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| Mendeliome v2.305 | TES | Rylee Peters Marked gene: TES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.305 | TES | Rylee Peters Gene: tes has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.305 | TES |
Rylee Peters gene: TES was added gene: TES was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TES was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TES were set to 33092471 Phenotypes for gene: TES were set to Thoracic aortic aneurysm, MONDO:0005396,TES-related Review for gene: TES was set to RED Added comment: PMID: 33092471 reports four individuals from four unrelated families with heterozygous missense TES variants (c.751T>C p.Y251H in three families however has 20 hets in gnomAD and c.838T>C p.Y280H in one family) presenting with early‑onset isolated thoracic aortic aneurysm (<50 years). Functional studies with homozygous mouse knock‑in of the orthologous p.Y251H and Tes‑/‑ knockout showed that the thoracic aorta was spontaneously dilated showed reduced Tes expression. Sources: Literature |
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| Mendeliome v2.299 | CCDC201 |
Sangavi Sivagnanasundram gene: CCDC201 was added gene: CCDC201 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC201 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC201 were set to 39192094 Phenotypes for gene: CCDC201 were set to Infertility disorder, MONDO:0005047 Review for gene: CCDC201 was set to RED Added comment: PMID 39192094 This publication reports 27 individuals from 27 families presenting with primary ovarian insufficiency (menopause <40 y) and early menopause (menopause <45 y). One variant was reported in all the reported individuals p.Arg162Ter. The FAF of the reported variant is 0.5037% and there have been 2 homozygotes reported in gnomAD v4.1. The publication is based off population screening, therefore the GDA to remain as RED until further supportive evidence is published. Sources: Literature |
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| Mendeliome v2.296 | CCER1 |
Zornitza Stark gene: CCER1 was added gene: CCER1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CCER1 were set to 38081819 Phenotypes for gene: CCER1 were set to Infertility disorder, MONDO:0005047 Review for gene: CCER1 was set to GREEN Added comment: PMID 38081819 reports 5 individuals from 5 families with heterozygous loss-of-function CCER1 variants presenting with nonobstructive azoospermia (NOA). Mouse knockout recapitulates male infertility and patient-derived mutant proteins lack phase‑separated nuclear condensates, supporting a loss‑of‑function (haploinsufficiency) mechanism. Sources: Literature |
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| Mendeliome v2.285 | DIS3 |
Bryony Thompson gene: DIS3 was added gene: DIS3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DIS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DIS3 were set to 39400047; 36869713 Phenotypes for gene: DIS3 were set to Infertility disorder, MONDO:0005047 Review for gene: DIS3 was set to AMBER Added comment: PMID 39400047 reports 1 individual from a consanguineous family and PMID 36869713 reports 2 individuals with primary ovarian insufficiency (amenorrhea, elevated FSH, atrophic ovaries) with adolescent onset, occasionally accompanied by short stature from a sibling pair with biallelic DIS3 variants. Functional studies, including a Drosophila rescue assay that demonstrates a hypomorphic allele fails to rescue ovarian development, support loss‑of‑function as the disease mechanism. Sources: Literature |
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| Mendeliome v2.280 | SARDH |
Bryony Thompson edited their review of gene: SARDH: Added comment: Variable phenotype including normal individuals - assigning to amber **New evidence**: PMID 31815201 reports 11 cases with sarcosinemia and cognitive decline homozygous for three distinct loss‑of‑function SARDH variants (c.1553G>T, c.1540C>T, c.860C>T) and demonstrates markedly reduced blood SARDH activity and low urinary formaldehyde. Unsure if cases are related. PMID 42337718 adds one further case with compound heterozygous SARDH variants (c.293G>C missense and c.679C>T nonsense) presenting with acute childhood leukoencephalopathy and cytotoxic white‑matter edema. **Prior evidence**: PMID 22825317 reports 3 consanguineous and 1 UPD case with homozygous variants and variable clinical features, including normal phenotype (in 2 individuals), cardiomyopathy, and developmental delay.; Changed rating: AMBER; Changed publications: 42337718, 31815201, 22825317; Changed phenotypes: sarcosinemia, MONDO:0010008 |
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| Mendeliome v2.270 | AGTPBP1 |
Zornitza Stark edited their review of gene: AGTPBP1: Added comment: Newly reported association with teratozoospermia (monoallelic): the heterozygous p.Arg811His missense variant is identified in two unrelated families (PMID 41160201, PMID 37937809). A CRISPR‑engineered mouse knock‑in recapitulates the sperm head‑ and tail‑defect phenotype, providing variant‑specific functional evidence. RED for the mono-allelic association as it appears confined to this single missense variant, further reports needed.; Changed publications: 42358771, 41160201, 38587696, 38153683, 37937809, 34324503, 33909173, 33624935, 31102495, 30976113, 30237576; Changed phenotypes: Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650, Infertility disorder, MONDO:0005047 |
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| Mendeliome v2.268 | PTPRU |
Sarah Milton gene: PTPRU was added gene: PTPRU was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPRU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTPRU were set to 37056996 Phenotypes for gene: PTPRU were set to Neurodevelopmental disorder, MONDO:0700092, PTPRU-related Review for gene: PTPRU was set to RED Added comment: PMID 37056996 reports candidate neurodevelopmental genes and notes 3 individuals from 3 families with de novo heterozygous missense variants in PTPRU. The individuals presented with intellectual disability. No variant‑specific functional assays were performed and all variants are absent from or extremely rare in population databases. Further research is required to establish this gene disease association. Sources: Literature |
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| Mendeliome v2.244 | NQO1 |
Bryony Thompson gene: NQO1 was added gene: NQO1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NQO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NQO1 were set to 42267673 Phenotypes for gene: NQO1 were set to epithelial recurrent erosion dystrophy MONDO:0007381 Review for gene: NQO1 was set to RED Added comment: PMID 42267673 reports 30 individuals from 1 family with autosomal dominant missense variant p.Phe179Ile (c.535T>A) presenting with early‑onset corneal epithelial erosion dystrophy (Dystrophia Smolandiensis/ERED2). The variant co‑segregates across 49 informative meioses, is absent from gnomAD, and is hypothesised to act via toxic gain‑of‑function, although no variant‑specific functional assays were performed. Sources: Literature |
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| Mendeliome v2.232 | HDAC4 | chirag patel Phenotypes for gene: HDAC4 were changed from Neurodevelopmental disorder with central hypotonia and dysmorphic facies MIM#619797; Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome; Monogenic diabetes, MONDO:0015967 to Neurodevelopmental disorder with central hypotonia and dysmorphic facies MIM#619797; Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome; Monogenic diabetes, MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.231 | HDAC4 | chirag patel Phenotypes for gene: HDAC4 were changed from Neurodevelopmental disorder with central hypotonia and dysmorphic facies MIM#619797; Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome to Neurodevelopmental disorder with central hypotonia and dysmorphic facies MIM#619797; Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome; Monogenic diabetes, MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.230 | chirag patel Added reviews for gene HDAC4 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.222 | EGFR |
chirag patel changed review comment from: Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481; Green rating PMID: 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400 Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families. Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years. PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400). -------------------------------------------------------------------------------------- Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035 Amber rating PMID: 41533385 3 unrelated individuals presenting with widespread acanthosis nigricans, woolly hair, palmoplantar keratoderma and pulmonary nodules (consistent with atypical adenomatous hyperplasia). They all had the same heterozygous variant in EGFR (p.L858R). Two were shown to be de novo, and one was in post‑zygotic mosaic state. Patient‑cell assays show increased EGFR‑signalling supporting a gain of function mechanism. Therapy with an EGFR inhibitor in the 2 patients with germline variants showed marked improvement in skin and lung manifestations.; to: Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481; Biallelic - LOF Green rating PMID: 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400 Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families. Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years. PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400). -------------------------------------------------------------------------------------- Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035 Monoallelic - GOF Amber rating PMID: 41533385 3 unrelated individuals presenting with widespread acanthosis nigricans, woolly hair, palmoplantar keratoderma and pulmonary nodules (consistent with atypical adenomatous hyperplasia). They all had the same heterozygous variant in EGFR (p.L858R). Two were shown to be de novo, and one was in post‑zygotic mosaic state. Patient‑cell assays show increased EGFR‑signalling supporting a gain of function mechanism. Therapy with an EGFR inhibitor in the 2 patients with germline variants showed marked improvement in skin and lung manifestations. |
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| Mendeliome v2.222 | EGFR |
chirag patel edited their review of gene: EGFR: Added comment: Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481; Green rating PMID: 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400 Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families. Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years. PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400). -------------------------------------------------------------------------------------- Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035 Amber rating PMID: 41533385 3 unrelated individuals presenting with widespread acanthosis nigricans, woolly hair, palmoplantar keratoderma and pulmonary nodules (consistent with atypical adenomatous hyperplasia). They all had the same heterozygous variant in EGFR (p.L858R). Two were shown to be de novo, and one was in post‑zygotic mosaic state. Patient‑cell assays show increased EGFR‑signalling supporting a gain of function mechanism. Therapy with an EGFR inhibitor in the 2 patients with germline variants showed marked improvement in skin and lung manifestations.; Changed rating: GREEN; Changed publications: 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400,41533385; Changed phenotypes: Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481, Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492, Acanthosis nigricans MONDO:0007035 |
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| Mendeliome v2.217 | EGFR |
chirag patel changed review comment from: Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families. Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years. PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400).; to: Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families. Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years. PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400). |
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| Mendeliome v2.191 | USP34 |
Sarah Milton gene: USP34 was added gene: USP34 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: USP34 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: USP34 were set to 42315110; 39117575 Phenotypes for gene: USP34 were set to Neurodevelopmental disorder, MONDO:0700092-USP34 related Review for gene: USP34 was set to GREEN Added comment: USP34 encodes a deubiquitinating enzyme that stabilises Axin and positively regulates canonical Wnt/β‑catenin signalling. The gene lies within a known recurrent deletional syndrome - 2p15p16.1 region, ISCA-37408. PMID: 42315110 reports six unrelated individuals with heterozygous de novo loss‑of‑function USP34 variants presenting with a neurodevelopmental disorder characterised by global developmental delay, speech impairment and autism. USP34 is highly constrained for loss of function with few NMD predicted variants present in the population database gnomAD. PMID: 39117575 reports a de novo heterozygous NMD predicted variant in USP34 in a fetus diagnosed with agenesis of the corpus callosum, as of 3 years of age the child had normal development. No other contradictory evidence has been published. Sources: Literature |
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| Mendeliome v2.183 | GIT1 |
Sarah Milton gene: GIT1 was added gene: GIT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GIT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GIT1 were set to 42360756 Phenotypes for gene: GIT1 were set to Neurodevelopmental disorder, MONDO:0700092, GIT1-related Review for gene: GIT1 was set to GREEN Added comment: GIT1 encodes G-protein-coupled receptor kinase-interacting protein 1 which is a scaffold protein that plays roles in the actin cytoskeletal dynamics, focal adhesion assembly, membrane trafficking, intracellular signalling and neuronal development. PMID 42360756 reports nine individuals from three families with biallelic loss-of-function GIT1 variants presenting with microcephaly, severe developmental delay/intellectual disability, seizures, enlarged ventricles and variable other congenital brain anomalies, facial dysmorphism and intrauterine growth restriction/poor growth. 2 of the families had a shared haplotype and the same homozygous variant with the third family unrelated with a different loss of function variant. GIT1 is constrained for loss of function in gnomAD v4, there are no homozygous loss of function individuals present. Extensive functional studies support the association with zebrafish knock‑down recapitulates microcephaly and is rescued by wild‑type human GIT1 mRNA but not mRNA containing variants from affected patients, knockout mice have microcephaly and developmental delay, patient fibroblasts lack GIT1 protein and show reduced actin‑cytoskeleton dynamics. Sources: Literature |
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| Mendeliome v2.174 | ZMPSTE24 | chirag patel Phenotypes for gene: ZMPSTE24 were changed from Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210, MONDO:0010143; Familial partial lipodystrophy, MONDO:0020088; monogenic diabetes, MONDO:0015967 to Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210, MONDO:0010143; Familial partial lipodystrophy, MONDO:0020088; monogenic diabetes, MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.173 | ZMPSTE24 | chirag patel Phenotypes for gene: ZMPSTE24 were changed from Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612; MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210; MONDO:0010143 to Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, MONDO:0012074; Restrictive dermopathy, lethal, MIM# 275210, MONDO:0010143; Familial partial lipodystrophy, MONDO:0020088; monogenic diabetes, MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.170 | SLC19A2 | chirag patel Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270; Diabetes mellitus, MONDO:0005015 to Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270; Diabetes mellitus, MONDO:0005015 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.169 | SLC19A2 | chirag patel Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270 to Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270; Diabetes mellitus, MONDO:0005015 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.166 | chirag patel Added reviews for gene SLC19A2 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.164 | chirag patel Added reviews for gene SLC19A2 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.163 | PDX1 | chirag patel Phenotypes for gene: PDX1 were changed from Pancreatic agenesis 1 - MIM#260370 (AR); MODY, type IV - MIM#606392(AD) to Pancreatic agenesis 1 - MIM#260370 (AR); Maturity-onset diabetes of the young type 4, MONDO:0011667 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.161 | chirag patel Added reviews for gene PDX1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.160 | chirag patel Added reviews for gene NFKB1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.160 | chirag patel Added reviews for gene NFKB1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.141 | TENT5D |
Lucy Spencer gene: TENT5D was added gene: TENT5D was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TENT5D was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TENT5D were set to 35256600; 36746179; 38228861 Phenotypes for gene: TENT5D were set to male infertility MONDO:0005372, TENT5D-related Review for gene: TENT5D was set to GREEN Added comment: PMID 35256600, PMID 36746179, and PMID 38228861 report 5 males from 4 families with oligoasthenoteratozoospermia or teratozoospermia and hemizygous variants in TENT5D. 2 nonsense and 2 missense, all rare in gnomand with no hemizygotes. Western blot on cells transfected with the missense variants showed reduced protein expression, reduced TENT5D expression in patient sperm samples was also observed. Sources: Literature |
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| Mendeliome v2.123 | ZRANB1 |
chirag patel gene: ZRANB1 was added gene: ZRANB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZRANB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZRANB1 were set to 38099646 Phenotypes for gene: ZRANB1 were set to Neurodevelopmental disorder, MONDO:0700092, ZRANB1-related Review for gene: ZRANB1 was set to AMBER Added comment: PMID 38099646 reports 2 unrelated individuals presenting with a neurodevelopmental disorder (developmental delay, ASD, microcephaly, seizures, constipation, and craniofacial anomalies). They report 2 rare heterozygous missense ZRANB1 variants but no segregation data is available. Functional assays demonstrate loss of deubiquitylating activity for p.R438W and loss of STRIPAK binding for p.A451V, and are both rescued by wild‑type Trabid. Knock‑in mouse models showed reduced neuronal and glial cell densities in the brain, motor impairment, and impaired APC trafficking in neurites. Sources: Literature |
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| Mendeliome v2.111 | CDC27 |
Bryony Thompson gene: CDC27 was added gene: CDC27 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDC27 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDC27 were set to 38731925 Phenotypes for gene: CDC27 were set to craniofacial microsomia MONDO:0015397 Review for gene: CDC27 was set to GREEN Added comment: PMID 38731925 reports three individuals with de novo heterozygous variants (including missense and a stopgain) in CDC27 presenting with hemifacial microsomia – unilateral microtia, mandibular hypoplasia, facial asymmetry and conductive hearing loss with early‑childhood onset; zebrafish cdc27 knockout recapitulates the craniofacial phenotype and rescue experiments partially restore the defects. Sources: Literature |
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| Mendeliome v2.110 | ST6GALNAC1 |
Sarah Milton gene: ST6GALNAC1 was added gene: ST6GALNAC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ST6GALNAC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ST6GALNAC1 were set to 35303419 Phenotypes for gene: ST6GALNAC1 were set to Inflammatory bowel disease, MONDO:0005265, ST6GALNAC1-related Review for gene: ST6GALNAC1 was set to RED Added comment: ST6GALNAC1 encodes a protein involved in terminal sialyation of intestinal mucin proteins which act as a barrier, part of innate defenses in the gut. PMID 35303419 reports 3 individuals from 3 families with biallelic missense variants in ST6GALNAC1 presenting with early onset inflammatory bowel disease. However family 1 were consanguineous, family 2 had unaffected sibling with the same variants, 2 of the missense variants reported in affected individuals had 9 homozygotes in gnomAD v4. Loss of function was the proposed mechanism with reduced penetrance proposed by the authors. Functional studies with transfection of a patient variant in mice found no GI abnormalities consistent with IBD however thinning of intestinal mucus was noted. Cell models supported loss of function for the reported missense variants. Further papers are required to establish evidence for this gene disease association. Sources: Literature |
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| Mendeliome v2.107 | DND1 |
Sarah Milton changed review comment from: DND1 encodes an RNA‑binding protein thought to be involved in inhibition of microRNA mediated repression. PMID: 36246621 reported 3 males in one family with a homozygous missense variant in DND1 presenting with azospermia. Functional studies demonstrated reduced protein expression in cell models transfected with the variant NANOS2 interaction from coimmunoprecipitation. PMID: 39999035 reports one female with a biallelic loss of function variant in DND1 presenting with primary ovarian failure. PMID: 36807972 reports 5 males with 4 different heterozygous variants in DND1 (missense and one frameshift) presenting with azospermia and oligozoospermia. Functional studies were performed in zebrafish however homozygous knockout was performed with mRNA containing patient variants introduced resulting in abnormal primordial germ cell development. Authors state unclear whether the mechanism of inheritance is autosomal recessive vs semidominant. Supportive mouse and zebrafish knockout models have been published indicating sterility in male animals and reduced number of oocytes in females. It appears there is more evidence for the biallelic disease association however given only 2 affected unrelated patients have been published for this MOI more literature is required. Sources: Literature; to: DND1 encodes an RNA‑binding protein thought to be involved in inhibition of microRNA mediated repression. PMID: 36246621 reported 3 males in one family with a homozygous missense variant in DND1 presenting with azospermia. Functional studies demonstrated reduced protein expression in cell models transfected with the variant and reduced NANOS2 interaction from coimmunoprecipitation studies. PMID: 39999035 reports one female with a biallelic loss of function variant in DND1 presenting with primary ovarian failure. PMID: 36807972 reports 5 males with 4 different heterozygous variants in DND1 (missense and one frameshift) presenting with azospermia and oligozoospermia. Functional studies were performed in zebrafish however homozygous knockout was performed with mRNA containing patient variants introduced resulting in abnormal primordial germ cell development. Authors state unclear whether the mechanism of inheritance is autosomal recessive vs semidominant. Supportive mouse and zebrafish knockout models have been published indicating sterility in male animals and reduced number of oocytes in females. It appears there is more evidence for the biallelic disease association however given only 2 affected unrelated patients have been published for this MOI more literature is required. Sources: Literature |
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| Mendeliome v2.107 | DND1 |
Sarah Milton changed review comment from: DND1 encodes an RNA‑binding protein thought to be involved in inhibition of microRNA mediated repression. PMID: 36246621 reported 3 males in one family with a homozygous missense variant in DND1 presenting with azospermia. Demonstrated reduced protein expression in cell models transfected with the variant NANOS2 interaction from coimmunoprecipitation. PMID: 39999035 reports one female with a biallelic loss of function variant in DND1 presenting with primary ovarian failure. PMID: 36807972 reports 5 males with 4 different heterozygous variants in DND1 (missense and one frameshift) presenting with azospermia and oligozoospermia. Functional studies were performed in zebrafish however homozygous knockout was performed with mRNA containing patient variants introduced resulting in abnormal primordial germ cell development. Authors state unclear whether the mechanism of inheritance is autosomal recessive vs semidominant. Supportive mouse and zebrafish knockout models have been published indicating sterility in male animals and reduced number of oocytes in females. It appears there is more evidence for the biallelic disease association however given only 2 affected unrelated patients have been published for this MOI more literature is required. Sources: Literature; to: DND1 encodes an RNA‑binding protein thought to be involved in inhibition of microRNA mediated repression. PMID: 36246621 reported 3 males in one family with a homozygous missense variant in DND1 presenting with azospermia. Functional studies demonstrated reduced protein expression in cell models transfected with the variant NANOS2 interaction from coimmunoprecipitation. PMID: 39999035 reports one female with a biallelic loss of function variant in DND1 presenting with primary ovarian failure. PMID: 36807972 reports 5 males with 4 different heterozygous variants in DND1 (missense and one frameshift) presenting with azospermia and oligozoospermia. Functional studies were performed in zebrafish however homozygous knockout was performed with mRNA containing patient variants introduced resulting in abnormal primordial germ cell development. Authors state unclear whether the mechanism of inheritance is autosomal recessive vs semidominant. Supportive mouse and zebrafish knockout models have been published indicating sterility in male animals and reduced number of oocytes in females. It appears there is more evidence for the biallelic disease association however given only 2 affected unrelated patients have been published for this MOI more literature is required. Sources: Literature |
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| Mendeliome v2.107 | DND1 |
