark Marked gene: RELB as ready
Mendeliome v0.1904 CD247 Zornitza Stark Marked gene: CD247 as ready
Mendeliome v0.1900 NSMCE2 Tiong Tan gene: NSMCE2 was added
gene: NSMCE2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NSMCE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSMCE2 were set to 25105364
Phenotypes for gene: NSMCE2 were set to SECKEL SYNDROME 10
Penetrance for gene: NSMCE2 were set to Complete
Review for gene: NSMCE2 was set to AMBER
Added comment: Biallelic hypomorphic variants in two unrelated women with microcephalic primordial dwarfism, insulin-resistant diabetes, fatty liver, and hypertriglyceridemia developing in childhood; and primary gonadal failure. Good quality functional evidence. No additional confirmatory cases since 2014 publication
Sources: Literature
Mendeliome v0.1898 TRPA1 Zornitza Stark Marked gene: TRPA1 as ready
Mendeliome v0.1896 PLEKHA5 Tiong Tan Marked gene: PLEKHA5 as ready
Mendeliome v0.1895 CNKSR1 Zornitza Stark Marked gene: CNKSR1 as ready
Mendeliome v0.1894 CNKSR1 Zornitza Stark gene: CNKSR1 was added
gene: CNKSR1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CNKSR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNKSR1 were set to 30450701; 30237576; 21937992
Phenotypes for gene: CNKSR1 were set to Intellectual disability
Review for gene: CNKSR1 was set to AMBER
Added comment: Three families reported, two as part of large cohorts reporting multiple novel genes. Note the family reported in PMID 30450701 appears to be the same family as reported in PMID 21937992. Some functional data in PMID 30450701, including Drosophila model.
Sources: Expert Review
Mendeliome v0.1893 FRMD4A Zornitza Stark Marked gene: FRMD4A as ready
Mendeliome v0.1892 FRMD4A Zornitza Stark gene: FRMD4A was added
gene: FRMD4A was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FRMD4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRMD4A were set to 25388005; 30214071
Phenotypes for gene: FRMD4A were set to Intellectual disability; microcephaly; Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia, MIM# 616819
Review for gene: FRMD4A was set to AMBER
Added comment: Single Bedouin Israeli family reported with homozygous variant initially. Good segregation data. No functional data. Another family reported as part of a large consanguineous microcephaly cohort, different variant.
Sources: Expert Review
Mendeliome v0.1891 NEK10 Zornitza Stark Marked gene: NEK10 as ready
Mendeliome v0.1890 NEK10 Zornitza Stark gene: NEK10 was added
gene: NEK10 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: NEK10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEK10 were set to 31959991
Phenotypes for gene: NEK10 were set to Primary ciliary dyskinesia; bronchiectasis
Review for gene: NEK10 was set to GREEN
Added comment: Nine individuals from 5 unrelated families, some functional data.
Sources: NHS GMS
Mendeliome v0.1889 PIGK Zornitza Stark Marked gene: PIGK as ready
Mendeliome v0.1888 PIGK Zornitza Stark gene: PIGK was added
gene: PIGK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Intellectual disability; seizures; cerebellar atrophy
Review for gene: PIGK was set to GREEN
Added comment: 12 individuals from 9 unrelated families reported.
Sources: Literature
Mendeliome v0.1887 ADARB1 Zornitza Stark Marked gene: ADARB1 as ready
Mendeliome v0.1887 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Green List (High Evidence).
Mendeliome v0.1887 ADARB1 Zornitza Stark Classified gene: ADARB1 as Green List (high evidence)
Mendeliome v0.1887 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Green List (High Evidence).
Mendeliome v0.1886 ADARB1 Zornitza Stark gene: ADARB1 was added
gene: ADARB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Intellectual disability; microcephaly; seizures
Review for gene: ADARB1 was set to GREEN
Added comment: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature
Mendeliome v0.1885 HSPB3 Zornitza Stark Marked gene: HSPB3 as ready
Mendeliome v0.1885 HSPB3 Zornitza Stark Phenotypes for gene: HSPB3 were changed from to Neuronopathy, distal hereditary motor, type IIC, MIM# 613376
Mendeliome v0.1881 HSPB3 Zornitza Stark reviewed gene: HSPB3: Rating: RED; Mode of pathogenicity: None; Publications: 20142617, 27549087; Phenotypes: Neuronopathy, distal hereditary motor, type IIC, MIM# 613376; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1881 FBXO38 Zornitza Stark Marked gene: FBXO38 as ready
Mendeliome v0.1881 FBXO38 Zornitza Stark Phenotypes for gene: FBXO38 were changed from to Neuropathy, distal hereditary motor, type IID, 615575; dHMN/dSMA
Mendeliome v0.1877 FBXO38 Zornitza Stark reviewed gene: FBXO38: Rating: AMBER; Mode of pathogenicity: None; Publications: 24207122, 31420593; Phenotypes: Neuronopathy, distal hereditary motor, type IID, 615575, dHMN/dSMA; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.1877 DRP2 Zornitza Stark Marked gene: DRP2 as ready
Mendeliome v0.1876 DRP2 Zornitza Stark gene: DRP2 was added
gene: DRP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DRP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DRP2 were set to 26227883; 11430802; 31217940; 22764250; 29473052
Phenotypes for gene: DRP2 were set to Charcot Marie Tooth, intermediate X-linked; HMSN
Review for gene: DRP2 was set to GREEN
Added comment: Three unrelated families, functional data.
Sources: Expert list
Mendeliome v0.1875 DGAT2 Zornitza Stark Marked gene: DGAT2 as ready
Mendeliome v0.1874 DGAT2 Zornitza Stark gene: DGAT2 was added
gene: DGAT2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DGAT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DGAT2 were set to 26786738
Phenotypes for gene: DGAT2 were set to axonal Charcot-Marie-Tooth disease
Review for gene: DGAT2 was set to AMBER
Added comment: Single family (father and son) reported, with supporting in vitro functional assays and a zebrafish model.
