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| Mendeliome v1.2187 | CLASP1 |
Ain Roesley gene: CLASP1 was added gene: CLASP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLASP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLASP1 were set to 39040917 Phenotypes for gene: CLASP1 were set to neurodevelopmental disorder MONDO:0700092, CLASP1-related Review for gene: CLASP1 was set to RED gene: CLASP1 was marked as current diagnostic Added comment: 3 siblings from a consanguineous family, homozygous for p.(Arg1481His) at birth, all had low weight and microcephaly (< 3-4SD), profound dev delay, spasticity, seizures and lissencephaly Arg1481His - 3 hets 0 Homs in v4 codon is highly conserved with a high REVEL score 0.83 Sources: Literature |
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| Mendeliome v1.2168 | PPP2R2B | Bryony Thompson edited their review of gene: PPP2R2B: Added comment: 5 cases with NDD and heterozygous missense (4/5 confirmed de novo): p.Thr246Lys (unknown inheritance), p.Asn310Lys (confirmed de novo), p.Glu37Lys (confirmed de novo, also had RNU4-2 path de novo Path variant), p.Ile427Thr (confirmed de novo, also had TAOK1 inherited Path variant), p.Arg149Pro (confirmed de novo). 5/5 with intellectual disability and developmental delay, 4/5 with seizures, 2/5 with hearing loss/auditory neuropathy. Study includes in vitro functional assays supporting a possible loss of function mechanism of disease. The 2 missense with additional diagnoses (E37K & I427T) demonstrated a partial reduction in PP2A holoenzyme assembly. Only 3 cases with a possible diagnosis that could be attributed to the PPP2R2B only, and only 2 were confirmed de novo.; Changed rating: AMBER; Changed publications: 25356899, 39565297; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2022 | PSKH1 |
Zornitza Stark gene: PSKH1 was added gene: PSKH1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSKH1 were set to 39132680 Phenotypes for gene: PSKH1 were set to Cholestasis, progressive familial intrahepatic, 13, MIM# 620962 Review for gene: PSKH1 was set to GREEN Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis: -1 patient died at 10mths with cholestasis/liver impairment and kidney impairment -3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity) -2 siblings with hepatic fibrosis (1 with unilateral renal agenesis) -2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis. Sources: Literature |
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| Mendeliome v1.1816 | ATXN7L3 |
Chirag Patel gene: ATXN7L3 was added gene: ATXN7L3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATXN7L3 were set to PMID: 38753057 Phenotypes for gene: ATXN7L3 were set to Neurodevelopmental disorder, MONDO_0100500 Review for gene: ATXN7L3 was set to GREEN gene: ATXN7L3 was marked as current diagnostic Added comment: This study reports 9 unrelated individuals with de novo heterozygous variants in ATXN7L3 identified through WES testing and GeneMatcher. Core clinical features included: global motor and language developmental delay, hypotonia, and dysmorphic features (hypertelorism, epicanthal folds, blepharoptosis, small nose, small mouth, and low-set posteriorly rotated ears). Variable features included: feeding difficulties, seizures, mild periventricular leukomalacia, and structural cardiac abnormalities. A recurrent nonsense variant [p.(Arg114Ter)] was found in 5/9 individuals. The other variants were 1 frameshift [p.(Ser112LysfsTer12)] and 3 missense variants [p.(Ile71Thr), p.(Ser92Arg), and p.(Leu106Pro)]. They investigated the effects of the recurrent nonsense variant [p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired (as indicated by an increase in histone H2Bub1 levels). This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. Pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Sources: Literature |
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| Mendeliome v1.1715 | KIAA1024L |
Achchuthan Shanmugasundram gene: KIAA1024L was added gene: KIAA1024L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KIAA1024L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA1024L were set to 35727972 Phenotypes for gene: KIAA1024L were set to Deafness, autosomal recessive 120, OMIM:620238 Review for gene: KIAA1024L was set to GREEN Added comment: New gene name - MINAR2 PMID:35727972 reported 13 patients from four unrelated families with non-syndromic sensorineural hearing loss. Four of these patients had prelingual onset of severe to profound, progressive bilateral hearing loss. The other nine patients had congenital onset of severe to profound bilateral hearing loss, which was not progressive on one patient, while data was not available for the other. Three different homozygous variants (c.144G > A/ p.Trp48Ter, c.412_419delCGGTTTTG/ p.Arg138Valfs*10 and c.393G > T/ p.Lys131Asn) were identified in MINAR2/ KIAA1024L gene in these patients. There is some functional evidence available for the p.Lys131Asn variant. In addition, mice with loss of function of the Minar2 protein present with rapidly progressive sensorineural hearing loss. This gene has also been associated with relevant phenotype in OMIM (MIM #620238). Sources: Literature |