Sarah Milton gene: DND1 was added gene: DND1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DND1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DND1 were set to 39999035; 36807972; 36246621; 30439356 Phenotypes for gene: DND1 were set to Infertility disorder, MONDO:0005047, DND1-related Review for gene: DND1 was set to AMBER Added comment: DND1 encodes an RNA‑binding protein thought to be involved in inhibition of microRNA mediated repression. PMID: 36246621 reported 3 males in one family with a homozygous missense variant in DND1 presenting with azospermia. Demonstrated reduced protein expression in cell models transfected with the variant NANOS2 interaction from coimmunoprecipitation. PMID: 39999035 reports one female with a biallelic loss of function variant in DND1 presenting with primary ovarian failure. PMID: 36807972 reports 5 males with 4 different heterozygous variants in DND1 (missense and one frameshift) presenting with azospermia and oligozoospermia. Functional studies were performed in zebrafish however homozygous knockout was performed with mRNA containing patient variants introduced resulting in abnormal primordial germ cell development. Authors state unclear whether the mechanism of inheritance is autosomal recessive vs semidominant. Supportive mouse and zebrafish knockout models have been published indicating sterility in male animals and reduced number of oocytes in females. It appears there is more evidence for the biallelic disease association however given only 2 affected unrelated patients have been published for this MOI more literature is required. Sources: Literature |
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| Mendeliome v2.106 | DNAH14 |
Lucy Spencer edited their review of gene: DNAH14: Added comment: PMID: 41596228 reports 2 siblings with teenage-onset balance disorders, ataxia, and impaired cognitive function/intellectual disability, homozygous for Leu1021fs. These siblings also have a pathogenic FXN repeat expansion associated with Freidreich's ataxia. Still quite a few NMD variants with many homozygotes in gnomad v4. remains red; Changed rating: RED; Changed publications: 41596228 |
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| Mendeliome v2.99 | CEP43 |
Zornitza Stark gene: CEP43 was added gene: CEP43 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP43 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP43 were set to 41715205 Phenotypes for gene: CEP43 were set to Ciliopathy, MONDO:0005308, CEP43-related Review for gene: CEP43 was set to AMBER Added comment: Bardet‑Biedl syndrome (biallelic, LoF): PMID 41715205 reports a single individual with a homozygous splice‑site CEP43 variant presenting with classic BBS features (post‑axial polydactyly, cone‑rod dystrophy, congenital hip dysplasia, mild intellectual disability, obesity). No parental testing was performed, and functional evidence is limited to a mouse knockout model. Cone‑rod dystrophy (biallelic, LoF): PMID 41715205 describes one patient from a second family carrying compound heterozygous missense (p.R72H) and splice‑site CEP43 variants with progressive visual loss and retinal pigmentary changes. Inheritance was inferred without segregation data. Severe skeletal dysplasia (biallelic, LoF): PMID 41715205 reports a fetus from a third family homozygous for missense p.E12V, showing lethal short‑rib thoracic dysplasia. Parental carrier status is not shown. Sources: Literature |
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| Mendeliome v2.84 | YPEL2 regulatory region |
Sarah Milton Region: YPEL2 regulatory region was added Region: YPEL2 regulatory region was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: YPEL2 regulatory region. Mode of inheritance for Region: YPEL2 regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: YPEL2 regulatory region were set to PMID: 33022222 Phenotypes for Region: YPEL2 regulatory region were set to Retinitis pigmentosa 17, MIM#600852 Review for Region: YPEL2 regulatory region was set to GREEN Added comment: GDPD1 encodes glycerophosphodiester phosphodiesterase 4 and is not normally expressed in the retina. YPEL2 encodes Yippe-like 2 and has ubiquitous expression highest in brain. It is also known to be expressed in rod photoreceptor cells. The function is not yet well established. PMID: 33022222 reports over 300 affected individuals from 22 families in which structural variants were identified in 17q22 involving YPEL2 with affected individuals demonstrating a retinitis pigmentosa phenotype. Variants included duplications, triplications and inverted duplications. Disease was reported to be fully penetrant however with some manifestations occurring in later life. The molecular mechanism of disease was investigated using Hi-C on transdifferentiated retinal organoid cells and quantitative PCR. Functional studies showed structural variants resulted in altered TAD structure causing inappropriate retinal expression of GDPD1. This was due to altered proximity of GDPD1 to retinal specific enhancers normally surrounding YPEL2. Note: coordinates used for this entry are that of the minimal sized contiguous duplication reported in an affected individual. Sources: Literature |
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| Mendeliome v2.74 | NIBAN3 |
Bryony Thompson gene: NIBAN3 was added gene: NIBAN3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NIBAN3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NIBAN3 were set to 42185265 Phenotypes for gene: NIBAN3 were set to achalasia MONDO:0008698 Review for gene: NIBAN3 was set to AMBER Added comment: PMID 42185265 reports 2 apparently unrelated individuals (1 identified through trio analysis and 1 from a sporadic cohort) with a homozygous loss-of-function frameshift variant p.Ala454fs in NIBAN3 presenting with achalasia (elevated lower‑esophageal sphincter pressure, impaired esophageal emptying). A CRISPR/Cas9‑engineered Fam129c mouse model recapitulates key achalasia features, and B‑cell depletion or IVIG partially rescues the phenotype, supporting a neuro‑immune mechanism. Sources: Literature |
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| Mendeliome v2.70 | EPHX3 |
Bryony Thompson gene: EPHX3 was added gene: EPHX3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EPHX3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EPHX3 were set to 42178907 Phenotypes for gene: EPHX3 were set to Ichthyosis MONDO:0019269 Review for gene: EPHX3 was set to GREEN Added comment: PMID 42178907 reports 5 individuals from 3 families with autosomal recessive loss‑of‑function variants presenting with nonsyndromic epidermal differentiation disorder (nEDD), infant‑onset generalised xerosis, erythematous scaling plaques and skin peeling. Functional assays in patient keratinocytes and HEK293T cells demonstrate markedly reduced EH3 enzymatic activity and disrupted skin‑barrier lipid composition. Sources: Literature |
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| Mendeliome v2.67 | FGFR4 |
Zornitza Stark gene: FGFR4 was added gene: FGFR4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FGFR4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGFR4 were set to 30564136 Phenotypes for gene: FGFR4 were set to Visceral heterotaxy, MONDO:0018677, FGFR4-related Review for gene: FGFR4 was set to RED Added comment: PMID 30564136 reports three individuals from three families with heterozygous FGFR4 variants (de novo missense p.Asp297Asn, inherited stopgain p.Gly705*, and an inherited splice variant) presenting with heterotaxy and congenital heart disease (including hypoplastic left heart syndrome, L‑transposition of the great arteries, tricuspid atresia, hypoplastic pulmonary artery, left superior vena cava). Xenopus fgfr4 knockdown recapitulates heterotaxy‑like phenotypes, supporting a loss‑of‑function mechanism. However, two of the variants are inherited, hence Red rating. Sources: Literature |
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| Mendeliome v2.60 | NEURL1 |
Zornitza Stark gene: NEURL1 was added gene: NEURL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NEURL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEURL1 were set to 42192612 Phenotypes for gene: NEURL1 were set to Congenital hypothyroidism, MONDO:0018612, NEURL1-related Review for gene: NEURL1 was set to RED Added comment: PMID 42192612 reports one individual with biallelic missense NEURL1 variants (p.H68Y) causing isolated congenital hypothyroidism (childhood‑onset). Segregation analysis shows biparental inheritance. Zebrafish neurl1aa morpholino knockdown recapitulates thyroid defects. Sources: Literature |
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| Mendeliome v2.51 | ID4 downstream regulatory region |
Sarah Milton changed review comment from: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions of around 2mb in size and one inversion) affecting the region downstream of ID4 at 6p22.3. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype as such dysregulation as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature; to: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions of around 2mb in size and one inversion) affecting the region downstream of ID4 at 6p22.3. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype, as such, dysregulated expression as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature |
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| Mendeliome v2.51 | ID4 downstream regulatory region |
Sarah Milton changed review comment from: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions and one inversion) affecting the region downstream of ID4. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype as such dysregulation as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature; to: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions of around 2mb in size and one inversion) affecting the region downstream of ID4 at 6p22.3. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype as such dysregulation as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature |
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| Mendeliome v2.51 | ID4 downstream regulatory region |
Sarah Milton Region: ID4 downstream regulatory region was added Region: ID4 downstream regulatory region was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: ID4 downstream regulatory region. Mode of inheritance for Region: ID4 downstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: ID4 downstream regulatory region were set to 42069959; 26032025; 24628666 Phenotypes for Region: ID4 downstream regulatory region were set to Mesomelic dysplasia, Savarirayan type, MIM#605274 Review for Region: ID4 downstream regulatory region was set to GREEN Added comment: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions and one inversion) affecting the region downstream of ID4. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype as such dysregulation as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature |
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| Mendeliome v2.50 | MEIOSIN |
Sangavi Sivagnanasundram gene: MEIOSIN was added gene: MEIOSIN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MEIOSIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MEIOSIN were set to 42177587; 37982418 Phenotypes for gene: MEIOSIN were set to MEIOSIN-related premature ovarian insufficiency (POI) MONDO:0005047 Review for gene: MEIOSIN was set to AMBER Added comment: PMID: 379882418 - A female proband from a consanguineous family with POI. Homozygous missense variant - R579W (singleton - AF 0.0004%). Her sisters are heterozygous carriers for this variant and were clinically unaffected. PMID: 42177587 - Two Chinese sisters from non-consanguineous parents presenting with POI. Compound heterozygous variants identified in trans Leu327Pro; His356fs*14 - both variants absent from gnomAD v4.1. Supportive functional assays (dual‑luciferase reporter) show reduced transcriptional activation of meiotic genes, and a knock‑in mouse model carrying the homozygous variant recapitulates infertility, supporting a loss‑of‑function mechanism however, further evidence is required to definitely support the mechanism of disease. There is no Morbid OMIM entry for this gene disease association. Only one variant in this gene has been reported in ClinVar (p.Ser462_Ser465dup, has been classified as likely Benign). According to GTex, this gene is highly expressed in the testis but has low expression in the ovaries. Remain as AMBER pending further evidence. Sources: Literature |
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| Mendeliome v2.46 | PAM |
chirag patel gene: PAM was added gene: PAM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAM were set to 37388215 Phenotypes for gene: PAM were set to Pituitary gland adenoma MONDO:0006373 Review for gene: PAM was set to AMBER Added comment: PMID 37388215 reports 7 individuals from 5 unrelated families with heterozygous loss-of-function PAM variants causing pituitary hypersecretion (3 x childhood‑onset gigantism or adult acromegaly, 2 x paediatric ACTH‑dependent Cushing disease). All variants (3 x missense, 1 x frameshift, 1 x 5'UTR) were rare and shown to be loss of function using protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. Sources: Literature |
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| Mendeliome v2.41 | MAGED1 |
Sarah Milton gene: MAGED1 was added gene: MAGED1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAGED1 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: MAGED1 were set to 42162770 Phenotypes for gene: MAGED1 were set to Neurodevelopmental disorder, MONDO:0700092, MAGED1-related Review for gene: MAGED1 was set to AMBER Added comment: MAGED1 encodes Melanoma-Associated Antigen D1. It is expressed in the developing brain and is involved in controlling cell cycle progression and neuronal apoptosis. PMID 42162770 reports two unrelated male probands with de novo variants in MAGED1 presenting with epileptic spasms and severe intellectual disability. One frameshift and one missense variant we observed. It should be noted the missense variant was present in gnomAD v4 with 3 heterozygotes. Functional studies were performed demonstrating altered protein interactions and changes to cell cycle progression. Proposed mechanism of disease (GOF vs LOF) remains unclear. Sources: Literature |
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| Mendeliome v2.37 | PERCC1 |
chirag patel gene: PERCC1 was added gene: PERCC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PERCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PERCC1 were set to 41577959; 42110144; 39473069; 36076104; 31217582; 39359949; 40174224 Phenotypes for gene: PERCC1 were set to Congenital diarrhea, MONDO:0000824, PERCC1-related Review for gene: PERCC1 was set to GREEN Added comment: 16 individuals from 13 families (6 consanguineous) with biallelic loss-of-function PERCC1 variants causing congenital enteropathy characterised by infancy‑onset intractable diarrhoea, failure to thrive and intestinal failure. Variant types include nonsense and deletions (intragenic and whole gene). Mouse models showed that targeted deletion of PERCC1 led to reduced body weight and intestinal dysfunction, reversible by PERCC1 transgene insertion. RNA sequencing demonstrated that mice with the disrupted gene had reduced gastrin, somatostatin and ghrelin expression from enteroendocrine cells (EEC), and low serum gastrin implicating PERCC1 in normal EEC function. Sources: Literature |
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| Mendeliome v2.32 | DOP1A |
Zornitza Stark gene: DOP1A was added gene: DOP1A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DOP1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DOP1A were set to 42164854; 38818041 Phenotypes for gene: DOP1A were set to Neurodevelopmental disorder, MONDO:0700092, DOP1A-related Review for gene: DOP1A was set to GREEN Added comment: PMID 42164854 reports five individuals from five families with de novo heterozygous loss‑of‑function or missense DOP1A variants causing a dominant neurodevelopmental disorder characterised by intellectual disability, developmental delay, seizures and autism. PMID 42164854 also reports two families with homozygous variants, adding to the one previously described in PMID 38818041presenting with a recessive neurodevelopmental disorder that includes intellectual disability, developmental delay, seizures, brain malformations, ataxia, spasticity and nystagmus. Extensive functional data including DOP1A knock‑down in Neuro2a cells which demonstrates increased nuclear phospholipids and lipid droplets; and a mouse knockout which recapitulates neuronal overgrowth, CDK2 nuclear accumulation and behavioural deficits. Sources: Literature |
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| Mendeliome v2.23 | BIRC6 |
chirag patel gene: BIRC6 was added gene: BIRC6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BIRC6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BIRC6 were set to 42082826 Phenotypes for gene: BIRC6 were set to Premature ovarian failure, MONDO:0019852, BIRC6-related Review for gene: BIRC6 was set to RED Added comment: PMID 42082826 reports 5 affected females from a single consanguineous Iranian family with premature ovarian insufficiency and a homozygous missense variant in BIRC6 (p.Arg3756Cys). The variant segregated in 4 affected females (5th not tested) and in an unaffected male sibling, indicating female‑limited penetrance. Mother was an unaffected carrier. A zebrafish birc6 knockout recapitulates POI‑like reproductive deficits (reduced fecundity, aberrant oocyte morphology, and elevated embryonic death). BIRC6 encodes a large inhibitor of apoptosis (IAP) protein that suppresses programmed cell death by targeting executioner caspases for ubiquitin‑mediated degradation and participates in autophagy and DNA‑damage response. Sources: Literature |
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| Mendeliome v2.15 | ACTRT1 |
Lucy Spencer gene: ACTRT1 was added gene: ACTRT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACTRT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ACTRT1 were set to 34422805; 39267058; 33972689; 28869610 Phenotypes for gene: ACTRT1 were set to Infertility disorder, MONDO:0005047, ACTRT1-related; Bazex-Dupre-Christol syndrome MONDO:0010535, ACTRT1-related Review for gene: ACTRT1 was set to RED Added comment: PMID: 28869610 p.Met183Asnfs*17 in ACTRT identified in 2 families with Bazex–Dupré–Christol syndrome (BDCS) - congenital hypotrichosis, follicular atrophoderma, and predisposition to basal cell carcinoma. This variant is very common in gnomad with thousands of hets, over 900 hemizygotes and 6 homozygotes. 4 other families with BDCS were also investigated but only non-coding variants in far upstream/downstream regions were identified. These regions were postulated to be enhancers and the variants were shown to impair the enhancers activity and ACTRT1 expression. PMID: 33972689 no new patients but provides further functional support for ACTRT1 and the p.Met183Asnfs*17 variant’s role in BDCS. Bazex-Dupre-Christol syndrome MONDO:0010535, ACTRT1-related - RED PMID: 34422805 Identified ACTRT1 missense variants in two individuals with acephalic spermatozoa. Arg32His has 5 hemizygotes in gnomad while Tyr221Cys is absent. Both variants were maternally inherited. ACTRT1 knockout mice showed acephalic spermatozoa. PMID: 39267058 Identified Val57Met in a male with oligoasthenoteratozoospermia. This variant has 10 hemizygotes in gnomad Infertility disorder, MONDO:0005047, ACTRT1-related - RED/AMBER Sources: Literature |
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| Mendeliome v2.13 | HDAC2 |
Lucy Spencer gene: HDAC2 was added gene: HDAC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HDAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HDAC2 were set to 30806031; 27620904; 38753158 Phenotypes for gene: HDAC2 were set to Neurodevelopmental disorder (MONDO:0700092), HDAC2-related Review for gene: HDAC2 was set to GREEN Added comment: PMID: 27620904 In a large syndromic ID cohort one de novo missense in HDAC2 was identified Gly28Asp (filtered out in gnomad). This individual is also present in DECIPHER where the phenotype listed are: hypotonia, autistic behaviour, delayed speech and language development, developmental regression, hyperactivity, intellectual disability, motor stereotypy, and symptomatic seizures. PMID: 30806031 Met31Ile identified as de novo in an individual with a phenotype resembling Cornelia de Lange syndrome - severe developmental delay, limb abnormalities, congenital heart defect, cryptorchidism and hypoplastic genitalia, growth retardation, and characteristic craniofacial features. The variant is absent from gnomad. This individual also had a 5.6Mb copy number gain at 15q11.2q13.1 which is associated with a developmental disorder. PMID: 38753158 An individual clinically diagnosed with Rubenstein Tabi syndrome who had negative genetic testing for known RSTS genes. Phenotype included ID, growth and motor delay, dysmorphisms (synophrys, prominent columella, short philtrum, high nasal root, abnormal ears with prominent antihelix), broad halluces, speech delay, feeding problems and recurrent infections, vertebral anomalies, hypoplasia of corpus callosum, hypermetropia and early puberty. Identified a de novo frameshift p.(K444Lfs*61) in HDAC2 which is an elongation variant. This variant is absent from gnomad but other elongation variants are present with 4-13 hets. The variant was predicted to disrupt the NLS and studies in transfected cells showed protein mislocalisation. HDAC2 protein abundance was also reduced in patient cells, and patient cells showed similar differentially expressed genes to RSTS patients. The two missense are near each other and are present at or near annotated binding sites in DECIPHER, both very well conserved residues and one of the paper described this region as needed for the catalytic activity of the deacetylase. Borderline amber/green due to lack of functional evidence for the missense variants and the presence of other elongation variants in gnomad (however it is unclear if they also affect the NLS). Sources: Literature |
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| Mendeliome v2.1 | KCNJ11 | Sangavi Sivagnanasundram reviewed gene: KCNJ11: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: monogenic diabetes MONDO:0015967, hyperinsulinemic hypoglycemia, familial, 2 MONDO:0011153; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v2.1 | GCK |
Sangavi Sivagnanasundram changed review comment from: Classified as DEFINITIVE by ClinGen Monogenic Diabetes VCEP on 02/06/2026 - https://search.clinicalgenome.org/CCID:009345; to: Classified as DEFINITIVE by ClinGen Monogenic Diabetes VCEP on 02/06/2026 - https://search.clinicalgenome.org/CCID:009345 Mechanism of disease is LoF. |
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| Mendeliome v2.1 | GCK | Sangavi Sivagnanasundram reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.5025 | CLUAP1 |
Sarah Milton changed review comment from: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature; to: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in 2 individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature |
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| Mendeliome v1.5024 | CLUAP1 |
Sarah Milton gene: CLUAP1 was added gene: CLUAP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLUAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLUAP1 were set to 34209753; 28679688; 26820066 Phenotypes for gene: CLUAP1 were set to Leber congenital amaurosis, MONDO:0018998, CLUAP1-related; Ciliopathy, MONDO:0005308, CLUAP1-related Review for gene: CLUAP1 was set to AMBER Added comment: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature |
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| Mendeliome v1.5022 | PTPRD |
Sarah Milton changed review comment from: PTPRD encodes protein-tyrosine phosphatase, receptor type D. PMID 31088393 and PMID 37056996 both list PTPRD as a candidate gene for a neurodevelopmental disorder. PMID 31088393 reports a 5 year old with a de novo canonical splice variant in the gene presenting with moderate non syndromic developmental delay. PMID 37056996 notes 2 missense variants in the gene in individuals with speech and language delay however minimal variant and phenotypic information are provided. GWAS studies have previously linked polymorphisms in the gene to ASD/ADHD/OCD. Supportive functional evidence with loss of PTPRD expression in mice induces aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. Sources: Literature; to: PTPRD encodes protein-tyrosine phosphatase, receptor type D. PMID 31088393 and PMID 37056996 both list PTPRD as a candidate gene for a neurodevelopmental disorder. PMID 31088393 reports a 5 year old with a de novo canonical splice variant in the gene presenting with moderate non syndromic developmental delay. PMID 37056996 notes 2 heterozygous missense variants in the gene in individuals with speech and language delay however minimal variant and phenotypic information are provided. PTPRD is constrained for loss of function with very few heterozygous NMD predicted variants in the population database gnomAD v4. GWAS studies have previously linked polymorphisms in the gene to ASD/ADHD/OCD. Supportive functional evidence with loss of PTPRD expression in mice induces aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. Sources: Literature |
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| Mendeliome v1.5021 | PTPRD |
Sarah Milton gene: PTPRD was added gene: PTPRD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTPRD were set to 37056996; 31088393; 38890753 Phenotypes for gene: PTPRD were set to Neurodevelopmental disorder, MONDO:0700092, PTPRD related Review for gene: PTPRD was set to AMBER Added comment: PTPRD encodes protein-tyrosine phosphatase, receptor type D. PMID 31088393 and PMID 37056996 both list PTPRD as a candidate gene for a neurodevelopmental disorder. PMID 31088393 reports a 5 year old with a de novo canonical splice variant in the gene presenting with moderate non syndromic developmental delay. PMID 37056996 notes 2 missense variants in the gene in individuals with speech and language delay however minimal variant and phenotypic information are provided. GWAS studies have previously linked polymorphisms in the gene to ASD/ADHD/OCD. Supportive functional evidence with loss of PTPRD expression in mice induces aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. Sources: Literature |
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| Mendeliome v1.5016 | ADAD2 |
Sarah Milton gene: ADAD2 was added gene: ADAD2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADAD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAD2 were set to 39267058; 37325547; 36708028; 32741963 Phenotypes for gene: ADAD2 were set to Spermatogenic failure, MONDO:0004983, ADAD2-related Review for gene: ADAD2 was set to GREEN Added comment: ADAD2 encodes a testis-specific adenosine deaminase domain-containing (ADAD) protein. PMID 32741963, PMID 36708028, PMID 37325547 and PMID 39267058 report biallelic loss of function/missense variants in ADAD2 in 6 unrelated families (10 individuals). Clinical features included non‑obstructive azoospermia, spermatogonial arrest or severe oligoasthenoteratozoospermia. Variants were at appropriate carrier frequency in the population database gnomAD v4 for a rare recessive disorder. Supportive functional studies included mouse knockout recapitulating the spermatogenic failure phenotype and western blot loss of expression. Sources: Literature |