Sources: Expert Review
Mendeliome v0.1872 ERLIN1 Bryony Thompson gene: ERLIN1 was added
gene: ERLIN1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ERLIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERLIN1 were set to 24482476
Phenotypes for gene: ERLIN1 were set to Spastic paraplegia 62 MIM#615681
Review for gene: ERLIN1 was set to GREEN
Added comment: Three unrelated consanguineous families with early onset pure HSP.
Sources: Expert list
Mendeliome v0.1871 BTBD7 Zornitza Stark Marked gene: BTBD7 as ready
Mendeliome v0.1871 BTBD7 Zornitza Stark Added comment: Comment when marking as ready: Agreed, no evidence currently for Mendelian gene-disease association.
Mendeliome v0.1870 NOS1AP Zornitza Stark Marked gene: NOS1AP as ready
Mendeliome v0.1870 NOS1AP Zornitza Stark Added comment: Comment when marking as ready: Agreed, cannot find evidence for Mendelian gene-disease association.
Mendeliome v0.1869 ARID2 Zornitza Stark Marked gene: ARID2 as ready
Mendeliome v0.1869 ARID2 Zornitza Stark Gene: arid2 has been classified as Green List (High Evidence).
Mendeliome v0.1869 ARID2 Zornitza Stark Phenotypes for gene: ARID2 were changed from to Coffin-Siris syndrome 6, MIM#617808
Mendeliome v0.1868 ARID2 Zornitza Stark Publications for gene: ARID2 were set to 30838730
Mendeliome v0.1867 ARID2 Zornitza Stark Publications for gene: ARID2 were set to
Mendeliome v0.1866 ARID2 Zornitza Stark Mode of inheritance for gene: ARID2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1865 DYNC1H1 Zornitza Stark Marked gene: DYNC1H1 as ready
Mendeliome v0.1865 DYNC1H1 Zornitza Stark Phenotypes for gene: DYNC1H1 were changed from to Charcot-Marie-Tooth disease, axonal, type 20; Mental retardation, autosomal dominant 13; Spinal muscular atrophy, lower extremity-predominant 1
Mendeliome v0.1861 PQBP1 Zornitza Stark Marked gene: PQBP1 as ready
Mendeliome v0.1857 CHD3 Zornitza Stark Marked gene: CHD3 as ready
Mendeliome v0.1857 CHD3 Zornitza Stark Added comment: Comment when marking as ready: Over 30 unrelated individuals reported.
Mendeliome v0.1853 DLG3 Zornitza Stark Marked gene: DLG3 as ready
Mendeliome v0.1853 DLG3 Zornitza Stark Phenotypes for gene: DLG3 were changed from to Mental retardation, X-linked 90, MIM#300850
Mendeliome v0.1850 FBN2 Zornitza Stark Marked gene: FBN2 as ready
Mendeliome v0.1850 FBN2 Zornitza Stark Added comment: Comment when marking as ready: The gene-disease association with Contractual arachnodactyly is extremely well established. The gene-disease association with macular degeneration much less so. There are ~4 families reported in the literature, and some discussion about whether the contribution of rare FBN2 variants in this context are under a 'monogenic' or 'polygenic' model.
Mendeliome v0.1849 FBN2 Zornitza Stark Phenotypes for gene: FBN2 were changed from to Contractural arachnodactyly, congenital 121050; Macular degeneration, early-onset 616118
Mendeliome v0.1846 AGTPBP1 Zornitza Stark Marked gene: AGTPBP1 as ready
Mendeliome v0.1845 AGTPBP1 Zornitza Stark gene: AGTPBP1 was added
gene: AGTPBP1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTPBP1 were set to 30420557
Phenotypes for gene: AGTPBP1 were set to Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276
Review for gene: AGTPBP1 was set to GREEN
Added comment: Thirteen individuals with bi-allelic variants in this gene, complex neurological phenotype of dev delay/ID, cerebellar atrophy and neuropathy, severe progressive course in six.
Sources: NHS GMS
Mendeliome v0.1842 ADGRG6 Zornitza Stark edited their review of gene: ADGRG6: Added comment: Three families reported originally with severe prenatal-onset arthrogryposis (PMID: 26004201), one family with more complex neurological phenotype (PMID:30549416).; Changed rating: GREEN; Changed publications: 30549416, 26004201; Changed phenotypes: Lethal congenital contracture syndrome 9, OMIM #616503; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1842 ARID2 Elena Savva reviewed gene: ARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:30838730; Phenotypes: Coffin-Siris syndrome 6; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.1842 DYNC1H1 Elena Savva reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25512093, 28196890; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 20, Mental retardation, autosomal dominant 13, Spinal muscular atrophy, lower extremity-predominant 1; Mode of inheritance: None
Mendeliome v0.1842 DLG3 Elena Savva reviewed gene: DLG3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 28777483; Phenotypes: Mental retardation, X-linked 90; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.1842 FBN2 Elena Savva reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 19473076, 11068201; Phenotypes: Contractural arachnodactyly, congenital 121050, Macular degeneration, early-onset 616118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.1842 EIF2AK2 Zornitza Stark Marked gene: EIF2AK2 as ready
Mendeliome v0.1841 EIF2AK2 Zornitza Stark gene: EIF2AK2 was added
gene: EIF2AK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness
Review for gene: EIF2AK2 was set to GREEN
Added comment: Eight individuals with de novo variants and complex neurodevelopmental phenotype.
Sources: Literature
Mendeliome v0.1840 EIF2AK1 Zornitza Stark Marked gene: EIF2AK1 as ready
Mendeliome v0.1840 EIF2AK1 Zornitza Stark gene: EIF2AK1 was added
gene: EIF2AK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF2AK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK1 were set to 32197074
Phenotypes for gene: EIF2AK1 were set to Intellectual disability; white matter abnormalities
Review for gene: EIF2AK1 was set to RED
Added comment: Single individual reported with de novo variant in this gene.