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| Mendeliome v1.1689 | PSMA5 |
Zornitza Stark gene: PSMA5 was added gene: PSMA5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSMA5 was set to Other Publications for gene: PSMA5 were set to 37600812 Phenotypes for gene: PSMA5 were set to Inborn error of immunity, MONDO:0003778, PSMA5-related; PRAAS/CANDLE Review for gene: PSMA5 was set to RED Added comment: Single patient with heterozygous PSMB8 variant and de-novo PSMA5 truncating variant (p.Arg168*) with clinical features of CANDLE. Patient also had splice site variant in PSMC5. In silico modelling showing interaction of PSMB8 and PSMA5. PSMA5/a5 is a constitutive component of the 20S core proteasome, ? digenic model of disease. Sources: Literature |
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| Mendeliome v1.1634 | FEM1B | Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications: 31036916, 38465576; Changed phenotypes: Syndromic disease MONDO:0002254, FEM1B-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1616 | FHL2 |
Zornitza Stark gene: FHL2 was added gene: FHL2 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FHL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FHL2 were set to 36854411; 25358972 Phenotypes for gene: FHL2 were set to Cardiomyopathy, MONDO:0004994, FHL2-related Review for gene: FHL2 was set to AMBER Added comment: Emerging evidence that variants in this gene may be associated with cardiomyopathy. Reports of HCM and DCM. c.391C>T (p.Arg131Cys) may be recurrent in early-onset DCM. Sources: Expert Review |
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| Mendeliome v1.1502 | SH2B3 |
Ain Roesley commented on gene: SH2B3: PMID:37206266 2x families - hom missense variant Val402Met: functional performed on patient's fibroblasts demonstrated increased basal pSTAT5, pSTAT3 and increased pJAK2 + pSTAT5 after stimulation with IL-3, GH, GM-CSF and EPO - hom fs Arg148Profs*40 functional performed in zebrafish demonstrated increased number of macrophages and thrombocytes PMID:23908464; 1 fam with 2 affecteds with dev delay + autoimmunity + (1x) ALL, hom for Asp231Gly fs*3 PMID:38152053; JMML cohort - 2x hom missense + 2x het PTCs |
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| Mendeliome v1.1330 | LRRC23 |
Belinda Chong gene: LRRC23 was added gene: LRRC23 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LRRC23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRC23 were set to 37804054 Phenotypes for gene: LRRC23 were set to Non-syndromic male infertility due to sperm motility disorder MONDO:0017173 Review for gene: LRRC23 was set to RED Added comment: PMID 37804054: A homozygous nonsense mutation in LRRC23 (c.376C>T: p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection. Sources: Literature |
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| Mendeliome v1.1330 | MIEF1 |
Lucy Spencer gene: MIEF1 was added gene: MIEF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MIEF1 were set to 33632269 Phenotypes for gene: MIEF1 were set to Optic atrophy 14 (MIM#620550) Review for gene: MIEF1 was set to AMBER Added comment: PMID: 33632269 Inherited optic neuropathies cohort from france with nothing found in OPA1, OPA3 and WFS1 or mtDNA. 2 individuals (55 and 47yo) found to have missense variant in MIEF1, p.Arg146Trp has 35 hets 0 homs in gnomad, p.Tyr240Asn is absent. Both have non-syndromic late onset inherited optic neuropathies characterized by initial loss of peripheral visual fields. Functional studies in HeLa cells- both missense localised to the mitochondria and formed oligomers similar to WT. MIEF1 normally regulates mitochondrial fission dynamics and causes an increase in mitochondrial fusion events, however both missense variants caused a significantly decreased mitochondrial fusion events. Sources: Literature |
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| Mendeliome v1.1254 | CFAP20 |
Sarah Pantaleo gene: CFAP20 was added gene: CFAP20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP20 were set to PMID:36329026 Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200) Review for gene: CFAP20 was set to GREEN Added comment: CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy (retinitis pigments). Hence, CFAP20 functions within a structural./functional hub centred on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associaetd domains or macromolecular complexes. Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin. Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate. Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5) Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly). Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys) For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old). Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues. Sources: Literature |
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| Mendeliome v1.1251 | GPRASP1 |