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| Mendeliome v1.5012 | ZMYND12 |
Bryony Thompson gene: ZMYND12 was added gene: ZMYND12 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZMYND12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZMYND12 were set to 39066891; 37934199 Phenotypes for gene: ZMYND12 were set to Infertility disorder, MONDO:0005047 Review for gene: ZMYND12 was set to GREEN Added comment: PMID 39066891 and PMID 37934199 report five individuals from five unrelated families with biallelic loss-of-function ZMYND12 variants presenting with severe male infertility, including asthenozoospermia and multiple morphological abnormalities of the sperm flagellum. Affected men exhibit markedly reduced progressive sperm motility and abnormal flagellar morphology leading to primary infertility. Mouse Zmynd12 knockout recapitulates subfertility and reduced sperm velocity, and RNAi knock‑down of the ortholog in Trypanosoma reproduces flagellar motility defects, though rescue experiments are lacking. The recurrent c.433C>T stop‑gain variant occurs in three families across distinct populations, with evidence of independent origins. Sources: Literature |
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| Mendeliome v1.5005 | PPP2R1B |
Zornitza Stark gene: PPP2R1B was added gene: PPP2R1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPP2R1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PPP2R1B were set to 33913576 Phenotypes for gene: PPP2R1B were set to Infertility disorder, MONDO:0005047, PPP2R1B-related Review for gene: PPP2R1B was set to AMBER Added comment: PMID 33913576 reports 5 individuals from 3 unrelated families with heterozygous missense PPP2R1B variants causing non‑obstructive azoospermia with meiotic arrest, and an additional individual with Sertoli‑cell‑only syndrome. Affected males present with meiotic arrest leading to infertility; the Sertoli‑cell‑only case shows a distinct histological phenotype. Cellular assays demonstrate reduced protein stability and increased ubiquitination for the meiotic‑arrest variants, whereas the Sertoli‑cell‑only variant shows normal stability. Homozygous deletion of Ppp2r1b in Mus musculus impaired meiotic recombination and caused meiotic arrest in spermatocytes. All the variants are missense and present in gnomAD, including the p.Arg410His variant in 32 hets. Lack of segregation data. All the variants would be classified as VOUS, hence Amber rating. Sources: Literature |
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| Mendeliome v1.4981 | ARHGAP24 |
Zornitza Stark edited their review of gene: ARHGAP24: Added comment: PMID 39484266 adds 5 unrelated families (11 affected individuals) with autosomal dominant ARHGAP24 variants causing isolated posterior mitral valve prolapse. Variant‑specific functional assays demonstrate reduced Rac1‑GAP activity, and zebrafish morpholino knockdown recapitulates valvular regurgitation. 4 of the variants are missense, one LoF. All are present in gnomAD, some at high frequencies (e.g. NP_001020787.2:p.Thr481Met is present in over 2,000 individuals).; Changed publications: 39484266; Changed phenotypes: Mitral valve prolapse, MONDO:0004910, ARHGAP24-related |
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| Mendeliome v1.4977 | NLGN1 |
Zornitza Stark edited their review of gene: NLGN1: Added comment: PMID 28841651 adds five unrelated families with heterozygous missense NLGN1 variants causing autism; functional assays demonstrate loss‑of‑function and a P89L knock‑in mouse recapitulates social deficits. PMID 38739110 adds two families (one de novo) with a neurodevelopmental disorder including intellectual disability, autism and epilepsy harbouring missense NLGN1 variants. At least one of the variants reported has a relatively high population frequency, not consistent with a monogenic disorder (e.g. p.Thr90Ile with 162 hets).; Changed rating: AMBER; Changed publications: 38739110, 28841651; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, autism, susceptibility to, 20, MONDO:0030004; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Mendeliome v1.4963 | ADAM17 | Zornitza Stark edited their review of gene: ADAM17: Added comment: PMID 34993966: single individual with biallelic loss‑of‑function ADAM17 variants (c.2082+2dupT and c.620-385_843+1015del) presenting with neonatal inflammatory skin and bowel disease type 1 (erythroderma, atrichia, nail dystrophy, oesophageal stricture, intractable diarrhoea, failure‑to‑thrive, recurrent infections). The splice variant causes exon 17 skipping; the deletion removes exons 6‑7. Skin improved with combined ustekinumab and certolizumab; intestinal disease responded to budesonide.; Changed publications: 38771644, 42015567, 40968583, 34993966 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4947 | FAT3 |
Lucy Spencer gene: FAT3 was added gene: FAT3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAT3 were set to 41937739; 35853984; 31486992; 26559152 Phenotypes for gene: FAT3 were set to Peripheral neuropathy MONDO:0005244, FAT3-related Review for gene: FAT3 was set to AMBER Added comment: AMBER for peripheral neuropathy PMID: 41937739 3 probands with peripheral neuropathies: distal muscle weakness, cranial nerve involvement, dysarthria, and bulbar involvement or respiratory failure. 2 probands had early childhood onset while the third had onset in their 30's. One proband was more severely affected with developmental abnormalities including congenital scoliosis, intestinal obstruction, ventriculomegaly, and corpus callosum thinning. All had homozygous or compound heterozygous missense (p.(Pro2041His, Cys3776Tyr, Met1749Val, Arg3276Gln), all fairly rare in gnomad with no homs. A neuron-specific knockdown of FAT3 in flies impaired motility, reduced lifespan and reduced synaptic branch length. intercrosses of mice heterozygous for the patient variant Pro2041His showed markedly fewer homozygotes than expected suggesting it is lethal in the homozygous state. KO mice and mice with Pro2041His exhibited CNS abnormalities including cerebellar abnormalities. Wide phenotypic variability and age of onset, only missense reported with functional studies only performed on one variant. RED for Hirschprung PMID: 26559152 6 FAT3 variant across 5 families with Hirscprung disease. However 3 of the variants are common in gnomad (77 hets or more, 2 with homs). The paper also mentions non-segregation of the phenotype with the variant within some of these families. RED for hyperparathyroidism PMID: 31486992 3 families with hyperparathyroidism and heterozygous missense variants in FAT3. 2 of the variants did not segregate well (observed in unaffected adult family members and/or not observed in affected family members). 2 of the variants were also very common in gnomad including homozygotes. Red for isolated scoliosis PMID: 35853984 2 compound heterozygous missense in 3 siblings with adolescent scoliosis. the variants were common in gnomad with homozygotes. Sources: Literature |
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| Mendeliome v1.4931 | RPN1 |
Krithika Murali gene: RPN1 was added gene: RPN1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPN1 were set to 41935956 Phenotypes for gene: RPN1 were set to Syndromic disease, MONDO:0002254 Review for gene: RPN1 was set to RED Added comment: RPN1 encodes ribophorin I, a subunit of the oligosaccharyltransferase complex that mediates N‑linked protein glycosylation. PMID 41935956 report two affected siblings from a consanguineous family harbouring a homozygous nonsense variant c.1654C>T (p.Gln552*) who present with a congenital disorder of glycosylation characterised by neurodevelopmental delay, dysmorphic features and a type I transferrin profile. Biochemical analyses show a truncated RPN1 protein and reduced OST complex components, and CRISPR knock‑in of the variant in HEK293 cells reproduces the glycosylation defect, supporting a loss‑of‑function mechanism. Sources: Literature |
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| Mendeliome v1.4927 | ARHGEF6 | Zornitza Stark edited their review of gene: ARHGEF6: Added comment: PMID 36414417 reports 6 unrelated families (8 individuals) with hemizygous X‑linked ARHGEF6 variants and congenital anomalies of the kidneys and urinary tract (CAKUT). Loss‑of‑function truncating variants and one missense variant that segregates with three affected males provide. However, the missense variants have relatively high pop frequencies in gnomAD. Functional assays demonstrate loss of RAC1/CDC42 activation in cells and mouse/Xenopus knockouts recapitulate CAKUT.; Changed rating: AMBER; Changed publications: 36414417; Changed phenotypes: congenital anomaly of kidney and urinary tract, MONDO:0019719, ARHGEF6-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4918 | MELK |
Zornitza Stark changed review comment from: PMID 41973119 reports four unrelated individuals from four families each carrying a heterozygous loss‑of‑function MELK variant (stop‑gain or start‑loss) and presenting with autism spectrum disorder (ASD). Mouse cortex MELK knockdown replicates cortical progenitor defects, and the authors propose MELK haploinsufficiency as a rare risk factor for ASD. Parental segregation information lacking. One of the variants is present in 10 hets in gnomAD. Sources: Literature; to: PMID 41973119 reports four unrelated individuals from four families each carrying a heterozygous loss‑of‑function MELK variant (stop‑gain or start‑loss) and presenting with autism spectrum disorder (ASD). Mouse cortex MELK knockdown replicates cortical progenitor defects, and the authors propose MELK haploinsufficiency as a rare risk factor for ASD. Parental segregation information lacking. One of the variants is present in 10 hets in gnomAD. Plenty of other LoF in gnomAD. Sources: Literature |
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| Mendeliome v1.4918 | MELK |
Zornitza Stark gene: MELK was added gene: MELK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MELK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MELK were set to 41973119 Phenotypes for gene: MELK were set to Neurodevelopmental disorder, MONDO:0700092, MELK-related Review for gene: MELK was set to RED Added comment: PMID 41973119 reports four unrelated individuals from four families each carrying a heterozygous loss‑of‑function MELK variant (stop‑gain or start‑loss) and presenting with autism spectrum disorder (ASD). Mouse cortex MELK knockdown replicates cortical progenitor defects, and the authors propose MELK haploinsufficiency as a rare risk factor for ASD. Parental segregation information lacking. One of the variants is present in 10 hets in gnomAD. Sources: Literature |
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| Mendeliome v1.4913 | CECR2 |
Lucy Spencer gene: CECR2 was added gene: CECR2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CECR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CECR2 were set to 41964217; 37424722 Phenotypes for gene: CECR2 were set to Neurodevelopmental disorder, MONDO:0700092, CECR2-related; neural tube defects, susceptibility to MONDO:0020705, CECR2-related Review for gene: CECR2 was set to GREEN Added comment: PMID 41964217 reports six individuals from six unrelated families with heterozygous nonsense, frameshift or missense CECR2 variants causing a neurodevelopmental disorder characterized by developmental and speech delay, growth restriction, microcephaly/small head circumference, intellectual disability and variable congenital anomalies. Other common features included gastrointestinal dysmotility, abnormal brain morphology, cardiac anomalies, ophthalmologic anomalies, and seizures/epilepsy in 3 patients. Two variants were confirmed de novo (1 missense 1 nonsense), inheritance information was no available for the other 4. All variant were either absent from gnomad v4 or had only 1 het. all missense were towards the end of the protein p.1385-1428. PMID 37424722 9 CECR2 variants in 12 patients with neural tube defects. All variants were missense from p. 327-1023 and 5 of them had over 11 hets in gnomad. Phenotypes included anencephaly, hydrocephalus, spina bifida, atelectasis, visceral congestion and more. The paper mentions a mouse model has previous shown LOF of CECR2 results in NTDs and that high homocysteine levels could further reduce CECR2 expression. Functional analysis on 4 missense in this cohort showed reduced CECR2 protein expression on western blot for 3, exposure to homocysteine thiolactone further reduced this expression in increase apoptosis activity while folic acid supplementation counteracted CECR2 expression decline and reduced apoptosis. No inheritance information was available for these variants. Green for the neurodevelopmental disorder, amber/red for neural tube defects similar to other genes with this association ie VANGL2. Sources: Literature |
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| Mendeliome v1.4902 | TMEM65 | Zornitza Stark edited their review of gene: TMEM65: Added comment: PMID 41980949 provides mouse whole‑body, neuronal‑specific and skeletal‑muscle‑specific TMEM65 knockout models that recapitulate severe mitochondrial encephalomyopathy and adult‑onset myopathy; rescue of early lethality by MCU knockout demonstrates that loss‑of‑function of TMEM65 is pathogenic.; Changed rating: RED; Changed publications: 41980949; Changed phenotypes: Mitochondrial disease, MONDO:0044970 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4902 | ERBB2 |
chirag patel changed review comment from: Main paper for cases described in PMID 33720042. 2 siblings from consanguineous Turkish family with intestinal dysmotility, severe constipation (aganglionosis in submucosa at rectum), peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, sensorineural hearing loss, and clubfeet. They had a homozygous rare missense variant in ERBB2 gene (A710V) and parents were heterozygous carriers. No functional studies; to: Main paper for cases described in PMID 33720042. 2 siblings from consanguineous Turkish family with intestinal dysmotility, severe constipation (aganglionosis in submucosa at rectum), peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, sensorineural hearing loss, and clubfeet. They had a homozygous rare missense variant in ERBB2 gene (A710V) and parents were heterozygous carriers. Western blot analysis revealed a drastic decrease of both ERBB2 and ERBB3 phosphorylation. Other papers showed mice knockout of Erbb2 results in the absence or severe depletion of various neural crest–derived cells. |
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| Mendeliome v1.4895 | SRRM4 |
chirag patel changed review comment from: 3 unrelated individuals with developmental delay, absent speech, intellectual impairment, epilepsy, early‑onset dystonia and chorea (6mths-20mths). Trio WES/WGS identified a de novo canonical splice‑donor variant in SRRM4 in each individual (c.464+2T>C or c.464+2T>A). SRRM4 is an exclusively neural-expressed splicing-factor gene. RNA-sequencing in patient fibroblasts revealed 2 variant-specific mutant SRRM4-mRNA isoforms (1 x isoform lacking exon 5, and 1 x isoform containing a 69-nucleotide elongation of exon 5) suggestive of a mechanism other than loss-of-function. Additionally, they uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts. Sources: Literature; to: 3 unrelated individuals with developmental delay, absent speech, intellectual impairment, epilepsy, early‑onset dystonia and chorea (6mths-20mths). Trio WES/WGS identified a rare de novo canonical splice‑donor variant in SRRM4 in each individual (c.464+2T>C or c.464+2T>A). SRRM4 is an exclusively neural-expressed splicing-factor gene. RNA-sequencing in patient fibroblasts revealed 2 variant-specific mutant SRRM4-mRNA isoforms (1 x isoform lacking exon 5, and 1 x isoform containing a 69-nucleotide elongation of exon 5) suggestive of a mechanism other than loss-of-function. Additionally, they uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts. Sources: Literature |
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| Mendeliome v1.4895 | SRRM4 |
chirag patel gene: SRRM4 was added gene: SRRM4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SRRM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SRRM4 were set to 41958152 Phenotypes for gene: SRRM4 were set to Neurodevelopmental disorder, MONDO:0700092, SRRM4-related Mode of pathogenicity for gene: SRRM4 was set to Other Review for gene: SRRM4 was set to GREEN Added comment: 3 unrelated individuals with developmental delay, absent speech, intellectual impairment, epilepsy, early‑onset dystonia and chorea (6mths-20mths). Trio WES/WGS identified a de novo canonical splice‑donor variant in SRRM4 in each individual (c.464+2T>C or c.464+2T>A). SRRM4 is an exclusively neural-expressed splicing-factor gene. RNA-sequencing in patient fibroblasts revealed 2 variant-specific mutant SRRM4-mRNA isoforms (1 x isoform lacking exon 5, and 1 x isoform containing a 69-nucleotide elongation of exon 5) suggestive of a mechanism other than loss-of-function. Additionally, they uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts. Sources: Literature |
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| Mendeliome v1.4875 | PTCHD3 |
chirag patel gene: PTCHD3 was added gene: PTCHD3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTCHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTCHD3 were set to 41848310 Phenotypes for gene: PTCHD3 were set to Syndromic disease, MONDO:0002254 Review for gene: PTCHD3 was set to RED Added comment: 2 individuals from 1 unrelated family (father-daughter) with a monoallelic variant in PTCHD3 presenting with Basal Cell Nevus Syndrome (BCNS). Clinical features include multiple odontogenic keratocysts, facial pigmented nevi, hypertelorism, and frontal-parietal bone protrusion. The authors propose the variant activates the Hedgehog pathway, supported by molecular docking simulations and increased expression of matrix metalloproteinases in patient-derived fibroblasts. Sources: Literature |
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| Mendeliome v1.4874 | NEFM |
chirag patel gene: NEFM was added gene: NEFM was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NEFM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEFM were set to 41913087 Phenotypes for gene: NEFM were set to Cerebellar ataxia, MONDO:0000437 Review for gene: NEFM was set to RED Added comment: 2 individuals from 1 family with compound heterozygous rare missense variants in NEFM, which encodes for a neurofilament protein. They presented with pure cerebellar ataxia (post-puberty onset of dysmetria of upper and lower limbs, speech ataxia, wide-based stance, and gait oscillations). The variants segregated within the family. Evidence is supported by in silico analysis predicting dysregulation of phosphorylation sites, though experimental functional validation of the patient variants was not performed. Sources: Literature |
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| Mendeliome v1.4862 | POU3F4 upstream regulatory region |
Sarah Milton changed review comment from: POU3F4 encodes POU domain, class III, transcriptional factor 4, a transcription factor with functional targets not fully elucidated but known to affect expression of GJB6, EPHA4 and EFNB2 in development. 17 patients reported across a number of publications with deletions sized between 8kb to 1.74mb upstream of POU3F4 presented with X linked deafness. Yang et al PMID: 41170199 reported 4 male individuals from one pedigree with deafness segregating with the upstream deletion. qPCR demonstrated reduced mRNA expression of POU3F4 in two affected males with the deletion with normal levels in their unaffected father. It is proposed this deletion is removing an upstream enhancer element however functional studies have not been performed to demonstrate this as of yet. The coordinates used in this entry are the largest reported to cause the phenotype most deletions reported in affected individuals were smaller. Sources: Literature; to: POU3F4 encodes POU domain, class III, transcriptional factor 4, a transcription factor with functional targets not fully elucidated but known to affect expression of GJB6, EPHA4 and EFNB2 in development. 17 patients reported across a number of publications with deletions sized between 8kb to 1.74mb upstream of POU3F4 presented with X linked deafness - mixed conductive and sensorineural. A typical temporal bone deformity is often seen that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn. Yang et al PMID: 41170199 reported 4 male individuals from one pedigree with deafness segregating with the upstream deletion. qPCR demonstrated reduced mRNA expression of POU3F4 in two affected males with the deletion with normal levels in their unaffected father. It is proposed this deletion is removing an upstream enhancer element however this has not been clearly demonstrated yet. The coordinates used in this entry are the largest reported to cause the phenotype most deletions reported in affected individuals were smaller. Sources: Literature |
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| Mendeliome v1.4852 | ARHGAP36 downstream regulatory region |
Sarah Milton Region: ARHGAP36 downstream regulatory region was added Region: ARHGAP36 downstream regulatory region was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: ARHGAP36 downstream regulatory region. Mode of inheritance for Region: ARHGAP36 downstream regulatory region 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 Region: ARHGAP36 downstream regulatory region were set to PMID: 40015599; 35986704; 38713094 Phenotypes for Region: ARHGAP36 downstream regulatory region were set to Bazex-Dupre-Christol syndrome, MIM#301845 Review for Region: ARHGAP36 downstream regulatory region was set to GREEN Added comment: ARHGAP36 is part of the Rho GTPase family and is a positive regulator of the SHH pathway. At least 10 families have been reported in the literature with duplications in an agenic region downstream of ARHGAP36 presenting with Bazex-Dupre-Christol syndrome. This syndrome is characterised by a triad of follicular atrophoderma, hypotrichosis and basal cell neoplasms. The duplications seen in affected individuals range from 18-135kb in size with the region thought to contain enhancers which increase expression of ARHGAP36. Functional studies involving immunofluorescence of hair of affected individuals in telogen demonstrated increased expression of ARHGAP36. Note: Coordinates used are the minimal region known to be duplicated in the reported cases. Sources: Literature |
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| Mendeliome v1.4822 | RPL18 |
Zornitza Stark changed review comment from: Three recent studies add 3 unrelated families with Diamond‑Blackfan anaemia and RPL18 variants. PMID 40510848 reports one autosomal‑recessive family with compound‑heterozygous missense variants (p.Phe43Ser, p.Asp348Asn). LIMITED evidence for this MOI. Leschchynska2026 describes one autosomal‑dominant family (3 affected family members) with heterozygous p.G133R and VACTERL anomalies and anaemia; functional assays show protein instability and 22 % reduced protein synthesis. However, another RPS6 variant co-segregates with disease also. PMID 28280134 reports one autosomal‑dominant family (father‑son) with heterozygous p.L51S; patient mononuclear cells display 36S pre‑rRNA accumulation, indicating a ribosome‑biogenesis defect. All variants are absent from gnomAD.; to: Two recent studies add 2 unrelated families with Diamond‑Blackfan anaemia and RPL18 variants. PMID 40510848 reports one autosomal‑recessive family with compound‑heterozygous missense variants (p.Phe43Ser, p.Asp348Asn). LIMITED evidence for this MOI. Leschchynska2026 describes one autosomal‑dominant family (3 affected family members) with heterozygous p.G133R and VACTERL anomalies and anaemia; functional assays show protein instability and 22 % reduced protein synthesis. However, another RPS6 variant co-segregates with disease also. All variants are absent from gnomAD. |
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| Mendeliome v1.4822 | RPL18 |
Zornitza Stark edited their review of gene: RPL18: Added comment: Three recent studies add 3 unrelated families with Diamond‑Blackfan anaemia and RPL18 variants. PMID 40510848 reports one autosomal‑recessive family with compound‑heterozygous missense variants (p.Phe43Ser, p.Asp348Asn). LIMITED evidence for this MOI. Leschchynska2026 describes one autosomal‑dominant family (3 affected family members) with heterozygous p.G133R and VACTERL anomalies and anaemia; functional assays show protein instability and 22 % reduced protein synthesis. However, another RPS6 variant co-segregates with disease also. PMID 28280134 reports one autosomal‑dominant family (father‑son) with heterozygous p.L51S; patient mononuclear cells display 36S pre‑rRNA accumulation, indicating a ribosome‑biogenesis defect. All variants are absent from gnomAD.; Changed rating: GREEN; Changed publications: 41851260, 40510848, 28280134; Changed phenotypes: Diamond-Blackfan anemia 18, MONDO:0032668 |
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| Mendeliome v1.4818 | SUPT4H1 |
Sarah Milton gene: SUPT4H1 was added gene: SUPT4H1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SUPT4H1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUPT4H1 were set to 41842694 Phenotypes for gene: SUPT4H1 were set to Syndromic disease, MONDO:0002254, SUPT4H1-related Review for gene: SUPT4H1 was set to GREEN Added comment: SUPT4H1 encodes SPT4 which is a subunit of the DSIF complex that regulates RNA polymerase II transcription. PMID 41842694 reports six individuals from three unrelated families with biallelic loss‑of‑function SUPT4H1 variants. 2 families were consanguineous, the other was not noted to have been. Clinical presentations of affected individuals included moderate to severe intellectual disability, dystonia, speech impairment, dysmorphism, skeletal anomalies including vertebral fusion/bifid vertebrae and complete enamel hypoplasia in 6/6 individuals. Variable additional features included epilepsy, spasticity and congenital heart defects. Variants were homozygous with one extension and 2 missense variants. Loss of function presumed mechanism. Supportive functional studies included altered transcriptomics and proteomics of other genes/proteins across patient samples. C. elegans knockout and variant knock‑in models demonstrated altered movement and behaviour. Sources: Literature |
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| Mendeliome v1.4800 | XPR1 |