Sources: Literature
Mendeliome v0.1839 NOVA2 Zornitza Stark Marked gene: NOVA2 as ready
Mendeliome v0.1838 NOVA2 Zornitza Stark gene: NOVA2 was added
gene: NOVA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to Intellectual disability; autism; hypotonia; spasticity; ataxia
Mode of pathogenicity for gene: NOVA2 was set to Other
Review for gene: NOVA2 was set to GREEN
Added comment: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature
Mendeliome v0.1836 GNB2 Sue White gene: GNB2 was added
gene: GNB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNB2 were set to 31698099
Phenotypes for gene: GNB2 were set to intellectual disability; dysmorphic features
Penetrance for gene: GNB2 were set to Complete
Review for gene: GNB2 was set to AMBER
Added comment: single report of patient with de novo missense variant in GNB2 and intellectual disability. Emerging evidence of other de no missense variants in GNB2 and ID
Sources: Literature
Mendeliome v0.1834 NRROS Sue White gene: NRROS was added
gene: NRROS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Penetrance for gene: NRROS were set to Complete
Review for gene: NRROS was set to GREEN
Added comment: normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy
biallelic LOF mutations with functional evidence of pathogenicity
Sources: Literature
Mendeliome v0.1833 CNOT3 Zornitza Stark Marked gene: CNOT3 as ready
Mendeliome v0.1830 CBS Zornitza Stark Marked gene: CBS as ready
Mendeliome v0.1827 HTR3C Zornitza Stark Marked gene: HTR3C as ready
Mendeliome v0.1827 HTR3C Zornitza Stark Added comment: Comment when marking as ready: Agree no evidence for Mendelian gene-disease association currently.
Mendeliome v0.1825 ZFP42 Zornitza Stark Marked gene: ZFP42 as ready
Mendeliome v0.1824 SLC25A21 Zornitza Stark Marked gene: SLC25A21 as ready
Mendeliome v0.1823 SLC25A21 Zornitza Stark gene: SLC25A21 was added
gene: SLC25A21 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: SLC25A21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A21 were set to 29517768
Phenotypes for gene: SLC25A21 were set to Mitochondrial DNA depletion syndrome-18, MIM#618811
Review for gene: SLC25A21 was set to AMBER
Added comment: One case with a homozygous variant and functional assays showing mitochondrial dysfunction.
Sources: NHS GMS
Mendeliome v0.1822 SLC25A10 Zornitza Stark Marked gene: SLC25A10 as ready
Mendeliome v0.1821 SLC25A10 Zornitza Stark gene: SLC25A10 was added
gene: SLC25A10 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: SLC25A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A10 were set to 29211846
Phenotypes for gene: SLC25A10 were set to Intractable epileptic encephalopathy
Review for gene: SLC25A10 was set to AMBER
Added comment: One case with intractable epileptic encephalopathy with complex I deficiency, with biallelic variants. Yeast SLC25A10 ortholog lack-of-function causes impairment in mitochondrial respiration, reduced mtDNA copy number and oxidative stress vulnerability.
Sources: NHS GMS
Mendeliome v0.1820 QARS Zornitza Stark Marked gene: QARS as ready
Mendeliome v0.1820 QARS Zornitza Stark Gene: qars has been classified as Green List (High Evidence).
Mendeliome v0.1820 QARS Zornitza Stark Phenotypes for gene: QARS were changed from to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760
Mendeliome v0.1819 QARS Zornitza Stark Publications for gene: QARS were set to Encodes t-RNA synthetase, over 20 individuals reported, include in mito panel in line with other t-RNA synthetases.
Mendeliome v0.1818 QARS Zornitza Stark Publications for gene: QARS were set to
Mendeliome v0.1817 QARS Zornitza Stark Mode of inheritance for gene: QARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1816 QARS Zornitza Stark reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28620870, 25471517, 25432320, 25041233, 24656866, 32042906; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1816 PTCD3 Zornitza Stark Marked gene: PTCD3 as ready
Mendeliome v0.1814 PTCD1 Zornitza Stark gene: PTCD1 was added
gene: PTCD1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: PTCD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCD1 were set to 25058219
Phenotypes for gene: PTCD1 were set to Cardiomyopathy
Review for gene: PTCD1 was set to RED
Added comment: Single case reported with no functional characterisation. Biochemical analyses of heart tissue identified global COX defect. No OMIM phenotype.
Sources: NHS GMS
Mendeliome v0.1813 PNPLA4 Zornitza Stark Marked gene: PNPLA4 as ready
Mendeliome v0.1810 OXA1L Zornitza Stark Marked gene: OXA1L as ready
Mendeliome v0.1809 OXA1L Zornitza Stark gene: OXA1L was added
gene: OXA1L was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: OXA1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXA1L were set to 30201738; 16435202
Phenotypes for gene: OXA1L were set to Encephalopathy; hypotonia; developmental delay
Review for gene: OXA1L was set to AMBER
Added comment: Single family reported with biochemical and molecular analyses of patient skeletal muscle and fibroblasts. In vitro functional assays in human cell lines, Drosophila model, and yeast-based assays. Loss of function affects oxidative phosphorylation complexes IV and V.
Sources: NHS GMS
Mendeliome v0.1808 NSUN3 Zornitza Stark Marked gene: NSUN3 as ready
Mendeliome v0.1806 NDUFB10 Zornitza Stark Marked gene: NDUFB10 as ready
Mendeliome v0.1805 NDUFB10 Zornitza Stark gene: NDUFB10 was added
gene: NDUFB10 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: NDUFB10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFB10 were set to 28040730; 32025618
Phenotypes for gene: NDUFB10 were set to fatal infantile lactic acidosis; cardiomyopathy
Review for gene: NDUFB10 was set to AMBER
Added comment: Single compound heterozygote case and mitochondrial phenotype. Assays of respiratory chain enzyme activities and functions in patient tissues/fibroblasts and in vitro functional assays. Plant model system supporting mitochondrial complex I dysfunction.