Paul De Fazio gene: GPRASP1 was added gene: GPRASP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPRASP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GPRASP1 were set to 37787182 Phenotypes for gene: GPRASP1 were set to Arteriovenous hemangioma/malformation, GPRASP1-related, MONDO:0001256 Penetrance for gene: GPRASP1 were set to unknown Review for gene: GPRASP1 was set to AMBER gene: GPRASP1 was marked as current diagnostic Added comment: Two hemizygous germline missense variants, p.Arg1167Trp and p.Trp553Cys, were identified in three male patients presenting with spinal AVM, Cobb syndrome, or scalp AVM. The variants were inherited from unaffected heterozygous mothers. Note that p.Arg1167Trp has hemizygous (>70) and homozygous individuals reported in gnomAD. The variants were found to result in LoF in endothelial cells. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral hemorrhage, AVMs, and exhibited vascular anomalies in multiple organs. Sources: Literature |
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| Mendeliome v1.1125 | NEUROG1 |
Achchuthan Shanmugasundram gene: NEUROG1 was added gene: NEUROG1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078 Phenotypes for gene: NEUROG1 were set to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 Review for gene: NEUROG1 was set to GREEN Added comment: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be added with green rating in the intellectual disability panel. PMID:23419067 - A homozygous micro deletion of NEUROG1 was identified in a six year-old boy presenting with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild global developmental delay. His IQ was normal. PMID:26077850 - A homozygous NEUROG1 variant (p.Arg116Leu) was identified in a 12 year-old boy presented with syndromic corneal opacity, mild intellectual disability and absent corneal reflex. PMID:33439489 - A homozygous loss-of-function variant (p.Glu68Ter) was identified in a 12 year-old boy presenting with hypotonia, global developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. This patient had a global IQ of 62 at the age of ten. PMID:36647078 - A female proband was identified with a novel homozygous truncating frameshift variant (p.Thr78ProfsTer122 and was reported with profound global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her sister also had a similar, but less severe phenotype and also harboured the same variant at homozygous state. This gene has been associated with relevant phenotypes in OMIM (MIM #620469), but not in Gene2Phenotype. Sources: Literature |
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| Mendeliome v1.1049 | LAMA3 |
Sangavi Sivagnanasundram changed review comment from: Zhou et al. (2023) - Two heterozygous nonsense variants identified in two individuals of the same family [p.Arg1126Ter and p.Gln1507Ter] that was shown to segregate in the family with reduced penetrance. The authors hypothesize that function of laminin 𝛼3 is altered as it changes its ability to form heterotrimeric laminins. In vivo functional study using CRISPR/Cas-9 mediated LAMA3 knockout mice. Results of the functional assay showed development of tricuspid valve and right ventricle abnormalities in the presence of a homozygous LoF variant in LAMA3.; to: Novel gene-disease association Zhou et al. (2023) - Two heterozygous nonsense variants identified in two individuals of the same family [p.Arg1126Ter and p.Gln1507Ter] that was shown to segregate in the family with reduced penetrance. The authors hypothesize that function of laminin 𝛼3 is altered as it changes its ability to form heterotrimeric laminins. In vivo functional study using CRISPR/Cas-9 mediated LAMA3 knockout mice. Results of the functional assay showed development of tricuspid valve and right ventricle abnormalities in the presence of a homozygous LoF variant in LAMA3. |
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| Mendeliome v1.997 | PMVK |
Zornitza Stark changed review comment from: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; to: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype. Amber for bi-allelic disease association. |
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| Mendeliome v1.997 | PMVK |
Zornitza Stark edited their review of gene: PMVK: Added comment: Association with auto inflammatory syndrome: Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; Changed publications: 26202976, 37364720, 36410683; Changed phenotypes: Porokeratosis 1, multiple types, MIM# 175800, Autoinflammatory syndrome, MONDO:0019751, PMVK-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.941 | CHD4 |