Zornitza Stark edited their review of gene: XPR1: Added comment: PMID 41834789 reports 13 affected individuals from 4 consanguineous families with a homozygous loss‑of‑function missense variant (c.1811G>A; p.Arg604Gln) causing neonatal‑onset severe multisystem disease (brain calcifications, developmental delay, hypophosphataemia, cardiopulmonary involvement). Likely founder variant. Remains to be seen whether the biallelic disease relates specifically to this variant. Amber for this association -- caution with other variants warranted.; Changed publications: 41834789; Changed phenotypes: Basal ganglia calcification, idiopathic, 6, MONDO:0014628; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.4800 | SOX9 upstream regulatory region gain |
Sarah Milton changed review comment from: The upstream regulatory region of SOX9 has been demonstrated to have key roles in transcription factor binding including binding of SRY. Increased dosage of this agenic region has been demonstrated in a number of individuals to result in 46XX sex reversal with a varying phenotype from DSD to phenotypic male. The coordinates used in this entry are the minimal critical region however reported duplications range from 3.7kb to 780kb. Incomplete penetrance has been observed. Supportive functional studies in the form of mouse models and luciferase reporter assays have been published. Note: Duplications of this region in 46,XY individuals don't result in a phenotype. Refer to ISCA-46303 loss entry. Sources: Literature; to: The upstream regulatory region of SOX9 has been demonstrated to have key roles in transcription factor binding including binding of SRY. Increased dosage of this agenic region has been demonstrated in a number of individuals to result in 46XX sex reversal with a varying phenotype from DSD to phenotypic male. The coordinates used in this entry are the minimal critical region affecting XYSR enhancer however reported duplications range from 3.7kb to 780kb. Incomplete penetrance has been observed. Supportive functional studies in the form of mouse models and luciferase reporter assays have been published. Note: Duplications of this region in 46,XY individuals don't result in a phenotype. Refer to ISCA-46303 loss entry. Sources: Literature |
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| Mendeliome v1.4800 | SOX9 upstream regulatory region gain |
Sarah Milton Region: SOX9 upstream regulatory region gain was added Region: SOX9 upstream regulatory region gain was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: SOX9 upstream regulatory region gain. Mode of inheritance for Region: SOX9 upstream regulatory region gain was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: SOX9 upstream regulatory region gain were set to PMID: 37551848; 30552336; 31661700 Phenotypes for Region: SOX9 upstream regulatory region gain were set to 46XX sex reversal 2, MIM#278850 Penetrance for Region: SOX9 upstream regulatory region gain were set to Incomplete Review for Region: SOX9 upstream regulatory region gain was set to GREEN Added comment: The upstream regulatory region of SOX9 has been demonstrated to have key roles in transcription factor binding including binding of SRY. Increased dosage of this agenic region has been demonstrated in a number of individuals to result in 46XX sex reversal with a varying phenotype from DSD to phenotypic male. The coordinates used in this entry are the minimal critical region however reported duplications range from 3.7kb to 780kb. Incomplete penetrance has been observed. Supportive functional studies in the form of mouse models and luciferase reporter assays have been published. Note: Duplications of this region in 46,XY individuals don't result in a phenotype. Refer to ISCA-46303 loss entry. Sources: Literature |
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| Mendeliome v1.4767 | SCP2 | Zornitza Stark edited their review of gene: SCP2: Added comment: PMID 39941065 reports 2 individuals from 2 unrelated families with de novo heterozygous missense CTDSP2 (c.332C>A, p.T111N) variants presenting with hemifacial microsomia (unilateral facial hypoplasia, ear malformations, mandibular underdevelopment). Zebrafish ctdsp2 knockout recapitulates the craniofacial phenotype and rescue by wild‑type ctdsp2 mRNA or tp53 knockout restores normal cartilage, providing functional support.; Changed publications: 26497993, 39941065; Changed phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724, Craniofacial microsomia, MONDO:0015397, SCP2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4725 | DLX5 downstream regulatory region |
Sarah Milton changed review comment from: DLX5 encodes a transcription factor essential for epidermal morphogenesis and limb development. Expression is known to be regulated by p63 (encoded for by TP63). Over 20 families have been reported with deletions or translocations involving a region downstream from DLX5 with split-hand foot malformation with incomplete penetrance. Deletions are highly variable in size ranging from 17kb to megabase in size. The region deleted is located within the protein coding gene DYNC1I1. However haploinsufficiency of this gene is not thought to be the mechanism of disease . It has been demonstrated enhancer elements that regulate expression of DLX5 are located within exons 14-17 of DYNC1I1 with individuals with balanced translocations disrupting the region also having a similar phenotype. Note: coordinates used for this entry are that of the refseq for DYNC1I1, much larger or smaller deletions or disruption to the region from translocations/inversions may still be causative of disease. Sources: Literature; to: DLX5 encodes a transcription factor essential for epidermal morphogenesis and limb development. Expression is known to be regulated by p63 (encoded for by TP63). Over 20 families have been reported with deletions or translocations involving a region downstream from DLX5 with split-hand foot malformation with incomplete penetrance. Deletions are highly variable in size ranging from 17kb to megabase in size. The region deleted is located within the protein coding gene DYNC1I1. However haploinsufficiency of this gene is not thought to be the mechanism of disease . It has been demonstrated enhancer elements that regulate expression of DLX5 are located within exons 14-17 of DYNC1I1 with individuals with balanced translocations disrupting the region also having a similar phenotype. Note: coordinates used for this entry encompass exons 14 to 17 of DYNC1I1 much larger deletions or disruption to the region from translocations/inversions may still be causative of disease. Sources: Literature |
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| Mendeliome v1.4724 | DLX5 downstream regulatory region |
Sarah Milton Region: DLX5 downstream regulatory region was added Region: DLX5 downstream regulatory region was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: DLX5 downstream regulatory region. Mode of inheritance for Region: DLX5 downstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: DLX5 downstream regulatory region were set to PMID: 26839112; 37916192; 26075025; 24459211 Phenotypes for Region: DLX5 downstream regulatory region were set to Split-hand/foot malformation 1 MIM#183600 Penetrance for Region: DLX5 downstream regulatory region were set to Incomplete Review for Region: DLX5 downstream regulatory region was set to GREEN Added comment: DLX5 encodes a transcription factor essential for epidermal morphogenesis and limb development. Expression is known to be regulated by p63 (encoded for by TP63). Over 20 families have been reported with deletions or translocations involving a region downstream from DLX5 with split-hand foot malformation with incomplete penetrance. Deletions are highly variable in size ranging from 17kb to megabase in size. The region deleted is located within the protein coding gene DYNC1I1. However haploinsufficiency of this gene is not thought to be the mechanism of disease . It has been demonstrated enhancer elements that regulate expression of DLX5 are located within exons 14-17 of DYNC1I1 with individuals with balanced translocations disrupting the region also having a similar phenotype. Note: coordinates used for this entry are that of the refseq for DYNC1I1, much larger or smaller deletions or disruption to the region from translocations/inversions may still be causative of disease. Sources: Literature |
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| Mendeliome v1.4695 | KCNJ4 |
chirag patel changed review comment from: PMID 41830586 reports 4 individuals from 4 families with heterozygous missense KCNJ4 variants presenting with refractory epilepsy and neurodevelopmental delay/intellectual disability. Clinical features range from isolated epilepsy to severe developmental and epileptic encephalopathy. Two variants arose de novo and two had unknown segregation status. Electrophysiology in Xenopus oocytes demonstrates variant‑specific gain‑of‑function (Gly136Ser and Glu384Lys) or loss‑of‑function effects (Val206Met and Met293Lys). Sources: Literature; to: PMID 41830586 reports 4 individuals from 4 families with rare heterozygous missense KCNJ4 variants presenting with refractory epilepsy and neurodevelopmental delay/intellectual disability. Clinical features range from isolated epilepsy to severe developmental and epileptic encephalopathy. Two variants arose de novo and two had unknown segregation status. Electrophysiology in Xenopus oocytes demonstrates variant‑specific gain‑of‑function (Gly136Ser and Glu384Lys) or loss‑of‑function effects (Val206Met and Met293Lys). Sources: Literature |
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| Mendeliome v1.4694 | KCNJ4 |
chirag patel gene: KCNJ4 was added gene: KCNJ4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCNJ4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNJ4 were set to 41830586 Phenotypes for gene: KCNJ4 were set to Neurodevelopmental disorder, MONDO:0700092, KCNJ4-related Mode of pathogenicity for gene: KCNJ4 was set to Other Review for gene: KCNJ4 was set to GREEN Added comment: PMID 41830586 reports 4 individuals from 4 families with heterozygous missense KCNJ4 variants presenting with refractory epilepsy and neurodevelopmental delay/intellectual disability. Clinical features range from isolated epilepsy to severe developmental and epileptic encephalopathy. Two variants arose de novo and two had unknown segregation status. Electrophysiology in Xenopus oocytes demonstrates variant‑specific gain‑of‑function (Gly136Ser and Glu384Lys) or loss‑of‑function effects (Val206Met and Met293Lys). Sources: Literature |
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| Mendeliome v1.4691 | APPL1 | Sangavi Sivagnanasundram reviewed gene: APPL1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004159; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4681 | WWP1 |
Sarah Milton gene: WWP1 was added gene: WWP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WWP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WWP1 were set to 41786693; 32699206 Phenotypes for gene: WWP1 were set to Neurodevelopmental disorder, MONDO:0700092, WWP1-related Review for gene: WWP1 was set to RED Added comment: WWP1 encodes a E3 ubiquitin ligase involved in protein trafficking. PMID: 32699206 describes 10 individuals with autism found to have missense or splice variants in WWP1 with an autism phenotype. Variants were all found to be inherited apart from 2 in which inheritance was unknown. Phenotypes of parents were not included in the publication. Authors propose variants in this gene are more common in neurodevelopmental cohorts than control populations. All variants apart from 1 detected in affected individuals were present in gnomad v4, with allele frequencies ranging from 4 heterozygotes to 4000 heterozygotes. PMID: 41786693 describes another affected individual with development epileptic encephalopathy and regression with a de novo missense in WWP1. This variant was present in 4 heterozygotes in gnomad v4. Extensive functional studies were performed in this paper in mice and cell lines showing gain of function variants in WWP1 in mice embryos resulted in abnormal neuronal migration and increased neuronal apoptosis. Further studies are needed to demonstrate a Mendelian gene disease association. Sources: Literature |
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| Mendeliome v1.4680 | RARG |
Zornitza Stark changed review comment from: PMID 41830175 reports four affected members from a single family with a heterozygous truncating RARG variant (c.1237C>T, p.Arg413*) causing childhood‑onset urothelial keratinising squamous metaplasia (KDSM) and associated ectodermal features; the variant segregates in an autosomal‑dominant pattern and functional assays demonstrate dominant‑negative loss‑of‑function, but evidence is limited to one family. Sources: Literature; to: PMID 41830175 reports four affected members from a single family with a heterozygous truncating RARG variant (c.1237C>T, p.Arg413*) causing childhood‑onset urothelial keratinising squamous metaplasia (KDSM) and associated ectodermal features. The truncating variant does not destabilise the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RARγ, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinising squamous metaplasia of the urothelium. Sources: Literature |
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| Mendeliome v1.4680 | RARG |
Zornitza Stark gene: RARG was added gene: RARG was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RARG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RARG were set to 41830175 Phenotypes for gene: RARG were set to Ectodermal dysplasia syndrome, MONDO:0019287, RARG-related Review for gene: RARG was set to RED Added comment: PMID 41830175 reports four affected members from a single family with a heterozygous truncating RARG variant (c.1237C>T, p.Arg413*) causing childhood‑onset urothelial keratinising squamous metaplasia (KDSM) and associated ectodermal features; the variant segregates in an autosomal‑dominant pattern and functional assays demonstrate dominant‑negative loss‑of‑function, but evidence is limited to one family. Sources: Literature |
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| Mendeliome v1.4648 | RNU6ATAC | Zornitza Stark Phenotypes for gene: RNU6ATAC were changed from Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related; neonatal diabetes to Syndromic disease, MONDO:0002254, RNU6ATAC-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4625 | PITX1 upstream regulatory region |
Sarah Milton Region: PITX1 upstream regulatory region was added Region: PITX1 upstream regulatory region was added to Mendeliome. Sources: Literature Mode of inheritance for Region: PITX1 upstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: PITX1 upstream regulatory region were set to PMID: 30711920; 23022097; 25124102; 23587911 Phenotypes for Region: PITX1 upstream regulatory region were set to Liebenberg syndrome, MIM#186550 Review for Region: PITX1 upstream regulatory region was set to GREEN Added comment: PITX1 is a transcription factor expressed solely in the hindlimb during limb development where it ensures proper outgrowth and patterning of this tissue. Over 25 individuals have been reported in the literature with deletions upstream of PITX1 presenting with Liebenberg syndrome characterised by dysplastic elbow joints and the fusion of wrist bones and the consequent radial deviation. With upper limb features resembling some of those seen in the lower limb. The deletions seen in affected individuals range from 8kb to 134kb in size and are thought to result in overexpression of PITX1 by affecting the proximity between the coding sequence and an upstream enhancer (referred to variably as 'Pen' or 'hs1473'). The deletion removes part of a different protein coding gene - MACROH2A1 which is not thought to contribute to the pathogenesis (knockout mice do not present with a similar phenotype to Liebenberg). Authors of PMID: 30711920 suggest the promoter of MACROH2A1 acts as an insulator between the upstream enhancer and PITX1 however further functional studies are required to establish this. Functional studies involving transgenic mice with the enhancer element just upstream of PITX1 resulting in a similar phenotype to affected individuals. Note: Maximal reported deletion coordinates at time of writing: chr5:135288912-135423802 Minimum: chr5:135393716-135402219: Sources: Literature |
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| Mendeliome v1.4623 | IHH upstream regulatory region |
Sarah Milton Region: IHH upstream regulatory region was added Region: IHH upstream regulatory region was added to Mendeliome. Sources: Literature Mode of inheritance for Region: IHH upstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: IHH upstream regulatory region were set to PMID: 21167467 Phenotypes for Region: IHH upstream regulatory region were set to Craniosynostosis, Philadelphia type, with syndactyly, MIM#185900; Syndactyly, type 1, MIM#185900 Review for Region: IHH upstream regulatory region was set to GREEN Added comment: IHH belongs to the hedgehog family, and is required for endochondral bone formation by regulating the proliferation and differentiation of chondrocytes. During development IHH is predominantly expressed in prehypertrophic chondrocytes. PMID: 21167467 describes 3 families with over 80 affected individuals with duplications either including IHH or entirely upstream (in an intron of NHEJ1). These individuals were affected with variable degrees of cutaneous and distal osseus syndactyly and craniosynostosis. Authors identified duplications in affected families involving conserved non coding elements (either 1 or up to 3 in those with the largest duplications) and cloned an orthologous region into mouse with a fluorescent reporter vector and found staining of chondrocytes indicating this region was a possible enhancer. Note: OMIM uses coordinates chr2:208,200,001-230,100,000 for this duplication (maximal breakpoints). Minimal region overlap from literature used for Panelapp entry. Further functional studies required to define exact breakpoints. Sources: Literature |
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| Mendeliome v1.4608 | KNG1 | Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 36700498 aggregates 48 patients from 41 unrelated families with biallelic truncating or splice‑site KNG1 variants. Prolonged aPTT and but lack of evidence for increased incidence of major bleeding episodes.; Changed publications: 41634406, 40848077, 36700498, 33114181, 32185598, 31858768, 31087670; Changed phenotypes: angioedema, hereditary, 6, MONDO:0023660, congenital high-molecular-weight kininogen deficiency, MONDO:0009234; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4592 | RHOB |
Lucy Spencer edited their review of gene: RHOB: Added comment: PMID: 32989326 2 CP patients de novo for the same missense S73F, absent from gnomad PMID: 39080495 no new patients, created a KI rabbit model of S73F which showed CP symptoms ie periventricular leukomalacia and spastic-dystonic diplegia. Also showed the variant activates ACAT1 altering lipid levels which may lead to neuronal and white matter damage resulting in CP. Still only 2 patients with the same variant reported - amber; Changed rating: AMBER; Changed publications: 32989326, 39080495; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Mendeliome v1.4586 | POU3F4 upstream regulatory region |
Sarah Milton Region: POU3F4 upstream regulatory region was added Region: POU3F4 upstream regulatory region was added to Mendeliome. Sources: Literature Mode of inheritance for Region: POU3F4 upstream regulatory region was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for Region: POU3F4 upstream regulatory region were set to PMID: 41170199, 35189936, 33860785 Phenotypes for Region: POU3F4 upstream regulatory region were set to Deafness, X-linked 2 MIM#304400 Review for Region: POU3F4 upstream regulatory region was set to AMBER Added comment: POU3F4 encodes POU domain, class III, transcriptional factor 4, a transcription factor with functional targets not fully elucidated but known to affect expression of GJB6, EPHA4 and EFNB2 in development. 17 patients reported across a number of publications with deletions sized between 8kb to 1.74mb upstream of POU3F4 presented with X linked deafness. Yang et al PMID: 41170199 reported 4 male individuals from one pedigree with deafness segregating with the upstream deletion. qPCR demonstrated reduced mRNA expression of POU3F4 in two affected males with the deletion with normal levels in their unaffected father. It is proposed this deletion is removing an upstream enhancer element however functional studies have not been performed to demonstrate this as of yet. The coordinates used in this entry are the largest reported to cause the phenotype most deletions reported in affected individuals were smaller. Sources: Literature |
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| Mendeliome v1.4582 | GLTP |
chirag patel gene: GLTP was added gene: GLTP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GLTP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GLTP were set to 41642656 Phenotypes for gene: GLTP were set to Ichthyosis, MONDO:0019269; Epidermal differentiation disorder Review for gene: GLTP was set to GREEN Added comment: PMID 41642656 reports 6 individuals from 5 unrelated families with rare biallelic loss‑of‑function GLTP variants (c.58_62del, c.98delT, c.162+2T>C). Individuals presented with non-syndromic epidermal differentiation disorder (generalized scaling, hyperkeratosis, and pruritus from birth, without extra‑dermal anomalies). GLTP encodes a glycolipid transfer protein that mediates inter‑membrane transport of glucosylceramide. The variants segregated with disease. Functional studies (CRISPR mouse knockout, keratinocyte knockdown, and rescue by eliglustat) demonstrate loss of GLTP expression and disrupted GlcCer trafficking, supporting a loss‑of‑function disease mechanism. Sources: Literature |
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| Mendeliome v1.4566 | BICC1 |
chirag patel edited their review of gene: BICC1: Added comment: PMID 41677782 provides 4 individuals from 3 families with very early‑onset polycystic kidney disease (VEO-PKD). -2 siblings from consanguineous family with homozygous missense BICC1 variant (p.Ser240Pro)(absent gnomAD). One of the siblings also had a PKD2 variant (c.1445T>G, p.Phe482Cys). -1 individual with BICC1 missense variant (c.2462G>A, p.Gly821Glu)(3025 HTZ gnomAD) inherited from his father (2 small renal cysts in 1 kidney), and a de novo PKD2 variant (c.1894T>C, p.Cys632Arg). -1 individual with BICC1 splice variant (c.1179+1G>T)(absent gnomAD) inherited from his father, and a de novo PKD1 variant (c.11942C>T, p.Ala3981Val). Functional assays of the p.Ser240Pro and p.Gly821Glu variants demonstrated hypomorphic loss‑of‑function (CRISPR knock‑in HEK293T, Xenopus rescue, protein stability). Hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and that BICC1 variants may aggravate PKD severity.; Changed publications: 41677782; Changed phenotypes: Polycystic kidney disease, MONDO:0020642; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v1.4561 | C11orf80 |
Zornitza Stark edited their review of gene: C11orf80: Added comment: PMID 41644825 reports a Turkish consanguineous family with a homozygous splice‑site TOP6BL variant (c.523+1G>C) causing adult‑onset non‑obstructive azoospermia (NOA) and meiotic arrest; mouse Top6bl knockout recapitulates the male‑infertility phenotype. PMID 30388401 describes two unrelated families with biallelic TOP6BL loss‑of‑function alleles (c.783dup and c.1501T>C) presenting with recurrent complete hydatidiform mole (CHM) and miscarriage. Maintain Amber rating as unclear whether these two disease associations are related or distinct.; Changed publications: 41644825, 30388401; Changed phenotypes: Infertility disorder, MONDO:0005047, C11orf80-related, hydatidiform mole, recurrent, 4, MONDO:0032747 |
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| Mendeliome v1.4545 | ZNF124 |
Zornitza Stark gene: ZNF124 was added gene: ZNF124 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF124 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF124 were set to 41708596 Phenotypes for gene: ZNF124 were set to Retinitis pigmentosa, MONDO:0019200, ZNF124-related Review for gene: ZNF124 was set to RED Added comment: PMID 41708596 report 2 individuals from a consanguineous family with retinitis pigmentosa and a homozygous splice‑site loss‑of‑function variant c.219‑1delG in ZNF124. The variant co‑segregates with disease and mouse retina‑specific knockout recapitulates the retinal degeneration phenotype through loss of ZNF124‑mediated activation of MSX2. Sources: Literature |
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| Mendeliome v1.4532 | RAD51AP2 |
Zornitza Stark gene: RAD51AP2 was added gene: RAD51AP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAD51AP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD51AP2 were set to 41644825; 36153927 Phenotypes for gene: RAD51AP2 were set to Infertility disorder, MONDO:0005047, RAD51AP2-related Review for gene: RAD51AP2 was set to AMBER Added comment: PMID 41644825 reports one male patient from a Turkish consanguineous family and PMID 36153927 reports two brothers from an unrelated family; together three individuals from two unrelated families carry biallelic loss‑of‑function RAD51AP2 variants and present with non‑obstructive azoospermia and meiotic arrest. Both studies demonstrate autosomal recessive inheritance, and a mouse Rad51ap2 knockout recapitulates the infertility phenotype, providing functional support for causality. Sources: Literature |
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| Mendeliome v1.4530 | PIWIL1 |
Zornitza Stark gene: PIWIL1 was added gene: PIWIL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PIWIL1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: PIWIL1 were set to 41706354; 39122675; 37335463; 36379263; 33877510; 28552346 Phenotypes for gene: PIWIL1 were set to Infertility disorder, MONDO:0005047, PIWIL1-related Review for gene: PIWIL1 was set to AMBER Added comment: PMID 28552346 reports three unrelated families with heterozygous PIWIL1 missense variants causing idiopathic azoospermia; mouse knock‑in and rescue experiments provide functional support. PMID 41706354 and PMID 39122675 describe two unrelated families with recessive loss‑of‑function PIWIL1 frameshift/stop‑gain variants leading to non‑obstructive azoospermia and spermatogenic arrest, confirmed by immunohistochemistry and piRNA profiling. PMID 37335463 identifies a compound‑heterozygous patient and four heterozygous carriers of rare missense/truncating PIWIL1 variants, and a Miwi R371W knock‑in mouse recapitulates subfertility. Sources: Literature |
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| Mendeliome v1.4524 | ASCL5 |