Sources: NHS GMS
Mendeliome v0.1803 MRPS14 Zornitza Stark Marked gene: MRPS14 as ready
Mendeliome v0.1802 MRM2 Zornitza Stark Marked gene: MRM2 as ready
Mendeliome v0.1799 IDH3A Zornitza Stark Marked gene: IDH3A as ready
Mendeliome v0.1797 GATC Zornitza Stark Marked gene: GATC as ready
Mendeliome v0.1797 GATC Zornitza Stark gene: GATC was added
gene: GATC was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: GATC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GATC were set to 30283131
Phenotypes for gene: GATC were set to Mitochondrial cardiomyopathy
Review for gene: GATC was set to RED
Added comment: Two families with 6 affected individuals reported; same homozygous variant.
Sources: NHS GMS
Mendeliome v0.1796 GATB Zornitza Stark Marked gene: GATB as ready
Mendeliome v0.1796 GATB Zornitza Stark gene: GATB was added
gene: GATB was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: GATB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GATB were set to 30283131
Phenotypes for gene: GATB were set to Mitochondrial cardiomyopathy
Review for gene: GATB was set to RED
Added comment: Single family reported with two affected siblings
Sources: NHS GMS
Mendeliome v0.1795 IFT172 Elena Savva reviewed gene: IFT172: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26763875; Phenotypes: Retinitis pigmentosa 71 616394, Short-rib thoracic dysplasia 10 with or without polydactyly - 615630, Bardet-Biedl syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1795 FECH Zornitza Stark Marked gene: FECH as ready
Mendeliome v0.1795 FECH Zornitza Stark Added comment: Comment when marking as ready: Evidence for dominant disease is limited. Please note there is a common, hypomorphic deep intronic variant, IVS3-48T-C, as well as an exon 10 deletion reported.
Mendeliome v0.1795 FECH Zornitza Stark Phenotypes for gene: FECH were changed from to Protoporphyria, erythropoietic, 1 177000 AR
Mendeliome v0.1792 ADAM17 Zornitza Stark Marked gene: ADAM17 as ready
Mendeliome v0.1792 ADAM17 Zornitza Stark Added comment: Comment when marking as ready: Two families and a mouse model.
Mendeliome v0.1788 ZNF462 Zornitza Stark Marked gene: ZNF462 as ready
Mendeliome v0.1788 ZNF462 Zornitza Stark Added comment: Comment when marking as ready: Multiple congenital anomaly syndrome characterised by variable but usually mild global developmental delay and common craniofacial abnormalities, including ptosis, abnormal head shape, downslanting palpebral fissures, epicanthal folds, arched eyebrows, and short upturned nose. Many patients have hypotonia and feeding difficulties. A few patients show agenesis of the corpus callosum on brain imaging. Most cases occur sporadically, but there are rare familial cases that show highly variable expressivity in the phenotypic manifestations.
Mendeliome v0.1784 HCFC1 Zornitza Stark Marked gene: HCFC1 as ready
Mendeliome v0.1784 HCFC1 Zornitza Stark Phenotypes for gene: HCFC1 were changed from to Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ) 309541
Mendeliome v0.1781 TFAM Zornitza Stark gene: TFAM was added
gene: TFAM was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: TFAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFAM were set to 27448789; 29021295; 9500544
Phenotypes for gene: TFAM were set to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) MIM#617156
Review for gene: TFAM was set to AMBER
Added comment: One consanguineous family segregates a homozygous variant. Tfam knockout mouse has a mitochondrial cardiomyopathy phenotype and severe mtDNA depletion with abolished oxidative phosphorylation.
Sources: NHS GMS
Mendeliome v0.1780 TIMM22 Zornitza Stark Marked gene: TIMM22 as ready
Mendeliome v0.1778 TIMMDC1 Zornitza Stark Marked gene: TIMMDC1 as ready
Mendeliome v0.1777 TIMMDC1 Zornitza Stark gene: TIMMDC1 was added
gene: TIMMDC1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: TIMMDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMMDC1 were set to 28604674; 30981218
Phenotypes for gene: TIMMDC1 were set to Mitochondrial complex I deficiency, nuclear type 31 MIM#618251
Review for gene: TIMMDC1 was set to AMBER
Added comment: A deep intronic variant (c.597-1340A>G, only detectable by WGS) that causes a splicing aberration was identified in a homozygous state in 3 unrelated cases from different ethnic backgrounds. A patient with Leigh-like syndrome had a homozygous stopgain variant in PDHX and a homozygous stopgain variant in TIMMDC1 (p.Arg225*). The TIMMDC1 mutant protein could still rescue complex I assembly in TIMMDC1 knockout cells and the patient’s clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect.
Sources: NHS GMS
Mendeliome v0.1776 TMEM65 Zornitza Stark Marked gene: TMEM65 as ready
Mendeliome v0.1774 FECH Michelle Torres reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 20105171, 23016163; Phenotypes: Protoporphyria, erythropoietic, 1 177000 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.1774 SSBP1 Bryony Thompson Marked gene: SSBP1 as ready
Mendeliome v0.1773 SSBP1 Bryony Thompson gene: SSBP1 was added
gene: SSBP1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: SSBP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SSBP1 were set to 31298765; 31479473; 31550237; 31550240
Phenotypes for gene: SSBP1 were set to Optic atrophy with or without extraocular phenotypes
Review for gene: SSBP1 was set to GREEN
Added comment: At least 9 dominant families/cases and 1 recessive with optic atrophy with/without additional clinical features, including retinal macular dystrophy, sensorineural deafness, mitochondrial myopathy, and kidney failure. Supporting evidence in functional assays and zebrafish model.
Sources: NHS GMS
Mendeliome v0.1772 HCFC1 Elena Savva reviewed gene: HCFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23000143; Phenotypes: Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ) 309541; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.1772 COX6A2 Zornitza Stark Marked gene: COX6A2 as ready
Mendeliome v0.1770 YME1L1 Zornitza Stark Marked gene: YME1L1 as ready
Mendeliome v0.1769 YME1L1 Zornitza Stark gene: YME1L1 was added
gene: YME1L1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: YME1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YME1L1 were set to 30544562; 27495975
Phenotypes for gene: YME1L1 were set to Optic atrophy 11, MIM#617302
Review for gene: YME1L1 was set to AMBER
Added comment: One consanguineous family with a homozygous variant and functional assays. YME1L leads to mitochondrial fragmentation and severely disorganized and attenuated cristae architecture in in vitro functional assays.