Achchuthan Shanmugasundram changed review comment from: This gene should be added to the Clefting disorders panel with a green rating as there are four unrelated cases presenting with either cleft palate and/or bifid uvula. PMID:3138819 reported a patient with heterozygous variant (p.Gln715Ter) in CHD4 that had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula. In addition, DDD study reported two patients with likely pathogenic heterozygous variants who had cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288); to: Although there are four unrelated cases presenting with either cleft palate and/or bifid uvula, this phenotype is not consistent among patients identified with monoallelic variants in CHD4 gene. Hence, this gene should be added to the Clefting disorders panel with amber rating. PMID:31388190 reported 32 patients with heterozygous variants in CHD4 gene, of which one patient (p.Gln715Ter) had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula. In addition, 2 out of 10 patients with pathogenic/ likely pathogenic heterozygous variants from the DDD study were reported with cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288). |
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| Mendeliome v1.819 | INTS11 |
Achchuthan Shanmugasundram gene: INTS11 was added gene: INTS11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS11 were set to 37054711 Review for gene: INTS11 was set to GREEN Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association. PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Sources: Literature |
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| Mendeliome v1.781 | VWA8 |
Dean Phelan gene: VWA8 was added gene: VWA8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VWA8 were set to PMID: 37012052 Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related Review for gene: VWA8 was set to AMBER Added comment: PMID: 37012052 - Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype. Sources: Literature |
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| Mendeliome v1.717 | RBSN |
Zornitza Stark gene: RBSN was added gene: RBSN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RBSN were set to 25233840; 29784638; 35652444 Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related Review for gene: RBSN was set to GREEN Added comment: Four unrelated families reported, consistent feature is ID. PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis. PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal. PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism. Sources: Literature |
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| Mendeliome v1.626 | THBS1 |
Zornitza Stark gene: THBS1 was added gene: THBS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: THBS1 were set to 36453543 Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related Review for gene: THBS1 was set to GREEN Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Sources: Literature |
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| Mendeliome v1.625 | NPTX1 |
Ain Roesley gene: NPTX1 was added gene: NPTX1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436 Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related Review for gene: NPTX1 was set to GREEN gene: NPTX1 was marked as current diagnostic Added comment: PMID:34788392 5 families with multigenerational segregations - late onset ataxia 4 families with p.(Gly389Arg) + 1x p.(Glu327Gly) functional studies done Note: case report of a family member published elsewhere (PMID:35288776) PMID:35285082 1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome p.(Arg143Leu) PMID:35560436 1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy p.(Gln370Arg) Sources: Literature |
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| Mendeliome v1.601 | TRPC5 |
Hazel Phillimore gene: TRPC5 was added gene: TRPC5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890 Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder Review for gene: TRPC5 was set to AMBER Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570: Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents. Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened). (This variant is absent in gnomAD v2.1.1). Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted. Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include: PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested). In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*). NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1). However, looking further into the three references, the evidence is not as clear or as accurate as was stated. The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929). Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned. Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2). Sources: Literature |
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| Mendeliome v1.572 | ZMYM3 |
Belinda Chong gene: ZMYM3 was added gene: ZMYM3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZMYM3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ZMYM3 were set to 36586412; 24721225 Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs) Review for gene: ZMYM3 was set to GREEN Added comment: PMID: 36586412 Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants. Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. Sources: Literature |
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| Mendeliome v1.366 | MED11 |