Zornitza Stark gene: ASCL5 was added gene: ASCL5 was added to Mendeliome. Sources: Literature founder tags were added to gene: ASCL5. Mode of inheritance for gene: ASCL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASCL5 were set to 41673016 Phenotypes for gene: ASCL5 were set to Tooth disorder, MONDO:0006999, ASCL5-related Review for gene: ASCL5 was set to AMBER Added comment: [PMID 41673016] reports 17 individuals from 6 unrelated families with heterozygous missense ASCL5 c.274G>A (p.Glu92Lys) variants presenting with autosomal‑dominant lobodontia, characterized by supernumerary cusps, single pyramidal roots, and taurodontism. The variant fully co‑segregates with disease, is absent from population databases, and functional studies (CRISPR knock‑in mouse, luciferase reporter, RNA‑seq) demonstrate loss‑of‑function of ASCL5 transcriptional activation. Amber rating due to this being a likely founder variant and not necessarily perceived as disease. Sources: Literature |
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| Mendeliome v1.4512 | LMNB1 upstream region |
Sarah Milton Region: LMNB1 upstream region was added Region: LMNB1 upstream region was added to Mendeliome. Sources: Literature Mode of inheritance for Region: LMNB1 upstream region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: LMNB1 upstream region were set to PMID: 30842973; 30697589; 25701871 Phenotypes for Region: LMNB1 upstream region were set to Adult-onset autosomal dominant demyelinating leukodystrophy, MONDO:0008215 Review for Region: LMNB1 upstream region was set to GREEN Added comment: LMNB1 encodes an intermediate filament proteins which play a role in forming the nuclear lamina lining the inner nuclear membrane. Overexpression of LMNB1 via gene duplication has been well established to cause adult-onset autosomal dominant demyelinating leukodystrophy, MONDO:0008215. PMID: 30842973; 30697589; 25701871 report deletional forms of the phenotype. With an approx 167kb minimal critical region upstream of LMNB1 that has been associated with adult-onset autosomal dominant demyelinating leukodystrophy in 5 families with over 35 individuals affected. The deletion is upstream of the promoter of LMNB1 and involves other protein coding genes (ALDH7A1/PHAX) that are thought to be bystanders. The proposed molecular mechanism of disease for these deletions is disruption of a topologically associated domain boundary resulting in overexpression of LMNB1. This occurs by placing the promoter in closer proximity to an upstream enhancer element. Extensive functional studies support this hypothesis and affected individuals have been shown to have upregulated LMNB1 protein on Western blot. Note the coordinates differ between families with much larger deletions reported in many affected individuals. Sources: Literature |
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| Mendeliome v1.4509 | ADIPOR1 | Zornitza Stark edited their review of gene: ADIPOR1: Added comment: PMID 33523960 reports five individuals from four unrelated South‑Asian families carrying heterozygous missense variants (c.470T>A p.L157H, c.436G>A p.V146M, c.433T>A p.F145I) who present with HCM; three of the five also have diabetes mellitus. All variants are absent or ultra‑rare in public databases, three are de novo events, and functional assays in rat cardiomyocytes and a Cre‑V146M transgenic mouse model show hyperactivation of p38/mTOR and/or ERK pathways, cardiomyocyte hypertrophy, metabolic dysregulation and rescue by rapamycin.; Changed publications: 27655171, 26662040, 33523960; Changed phenotypes: Retinitis pigmentosa, MONDO:0019200, ADIPOR1-related, Hypertrophic cardiomyopathy, MONDO:0005045, ADIPOR1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4489 | SREBF2 | Zornitza Stark edited their review of gene: SREBF2: Added comment: PMID 39814172: reports three homozygous missense variants (p.L604W, p.T984A, p.S517F) in three unrelated families (two consanguineous families). Detailed clinical descriptions are provided for two families: Family 1 (two affected siblings, onset 39 y and 25 y, progressive spastic gait, pyramidal signs, no cognitive or peripheral neuropathy) and Family 2 (single female, onset 24 y, spastic gait, internal foot deformity, normal cognition). All carriers are asymptomatic. Functional assays in patient‑derived fibroblasts show increased mature SREBP2, cholesterol accumulation, and autophagosome/lysosome enlargement. Overexpression of the nuclear SREBP2 in Drosophila recapitulates locomotor deficits. The authors conclude that biallelic SREBF2 missense variants cause an autosomal recessive hereditary spastic paraplegia through gain‑of‑function overactivation of SREBP2.; Changed publications: 38847193, 39814172; Changed phenotypes: Neurocutaneous syndrome, MONDO:0042983, SREBF2-related, Hereditary spastic paraplegia, MONDO:0019064, SREBF2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4476 | FOXF1 upstream regulatory region |
Sarah Milton Region: FOXF1 upstream regulatory region was added Region: FOXF1 upstream regulatory region was added to Mendeliome. Sources: Literature Mode of inheritance for Region: FOXF1 upstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: FOXF1 upstream regulatory region were set to PMID: 27822317, 27071622, 23034409, 24842713 Phenotypes for Region: FOXF1 upstream regulatory region were set to Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380 Review for Region: FOXF1 upstream regulatory region was set to GREEN Added comment: FOXF1 is a transcription factor involved in maintaining endothelial barrier through activation of S1P/S1PR1 signalling for integrity of adherens junctions. An approximately 60kb enhancer 270kb upstream of the FOXF1 gene has been identified with copy number changes in this region seen in over 10 affected individuals with biopsy confirmed alveolar capillary dysplasia with misalignment of pulmonary veins. Interestingly a large number of the deletions identified were de novo on the maternal allele. Deletion size ranged between 104kb to 2625kb, coordinates from this entry are from a minimal overlapping region. The enhancer region has binding motifs for a number of transcription factors, as well as this there is a non coding RNA (LINC01081) within the region that is thought to play a role with regulation of FOXF1 transcription. Supportive functional studies with RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level. Sources: Literature |
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| Mendeliome v1.4443 | MIR204 |
Zornitza Stark changed review comment from: Third family reported in PMID 38867642: variant n.37C>T segregated with disease in 4 individuals from the same family, all with coloboma, at least two with RP as well. PMID 20713703: medaka fish model recapitulates coloboma and impaired lens development. Mouse model in PMID 31332443 recapitulates retinal phenotype.; to: Third family reported in PMID 38867642: variant n.37C>T segregated with disease in 4 individuals from the same family, all with coloboma, at least two with RP as well. PMID 20713703: medaka fish model recapitulates coloboma and impaired lens development. Mouse model in PMID 31332443 recapitulates retinal phenotype. MODERATE by ClinGen. |
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| Mendeliome v1.4443 | MIR204 |
Zornitza Stark changed review comment from: Third family reported in PMID 38867642: variant n.37C>T segregated with disease in 4 individuals from the same family, all with coloboma, at least two with RP as well. PMID 20713703: medaka fish model recapitulates coloboma and impaired lens development; to: Third family reported in PMID 38867642: variant n.37C>T segregated with disease in 4 individuals from the same family, all with coloboma, at least two with RP as well. PMID 20713703: medaka fish model recapitulates coloboma and impaired lens development. Mouse model in PMID 31332443 recapitulates retinal phenotype. |
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| Mendeliome v1.4443 | MIR204 |
Zornitza Stark changed review comment from: Two families only; to: Third family reported in PMID 38867642: variant n.37C>T segregated with disease in 4 individuals from the same family, all with coloboma, at least two with RP as well. PMID 20713703: medaka fish model recapitulates coloboma and impaired lens development |
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| Mendeliome v1.4406 | CELA2A |
Bryony Thompson gene: CELA2A was added gene: CELA2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CELA2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELA2A were set to 31358993 Phenotypes for gene: CELA2A were set to abdominal obesity-metabolic syndrome 4 MONDO:0032837 Review for gene: CELA2A was set to GREEN Added comment: 4 families/cases with a combination of the following features obesity, coronary artery disease, hypertriglyceridemia, hypertension, and type 2 diabetes. Segregation evidence in a large family and supporting in vitro fucntional studies. Sources: Literature |
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| Mendeliome v1.4352 | INSL3 | Zornitza Stark edited their review of gene: INSL3: Added comment: PMID 41369823 reports two unrelated Chinese Han individuals with homozygous frameshift INSL3 variants presenting with bilateral cryptorchidism, testicular atrophy, azoospermia and elevated FSH/LH. Functional assays (Western blot, immunofluorescence, Co‑IP) showed truncated proteins and loss of RXFP2 interaction; structural modelling predicted abnormal protein conformation; Changed publications: 12601553, 12970298, 11095425, 41369823 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4340 | PITX2 upstream regulatory region |
Sarah Milton Region: PITX2 upstream regulatory region was added Region: PITX2 upstream regulatory region was added to Mendeliome. Sources: Literature SV/CNV tags were added to Region: PITX2 upstream regulatory region. Mode of inheritance for Region: PITX2 upstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: PITX2 upstream regulatory region were set to PMID: 20881290, 28911203, 14991915, 9480756 Phenotypes for Region: PITX2 upstream regulatory region were set to Axenfeld-Rieger syndrome, MONDO:0019187 Review for Region: PITX2 upstream regulatory region was set to GREEN Added comment: PITX2 encodes a homeodomain containing transcription factor. There have been over 5 affected individuals across a number of publications with deletions in an agenic region approx 150kb upstream of PITX2 presenting with an Axenfeld Rieger phenotype. There have also been reports of individuals with balanced translocations transecting the region on 4p with a similar phenotype. Functional studies have interrogated this region identifying 11 conserved elements that are thought to represent enhancers. Zebrafish studies were performed by Volkmann et al with varying sized deletions in the region showing an effect on PITX2 gene expression. Protas et al used a zebrafish model modified by CRISPR/Cas9 to delete an orthologous region similar to that seen in an affected individual. This resulted in recapitulation of the phenotype. Note coordinates may not be precise (smaller deletions have been reported to cause disease). Sources: Literature |
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| Mendeliome v1.4336 | RNF213 |
Michelle Torres changed review comment from: The well-know East Asian founder variant, p.(Arg4810Lys) (aka p.(Arg4859Lys)), has been reported in multiple homozygous individuals with moyamoya disease. In a Japanese cohort, homozygous individuals had a significantly earlier age at onset compared with heterozygotes (PMID: 22377813). The evidence for AR as a MOI in association with other variants is not convincing (PMIDs: 30922903, 33960657).; to: The well-know East Asian founder variant, p.(Arg4810Lys) (aka p.(Arg4859Lys)), has been reported in multiple homozygous individuals with moyamoya disease. In a Japanese cohort, homozygous individuals had a significantly earlier age at onset compared with heterozygotes (PMID: 22377813). The evidence for AR as a MOI in association with other variants is not convincing (PMIDs: 30922903, 33960657). *Specific MONDO for this gene is Moyamoya disease 2 (MONDO:0011784). |
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| Mendeliome v1.4331 | TBC1D8 |
Sangavi Sivagnanasundram gene: TBC1D8 was added gene: TBC1D8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TBC1D8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TBC1D8 were set to 41556581; 35248088; 33584793 Phenotypes for gene: TBC1D8 were set to Lennox‑Gastaut syndrome MONDO:0016532; non-syndromic hearing loss MONDO:0019587; non obstructive azoospermia or cryptozoospermia MONDO:0005372 Review for gene: TBC1D8 was set to GREEN Added comment: GREEN AR - non-obstructive azoospermia or cryptozoospermia RED AD - Lennox‑Gastaut syndrome and non-syndromic hearing loss PMID: 41556581 - Two affected unrelated individuals with biallelic variants Immunofluorescence staining showed decreased protein expression in the testis of the affected individual compared to that of a fertile individual. PMID:35248088 - AD non-syndromic hearing loss De novo heterozygous missense variant in one individual presenting with hearing loss p.Ser666Leu - GrpMax FAF = 0.2% PMID: 33584793 - AD Lennox‑Gastaut syndrome 12yrM presented with tonic, atonic seizures however had normal MRI Assumed de novo missense variant identified Sources: Literature |
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| Mendeliome v1.4329 | ATP11C |
Lucy Spencer changed review comment from: PMID: 40869043 reports 3 unrelated families with haemolytic anaemia and ATP11C variants. Probands were all hemizygous boys who had maternally inherited variants, all variants were absent or only has 1 het in gnomad. One family had a frameshift, another ha 2 missense variants in cis, and the third had a -7 splice variant that RT-PCR showed resulted in an in frame insertion. 2 probands were shown to have normal G6PD activity and haemoglobin, the third was not tested. The proband with the ATP11C frameshift also had a de novo missense in ANK1 PMID: 37892263, 37671681, 26944472 report 3 hemizygous male haemolytic anaemia. However 2 of the patients had pathogenic variants in genes associated with spherocytosis SPTA1 and ANK1. The ATP11C variants were absent or rare in gnomad (note papers use different transcripts/p. numbering to gnomad). PMID: 41523080 reports 2 of the same patients as PMID:40869043 and additionally looked at Val972Met in a very large cohort of blood donors, but this variant is called Val969Met in gnomad where it has thousands of hets and hemizygotes. Sources: Literature; to: PMID: 40869043 reports 4 patients from 3 unrelated families with haemolytic anaemia and ATP11C variants. Probands were all hemizygous boys who had maternally inherited variants, all variants were absent or only has 1 het in gnomad. One family had a frameshift, another ha 2 missense variants in cis, and the third had a -7 splice variant that RT-PCR showed resulted in an in frame insertion. 2 probands were shown to have normal G6PD activity and haemoglobin, the third was not tested. The proband with the ATP11C frameshift also had a de novo missense in ANK1. Studies in patient RBS for all 4 patients showed reduced flippase activity. PMID: 37892263, 37671681, 26944472 report 3 hemizygous male haemolytic anaemia. However 2 of the patients had pathogenic variants in genes associated with spherocytosis SPTA1 and ANK1. The ATP11C variants were absent or rare in gnomad (note papers use different transcripts/p. numbering to gnomad). PMID: 41523080 reports 2 of the same patients as PMID:40869043 and additionally looked at Val972Met in a very large cohort of blood donors, but this variant is called Val969Met in gnomad where it has thousands of hets and hemizygotes. PMID: 37314652 One hemizygous male with a frameshift in ATP11C and agranulocytosis, recurrent acute liver failure and developmental delay. Previously published mouse models deficient in ATP11C displayed conjugated hyperbilirubinemia, hyperchloremia, and hemolytic anemia. Sources: Literature |
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| Mendeliome v1.4328 | ATP11C |
Lucy Spencer gene: ATP11C was added gene: ATP11C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP11C 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: ATP11C were set to 41523080; 40869043; 37892263; 37671681; 26944472 Phenotypes for gene: ATP11C were set to Hemolytic anemia, congenital, X-linked MIM#301015 Review for gene: ATP11C was set to AMBER Added comment: PMID: 40869043 reports 3 unrelated families with haemolytic anaemia and ATP11C variants. Probands were all hemizygous boys who had maternally inherited variants, all variants were absent or only has 1 het in gnomad. One family had a frameshift, another ha 2 missense variants in cis, and the third had a -7 splice variant that RT-PCR showed resulted in an in frame insertion. 2 probands were shown to have normal G6PD activity and haemoglobin, the third was not tested. The proband with the ATP11C frameshift also had a de novo missense in ANK1 PMID: 37892263, 37671681, 26944472 report 3 hemizygous male haemolytic anaemia. However 2 of the patients had pathogenic variants in genes associated with spherocytosis SPTA1 and ANK1. The ATP11C variants were absent or rare in gnomad (note papers use different transcripts/p. numbering to gnomad). PMID: 41523080 reports 2 of the same patients as PMID:40869043 and additionally looked at Val972Met in a very large cohort of blood donors, but this variant is called Val969Met in gnomad where it has thousands of hets and hemizygotes. Sources: Literature |
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| Mendeliome v1.4289 | GPD2 |
Bryony Thompson gene: GPD2 was added gene: GPD2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GPD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GPD2 were set to 9070847; 12093800 Phenotypes for gene: GPD2 were set to type 2 diabetes mellitus MONDO:0005148 Review for gene: GPD2 was set to RED Added comment: Single case with abnormally low activity of mitochondrial GDH and a rare missense variant. Knockout mouse model has features of both glycerol kinase deficiency and hereditary fructose intolerance. Sources: Literature |
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| Mendeliome v1.4261 | MAP2K4 |
Sangavi Sivagnanasundram gene: MAP2K4 was added gene: MAP2K4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAP2K4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAP2K4 were set to 41480045 Phenotypes for gene: MAP2K4 were set to Neurodevelopmental disorder, MONDO:0700092 Mode of pathogenicity for gene: MAP2K4 was set to Other Review for gene: MAP2K4 was set to GREEN Added comment: PMID 41480045 reports ten individuals from ten unrelated families with heterozygous de novo loss-of-function or missense MAP2K4 variants presenting with a syndromic neurodevelopmental disorder characterized by developmental delay/intellectual disability, epilepsy, and genitourinary and musculoskeletal congenital anomalies. All the reported variants were absent in gnomAD v4.1. DD, ID - present in the majority of the reported individuals CAKUT-like phenotypes reported in 5 individuals Reports of hypotonia in three individuals Epilepsy was reported in 4 individuals A functional study using CRISPR-edited iPSC-derived neurons demonstrates reduced MP2K4 protein and impaired JNK signalling however, more evidence is required to confirm loss of function as the mechanism of disease. There are no pathogenic variants reported in ClinVar in this gene in the germline context. Sources: Literature |
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| Mendeliome v1.4250 | NEUROD1 |
chirag patel changed review comment from: ClinGen DEFINITIVE (Mar 2021) https://search.clinicalgenome.org/CCID:005622 At least 5 variants (missense and nonsense) have been reported in at least 8 probands in association with a phenotype consisting of neonatal diabetes, intrauterine growth retardation, cerebellar hypoplasia, sensorineural deafness, visual impairment, and intellectual disability. This gene-disease relationship is supported by functional assays, expression studies, and animal models. Note: ClinGen LIMITED (Oct 2021) for autosomal dominant NEUROD1-related diabetes.; to: ClinGen MODERATE (Mar 2021) https://search.clinicalgenome.org/CCID:005622 At least 5 variants (missense and nonsense) have been reported in at least 8 probands in association with a phenotype consisting of neonatal diabetes, intrauterine growth retardation, cerebellar hypoplasia, sensorineural deafness, visual impairment, and intellectual disability. This gene-disease relationship is supported by functional assays, expression studies, and animal models. Note: ClinGen LIMITED (Oct 2021) for autosomal dominant NEUROD1-related diabetes. |
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| Mendeliome v1.4250 | NEUROD1 | chirag patel Phenotypes for gene: NEUROD1 were changed from Maturity-onset diabetes of the young 6, MIM#606394; Retinitis pigmentosa, retinopathy, permanent neonatal diabetes to Monogenic diabetes, MONDO:0015967; Retinitis pigmentosa | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4248 | chirag patel Added reviews for gene NEUROD1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4246 | chirag patel Added reviews for gene CAV1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4243 | RNU6ATAC | chirag patel Phenotypes for gene: RNU6ATAC were changed from Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related; neonatal diabetes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4241 | RNU6ATAC | chirag patel reviewed gene: RNU6ATAC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neonatal diabetes, humoral immunue defect, microcephaly, developmental delay.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4240 | chirag patel Added reviews for gene STAT1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4236 | chirag patel Added reviews for gene PLIN1 from panel Monogenic Diabetes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4202 | SKAP2 |
Zornitza Stark gene: SKAP2 was added gene: SKAP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SKAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SKAP2 were set to 40771593; 34172489 Phenotypes for gene: SKAP2 were set to Inborn error of immunity, MONDO:0003778 Review for gene: SKAP2 was set to RED Added comment: PMID 34172489 reports a de novo heterozygous SKAP2 missense variant (c.457G>A, p.Gly153Arg) in a child with childhood‑onset type 1 diabetes and multiple autoimmune disorders; functional studies in THP‑1 macrophages, patient‑derived macrophages and neutrophils show constitutive SKAP2 activation and hyper‑integrin signaling. The same variant was later described in PMID 40771593. Sources: Literature |
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| Mendeliome v1.4188 | SUN5 |
Zornitza Stark gene: SUN5 was added gene: SUN5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SUN5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUN5 were set to 34159570; 33671757; 27640305 Phenotypes for gene: SUN5 were set to Spermatogenic failure, MONDO:0004983, SUN5-related Review for gene: SUN5 was set to GREEN Added comment: SUN5 encodes a testis‑specific SUN‑domain protein that anchors the sperm head to the tail. Multiple independent studies have identified biallelic loss‑of‑function SUN5 variants in >30 individuals with acephalic spermatozoa syndrome. Functional studies—including Western blot, immunofluorescence, Sun5 knockout mouse models, HeLa splicing assays, Y2H/GST pull‑down and proteasome‑inhibition rescue—demonstrate loss of SUN5 protein and disrupted head‑tail coupling, supporting loss‑of‑function as the disease mechanism. Sources: Literature |
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| Mendeliome v1.4173 | MYO5B | Zornitza Stark edited their review of gene: MYO5B: Added comment: PMID 33525641 summarises data on 114 individuals with bi-allelic variants in MYO5B: (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED).; Changed publications: 30564347, 29266534, 28027573, 27532546, 33525641; Changed phenotypes: Microvillus inclusion disease, MIM# 251850, Cholestasis, progressive familial intrahepatic, 10, MIM# 619868 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4153 | PLXNA1 |
Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association The monoallelic assertion for a neurodevelopmental disorder in this gene is now RED, still GREEN for biallelic |
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| Mendeliome v1.4144 | ZNF185 | Lucy Spencer edited their review of gene: ZNF185: Added comment: PMID 41404552 describes a single female individual with cerebro‑oculo‑nasal syndrome and a de novo heterozygous X‑linked frameshift ZNF185. The proband presented with developmental delay, moderate ID, dysmorphic facial features, cleft lip/palate, nasal anomaly, CHD and anopthalmia. She was shown to have skewed X-inactivation 19:81, however it is not stated if the skewing was towards the allele with the variant. The variant in this individual (p.Gln102SerfsTer18) is NMD predicted and absent from gnomad, however there are at least 6 NMD variants present in gnomad as hemizygous (4 with over 4 hemis) all of which also have over 5 heterozygotes.; Changed publications: 41404552; Changed phenotypes: Cerebrooculonasal syndrome MONDO:0011575, ZNF185-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4130 | CCDC149 |
Zornitza Stark gene: CCDC149 was added gene: CCDC149 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC149 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC149 were set to 40459248 Phenotypes for gene: CCDC149 were set to Cryptorchidism, MONDO:0009047, CCDC149-related Review for gene: CCDC149 was set to RED Added comment: PMID 40459248 reports a single 8‑year‑old boy from a consanguineous family with bilateral cryptorchidism due to a homozygous nonsense CCDC149 variant (c.448C>T, p.Gln150Ter), biparental inheritance. Ccdc149 knockout mice recapitulate undescended testes and sperm abnormalities, supporting loss‑of‑function as the disease mechanism. Sources: Literature |
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| Mendeliome v1.4113 | BOC |
Zornitza Stark gene: BOC was added gene: BOC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BOC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BOC were set to 40464334; 28677295 Review for gene: BOC was set to RED Added comment: BOC encodes a cell‑surface co‑receptor for Sonic Hedgehog signaling. PMID 40464334 reports 4 unrelated families with heterozygous BOC variants causing non‑syndromic orofacial clefts (cleft palate and microform cleft lip); three variants are de novo and one segregates dominantly, and zebrafish and cell‑based assays confirm hypomorphic activity. PMID 28677295 and PMID 28915250 describe BOC missense variants in holoprosencephaly and Gorlin syndrome, respectively, but present them as modifier alleles without segregation or functional validation. However, all reported variants have relatively high gnomAD frequencies, raising the possibility that these are susceptibility alleles. Sources: Literature |