Sources: NHS GMS
Mendeliome v0.1766 ANXA11 Bryony Thompson gene: ANXA11 was added
gene: ANXA11 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 28469040; 29845112; 30109997
Phenotypes for gene: ANXA11 were set to Amytrophic lateral sclerosis 23 MIM#617839
Review for gene: ANXA11 was set to GREEN
Added comment: 4 different missense variants in 10 patients from 7 unrelated families with amyotrophic lateral sclerosis and functional assays supporting association.
Sources: Expert list
Mendeliome v0.1765 UQCRQ Zornitza Stark Marked gene: UQCRQ as ready
Mendeliome v0.1765 UQCRQ Zornitza Stark Phenotypes for gene: UQCRQ were changed from to Mitochondrial complex III deficiency, nuclear type 4, MIM# 615159
Mendeliome v0.1761 UQCRQ Zornitza Stark reviewed gene: UQCRQ: Rating: AMBER; Mode of pathogenicity: None; Publications: 18439546; Phenotypes: Mitochondrial complex III deficiency, nuclear type 4, MIM# 615159; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1761 UQCRC2 Zornitza Stark Marked gene: UQCRC2 as ready
Mendeliome v0.1761 UQCRC2 Zornitza Stark Phenotypes for gene: UQCRC2 were changed from to Mitochondrial complex III deficiency, nuclear type 5, MIM# 615160
Mendeliome v0.1757 UQCRC2 Zornitza Stark reviewed gene: UQCRC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28275242, 23281071; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, MIM# 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1757 UQCC3 Zornitza Stark Marked gene: UQCC3 as ready
Mendeliome v0.1757 UQCC3 Zornitza Stark Phenotypes for gene: UQCC3 were changed from to Mitochondrial complex III deficiency, nuclear type 9, MIM# 616111
Mendeliome v0.1753 UQCC3 Zornitza Stark reviewed gene: UQCC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25008109, 28804536; Phenotypes: Mitochondrial complex III deficiency, nuclear type 9, MIM# 616111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1753 TXN2 Zornitza Stark Marked gene: TXN2 as ready
Mendeliome v0.1749 TARS2 Zornitza Stark Marked gene: TARS2 as ready
Mendeliome v0.1749 TARS2 Zornitza Stark Gene: tars2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1749 TARS2 Zornitza Stark Phenotypes for gene: TARS2 were changed from to Combined oxidative phosphorylation deficiency 21, MIM# 615918
Mendeliome v0.1748 TARS2 Zornitza Stark Publications for gene: TARS2 were set to
Mendeliome v0.1747 TARS2 Zornitza Stark Mode of inheritance for gene: TARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1746 TARS2 Zornitza Stark Classified gene: TARS2 as Amber List (moderate evidence)
Mendeliome v0.1746 TARS2 Zornitza Stark Gene: tars2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1745 TARS2 Zornitza Stark reviewed gene: TARS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24827421, 26811336; Phenotypes: Combined oxidative phosphorylation deficiency 21, MIM# 615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1745 SLC25A32 Zornitza Stark Marked gene: SLC25A32 as ready
Mendeliome v0.1743 NFS1 Zornitza Stark Marked gene: NFS1 as ready
Mendeliome v0.1739 NDUFA6 Zornitza Stark Marked gene: NDUFA6 as ready
Mendeliome v0.1739 NDUFA6 Zornitza Stark Phenotypes for gene: NDUFA6 were changed from to Mitochondrial complex I deficiency, nuclear type 33, MIM# 618253
Mendeliome v0.1736 NDUFA6 Zornitza Stark reviewed gene: NDUFA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 30245030; Phenotypes: Mitochondrial complex I deficiency, nuclear type 33, MIM# 618253; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1736 NDUFA4 Zornitza Stark Marked gene: NDUFA4 as ready
Mendeliome v0.1732 NDUFA13 Zornitza Stark Marked gene: NDUFA13 as ready
Mendeliome v0.1732 NDUFA13 Zornitza Stark Phenotypes for gene: NDUFA13 were changed from to Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249
Mendeliome v0.1728 NDUFA13 Zornitza Stark reviewed gene: NDUFA13: Rating: RED; Mode of pathogenicity: None; Publications: 25901006; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1728 NADK2 Zornitza Stark Marked gene: NADK2 as ready
Mendeliome v0.1727 NADK2 Zornitza Stark gene: NADK2 was added
gene: NADK2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NADK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NADK2 were set to 24847004; 29388319; 27940755
Phenotypes for gene: NADK2 were set to 2,4-dienoyl-CoA reductase deficiency, MIM# 616034
Review for gene: NADK2 was set to GREEN
gene: NADK2 was marked as current diagnostic
Added comment: Mitochondrial dysfunction resulting in severe neurologic and metabolic dysfunction beginning in early infancy reported in two individuals with confirmed variants in this gene. Another individual with homozygous hypomorphic start loss variant g.36241900 A>G p. Met1Val and milder phenotype reported (PMID:29388319).
Sources: Expert list
Mendeliome v0.1726 ISCA1 Zornitza Stark Marked gene: ISCA1 as ready
Mendeliome v0.1725 ISCA1 Zornitza Stark gene: ISCA1 was added
gene: ISCA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122
Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613
Review for gene: ISCA1 was set to GREEN
gene: ISCA1 was marked as current diagnostic
Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families.
Sources: Expert list
Mendeliome v0.1724 ERCC5 Zornitza Stark Marked gene: ERCC5 as ready
Mendeliome v0.1721 BTD Zornitza Stark Marked gene: BTD as ready
Mendeliome v0.1718 CTNNB1 Zornitza Stark Marked gene: CTNNB1 as ready
Mendeliome v0.1714 TET2 Zornitza Stark Marked gene: TET2 as ready
Mendeliome v0.1713 ARL11 Zornitza Stark Marked gene: ARL11 as ready
Mendeliome v0.1713 ARL11 Zornitza Stark Gene: arl11 has been classified as Red List (Low Evidence).