Ain Roesley gene: MED11 was added gene: MED11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED11 were set to 36001086 Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related Review for gene: MED11 was set to GREEN gene: MED11 was marked as current diagnostic Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*). Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes NO evidence of founder effect from haplotype analysis 7/7 cerebral dysgyria, cortical atrophy 5/7 limb contracture 4/7 epilepsy 3/7 families with IUGR 3/7 GDD 3/7 hearing loss 3/7 undescended testis 2/7 nystagmus 1/7 congenital cataract Sources: Literature |
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| Mendeliome v1.364 | SLC13A1 |
Lucy Spencer gene: SLC13A1 was added gene: SLC13A1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC13A1 were set to 36175384 Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related Review for gene: SLC13A1 was set to RED Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad. Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype. Sources: Literature |
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| Mendeliome v1.343 | ARG1 | Zornitza Stark Tag treatable tag was added to gene: ARG1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.28 | SPTAN1 | Zornitza Stark edited their review of gene: SPTAN1: Added comment: Leveille et al (2019) - 2 patients with HSP with biallelic missense SPTAN1 variants Previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. Xie et al (2022) - 1 patient with complicated HSP and homozygous SPTAN1 mutation. Healthy parents and sister all carried the heterozygous mutation. Van de Vondel et al (2022) - 22 patients from 14 families with five novel heterozygous SPTAN1 variants. Presentations ranged from cerebellar ataxia, intellectual disability, epilepsy, and spastic paraplegia. A recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia. Through protein modeling they showed that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523; Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13792 | CD164 |
Alison Yeung gene: CD164 was added gene: CD164 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CD164 were set to 26197441; 35254497; 26197441 Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66, MIM# 616969 Review for gene: CD164 was set to GREEN Added comment: p.(Arg192Ter), a truncating variant that results in loss of 6 amino acids, was detected in two families (one Polish and one Korean) with hearing loss. Four affected (heterozygous) and two unaffected (neg) were tested, however 14 members had been diagnosed with HL in a large multi generational family (gene panel 237 genes). The second family (WES) had two affected heterozygous and no unaffected were tested. This same variant had previously been reported in a Danish family (12 affected heterozygous and 13 unaffected negative, but one younger member unaffected are heterozygous) with hearing loss (PMID: 26197441), for which functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments. The YHTL motif, deleted by the c.574C>T nonsense mutation, is a canonical sorting motif known to be recognized by specific adaptor proteins in the cytosol, leading to subcellular trafficking of the transmembrane protein to endosomes and lysosomes. Sources: Literature |
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| Mendeliome v0.11189 | IRX5 |
Zornitza Stark edited their review of gene: IRX5: Added comment: Third family with Hamamy syndrome and homozygous missense variant reported, p.Arg168His. Two cousins, >4 meioses, good segregation data. 4th family as part of large heterogenous cohort of consanguineous families also reported with homozygous frameshift (last exon), but limited phenotypic data.; Changed rating: GREEN; Changed publications: 22581230, 27453922, 34899143 |
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| 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 v0.10375 | ARG1 | Zornitza Stark Marked gene: ARG1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10375 | ARG1 | Zornitza Stark Gene: arg1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10375 | ARG1 | Zornitza Stark Phenotypes for gene: ARG1 were changed from to Argininaemia MIM#207800; Urea cycle disorders and inherited hyperammonaemias; disorder of arginine metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10374 | ARG1 | Zornitza Stark Publications for gene: ARG1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10373 | ARG1 | Zornitza Stark Mode of inheritance for gene: ARG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9025 | GINS2 |
Arina Puzriakova gene: GINS2 was added gene: GINS2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GINS2 were set to 34353863 Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis Review for gene: GINS2 was set to RED Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included. GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date. Sources: Literature |
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| Mendeliome v0.7192 | ADCY6 |
Zornitza Stark changed review comment from: Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Literature; to: - PMID: 33820833 (2021) - Further 2 sibs reported with a homozygous c.3346C>T:p.Arg1116Cys variant in the ADCY6 gene. The family was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and IUGR were detected prenatally. Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Literature |
