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| Mendeliome v1.1680 | BANF1 | Zornitza Stark changed review comment from: Two Spanish families reported but likely founder effect. One additional family. Lipoatrophy reported.; to: Bi-allelic disease: Two Spanish families reported with progeria but likely founder effect. One additional family. Lipoatrophy reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1279 | EPHX1 | Zornitza Stark Phenotypes for gene: EPHX1 were changed from Lipoatrophic diabetes to Hereditary lipodystrophy, MONDO:0020087, EPHX1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1026 | POPDC2 | Zornitza Stark Phenotypes for gene: POPDC2 were changed from Sinus node dysfunction to Sinoatrial node disorder, MONDO:0000469, POPDC2-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.987 | POPDC2 |
Chirag Patel gene: POPDC2 was added gene: POPDC2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POPDC2 were set to Sinus node dysfunction Review for gene: POPDC2 was set to GREEN gene: POPDC2 was marked as current diagnostic Added comment: ESHG 2023: 3 families with 7 affected with sinus node dysfunction (bradycardia) and AV block (2/7 HCM). 3 x HMZ variants found in POPDC2 (2 x missense, 1 x indel). Variants predicted to diminish cAMP binding of POPDC2, and shown to disrupt regulation of TREK1 channels (lowering of outward K+ current). POPDC2 is highly expressed in cardiac myocytes, sinoatrial node, and atrioventricular node. Knockdown in zebrafish leads to AV block, and knockout in mice leads to sinus node dysfunction. Sources: Other Sources: Other |
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| Mendeliome v1.757 | RNF212B |
Sangavi Sivagnanasundram gene: RNF212B was added gene: RNF212B was added to Mendeliome. Sources: Other Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189 Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047 Review for gene: RNF212B was set to AMBER Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family). Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs. Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries. Sources: Other |
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| Mendeliome v1.513 | NUP54 |
Hazel Phillimore gene: NUP54 was added gene: NUP54 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP54 were set to PMID: 36333996 Phenotypes for gene: NUP54 were set to Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia Mode of pathogenicity for gene: NUP54 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: NUP54 was set to AMBER Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544. Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia. Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser). Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu). Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe) The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum. Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina. Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts. Sources: Literature |
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| Mendeliome v1.37 | IREB2 | Lucy Spencer reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35602653; Phenotypes: Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12644 | NKX2-1 | Zornitza Stark reviewed gene: NKX2-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978, Chorea, hereditary benign MIM#118700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12214 | OAT | Zornitza Stark Marked gene: OAT as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12214 | OAT | Zornitza Stark Gene: oat has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12214 | OAT | Zornitza Stark Phenotypes for gene: OAT were changed from to Gyrate atrophy of choroid and retina with or without ornithinemia - MIM#258870 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12213 | OAT | Zornitza Stark Publications for gene: OAT were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12212 | OAT | Zornitza Stark Mode of inheritance for gene: OAT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12183 | OAT | Krithika Murali Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12183 | OAT | Krithika Murali edited their review of gene: OAT: Added comment: Biallelic variants associated with deficiency of mitochondrial enzyme ornithine aminotransferase and elevation of plasma ornithine levels without elevation of ammonia. Characterized by ocular anomalies; however, neurological and muscular features may also be present.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12183 | OAT | Krithika Murali reviewed gene: OAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 1618792, 2220818, 3339136, 3417397, 2916581, 1737786, 33463379; Phenotypes: Gyrate atrophy of choroid and retina with or without ornithinemia - MIM#258870; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12169 | NKX2-1 | Zornitza Stark Phenotypes for gene: NKX2-1 were changed from to Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11477 | IREB2 | Zornitza Stark Phenotypes for gene: IREB2 were changed from to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11460 | IREB2 | Zornitza Stark reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30915432, 31243445, 11175792; Phenotypes: Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11071 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants. Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6. Eventual previous genetic testing was not discussed. Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies. Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype. 3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2): - c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families], - c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents], - c.2T>C/p.(Met1?) [1 hmz individual born to related parents], - c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual. CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes. CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP. As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants]. Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc. CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect. In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine). Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively). NMD is thought to underly the deleterious effect of the frameshift one (not studied). The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein. Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714). There is no associated phenotype in OMIM, Gene2Phenotype or SysID. Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset). Sources: Literature |
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| Mendeliome v0.10701 | MBOAT7 | Zornitza Stark Marked gene: MBOAT7 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10701 | MBOAT7 | Zornitza Stark Gene: mboat7 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10701 | MBOAT7 | Zornitza Stark Phenotypes for gene: MBOAT7 were changed from to intellectual disability MIM#617188 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10700 | MBOAT7 | Zornitza Stark Publications for gene: MBOAT7 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10699 | MBOAT7 | Zornitza Stark Mode of inheritance for gene: MBOAT7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MBOAT7 | Ain Roesley reviewed gene: MBOAT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33335874, 32645526, 32744787, 31852446, 31282596, 30701556; Phenotypes: intellectual disability MIM#617188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9691 | SRCAP | Zornitza Stark Phenotypes for gene: SRCAP were changed from Floating-Harbor syndrome MIM#136140; Neurodevelopmental disorder, non-Floating Harbor to Floating-Harbor syndrome MIM#136140; Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, MIM# 619595 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9690 | SRCAP | Zornitza Stark edited their review of gene: SRCAP: Changed phenotypes: Floating-Harbor syndrome MIM#136140, Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, MIM# 619595 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8910 | EPHX1 | Zornitza Stark Phenotypes for gene: EPHX1 were changed from to Lipoatrophic diabetes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8906 | EPHX1 | Zornitza Stark reviewed gene: EPHX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34342583; Phenotypes: Lipoatrophic diabetes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7920 | SRCAP | Zornitza Stark Phenotypes for gene: SRCAP were changed from to Floating-Harbor syndrome MIM#136140; Neurodevelopmental disorder, non-Floating Harbor | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7917 | SRCAP | Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140, Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | SRCAP | Paul De Fazio reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7719 | CACNA1D | Zornitza Stark Phenotypes for gene: CACNA1D were changed from to Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474; MONDO:0014200; Sinoatrial node dysfunction and deafness, MIM# 614896 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7716 | CACNA1D | Zornitza Stark reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913001, 32336187, 30698561, 21131953, 15357422, 22678062; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474, MONDO:0014200, Sinoatrial node dysfunction and deafness, MIM# 614896; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5872 | PRRT2 | Zornitza Stark Phenotypes for gene: PRRT2 were changed from to Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5869 | PRRT2 | Zornitza Stark reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33126500; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis 602066, Episodic kinesigenic dyskinesia 1 128200, Seizures, benign familial infantile, 2 605751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| Mendeliome v0.0 | OAT |
Zornitza Stark gene: OAT was added gene: OAT was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: OAT was set to Unknown |
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| Mendeliome v0.0 | MBOAT7 |
Zornitza Stark gene: MBOAT7 was added gene: MBOAT7 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MBOAT7 was set to Unknown |
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