Mendeliome v0.1713 ARL11 Zornitza Stark Mode of inheritance for gene: ARL11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1712 ARL11 Zornitza Stark Classified gene: ARL11 as Red List (low evidence)
Mendeliome v0.1712 ARL11 Zornitza Stark Gene: arl11 has been classified as Red List (Low Evidence).
Mendeliome v0.1711 ARL11 Zornitza Stark reviewed gene: ARL11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1711 CLCN6 Zornitza Stark Marked gene: CLCN6 as ready
Mendeliome v0.1711 CLCN6 Zornitza Stark Phenotypes for gene: CLCN6 were changed from to Benign partial epilepsy; febrile seizures; NCL
Mendeliome v0.1707 CLCN6 Zornitza Stark reviewed gene: CLCN6: Rating: RED; Mode of pathogenicity: None; Publications: 25794116, 21107136; Phenotypes: Benign partial epilepsy, febrile seizures, NCL; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.1707 SEMA6B Zornitza Stark Marked gene: SEMA6B as ready
Mendeliome v0.1706 SEMA6B Zornitza Stark gene: SEMA6B was added
gene: SEMA6B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to 32169168
Phenotypes for gene: SEMA6B were set to Progressive myoclonic epilepsy
Mode of pathogenicity for gene: SEMA6B was set to Other
Review for gene: SEMA6B was set to GREEN
Added comment: Five individuals from unrelated families reported with de novo variants in the last exon, escaping NMD.
Sources: Literature
Mendeliome v0.1703 IFT74 Zornitza Stark edited their review of gene: IFT74: Added comment: Second individual with bi-allelic variants and BBS phenotype reported.; Changed rating: GREEN; Changed publications: 27486776, 32144365
Mendeliome v0.1703 CAMTA1 Zornitza Stark Marked gene: CAMTA1 as ready
Mendeliome v0.1703 CAMTA1 Zornitza Stark Phenotypes for gene: CAMTA1 were changed from to Cerebellar ataxia, nonprogressive, with mental retardation (614756 AD)
Mendeliome v0.1700 CAMTA1 Zornitza Stark reviewed gene: CAMTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32157189, 22693284; Phenotypes: Cerebellar ataxia, nonprogressive, with mental retardation (614756 AD); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1700 TNNI3K Zornitza Stark Marked gene: TNNI3K as ready
Mendeliome v0.1699 TNNI3K Zornitza Stark gene: TNNI3K was added
gene: TNNI3K was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TNNI3K was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNI3K were set to 30010057; 29355681
Phenotypes for gene: TNNI3K were set to Cardiac conduction disease with or without dilated cardiomyopathy, MIM# 616117
Review for gene: TNNI3K was set to GREEN
gene: TNNI3K was marked as current diagnostic
Added comment: At least 6 multigenerational families reported where variants segregated with disease.
Sources: Expert list
Mendeliome v0.1698 GPT2 Zornitza Stark Marked gene: GPT2 as ready
Mendeliome v0.1698 GPT2 Zornitza Stark Phenotypes for gene: GPT2 were changed from to Mental retardation, autosomal recessive 49, MIM#616281
Mendeliome v0.1695 GPT2 Zornitza Stark reviewed gene: GPT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27601654, 25758935; Phenotypes: Mental retardation, autosomal recessive 49, MIM#616281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1695 ERCC6L2 Zornitza Stark Marked gene: ERCC6L2 as ready
Mendeliome v0.1695 ERCC6L2 Zornitza Stark Phenotypes for gene: ERCC6L2 were changed from to Bone marrow failure syndrome 2, MIM# 615715
Mendeliome v0.1692 ERCC6L2 Zornitza Stark reviewed gene: ERCC6L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24507776, 27185855; Phenotypes: Bone marrow failure syndrome 2, MIM# 615715; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1692 PPM1E Zornitza Stark Marked gene: PPM1E as ready
Mendeliome v0.1692 PPM1E Zornitza Stark Added comment: Comment when marking as ready: Agreed, cannot find evidence for Mendelian gene-disease association.
Mendeliome v0.1691 SUPT16H Zornitza Stark Marked gene: SUPT16H as ready
Mendeliome v0.1690 SUPT16H Zornitza Stark gene: SUPT16H was added
gene: SUPT16H was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SUPT16H was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SUPT16H were set to 31924697
Phenotypes for gene: SUPT16H were set to Intellectual disability; Abnormality of the corpus callosum
Review for gene: SUPT16H was set to GREEN
Added comment: Four unrelated individuals with de novo missense variants in this gene. Publication also reports on a deletion, but note this includes other genes and the individual also had another CNV.
Sources: Literature
Mendeliome v0.1689 RARS Zornitza Stark Marked gene: RARS as ready
Mendeliome v0.1689 RARS Zornitza Stark Gene: rars has been classified as Green List (High Evidence).
Mendeliome v0.1689 RARS Zornitza Stark Phenotypes for gene: RARS were changed from to Leukodystrophy, hypomyelinating, 9 MIM# 616140
Mendeliome v0.1688 RARS Zornitza Stark Publications for gene: RARS were set to
Mendeliome v0.1687 RARS Zornitza Stark Mode of inheritance for gene: RARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1686 RARS Zornitza Stark reviewed gene: RARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31814314; Phenotypes: Leukodystrophy, hypomyelinating, 9 MIM# 616140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1685 CXorf56 Zornitza Stark edited their review of gene: CXorf56: Added comment: Additional 3 families reported, upgrade to Green.; Changed rating: GREEN; Changed publications: 29374277, 31822863; Changed phenotypes: Mental retardation, X-linked 107, MIM# 301013
Mendeliome v0.1685 TNR Zornitza Stark Marked gene: TNR as ready
Mendeliome v0.1684 TNR Zornitza Stark gene: TNR was added
gene: TNR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 32099069
Phenotypes for gene: TNR were set to Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus
Review for gene: TNR was set to GREEN
Added comment: 13 individuals from 8 unrelated families reported.