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| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson changed review comment from: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature; to: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system. Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.6463 | CLTCL1 |
Bryony Thompson gene: CLTCL1 was added gene: CLTCL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784 Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain Review for gene: CLTCL1 was set to AMBER Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons. PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system Other reports of associations with limited evidence: PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided. PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively. Sources: Literature |
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| Mendeliome v0.5646 | NANOS3 |
Bryony Thompson gene: NANOS3 was added gene: NANOS3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NANOS3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NANOS3 were set to 25054146; 24091668 Phenotypes for gene: NANOS3 were set to Primary ovarian insufficiency Review for gene: NANOS3 was set to AMBER Added comment: A homozygous missense (p.Glu120Lys) was identified in two Brazillian sisters with primary amenorrhea, and supporting in vitro functional assays. A heterozygous missense (p.Arg153Trp) was identified in a Chinese woman with POI, with supporting in vitro functional assays. Also, supporting null mouse model. Sources: Literature |
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| Mendeliome v0.5472 | AGBL1 |
Zornitza Stark gene: AGBL1 was added gene: AGBL1 was added to Mendeliome. Sources: Expert Review disputed tags were added to gene: AGBL1. Mode of inheritance for gene: AGBL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AGBL1 were set to 24094747; 31555324 Phenotypes for gene: AGBL1 were set to Corneal dystrophy, Fuchs endothelial, 8, MIM# 615523 Review for gene: AGBL1 was set to RED Added comment: Gene disease association first reported in 2013 in PMID 24094747, in a large multigenerational family. However, note the variant reported, p.Arg1028Ter is present in over 400 hets in gnomad. Another variant reported in same paper, p.Cys990Ser in three unrelated individuals, is present in over 300 hets in gnomad and 1 hom. Two further variants reported in PMID 31555324, one is missense, p.Arg748His, present in 60 hets, and the other, p.Arg1028Ter, is present is the variant identified in the previous publication, present in over 400 hets. These variant frequencies are out of keeping for a rare disorder. Sources: Expert Review |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.2386 | 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 |
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| Mendeliome v0.703 | AP2M1 |
Zornitza Stark gene: AP2M1 was added gene: AP2M1 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Intellectual developmental disorder 60 with seizures, MIM# 618587 Review for gene: AP2M1 was set to GREEN Added comment: Four unrelated individuals reported, recurrent variant, NM_004068.3:c.508C>T or p.Arg170Trp. Sources: Expert list |
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| Mendeliome v0.370 | KCNT2 |
Zornitza Stark gene: KCNT2 was added gene: KCNT2 was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNT2 were set to 29069600; 29740868 Phenotypes for gene: KCNT2 were set to Epileptic encephalopathy, early infantile, 57, MIM#617771; Developmental and epileptic encephalopathy Review for gene: KCNT2 was set to GREEN Added comment: Reviewed by E Palmer: Ambrosino et al described 2 unrelated females with de novo variants in KCNT2. The first patient had the variant p.(Arg190His) had with West syndrome followed by Lennox-Gastaut syndrome , the second patient had the variant p.(Arg190Pro) and DEE with migrating focal seizures. Both variants were absent gnomad and had supportive in silico support for pathogenicity. In an electrophisological model both KCNT2 R190P and KCNT2 R190H increased maximal current density and shifted toward more negative membrane potential values the activation curve of KCNT2 channels, consistent with gain of function effects. PMID: 29740868. Gururaj et al describe one male with de novo variant in KCNT2 p. (Phe240Leu) and early infantile epileptic encephalopathy. he variant was absent gnomad and supportive evidence of pathogenicity This variant was electrophysiologically modelled and revealed that the variant resulted in a 'change in function' demonstrating unusual altered selectivity in KNa channels.PMID: 29069600. Sources: Literature |
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| Mendeliome v0.0 | ARG1 |
Zornitza Stark gene: ARG1 was added gene: ARG1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ARG1 was set to Unknown |
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