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| Mendeliome v1.4111 | AXDND1 | Zornitza Stark edited their review of gene: AXDND1: Added comment: PMID 38997255: Reports 3 individuals from 3 unrelated families with autosomal recessive loss‑of‑function or missense variants in AXDND1 presenting with non‑obstructive azoospermia/severe oligozoospermia. One family carries a homozygous stop‑gain (p.R313X) and two families carry heterozygous missense variants (p.Leu536Gln; p.Lys817Asn) with phenotypes ranging from Sertoli‑cell‑only syndrome to hypospermatogenesis. A mouse Axdnd1 knockout recapitulates male infertility, defective spermatogenesis and abnormal sperm tail ultrastructure, providing strong functional validation of gene loss‑of‑function as the disease mechanism.; Changed rating: GREEN; Changed publications: 40457935, 38997255 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4102 | TENM4 |
Bryony Thompson gene: TENM4 was added gene: TENM4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TENM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TENM4 were set to 41449293; 36689009; 26188006; 29249217; 34589676; 22915103 Phenotypes for gene: TENM4 were set to Neurodevelopmental disorder, MONDO:0700092; tremor, hereditary essential, 5 MONDO:0014756; first branchial cleft anomaly MONDO:0015376 Review for gene: TENM4 was set to AMBER Added comment: TENM4 encodes a type II transmembrane teneurin involved in neuronal development and oligodendrocyte maturation. Amber for essential tremor - 2 families with rare missense and supporting segregation evidence, plus mouse & zebrafish models. 2 other GDAs have limited evidence. PMID 26188006 - 3 families reported with essential tremor with incomplete segregation. 2 of the variants (p.Ala1442Thr and p.Val1138Met) are more common than expected in gnomAD. p.Thr1367Asn is a rare missense and segregates with ET over 3 generations (2 unaffected carriers under the average age of onset). Functional assays demonstrate dominant‑negative effects in oligodendrocyte precursor cells and zebrafish axon‑guidance defects for all 3 variants. PMID 36689009 - rare heterozygous missense (p.P421L) segregating in 5 affected individuals with ET in a single family PMID 29249217 - a case with hereditary tremor‑like syndrome with palatal tremor but no description of the TENM4 variant in the paper. PMID 22915103 - myelination of small-diameter axons was dramatically reduced, and differentiation of oligodendrocytes, the myelin-forming cells in the CNS, was inhibited in null mouse model. PMID 34589676 - 2 rare missense in 2 patients with first branchial cleft anomalies. No other evidence. Multiple missense in different genes in one of the patients. - limited evidence for gene-disease association PMID 41449293 - rare splice variant identified in a single family (segregates in 6 individuals) with childhood‑onset intellectual disability with epilepsy. Splice‑site‑mediated exon 10 skipping leading to seizures in a mouse model, supporting a pathogenic role. - single family reported Sources: Literature |
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| Mendeliome v1.4095 | NOD2 |
Zornitza Stark edited their review of gene: NOD2: Added comment: PMID 33692434 reports 92 unrelated families with biallelic loss‑of‑function NOD2 variants causing early‑onset Crohn’s disease. Yao syndrome (YAOS) is an autoinflammatory disease characterized by periodic fever, dermatitis, arthritis, and swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. PMID 39372397 describes 152 adult‑onset Yao syndrome patients, many carrying the cis‑regulatory IVS8+158 variant that shows functional gain‑of‑function.; Changed publications: 15459013, 11385576, 17804789, 32463623, 33692434, 39372397; Changed phenotypes: Blau syndrome, MIM# 186580, {Inflammatory bowel disease 1, Crohn disease} 266600, {Yao syndrome} 617321; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.4073 | SPAG17 | Zornitza Stark edited their review of gene: SPAG17: Added comment: Recent studies (PMIDs 28548327, 39686771, 40330001 and supporting mouse data in PMID 29690537) expand SPAG17‑associated male infertility to four unrelated families (seven affected individuals) with biallelic loss‑of‑function variants causing severe asthenozoospermia, multiple morphological abnormalities of the flagella (MMAF) or oligoasthenoteratozoospermia. Detailed semen analyses, sperm ultrastructure, immunofluorescence, Western blot, qPCR and TEM demonstrate loss of SPAG17 protein and axonemal defects, while a Spag17 knockout mouse recapitulates the infertility phenotype.; Changed rating: GREEN; Changed publications: 40330001, 39686771, 28548327 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.4068 | MAEL |
Zornitza Stark gene: MAEL was added gene: MAEL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAEL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAEL were set to 40442410; 39122675 Phenotypes for gene: MAEL were set to Spermatogenic failure, MONDO:0004983, MAEL-related Review for gene: MAEL was set to AMBER Added comment: PMID 39122675 reports 1 individual and PMID 40442410 reports a second individual, together 2 unrelated families with autosomal recessive loss‑of‑function MAEL variants causing non‑obstructive azoospermia with meiotic arrest (male infertility). Functional evidence includes a minigene splicing assay and IHC loss of MAEL protein, as well as protein structural modelling, evolutionary conservation analysis, and a mouse knockout model that recapitulates spermatogenic failure. Sources: Literature |
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| Mendeliome v1.4064 | DUSP1 |
Zornitza Stark gene: DUSP1 was added gene: DUSP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DUSP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DUSP1 were set to 40359362 Phenotypes for gene: DUSP1 were set to Hereditary palmoplantar keratoderma, MONDO:0019272, DUSP1-related Review for gene: DUSP1 was set to RED Added comment: PMID 40359362 reports four individuals from two unrelated families with heterozygous and homozygous missense variants in DUSP1 presenting with semidominant palmoplantar keratoderma, focal hyperkeratosis, and, in homozygotes, severe PPK with hearing loss. Functional assays in primary keratinocytes and 3‑D skin equivalents demonstrate reduced DUSP1 protein, increased ERK1/2 phosphorylation, and rescue by ERK1/2 inhibition. The inheritance is postulated to be semidominant (monoallelic and biallelic) with dose‑dependent severity -- one family has two heterozygous individuals (insufficient segregation) and second family has a more severely affected homozygous individual and affected parent. Sources: Literature |
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| Mendeliome v1.4057 | LATS1 |
Sangavi Sivagnanasundram gene: LATS1 was added gene: LATS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: LATS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LATS1 were set to 35986120 Phenotypes for gene: LATS1 were set to cerebral cavernous malformations MONDO:0031037 Review for gene: LATS1 was set to RED Added comment: LATS1 encodes a serine‑threonine kinase in the Hippo signaling pathway that regulates YAP activity. One reported Chinese family with missense variant (c.821C>T, p.Thr274Ile) in LATS1 and a phenotype consistent with CCM on imaging. The variant appeared to segregate in the family in affected individuals however there are multiple individuals that weren't assessed. Sources: Literature |
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| Mendeliome v1.4030 | MAU2 |
Lucy Spencer gene: MAU2 was added gene: MAU2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MAU2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAU2 were set to 41332805; 37962004; 32433956 Phenotypes for gene: MAU2 were set to Cornelia de Lange syndrome MONDO:0016033, MAU2-related Review for gene: MAU2 was set to GREEN Added comment: PMID 41332805 report a total of 18 individuals from 15 unrelated families with heterozygous MAU2 variants causing Cornelia de Lange syndrome (1 of these patients was previously reported in PMID: 32433956). The main phenotypes in this cohort were short stature, microcephaly and ID, around half also had a mix of the characteristic CDLS facial features like synophrys, long smooth philtrum, thick eyebrows, thin upper lip vermilion and anteverted nares. Variants include loss‑of‑function (nonsense, frameshift, splice‑affecting) that cause haploinsufficiency, and missense/in‑frame deletions some of which were shown to disrupt NIPBL‑MAU2 interaction. Most were de novo but several were transmitted from affected parents, and for 5 cases inheritance was unknown. All but one of the missense/inframe deletion variants is absent from gnomad v4, p.Cys50Ser is present with 6 heterozygotes and may not be pathogenic. PMID: 37962004 has one additional patient with atypical Cornelia de Lange syndrome who has a de novo missense variant, absent from gnomad. Sources: Literature |
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| Mendeliome v1.4029 | SMC1B |
Zornitza Stark gene: SMC1B was added gene: SMC1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SMC1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMC1B were set to 40180776; 27603904 Phenotypes for gene: SMC1B were set to Infertility disorder, MONDO:0005047, SMC1B-related Review for gene: SMC1B was set to RED Added comment: [PMID 27603904] reports 2 individuals from 2 families with heterozygous missense SMC1B variants (p.I221T, p.Q1177L) presenting with primary ovarian insufficiency. [PMID 40180776] reports 1 individual from 1 family with a heterozygous missense p.C619F variant causing severe necrozoospermia; the variant segregates from a carrier mother and functional assays show reduced SMC1B protein, indicating a loss‑of‑function mechanism. All three variants are present in the population, p.Q1177L at an implausibly high frequency. Sources: Literature |
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| Mendeliome v1.4017 | TMEM251 |
Zornitza Stark edited their review of gene: TMEM251: Added comment: PMID 40171858: reports 2 siblings from an Iranian consanguineous family and six previously reported families (8 patients, 7 unrelated families) with biallelic loss‑of‑function LYSET variants presenting with MLII‑like mucolipidosis; core features include dysostosis multiplex, coarse facial features, hepatomegaly, joint contractures, developmental delay; mouse knockout recapitulates the phenotype, supporting gene‑disease causality. HGNC approved name is LYSET.; Changed rating: GREEN; Changed publications: 40171858 |
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| Mendeliome v1.3990 | UNC45A | Zornitza Stark edited their review of gene: UNC45A: Added comment: PMIDs 29429573, 35575086, 36699472, 37328071, 39887522, 40125554, 40129845, 32013205 add 33 unrelated families to the previously reviewed three families, bringing the total to 37 unrelated families. Eleven families present with osteo‑oto‑hepato‑enteric (O2HE) syndrome (neonatal cholestasis, intractable diarrhea, bone fragility, sensorineural hearing loss) and carry loss‑of‑function or protein‑unstable missense variants. Functional validation (Western blot, zebrafish morpholino knock‑down, rescue experiments, CRISPR‑KO in Caco‑2/U2OS cells) demonstrates pathogenicity. Twenty‑five families have Aagenaes syndrome (lymphedema‑cholestasis syndrome) caused by a recurrent 5′‑UTR regulatory variant (c.-98G>T) plus loss‑of‑function exonic alleles, with reduced UNC45A expression confirmed in patient blood and CRISPR‑edited cells.; Changed publications: 29429573, 35575086, 36699472, 37328071, 39887522, 40125554, 40129845, 32013205 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3981 | WDR83 |
chirag patel gene: WDR83 was added gene: WDR83 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR83 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WDR83 were set to 41381792 Phenotypes for gene: WDR83 were set to Neurodevelopmental disorder, MONDO:0700092, WDR83-related Mode of pathogenicity for gene: WDR83 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: WDR83 was set to RED Added comment: 1 individual from 1 unrelated family with a de novo heterozygous missense variant (p.L218P) in WDR83 gene. Clinical presentation of a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, growth retardation and dysmorphic facial features. WDR83 encodes a WD‑repeat scaffold protein (MORG1) that regulates MAPK/ERK signalling, HIF‑1α degradation, cell polarity and autophagy. In vivo, acute expression via in utero electroporation promoted premature cell cycle exit of neural stem cells, impaired cortical neuron migration, and disrupted dendritic arborization, whereas axonal projections to the contralateral hemisphere remained unaffected. Cortical neurons expressing WDR83-L218P exhibited reduced spine head diameter. In vitro, WDR83-L218P expression inhibited axon elongation in primary cultured hippocampal neurons. The variant is suspected to exert a dominant-negative effect. Sources: Literature |
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| Mendeliome v1.3974 | FIBP | Zornitza Stark edited their review of gene: FIBP: Added comment: Beyond the two families previously reviewed (PMIDs 26660953; 27183861), four additional studies (PMIDs 36919607, 37218527, 37876348, 40099975) contribute four new unrelated families (total six unrelated families, nine patients) with a consistent autosomal‑recessive overgrowth syndrome. All six families have biallelic loss‑of‑function FIBP variants (nonsense or frameshift leading to NMD). Detailed clinical descriptions include overgrowth, macrocephaly, facial dysmorphism, developmental delay/intellectual disability, renal dysplasia and, in two families, early‑onset tumor predisposition. Segregation analyses confirm recessive inheritance in every case. Functional work (RT‑qPCR, fibroblast proliferation assays, mouse embryonic expression) demonstrates reduced FIBP expression and increased cell proliferation, supporting pathogenicity.; Changed rating: GREEN; Changed publications: 40099975, 37876348, 36919607, 27183861, 26660953 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3971 | SEC24C |
Zornitza Stark gene: SEC24C was added gene: SEC24C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEC24C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEC24C were set to 40131364 Phenotypes for gene: SEC24C were set to Neurodevelopmental disorder, MONDO:0700092, SEC24C-related Review for gene: SEC24C was set to RED Added comment: PMID 40131364 reports 4 individuals from a consanguineous Turkish family with biallelic loss-of-function frameshift c.333del (p.Ser112Profs*115) variant presenting with neonatal‑onset severe syndromic epileptic encephalopathy, congenital cataracts, primary microcephaly, macrocytic anaemia, sensorineural hearing loss, liver dysfunction and dysmorphic facial features. The variant segregates with autosomal recessive inheritance and functional studies in patient fibroblasts and zebrafish knockouts demonstrate >90% loss of SEC24C expression, impaired ER‑Golgi trafficking and recapitulation of cataract and neurodevelopmental phenotypes. Sources: Literature |
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| Mendeliome v1.3941 | FRMD4B |
Zornitza Stark gene: FRMD4B was added gene: FRMD4B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FRMD4B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FRMD4B were set to 40162949 Phenotypes for gene: FRMD4B were set to Duane retraction syndrome, MONDO:0007473, FRMD4B-related Review for gene: FRMD4B was set to RED Added comment: PMID 40162949 reports an individual with homozygous FRMD4B missense (c.380A>G, p.Lys127Arg) variant presenting with Duane retraction syndrome type III and syndromic features (hearing loss, developmental delay, atrial septal defect, gastrointestinal abnormalities). Zebrafish loss‑of‑function model recapitulates the cranial nerve phenotype, supporting a loss‑of‑function disease mechanism. Sources: Literature |
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| Mendeliome v1.3937 | ARMC2 |
Zornitza Stark gene: ARMC2 was added gene: ARMC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARMC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARMC2 were set to 40158138; 38492154; 35543806; 30686508 Phenotypes for gene: ARMC2 were set to Spermatogenic failure 38, MIM# 618433 Review for gene: ARMC2 was set to GREEN Added comment: ARMC2 encodes an 867‑amino‑acid armadillo‑repeat protein highly expressed in testis and implicated in assembly and stability of the central pair complex of motile cilia and sperm flagella. Ten unrelated families (ten patients) with biallelic loss‑of‑function or predicted loss‑of‑function ARMC2 variants have been reported with multiple morphological abnormalities of the sperm flagella (MMAF) causing severe asthenoteratozoospermia and male infertility; one of these families also presented with primary ciliary dyskinesia pulmonary manifestations. Supportive mouse model. Sources: Literature |
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| Mendeliome v1.3921 | TERB1 |
Zornitza Stark gene: TERB1 was added gene: TERB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TERB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TERB1 were set to 38277113; 35172124; 33211200; 32741963 Phenotypes for gene: TERB1 were set to Infertility disorder, MONDO:0005047, TERB1-related Review for gene: TERB1 was set to GREEN Added comment: PMIDs 32741963, 33211200, 35172124 and 38277113 report a total of 5 unrelated families with biallelic loss‑of‑function or missense TERB1 variants causing male infertility (non‑obstructive azoospermia with spermatogenic arrest) and 2 unrelated families with primary female infertility (diminished ovarian reserve). The variants include frameshift, stop‑gain and missense changes; mouse Terb1 knockout recapitulates the meiotic‑arrest phenotype. Sources: Literature |
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| Mendeliome v1.3916 | RBBP7 |
Zornitza Stark gene: RBBP7 was added gene: RBBP7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RBBP7 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: RBBP7 were set to 39932629; 37843278; 35809576 Phenotypes for gene: RBBP7 were set to Infertility disorder, MONDO:0005047, RBBP7-related Review for gene: RBBP7 was set to GREEN Added comment: PMID 35809576, 37843278, 39932629 report 12 individuals from 11 families with X-linked loss-of-function variants presenting with non‑obstructive azoospermia (severe spermatogenic failure), including maturation arrest and, in one family, Leydig cell tumor. Clinical features include small testes, elevated FSH, absence of spermatocytes and infertility. Functional evidence from Drosophila knock‑down and rescue experiments and mouse germ‑cell line knock‑down supports a loss‑of‑function (haploinsufficiency) mechanism. No contradictory evidence has been reported. Sources: Literature |
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| Mendeliome v1.3875 | OTP |
Zornitza Stark gene: OTP was added gene: OTP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OTP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: OTP were set to 39813316; 29107289 Phenotypes for gene: OTP were set to Obesity disorder, MONDO:0011122, OTP-related Review for gene: OTP was set to AMBER Added comment: PMID 29107289 reports a single individual with a heterozygous missense OTP variant (p.Q153R) presenting with severe early‑onset obesity and attention‑deficit disorder. PMID 39813316 adds five unrelated individuals carrying predicted loss‑of‑function OTP variants and confirms the Q153R case, together implicating heterozygous loss‑of‑function OTP as a cause of early‑onset severe obesity with metabolic comorbidities (type 2 diabetes, dyslipidemia, hepatic steatosis). However, individuals are ascertained from UK Biobank, hence clinical details are sparse. Mouse models with OTP haploinsufficiency or a Q153R knock‑in recapitulate hyperphagia and obesity, providing functional support. Sources: Literature |
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| Mendeliome v1.3867 | NUBP2 |
Zornitza Stark gene: NUBP2 was added gene: NUBP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NUBP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUBP2 were set to 39867373 Phenotypes for gene: NUBP2 were set to Neurodevelopmental disorder, MONDO:0700092 Review for gene: NUBP2 was set to AMBER Added comment: PMID 39867373 reports 2 individuals from 2 unrelated families with biallelic missense variants in NUBP2 presenting with congenital primary microcephaly, intrauterine growth restriction, severe joint contractures and facial dysmorphism. A forebrain‑specific conditional Nubp2 knockout mouse recapitulates the severe microcephaly, and rescue assays show patient alleles fail to restore growth, supporting a loss‑of‑function mechanism. Preprint. Sources: Literature |
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| Mendeliome v1.3861 | LETM1 | Zornitza Stark commented on gene: LETM1: The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3795 | HSPB6 |
Sarah Milton edited their review of gene: HSPB6: Added comment: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. In skeletal muscle HSBP6 is thought to function in promoting smooth muscle relaxation through depolymerising actin cytoskeleton. PMID: 41294008 describes one individual with adult onset cataract and progressive weakness. His similarly affected mother was not genetically tested. Muscle biopsy demonstrated rimmed vacuoles and accumulation of HSPB6. Variant was a c terminal extension variant (c.464delC|p.(Pro155Argfs*25) which was thought to result in aggregation of protein and was absent from gnomAD v4. Other similar extension variants present in gnomAD v4 were transfected into cell models with those that had unstable mRNA transcripts not recapitulating findings however one other demonstrated accumulation of protein in certain settings. Further literature is required.; Changed publications: 41294008; Changed phenotypes: Myopathy, MONDO:0005336, HSPB6-related |
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| Mendeliome v1.3795 | HSPB6 |
Sarah Milton changed review comment from: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress. PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.( with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis. This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations. As such further literature is required to establish it's role in disease. Sources: Literature; to: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress. PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.(Ser10Phe) with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis. This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations. As such further literature is required to establish it's role in disease. Sources: Literature |
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| Mendeliome v1.3795 | HSPB6 |
Sarah Milton gene: HSPB6 was added gene: HSPB6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HSPB6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HSPB6 were set to 29157081 Phenotypes for gene: HSPB6 were set to Dilated cardiomyopathy, MONDO:0005021, HSPB6-related Review for gene: HSPB6 was set to RED Added comment: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress. PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.( with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis. This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations. As such further literature is required to establish it's role in disease. Sources: Literature |
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| Mendeliome v1.3772 | PLXNA1 |
Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association The monoallelic assertion for this gene is now RED, still GREEN for biallelic |
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| Mendeliome v1.3772 | PLXNA1 |
Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association The monoallelic assertion for this gene is now RED, still GREEN for biallelic |
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| Mendeliome v1.3762 | KCNQ3 |
Lucy Spencer changed review comment from: From ClinGen: Definitive for DOMINANT complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related - 24 probands across 7 publications, mostly de novo variants. Mutations are clustered at p.Arg227 and p.Arg230, with a gain of function mechanism PMID: 24851285. Moderate for DOMINANT self-limited familial neonatal epilepsy (Seizures, benign neonatal, 2 (MIM#121201)) - 15 missense in 18 probands across 16 publications. Variants clustered in the pore region (S5, S6, and intervening loop) and result in loss of function of channel activity PMID: 24851285. Note- there are several NMD predicted variants in this gene with over 10 hets in gnomad. Limited for RECESSIVE genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related - 1 individual and 1 family from 2 publications with homozygous frameshifts PMID: 29852413; 31440727. All have seizures, various brain MRI findings, developmental delay and intellectual disability. The family had 3 similarly affected siblings, all homozygous for an NMD frameshift. The unrelated patient had a mildly affected uncle with learning difficulties and transient neonatal seizures, he was not tested for the variant. A third recessive patient not reported by ClinGen PMID: 29383681: 7yo girl with seizures, severe neurological impairment, and developmental delay. Compound heterozygous for two missense variants Val359Leu and Asp542Asn. Patch clamp studies showed that expression of either variant alone did not affect current density, but co-expression of both variants lead to a significant current reduction.; to: From ClinGen: Definitive for DOMINANT complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related - 24 probands across 7 publications, mostly de novo variants. Mutations are clustered at p.Arg227 and p.Arg230, with a gain of function mechanism PMID: 24851285. Moderate for DOMINANT self-limited familial neonatal epilepsy (Seizures, benign neonatal, 2 (MIM#121201)) - 15 missense in 18 probands across 16 publications. Variants clustered in the pore region (S5, S6, and intervening loop) and result in loss of function of channel activity PMID: 24851285. Note- there are several NMD predicted variants in this gene with over 10 hets in gnomad. Limited for RECESSIVE genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related - 1 individual and 1 family from 2 publications with homozygous frameshifts PMID: 29852413; 31440727. All have seizures, various brain MRI findings, developmental delay and intellectual disability. The family had 3 similarly affected siblings, all homozygous for an NMD frameshift. The unrelated patient had a mildly affected uncle with learning difficulties and transient neonatal seizures, he was not tested for the variant. A third recessive patient not reported by ClinGen PMID: 29383681: 7yo girl with seizures, severe neurological impairment, and developmental delay. Compound heterozygous for two missense variants Val359Leu and Asp542Asn. Patch clamp studies showed that expression of either variant alone did not affect current density, but co-expression of both variants lead to a significant current reduction. borderline amber/green for recessive |