Sources: Literature
Mendeliome v0.1683 RSPRY1 Zornitza Stark Marked gene: RSPRY1 as ready
Mendeliome v0.1679 RPS23 Zornitza Stark Marked gene: RPS23 as ready
Mendeliome v0.1673 FUT6 Zornitza Stark Marked gene: FUT6 as ready
Mendeliome v0.1671 FUT2 Zornitza Stark Marked gene: FUT2 as ready
Mendeliome v0.1669 HMGA2 Zornitza Stark Marked gene: HMGA2 as ready
Mendeliome v0.1665 DTD1 Zornitza Stark Marked gene: DTD1 as ready
Mendeliome v0.1664 UTS2B Zornitza Stark Marked gene: UTS2B as ready
Mendeliome v0.1663 MFSD2A Zornitza Stark Marked gene: MFSD2A as ready
Mendeliome v0.1663 MFSD2A Zornitza Stark Phenotypes for gene: MFSD2A were changed from to Microcephaly 15, primary, autosomal recessive, MIM# 616486
Mendeliome v0.1660 MFSD2A Zornitza Stark reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005865, 26005868, 24828044; Phenotypes: Microcephaly 15, primary, autosomal recessive, MIM# 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1660 MED12L Zornitza Stark Marked gene: MED12L as ready
Mendeliome v0.1658 MCM3AP Zornitza Stark Marked gene: MCM3AP as ready
Mendeliome v0.1657 MCM3AP Zornitza Stark gene: MCM3AP was added
gene: MCM3AP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295
Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, MIM#618124
Review for gene: MCM3AP was set to GREEN
gene: MCM3AP was marked as current diagnostic
Added comment: At least 10 families reported.
Sources: Expert list
Mendeliome v0.1656 MAPRE2 Zornitza Stark Marked gene: MAPRE2 as ready
Mendeliome v0.1653 PURA Zornitza Stark Marked gene: PURA as ready
Mendeliome v0.1653 PURA Zornitza Stark Phenotypes for gene: PURA were changed from to Mental retardation, autosomal dominant 31, MIM# 616158
Mendeliome v0.1650 PURA Zornitza Stark reviewed gene: PURA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439098, 25342064, 12972605; Phenotypes: Mental retardation, autosomal dominant 31, MIM# 616158; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1650 BPTF Zornitza Stark Marked gene: BPTF as ready
Mendeliome v0.1647 TRIO Zornitza Stark Marked gene: TRIO as ready
Mendeliome v0.1647 TRIO Zornitza Stark Phenotypes for gene: TRIO were changed from to Mental retardation, autosomal dominant 44, MIM# 617061
Mendeliome v0.1644 TRIO Zornitza Stark reviewed gene: TRIO: Rating: GREEN; Mode of pathogenicity: None; Publications: 26721934, 32109419; Phenotypes: Mental retardation, autosomal dominant 44, MIM# 617061; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1644 MAN1B1 Zornitza Stark Marked gene: MAN1B1 as ready
Mendeliome v0.1644 MAN1B1 Zornitza Stark Phenotypes for gene: MAN1B1 were changed from to Mental retardation, autosomal recessive 15, MIM#614202
Mendeliome v0.1641 KMT2C Zornitza Stark Marked gene: KMT2C as ready
Mendeliome v0.1639 GLRX5 Zornitza Stark Marked gene: GLRX5 as ready
Mendeliome v0.1637 NUDT2 Zornitza Stark Marked gene: NUDT2 as ready
Mendeliome v0.1636 NUDT2 Zornitza Stark gene: NUDT2 was added
gene: NUDT2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NUDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDT2 were set to 27431290; 30059600
Phenotypes for gene: NUDT2 were set to Muscular hypotonia; Global developmental delay; Intellectual disability
Review for gene: NUDT2 was set to AMBER
Added comment: 7 affected individuals from 4 Saudi families, with same homozygous truncating variant.
Sources: Expert list
Mendeliome v0.1635 SLC26A4 Elena Savva reviewed gene: SLC26A4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24599119; Phenotypes: Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 600791, Pendred syndrome 274600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1635 MAP3K7 Michelle Torres reviewed gene: MAP3K7: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27426734, 27426733; Phenotypes: Cardiospondylocarpofacial syndrome 157800 AD, Frontometaphyseal dysplasia 2 617137 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1635 MAN1B1 Elena Savva reviewed gene: MAN1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24348268; Phenotypes: Mental retardation, autosomal recessive 15; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.1635 NKAP Zornitza Stark Marked gene: NKAP as ready
Mendeliome v0.1634 NKAP Zornitza Stark gene: NKAP was added
gene: NKAP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NKAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NKAP were set to 26358559; 26350204; 31587868
Phenotypes for gene: NKAP were set to Intellectual disability
Review for gene: NKAP was set to GREEN
gene: NKAP was marked as current diagnostic
Added comment: 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln)
Sources: Expert list
Mendeliome v0.1633 TBR1 Zornitza Stark Marked gene: TBR1 as ready
Mendeliome v0.1630 GNRHR Zornitza Stark Marked gene: GNRHR as ready
Mendeliome v0.1627 MYO9A Zornitza Stark Marked gene: MYO9A as ready
Mendeliome v0.1624 ZDHHC15 Zornitza Stark Marked gene: ZDHHC15 as ready
Mendeliome v0.1624 ZDHHC15 Zornitza Stark Phenotypes for gene: ZDHHC15 were changed from to Mental retardation, X-linked 91, 300577
Mendeliome v0.1621 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked 91, 300577; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.1621 ZBTB16 Zornitza Stark Marked gene: ZBTB16 as ready
Mendeliome v0.1621 ZBTB16 Zornitza Stark Phenotypes for gene: ZBTB16 were changed from to Skeletal defects, genital hypoplasia, and mental retardation, OMIM #612447
Mendeliome v0.1617 ZBTB16 Zornitza Stark reviewed gene: ZBTB16: Rating: AMBER; Mode of pathogenicity: None; Publications: 18611983; Phenotypes: Skeletal defects, genital hypoplasia, and mental retardation, OMIM #612447; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1617 ZBTB11 Zornitza Stark Marked gene: ZBTB11 as ready
Mendeliome v0.1613 WNT3 Zornitza Stark Marked gene: WNT3 as ready
Mendeliome v0.1609 RS1 Zornitza Stark Marked gene: RS1 as ready
Mendeliome v0.1606 SMC1A Zornitza Stark Marked gene: SMC1A as ready
Mendeliome v0.1603 LOXHD1 Zornitza Stark Marked gene: LOXHD1 as ready
Mendeliome v0.1603 AIRE Zornitza Stark Marked gene: AIRE as ready
Mendeliome v0.1596 WFS1 Zornitza Stark Marked gene: WFS1 as ready
Mendeliome v0.1596 WFS1 Zornitza Stark Phenotypes for gene: WFS1 were changed from to ?Cataract 41; Deafness, autosomal dominant 6/14/38; Wolfram syndrome, autosomal recessive 1; Wolfram-like syndrome, autosomal dominant; {Diabetes mellitus, noninsulin-dependent, association with}
Mendeliome v0.1593 ING3 Zornitza Stark Marked gene: ING3 as ready
Mendeliome v0.1592 SYN3 Zornitza Stark Marked gene: SYN3 as ready
Mendeliome v0.1591 SIM1 Zornitza Stark Marked gene: SIM1 as ready
Mendeliome v0.1590 WFS1 Teresa Zhao reviewed gene: WFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25211237; Phenotypes: ?Cataract 41, Deafness, autosomal dominant 6/14/38, Wolfram syndrome 1, Wolfram-like syndrome, autosomal dominant, {Diabetes mellitus, noninsulin-dependent, association with}; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.1590 VARS Zornitza Stark Publications for gene: VARS were set to
Mendeliome v0.1589 VARS Zornitza Stark Mode of inheritance for gene: VARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1588 VARS Zornitza Stark reviewed gene: VARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30755616, 30755602, 26539891, 29691655, 30275004; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, OMIM #617802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1588 KRT6A Zornitza Stark Marked gene: KRT6A as ready
Mendeliome v0.1583 TUBA8 Zornitza Stark Marked gene: TUBA8 as ready
Mendeliome v0.1579 RPL26 Zornitza Stark Marked gene: RPL26 as ready
Mendeliome v0.1575 ABCC6 Zornitza Stark Marked gene: ABCC6 as ready
Mendeliome v0.1570 TRIM8 Zornitza Stark Marked gene: TRIM8 as ready
Mendeliome v0.1567 TPH2 Zornitza Stark Marked gene: TPH2 as ready
Mendeliome v0.1563 SPOP Zornitza Stark Marked gene: SPOP as ready
Mendeliome v0.1562 SPOP Zornitza Stark gene: SPOP was added
gene: SPOP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPOP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPOP were set to 32109420
Phenotypes for gene: SPOP were set to Intellectual disability; dysmorphism; microcephaly; macrocephaly
Mode of pathogenicity for gene: SPOP was set to Other
Review for gene: SPOP was set to GREEN
Added comment: Seven individuals reported with de novo missense variants in this gene. Gain-of-function variants associated with microcephaly whereas dominant-negative variants associated with macrocephaly.
Sources: Literature
Mendeliome v0.1561 TNIK Zornitza Stark Marked gene: TNIK as ready
Mendeliome v0.1561 TNIK Zornitza Stark Phenotypes for gene: TNIK were changed from to Mental retardation, autosomal recessive 54, MIM# 617028
Mendeliome v0.1557 TNIK Zornitza Stark reviewed gene: TNIK: Rating: AMBER; Mode of pathogenicity: None; Publications: 27106596, 23035106; Phenotypes: Mental retardation, autosomal recessive 54, MIM# 617028; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1557 TMLHE Zornitza Stark Marked gene: TMLHE as ready
Mendeliome v0.1554 TMEM94 Zornitza Stark Marked gene: TMEM94 as ready
Mendeliome v0.1553 TMEM94 Zornitza Stark gene: TMEM94 was added
gene: TMEM94 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM94 were set to 30526868
Phenotypes for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies, MIM#618316
Review for gene: TMEM94 was set to GREEN
Added comment: 10 individuals from 6 unrelated families.
Sources: Expert list
Mendeliome v0.1552 TMEM260 Zornitza Stark Marked gene: TMEM260 as ready
Mendeliome v0.1552 TMEM260 Zornitza Stark Phenotypes for gene: TMEM260 were changed from to Structural heart defects and renal anomalies syndrome, MIM# 617478
Mendeliome v0.1548 TMEM260 Zornitza Stark reviewed gene: TMEM260: Rating: AMBER; Mode of pathogenicity: None; Publications: 28318500; Phenotypes: Structural heart defects and renal anomalies syndrome, MIM# 617478; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1548 TKT Zornitza Stark Marked gene: TKT as ready
Mendeliome v0.1548 TKT Zornitza Stark Phenotypes for gene: TKT were changed from to Short stature, developmental delay, and congenital heart defects; OMIM #617044
Mendeliome v0.1544 TKT Zornitza Stark reviewed gene: TKT: Rating: AMBER; Mode of pathogenicity: None; Publications: 27259054; Phenotypes: Short stature, developmental delay, and congenital heart defects, OMIM #617044; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1544 TELO2 Zornitza Stark Marked gene: TELO2 as ready
Mendeliome v0.1541 TECR Zornitza Stark Marked gene: TECR as ready
Mendeliome v0.1541 TECR Zornitza Stark Phenotypes for gene: TECR were changed from to Mental retardation, autosomal recessive, MIM#614020
Mendeliome v0.1537 TECR Zornitza Stark reviewed gene: TECR: Rating: RED; Mode of pathogenicity: None; Publications: 21212097; Phenotypes: Mental retardation, autosomal recessive, MIM#614020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.1537 TBC1D7 Zornitza Stark Marked gene: TBC1D7 as ready
Mendeliome v0.1533 TAF2 Zornitza Stark Marked gene: TAF2 as ready