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| Mendeliome v1.3751 | ELMSAN1 |
Zornitza Stark gene: ELMSAN1 was added gene: ELMSAN1 was added to Mendeliome. Sources: Literature new gene name tags were added to gene: ELMSAN1. Mode of inheritance for gene: ELMSAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ELMSAN1 were set to Neurodevelopmental disorder, MONDO:0700092, ELMSAN1-related Review for gene: ELMSAN1 was set to AMBER Added comment: PMID 41290615 reports 2 individuals from 2 unrelated families with the same heterozygous de novo missense variant p.Tyr654Ser presenting with a neurodevelopmental disorder characterized by speech delay, joint contractures, dysmorphic facial features, and gastrointestinal dysmotility. Functional studies demonstrated that the Y654S variant lies in an auto‑inhibitory loop of the MiDAC HDAC complex, causes a 3‑5‑fold increase in deacetylase activity, shows increased phosphorylation, and leads to reciprocal gene‑expression changes in patient fibroblasts versus loss‑of‑function models. New HGNC approved name is MIDEAS. Sources: Literature |
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| Mendeliome v1.3733 | COL10A1 |
Zornitza Stark changed review comment from: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher), however please note that to date, no Gly-X-Y substitutions in the collagen triple helix repeats have yet been reported, pathogenic or otherwise.; to: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher). Note that unlike with other collagens, Gly-X-Y substitutions in the collagen triple helix repeats are very rarely reported as disease-causing, and may result in a milder phenotype (PMID 31348255; 25542771). These should be interpreted with caution. |
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| Mendeliome v1.3695 | HELB |
Rylee Peters gene: HELB was added gene: HELB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HELB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HELB were set to 41212051 Phenotypes for gene: HELB were set to Premature ovarian failure, MONDO:0019852, HELB-related Review for gene: HELB was set to AMBER Added comment: PMID: 41212051 reports three individuals from a single family with a heterozygous missense HELB c.349G>T (p.Asp117Tyr) presenting with premature ovarian insufficiency and early menopause. The variant co-segregates with disease across three generations and is absent from population databases. A mouse knock-in model recapitulates the POI phenotype; RNA-seq and transcriptomic analysis showed dysregulation of genes associated with ovarian function in Helb-mutated mice. Sources: Literature |
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| Mendeliome v1.3638 | GATA6 | Zornitza Stark Phenotypes for gene: GATA6 were changed from GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; 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 to GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3630 | GATA6 | Lucy Spencer Phenotypes for gene: GATA6 were changed from 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 to GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; 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 v1.3629 | GATA6 | Lucy Spencer reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3590 | CFAP47 |
chirag patel changed review comment from: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.; to: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation. ClinGen DISPUTED - Feb 2025 |
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| Mendeliome v1.3559 | TXNIP |
Lucy Spencer gene: TXNIP was added gene: TXNIP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TXNIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TXNIP were set to 41116060; 30755400 Phenotypes for gene: TXNIP were set to Metabolic disease MONDO:0005066, TXNIP-related Review for gene: TXNIP was set to AMBER Added comment: TXNIP binds and inhibits TXN, controlling its activity. The TXN system is a major cellular system for control of redox state, antioxidant defense, and several signaling pathways. TXNIP can also activate the NLRP3 inflammasome and suppress of the activities of the nuclear factor (erythroid-derived 2)–like 2 (Nrf2) transcription factor. PMID 30755400 reports three affected siblings from a consanguineous Libyan family with autosomal recessive congenital lactic acidosis and low serum methionine. 2 of the three siblings have developed normally and appear to be mostly asymptomatic apart from variable hypoglycaemia, while the third had failure the thrive as an infant, slow development, ?autism, and slight muscular hypotonus. All three siblings were homozygous for TXNIP c.174_175delinsTT which creates a stopgain at p.Gly59* (and a missense at p.58). Patient‑derived fibroblasts and myoblasts show impaired pyruvate‑driven mitochondrial respiration that is rescued by TXNIP re‑constitution. However, patient cells showed no difference in cell growth or morphology, and had normal downstream TXN activity while Nrf2 target gene transcripts were upregulated. PMID 41116060 describes an additional individual with a severe metabolic disease; lactic acidosis, recurrent hypoglycaemia, significant developmental delay, epileptic seizures, and hypotonia. Homozygous for c.642_643insT p.(Ile215Tyrfs*59). Functional studies showed it disrupts SLC7A5-SLC3A2 endocytosis and cellular glucose uptake. Sources: Literature |
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| Mendeliome v1.3541 | CCNK |
Sangavi Sivagnanasundram changed review comment from: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features) 7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were either rare for AD gene or absent in gnomAD v4.1. Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease Sources: Literature; to: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features) 7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were absent in gnomAD v4.1. Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease Sources: Literature |
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| Mendeliome v1.3541 | CCNK |
Sangavi Sivagnanasundram gene: CCNK was added gene: CCNK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCNK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CCNK were set to 41101726; 37597256; 30122539 Phenotypes for gene: CCNK were set to CCNK-related neurodevelopmental disorder-severe intellectual disability-facial dysmorphism syndrome MONDO:0035775 Review for gene: CCNK was set to GREEN Added comment: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features) 7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were either rare for AD gene or absent in gnomAD v4.1. Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease Sources: Literature |
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| Mendeliome v1.3500 | SLC27A3 |
Sarah Milton gene: SLC27A3 was added gene: SLC27A3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC27A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC27A3 were set to PMID: 41054338 Phenotypes for gene: SLC27A3 were set to Inherited neurodegenerative disorder, MONDO:0024237, SLC27A3-related Review for gene: SLC27A3 was set to RED Added comment: SLC27A3 encodes for very long chain acyl CoA synthetase 3 which function to catalyse the formation of fatty acyl coA using long and very long chain fatty acids as substrates. PMID: 41054338 describes one individual with a presumed homozgous stop gain variant in SLC27A3 who presented with progressive ataxia, optic atrophy, cognitive deterioration, mood disorder and progressive cortical atrophy on MRI-B. Onset of symptoms at 18 months with significant progression from 12 years of age. Duo exome testing performed (not segregated in both parents). No homozygous LOF variants in gnomAD v4. Some supportive functional data in paper with no protein expressed in patient cells as detected by western blot and patient's cells were found to have more neutral lipids than controls. More literature is required to increase the robustness of this assertion. Sources: Literature |
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| Mendeliome v1.3460 | NLRP2 | Zornitza Stark edited their review of gene: NLRP2: Added comment: PMIDs 29574422, 30877238, 35643636, 39887367 and 41044650 report 15 unrelated families with rare NLRP2 variants. Maternal heterozygous variants cause multilocus imprinting disturbance (MLID) presenting as Beckwith‑Wiedemann syndrome, Silver‑Russell syndrome, transient neonatal diabetes mellitus, unspecified imprinting disorder and pseudohypoparathyroidism type‑1B. Biallelic loss‑of‑function variants cause autosomal recessive primary female infertility with early embryonic arrest (embryos arresting at the 2–4‑cell stage). Functional studies show reduced NLRP2 protein in patient‑derived cells and mouse Nlrp2 knockout recapitulating the embryonic arrest phenotype. No contradictory evidence exists for the well‑supported phenotypes.; Changed publications: 29574422, 30877238, 35643636, 39887367, 41044650 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3432 | PDIA6 | Zornitza Stark Phenotypes for gene: PDIA6 were changed from Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes to multiple congenital anomalies, MONDO:0019042, PDIA6-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3405 | ABCC8 |
chirag patel Source Victorian Clinical Genetics Services was removed from ABCC8. Source Expert list was added to ABCC8. Phenotypes for gene: ABCC8 were changed from Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 to Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800; Pulmonary arterial hypertension, MONDO:0015924, ABCC8-related Publications for gene ABCC8 were changed from 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138 to 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138 |
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| Mendeliome v1.3382 | MAFA |
Sangavi Sivagnanasundram gene: MAFA was added gene: MAFA was added to Mendeliome. Sources: Other Mode of inheritance for gene: MAFA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAFA were set to 29339498 Phenotypes for gene: MAFA were set to Insulinomatosis and diabetes mellitus, OMIM #:147630 Review for gene: MAFA was set to GREEN Added comment: Addition of this review to Mendeliome, was only on the hyperinsulinism panel 2 families with 36 individuals with AD inheritance of diabetes mellitus or insulinomatosis (adult-onset recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumours of pancreas). WES identified the same missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes in both families. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity. Sources: Other |
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| Mendeliome v1.3381 | INCENP |
Rylee Peters gene: INCENP was added gene: INCENP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INCENP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INCENP were set to 41005306 Phenotypes for gene: INCENP were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769, INCENP-related Review for gene: INCENP was set to AMBER Added comment: 3 unrelated women presenting with abnormal oocyte morphology and/or low fertilisation rate from a large cohort of 3627 individuals. WES identified biallelic missense variants: R267Q (gnomAD v4: 1717 hets, 12 homs), R280W (5 hets, 0 homs), P444L (207 hets, 0 homs), R693W (686 hets, 1 hom), K816T (110 hets, 1 hom), K890E (3 hets, 0 homs). siRNA-mediated knock-down of INCENP in mouse oocytes reduced polar-body extrusion rates, demonstrating that loss of function of the protein affects oocyte maturation. Sources: Literature |
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| Mendeliome v1.3381 | SWSAP1 |
Rylee Peters gene: SWSAP1 was added gene: SWSAP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SWSAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SWSAP1 were set to 40991243 Phenotypes for gene: SWSAP1 were set to Primary ovarian insufficiency, MONDO:0005387, SWSAP1-related Review for gene: SWSAP1 was set to RED Added comment: Cohort with severe isolated premature ovarian insufficiency. 1x individual homozygous for a frameshift SWSAP1 variant, c.353del, p.(Gly118AlafsTer2), absent from gnomAD v4. Functional: western-blot indicates reduced stability of the truncated protein; the truncated SWSAP1 variant fails to complement the IH-HR (interhomolog homologous recombination) defect of Swsap1−/− cells (undetected IH-HR activity). Sources: Literature |
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| Mendeliome v1.3368 | TRIM49 |
Bryony Thompson changed review comment from: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families. Sources: Literature; to: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not. This constitutes convincing functional evidence for pathogenicity in two families. Sources: Literature |
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| Mendeliome v1.3368 | TRIM49 |
Bryony Thompson gene: TRIM49 was added gene: TRIM49 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRIM49 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRIM49 were set to 40956390 Phenotypes for gene: TRIM49 were set to retinitis pigmentosa MONDO:0019200 Review for gene: TRIM49 was set to AMBER Added comment: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families. Sources: Literature |
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| Mendeliome v1.3362 | PTBP2 |
Lucy Spencer gene: PTBP2 was added gene: PTBP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTBP2 were set to 40965981 Phenotypes for gene: PTBP2 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP2-related Review for gene: PTBP2 was set to AMBER Added comment: PMID: 40965981 2 males with developmental delay, ID, autistic features. 1 had some dysmorphic features and tonic-clonic seizures. both probands had a de novo variant in PTBP2 NM_021190.4:c.2T>C (p.Met1?) and NM_021190.4:c.41G>C (p.Arg14Thr), absent from gnomad. Transfection of the variants in transfection in NIH-3T3 cells showed the missense had cytoplasmic retention and colocalization with processing bodies, and that there were 2 alternative downstream start sites Met32 and Met35 that may be used instead. Sources: Literature |
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| Mendeliome v1.3362 | GSTZ1 |
Lucy Spencer changed review comment from: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years. PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development. PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron. Sources: Literature; to: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years. PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development. PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron. Val99Met has 1170 hets and 4 homs in gnomad, as this condition appears to be clinically benign this is not a concern. Currently rated as moderate by ClinGen, the review does not include the most recent paper Sources: Literature |
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| Mendeliome v1.3362 | GSTZ1 |
Lucy Spencer gene: GSTZ1 was added gene: GSTZ1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GSTZ1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GSTZ1 were set to 27876694; 38535121; 41009955 Phenotypes for gene: GSTZ1 were set to Maleylacetoacetate isomerase deficiency MIM#617596 Review for gene: GSTZ1 was set to GREEN Added comment: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years. PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development. PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron. Sources: Literature |
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| Mendeliome v1.3348 | DHX37 |
chirag patel Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731 to 46,XY sex reversal 11, MONDO:8000015; Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731 Publications for gene DHX37 were changed from 31337883; 31745530; 31287541; 26539891; 31256877 to 31337883; 31745530; 31287541; 26539891; 31256877 |
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| Mendeliome v1.3346 | ZSWIM7 |
Sangavi Sivagnanasundram changed review comment from: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency Spermatogenic failure: PMID: 32719396 Homozygous males presenting with non-obstructive azoospermia c.201+1G>T - absent from gnomAD v4.1 c.231_232del;p.(Cys78Phefs*21) - FAF 0.04% PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21) CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest. Primary ovarian insufficiency (POI): PMID: 40991243 Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7 Patient 1: Homozygous deletion c.231_232del Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6) Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%) Paitent 4: Homozygous c.176C>T p.(Arg51Ter) PMID: 40991243 Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant Sources: Literature; to: Established gene-disease association. Biallelic variants reported in unrelated individuals with either azoospermia or primary ovarian insufficiency Spermatogenic failure: PMID: 32719396 Homozygous males presenting with non-obstructive azoospermia c.201+1G>T - absent from gnomAD v4.1 c.231_232del;p.(Cys78Phefs*21) - FAF 0.04% PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21) CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest. Primary ovarian insufficiency (POI): PMID: 40991243 Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7 Patient 1: Homozygous deletion c.231_232del Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6) Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%) Paitent 4: Homozygous c.176C>T p.(Arg51Ter) PMID: 40991243 Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant Sources: Literature |
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| Mendeliome v1.3346 | ZSWIM7 |
Sangavi Sivagnanasundram gene: ZSWIM7 was added gene: ZSWIM7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZSWIM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZSWIM7 were set to 32719396, 33713115, 40991243, 40991243 Phenotypes for gene: ZSWIM7 were set to Spermatogenic failure 71 MONDO:0030787; Ovarian dysgenesis 10 MONDO:0030736 Review for gene: ZSWIM7 was set to GREEN Added comment: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency Spermatogenic failure: PMID: 32719396 Homozygous males presenting with non-obstructive azoospermia c.201+1G>T - absent from gnomAD v4.1 c.231_232del;p.(Cys78Phefs*21) - FAF 0.04% PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21) CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest. Primary ovarian insufficiency (POI): PMID: 40991243 Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7 Patient 1: Homozygous deletion c.231_232del Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6) Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%) Paitent 4: Homozygous c.176C>T p.(Arg51Ter) PMID: 40991243 Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant Sources: Literature |
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| Mendeliome v1.3341 | PDIA6 | Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes and polycystic kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3329 | CNTD2 |
Sangavi Sivagnanasundram gene: CNTD2 was added gene: CNTD2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: CNTD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CNTD2 were set to 41005306 Phenotypes for gene: CNTD2 were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769 Review for gene: CNTD2 was set to GREEN Added comment: HGNC approved new gene name: CCNP 3 unrelated women presenting with primary infertility and oocyte/embryo defects in IVF. Different biallelic variants were identified - all variants were either absent or rare enough in gnomAD v4.1 for AR gene (p.L59Wfs*11, p.Y231N, and c.358-1G>A). In vivo mouse model showed that the overexpression of mutant CNTD2 mRNA in mouse zygotes led to early embryonic arrest. Sources: Other |
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| Mendeliome v1.3325 | PCDHA13 |
chirag patel gene: PCDHA13 was added gene: PCDHA13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PCDHA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PCDHA13 were set to 40988636 Phenotypes for gene: PCDHA13 were set to Hypoplastic left heart syndrome, MONDO:0004933 Review for gene: PCDHA13 was set to RED Added comment: WES in 68 subjects with HLHS identified 1 individual with co-occurrence (i.e. digenic) of a SAP130 gene variant (p. S639G) and PCDHA13 gene variant (p. A22V). GnomAD frequencies for variants are: 0.00003% (PCDHA13 variant) and 0.01% with numerous homozygotes (SAP130 variant). The PCDHA13 variant is situated in a region highly conserved across the PCDHA gene family (which is highly homologous), especially PCDHA10 which is the ortholog of mouse Pcdha9. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, and Pcdha9 increases penetrance of aortic valve abnormalities. Mutations in Sap130 and Pcdha9 were validated by CRISPR–Cas9 genome editing in mice as being digenic causes of HLHS. Sources: Literature |
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| Mendeliome v1.3323 | SPDYC |
chirag patel gene: SPDYC was added gene: SPDYC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SPDYC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPDYC were set to 41005306 Phenotypes for gene: SPDYC were set to Primary ovarian failure, MONDO:0005387 Review for gene: SPDYC was set to GREEN Added comment: 4 unrelated female patients with primary infertility caused by oocyte/embryo defects, from a large cohort of 3,627 patients. WES identified rare biallelic variants in SPDYC gene (p.R52Vfs∗50, p.R188C, p.P287H). Overexpression of mutant SPDYC mRNA in mouse oocytes caused disruption of the ability of the protein to overcome milrinone-mediated inhibition of meiotic resumption with two of the variants (p.R52Vfs∗50 and p.R188C). SPDYC is involved in crucial processes involving cyclin-dependent kinases during the phase transition of the mitotic cell cycle. Sources: Literature |
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| Mendeliome v1.3316 | MDC1 |
Sarah Milton gene: MDC1 was added gene: MDC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MDC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MDC1 were set to PMID: 40954969, 34089056 Phenotypes for gene: MDC1 were set to Oligoasthenoteratozoospermia, MONDO:0850098, MDC1-related Review for gene: MDC1 was set to AMBER Added comment: MDC1 encodes mediator of DNA damage checkpoint I protein. PMID: 40954969 describes 2 affected individuals with biallelic loss of function (nonsense and start loss) variants in MDC1 with reduced sperm count, abnormal morphology and poor motility. 1 family consanguineous. PMID: 34089056 describes 1 similarly affected individual with 2 loss of function variants not confirmed in trans. All adequately rare in gnomad v4. No homozygous NMD predicted variants in gnomad v4. Knockout mice models show meiotic arrest in spermatocytes which subsequently undergo apoptosis. Functional studies performed in PMID:40954969 showed lack of protein in affected patient cells and lack of colocalization usual partner protein. Didn't demonstrate conclusively loss of downstream function. Sources: Literature |
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| Mendeliome v1.3302 | MRPS36 |
Krithika Murali gene: MRPS36 was added gene: MRPS36 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS36 were set to PMID: 41018056; 38685873 Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related Review for gene: MRPS36 was set to AMBER Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported. Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific. Sources: Literature |
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| Mendeliome v1.3296 | DMRT2 |
Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature |
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| Mendeliome v1.3295 | DMRT2 |
Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature |
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| Mendeliome v1.3293 | DMRT2 |
Krithika Murali gene: DMRT2 was added gene: DMRT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292 Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related Review for gene: DMRT2 was set to AMBER Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature |
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| Mendeliome v1.3238 | AKT2 |
chirag patel Source Victorian Clinical Genetics Services was removed from AKT2. Source Literature was added to AKT2. Phenotypes for gene: AKT2 were changed from Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; Hypoinsulinemic hypoglycemia with hemihypertrophy, OMIM:240900; Diabetes mellitus, type II , MIM#125853 to Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; AKT2-related familial partial lipodystrophy MONDO:0019192 |
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| Mendeliome v1.3225 | MT-TW |
Zornitza Stark gene: MT-TW was added gene: MT-TW was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TW. Mode of inheritance for gene gene: MT-TW was set to MITOCHONDRIAL Publications for gene: MT-TW were set to 7695240; 9266739; 9673981; 12776230; 15054399; 18337306; 19809478; 26524491; 23841600; 30937556 Phenotypes for gene: MT-TW were set to Mitochondrial disease (MONDO:0044970), MT-TW-related Review for gene: MT-TW was set to GREEN Added comment: DEFINITIVE by ClinGen. At least 10 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, microcephaly, developmental delay and regression, cognitive decline, fatigue, seizures, ataxia, chorea, muscle wasting, axonal neuropathy, diabetes, liver steatosis and fibrosis, constipation, recurrent vomiting, failure to thrive, pigmentary retinopathy, ptosis, optic atrophy, ophthalmoplegia, sensorineural hearing loss, and hypertrophic and dilated cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS to generalized atrophy and white matter involvement. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels in affected individuals were highest in muscle and/or liver when multiple tissues were assessed (25 - >95 % in muscle, 1 to >95% in blood, >95% in liver, 1-92% in skin fibroblasts, and 5% in urine when assessed). Functional studies to support variant pathogenicity. Sources: Expert list |
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| Mendeliome v1.3223 | MT-TV |
Zornitza Stark gene: MT-TV was added gene: MT-TV was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TV. Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL Publications for gene: MT-TV were set to 9450773; 12056939; 19252805; 15320572; 18314141; 24691472 Phenotypes for gene: MT-TV were set to Mitochondrial disease (MONDO:0044970), MT-TV-related Review for gene: MT-TV was set to GREEN Added comment: DEFINITIVE by ClinGen. At least 8 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, cognitive decline, fatigue, migraines, seizures, myoclonic jerks, ataxia, dystonia, dysarthria, imbalance, muscle weakness, axonal sensorimotor polyneuropathy, diabetes, gastrointestinal dysmotility, cataracts, retinitis pigmentosa, sensorineural hearing loss, and hypertrophic cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar and cerebral atrophy, brainstem atrophy, and basal ganglia calcifications. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and normal to decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (67% to homoplasmic in muscle, 70% to homoplasmic in blood, and homoplasmic in skin fibroblasts). Sources: Expert list |
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| Mendeliome v1.3221 | MT-TT |
Zornitza Stark gene: MT-TT was added gene: MT-TT was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TT. Mode of inheritance for gene gene: MT-TT was set to MITOCHONDRIAL Publications for gene: MT-TT were set to 32083134; 8769114; 9367299; 1645537; 8511015; 22638997; 29760464; 30236074; 28187756; 35808913 Phenotypes for gene: MT-TT were set to Mitochondrial disease (MONDO:0044970), MT-TT-related Review for gene: MT-TT was set to GREEN Added comment: MODERATE by ClinGen. At least 10 probands reported with 5 unique variants. Age of onset in affected individuals varied from the neonatal period to more than 50 years. Clinical features in affected individuals included neonatal lactic acidosis; myoclonic epilepsy and ragged red fibers (MERRF); Leber Hereditary Optic Neuropathy (LHON); myopathy, seizures, migraines, pigmentary retinopathy, hearing loss, and diabetes. Brain imaging findings were variable. Muscle biopsies showed ragged red fibers and COX-deficient fibers. Lab investigations showed elevated lactate. Heteroplasmy levels were highest in muscle when multiple tissues were assessed, and ranged from 33% to homoplasmy in muscle. Sources: Expert list |
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| Mendeliome v1.3219 | MT-TS2 |
Zornitza Stark gene: MT-TS2 was added gene: MT-TS2 was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TS2. Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL Publications for gene: MT-TS2 were set to 9792552; 10090882; 16950817; 21257182; 22369973; 22378285 Phenotypes for gene: MT-TS2 were set to Mitochondrial disease (MONDO:0044970), MT-TS2-related Review for gene: MT-TS2 was set to GREEN Added comment: MODERATE by ClinGen. At least 7 individuals reported. Affected individuals had varying clinical features including cataracts, retinal dystrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, and hypogonadotropic hypogonadism. Lab investigations revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter. Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity. Sources: Expert list |
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| Mendeliome v1.3215 | MT-TR |
Zornitza Stark gene: MT-TR was added gene: MT-TR was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TR. Mode of inheritance for gene gene: MT-TR was set to MITOCHONDRIAL Publications for gene: MT-TR were set to 15286228; 17588757; 19809478; 22781096 Phenotypes for gene: MT-TR were set to mitochondrial disease (MONDO:0044970), MT-TR-related Review for gene: MT-TR was set to GREEN Added comment: MODERATE by ClinGen. At least 4 individuals reported. Cybrid studies and single fiber testing further supported the pathogenicity of several of the reported variants. Age of onset was in childhood and features seen in affected individuals included muscle weakness, ataxia, hypotonia, epilepsy, global developmental delay and regression, pigmentary retinopathy, optic atrophy, renal insufficiency, and hypertrophic cardiomyopathy. Muscle biopsies showed ragged red fibers and COX-negative fibers and variable respiratory chain enzyme deficiencies. Sources: Expert list |
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| Mendeliome v1.3212 | MT-TQ |
Zornitza Stark gene: MT-TQ was added gene: MT-TQ was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TQ. Mode of inheritance for gene gene: MT-TQ was set to MITOCHONDRIAL Publications for gene: MT-TQ were set to 11171912; 10996779; 17003408; 11335700 Review for gene: MT-TQ was set to AMBER Added comment: LIMITED by ClinGen. Three unique variants (m.4332G>A, m.4369_4370insA, m.4381A>G) reported in three probands across 3 publications. Single fiber testing further supported the pathogenicity of several of these variants. Age of onset in affected individuals was five years old, teens, and 20 years old. Clinical features in affected individuals included stroke-like episodes, hearing loss, myopathy, and Leber Hereditary Optic Neuropathy (LHON). Brain imaging was variable. Muscle biopsies showed ragged red fibers and COX-negative fibers. Metabolic screening investigations were only reported in one individual and showed high cerebrospinal fluid (CSF) lactate with normal blood lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-87% in muscle). Sources: Expert list |
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| Mendeliome v1.3203 | MT-TL1 |
Zornitza Stark gene: MT-TL1 was added gene: MT-TL1 was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TL1. Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL Publications for gene: MT-TL1 were set to 9323566; 12221518; 20471262; 23220830; 23273904; 24338029; 23582502; 11271374; 23258140 Phenotypes for gene: MT-TL1 were set to Mitochondrial disease (MONDO:0044970), MT-TL1-related Review for gene: MT-TL1 was set to GREEN Added comment: DEFINITIVE by ClinGen. Multiple individuals reported with a range of clinical presentations, including MELAS, myoclonus epilepsy, ragged red fibers (MERRF), Leigh syndrome spectrum, progressive external ophthalmoplegia (PEO), and maternally inherited deafness and diabetes (MIDD), as well as myopathy, hypertrophic cardiomyopathy, and renal disease. At least 7 unique variants reported with a substantial amount of functional evidence, including numerous cybrid analyses, single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects. Sources: Expert list |
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| Mendeliome v1.3200 | MT-TK |
Zornitza Stark gene: MT-TK was added gene: MT-TK was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TK. Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL Publications for gene: MT-TK were set to 9380435; 19618438; 17410322; 25559684; 1361099; 10868777; 35821181; 36675808 Phenotypes for gene: MT-TK were set to Mitochondrial disease (MONDO:0044970), MT-TK-relatednd Review for gene: MT-TK was set to GREEN Added comment: DEFINITIVE by ClinGen. Multiple individuals reported with wide spectrum of clinical presentations including MERRF, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome spectrum, and mitochondrial neurogastrointestinal encephalopathy (MNGIE), as well as lipomas, myopathy, hypertrophic cardiomyopathy, hearing loss, diabetes, and episodic ataxia. Variant pathogenicity is supported by cybrid analyses, single fiber studies, and respiratory chain studies showing clear evidence of OXPHOS defects. Sources: Expert list |
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| Mendeliome v1.3196 | MT-TH |
Zornitza Stark gene: MT-TH was added gene: MT-TH was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-TH. Mode of inheritance for gene gene: MT-TH was set to MITOCHONDRIAL Publications for gene: MT-TH were set to 12682337; 14967777; 15111688; 21704194; 21931169; 23696415; 35092007; 24920829; 21704194 Phenotypes for gene: MT-TH were set to Mitochondrial disease (MONDO:0044970), MT-TH-related Review for gene: MT-TH was set to GREEN Added comment: DEFINITIVE by ClinGen. More than 5 individuals reported. Age of onset in affected individuals varied from adolescence to the 40s. Clinical features included stroke-like episodes, seizures, myoclonus, ataxia, optic atrophy, retinal dystrophy, cataracts, hearing loss, hypogonadism, and mood disorder. Cerebellar vermis hypoplasia and signal changes in the basal ganglia, dentate nuclei, temporal lobes, and occipital lobes were seen on brain imaging. Tissue biopsies identified ragged red fibers and COX-negative fibers. Laboratory investigations showed increased blood and cerebrospinal fluid lactate. Decreased activities of complexes I and IV were variably seen in muscle. Heteroplasmy levels of the variants in affected individuals ranged from 81% to homoplasmic in muscle, 33-87% in urine, 1-60% in blood, and undetectable to homoplasmic in fibroblasts. Single fiber testing, cybrid analysis, and Northern blot analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alteration in patient and non-patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TH; PMID: 24920829, 21704194). Sources: Expert list |
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| Mendeliome v1.3194 | MT-TG |
Zornitza Stark gene: MT-TG was added gene: MT-TG was added to Mendeliome. Sources: Expert list Mode of inheritance for gene gene: MT-TG was set to MITOCHONDRIAL Publications for gene: MT-TG were set to 8079988; 9199564; 11971101; 16120360; 32337339; 35432167; 10090480 Phenotypes for gene: MT-TG were set to Mitochondrial disease (MONDO:0044970), MT-TG-related Review for gene: MT-TG was set to GREEN Added comment: MODERATE by ClinGen. Four variants reported in at least 6 individuals. Age of onset in affected individuals varied from early in life to the 20s. Clinical features included hypertrophic cardiomyopathy, myopathy, peripheral neuropathy, exercise intolerance, headache, seizures, ataxia, dystonic posturing, optic atrophy, retinal dystrophy, cataracts, and hearing loss. Progressive atrophy and bilateral basal ganglia calcifications were seen on brain imaging. Tissue biopsies identified ragged red fibers and decreased COX histochemical activity in muscle. Lab values showed increased blood lactate and increased creatine kinase. Decreased activities of complexes I, III, and IV were observed in biopsied muscle. Heteroplasmy levels of the variants in affected individuals ranged from 88-92% in muscle, 40-56% in urine, undetectable to 32% in blood, 27% in buccal samples, and was undetectable when assessed in fibroblasts. Single fiber testing and cybrid analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alterations in patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TG; PMID: 10090480). Sources: Expert list |
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| Mendeliome v1.3189 | MT-TE |
Zornitza Stark gene: MT-TE was added gene: MT-TE was added to Mendeliome. Sources: Expert list Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL Publications for gene: MT-TE were set to 8155739; 21194154; 17715279; 23334599; 7726155; 7726154; 9353617; 15048886; 15670724; 23847141; 23334599; 17266923; 17056256 Phenotypes for gene: MT-TE were set to Mitochondrial disease (MONDO:0044970), MT-TE-related Review for gene: MT-TE was set to GREEN Added comment: DEFINITIVE by ClinGen. More than 15 individuals reported. Age of onset in affected individuals varied from birth to 30s. Clinical features in affected individuals included (benign) infantile reversible COX deficiency myopathy (also referred to RIRCD); chronic external progressive ophthalmoplegia (CPEO), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap, myoclonic epilepsy and ragged red fibers (MERRF); pigmentary retinopathy, migraines, myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, and hearing loss. Brain imaging was variable. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and were variable in other tissues when tested. Sources: Expert list |
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| Mendeliome v1.3187 | MT-TD |
Zornitza Stark gene: MT-TD was added gene: MT-TD was added to Mendeliome. Sources: Expert list Mode of inheritance for gene gene: MT-TD was set to MITOCHONDRIAL Publications for gene: MT-TD were set to 9811342; 10488907; 16059939; 18676632; 23696415; 25447692; 27536005; 30030363; 3054486; 19535463 Phenotypes for gene: MT-TD were set to Mitochondrial disease (MONDO:0044970), MT-TD-related Review for gene: MT-TD was set to GREEN Added comment: MODERATE by ClinGen. At least 3 variants reported in unrelated individuals. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in MT-TD-related primary mitochondrial disease. Single fiber studies were performed in several individuals with results supporting variant pathogenicity. This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease (PMID: 30030363 ). Respiratory deficient yeast strains due to a single variant in MT-TD have been created and compelling rescue studies have been performed (PMIDs: 7024270, 3054486). E. coli carrying the m.7526A>G variant were also shown to have significantly decreased aminoacylation rates (PMID: 19535463). Sources: Expert list |
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| Mendeliome v1.3183 | MT-TA |
Zornitza Stark gene: MT-TA was added gene: MT-TA was added to Mendeliome. Sources: Expert list Mode of inheritance for gene gene: MT-TA was set to MITOCHONDRIAL Publications for gene: MT-TA were set to 11715067; 17825557; 14569122; 27014581; 20813205; 25873012; 16476954 Phenotypes for gene: MT-TA were set to Mitochondrial disease (MONDO:0044970), MT-TA-related Review for gene: MT-TA was set to GREEN Added comment: DEFINITIVE by ClinGen. More than 5 individuals reported. Variable age of onset. Features in affected individuals included myopathy (weakness, exercise intolerance), ptosis, ophthalmoplegia, lipomas, and hearing loss. Muscle biopsies showed ragged red fibers and COX-negative fibers, as well as respiratory chain enzyme deficiencies. Heteroplasmy levels in affected individuals tended to be highest in muscle when multiple tissues were assessed and were variable in other tissues when tested. Sources: Expert list |
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| Mendeliome v1.3177 | MT-ND5 |
Zornitza Stark gene: MT-ND5 was added gene: MT-ND5 was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-ND5. Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL Publications for gene: MT-ND5 were set to 17400793; 11938446; 12624137; 18495510; 23918514; 17535832; 29506874; 23034978; 16816025; 9299505; 18977334 Phenotypes for gene: MT-ND5 were set to Mitochondrial disease (MONDO:0044970), MT-ND5-related Review for gene: MT-ND5 was set to GREEN Added comment: DEFINITIVE by ClinGen. More than 20 individuals reported. Two variants are recurrent (m.13513G>A and m.13094T>C). Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; myoclonus epilepsy, ragged red fibers (MERRF); and cardiomyopathy. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsies variably revealed ragged red fibers, isolated complex I deficiency, and variable combined deficiencies of complexes I, III, and/or IV. Metabolic screening investigations showed elevated lactate in cerebrospinal fluid (CSF) and blood and urinary excretion of Krebs cycle intermediates. Heteroplasmy levels in affected individuals ranged from 28% - 90% in skeletal muscle, 23% to 77% in blood, undetectable to 90% in fibroblasts, 51% - 81% in urine; and ranged in healthy family members from undetectable to 20% in blood, undetectable to 25% to 95% in hair follicles, undetectable to 4-6% muscle, and ranged from 27%-45% in other tissues such as urine and buccal samples in healthy family members. Sources: Expert list |
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| Mendeliome v1.3173 | MT-ND4 |
Zornitza Stark gene: MT-ND4 was added gene: MT-ND4 was added to Mendeliome. Sources: Expert list mtDNA tags were added to gene: MT-ND4. Mode of inheritance for gene gene: MT-ND4 was set to MITOCHONDRIAL Publications for gene: MT-ND4 were set to 12707444; 16120329; 15576045; 20502985; 27761019; 32445240; 32659360; 3201231 Phenotypes for gene: MT-ND4 were set to Mitochondrial disease (MONDO:0044970), MT-ND4-related Review for gene: MT-ND4 was set to GREEN Added comment: DEFINITIVE by ClinGen. Multiple individuals reported presenting with a broad phenotypic spectrum of clinical features including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; cerebellar ataxia, migraines, regression, developmental delay, leukoencephalopathy, myoclonus, seizures, stroke-like episodes, cognitive decline, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, ophthalmoplegia, short stature, and hypertrophic cardiomyopathy. Age of onset varied from infancy to adulthood. Muscle biopsy showed COX-negative fibers and complex I deficiency. Heteroplasmy levels in affected individuals ranged from 60% - 83% in muscle, 40% - 80% in blood, and 76% - 78% in myoblasts, as well as from 57% - 73% in various other tissues (fibroblasts, liver, urine, buccal). Of note, the m.11778G>A common LHON variant was reported in affected individuals in the homoplasmic and heteroplasmic states. Sources: Expert list |
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| Mendeliome v1.3169 | MT-ND2 |
Zornitza Stark gene: MT-ND2 was added gene: MT-ND2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene gene: MT-ND2 was set to MITOCHONDRIAL Publications for gene: MT-ND2 were set to 26258512; 16738010; 15781840; 12192017 Phenotypes for gene: MT-ND2 were set to Mitochondrial disease (MONDO:0044970), MT-ND2-related Review for gene: MT-ND2 was set to GREEN Added comment: MODERATE by ClinGen. Multiple individuals reported. Age of onset in affected individuals ranged from 9 months old to childhood. Clinical features in affected individuals included Leigh syndrome spectrum, myopathy, ophthalmoplegia, and ptosis. Muscle biopsies revealed ragged red fibers and complex I deficiency. Metabolic screening labs showed elevated lactate and creatine kinase (CK). Heteroplasmy levels were >95% in blood, fibroblasts, and muscle in the individual with Leigh syndrome spectrum. However in the other two individuals with predominantly myopathic features, the variant was present at >94% in muscle and undetectable in other tissues tested. Sources: Expert list |
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| Mendeliome v1.3147 | BMPR1A | Zornitza Stark Phenotypes for gene: BMPR1A were changed from Polyposis, juvenile intestinal, MIM# 174900 to BMPR1A-related juvenile polyposis syndrome MONDO:0700348 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3142 | ANLN |
Zornitza Stark edited their review of gene: ANLN: Added comment: Further reports but evidence is conflicting, including variants with implausibly high pop frequency. Gbadegesin et al (2014); Hall et al (2018) 2 x families reported with FSGS (USA) and missense variants G618C (v4: absent) and R431C (v4: 63 hets, 0 hom). R431C was identified in 6 affected family members and absent in 6 unaffected family members. G618C was present in the proband and absent in 4 unaffected family members, the other 2 affected individuals from this family were not genotyped (deceased). Missense demostrated as LoF with both in vitro and in vivo (zebrafish). R431C was shown to disrupt interaction with CD2AP (primarily LoF effect), causing downstream hyperactivation of the PI3K/AKT/mTOR/Rac1 signaling pathway, which drives podocytes hypermotility. Geminiganesan et al (2021) 1 x 2 year old child (India) with early-onset steroid resistant nephrotic syndrome, whole-exome sequencing and genome-wide linkage studies, a missense variant in ANLN was identified p.Thr821Met (v4: 508 hets, 0 hom). Zhang et al (2023) 3 x children with steroid resistant nephrotic syndrome (China). 2 x missense (p.M1099I - LP (v4:1 het, 0 hom), p.S140T - VUS (v4: 6 hets, 0 hom) and 1 x stop gain reported p.R39X - LP ( v4: 1 het, 0 hom). Lin et al (2023) 3 x unrelated individuals with missense E841K (China, v4: 618 hets, 2 hom). In famly A the variant was de novo, in family 2 only the proband as tested, in family 3 the variant was inherited from an affected father. 4 x unaffected individuals did not have the variant. Knockout mouse model inconclusive, did not show any effect until 36 weeks. Zebrafish model was also inconclusive.; Changed publications: 24676636, 30002222, 34819827, 38322629, 37957688 |
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| Mendeliome v1.3138 | BAIAP3 |
Zornitza Stark gene: BAIAP3 was added gene: BAIAP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BAIAP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BAIAP3 were set to 40943168 Phenotypes for gene: BAIAP3 were set to Retinitis pigmentosa MONDO:0019200, BAIAP3-related Review for gene: BAIAP3 was set to RED Added comment: 1 individual with retinitis pigmentosa with onset at 18yrs. Trio WGS identified biallelic missense variants in BAIAP3 gene (c.556C>G [p.Arg186Gly] and c.3099C>G [p.His1033Gln]). Both variants were very rare in gnomAD, and the healthy brother was heterozygous for one variant. BAIAP3 interacts with SNARE proteins, whose function is essential for endosome-mediated retrograde trafficking. Single-cell RNA sequencing profiling showed enhanced expression of the BAIAP3 gene in ciliated cells, astrocytes, excitatory and inhibitory neurons, and enteroendocrine cells. Confocal microscopy analysis showed elongated cilia in patient-derived and BAIAP3-depleted fibroblasts compared to control cells. Sources: Literature |
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| Mendeliome v1.3133 | TMEM167A |
chirag patel gene: TMEM167A was added gene: TMEM167A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM167A were set to PMID: 40924476 Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related Review for gene: TMEM167A was set to GREEN Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6). Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper. Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. Sources: Literature |
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| Mendeliome v1.3105 | SKOR2 |
Bryony Thompson gene: SKOR2 was added gene: SKOR2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SKOR2 were set to 40890458; 29997391; 21937600 Phenotypes for gene: SKOR2 were set to complex neurodevelopmental disorder with motor features MONDO:0100516 Review for gene: SKOR2 was set to GREEN Added comment: 3 unrelated families with consistent phenotypes and a supportive mouse model: PMID: 40890458 - 2 unrelated consanguineous Iranian families with a combination of learning disability, facial dysmorphisms, and motor and speech impairments with homozygous variants (c.374 G>C: p.Arg125Pro & c.1271_1274del: p.K424Rfs*71). The homozygous missense variant segregated with disease in 8 individuals (no unaffected individuals tested were homozygous). PMID: 29997391 - proband with neurodevelopmental delay, hypotonia, ataxia, cerebellar dysplasia from a consanguineous Turkish family with a homozygous null variant (NM_001278063.1:c.2750C>G; p.Ser917*). None of the 4 healthy siblings were homozygous for the variant. PMID: 21937600 - Skor2 -/- mouse model had defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Mouse had unstable gait. Sources: Literature |
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| Mendeliome v1.3097 | TRPC4AP |
Zornitza Stark gene: TRPC4AP was added gene: TRPC4AP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRPC4AP were set to 32428920; 26786105 Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related Review for gene: TRPC4AP was set to AMBER Added comment: De novo LoF TRPC4AP variant identified on WES in a child with thyroid dyshormonogenesis. 179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs. Insufficient clinical cases for green. Candidate gene. Sources: Literature |
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| Mendeliome v1.3077 | DHRS3 |
Zornitza Stark gene: DHRS3 was added gene: DHRS3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHRS3 were set to 40519748 Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related Review for gene: DHRS3 was set to AMBER Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives. Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity. Sources: Literature |
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| Mendeliome v1.3073 | MTERF3 |
Zornitza Stark gene: MTERF3 was added gene: MTERF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTERF3 were set to 40543543 Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related Review for gene: MTERF3 was set to AMBER Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction. Sources: Literature |
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| Mendeliome v1.3070 | TFCP2L1 |
Zornitza Stark gene: TFCP2L1 was added gene: TFCP2L1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TFCP2L1 were set to 40569305; 33097957 Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related Review for gene: TFCP2L1 was set to AMBER Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis. PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant. TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Sources: Literature |
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| Mendeliome v1.3063 | ZNF319 |
Zornitza Stark gene: ZNF319 was added gene: ZNF319 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF319 were set to 40820230 Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related Review for gene: ZNF319 was set to RED Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser. 18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy. Sources: Literature |
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| Mendeliome v1.3050 | NXT2 |
Rylee Peters gene: NXT2 was added gene: NXT2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: NXT2 were set to PMID: 40624043; 35013161 Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related Review for gene: NXT2 was set to AMBER Added comment: PMID: 40624043 - 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis. - 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis. - Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene. Sources: Literature |
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| Mendeliome v1.3026 | TBCB |
Krithika Murali gene: TBCB was added gene: TBCB was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBCB were set to PMID: 40856104 Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related Review for gene: TBCB was set to AMBER Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall. Phenotypic features included: - Motor/speech delays in infancy (almost all) - ASD (8/10) - ADHD (5/10) - Mild ID - formal cognitive evaluation (5/8). - Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported. - Brain MRI was performed on five individuals - three displayed a thin corpus callosum, and two had decreased white matter. No prenatal features reported. Supportive Drosophilia models. Sources: Literature |
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| Mendeliome v1.3022 | KRT32 |
Bryony Thompson gene: KRT32 was added gene: KRT32 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KRT32 were set to 40814173; 39048559 Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908; Pityriasis rubra pilaris MONDO:0100017 Review for gene: KRT32 was set to GREEN Added comment: Sufficient evidence for Pityriasis rubra pilaris association, but limited for association with loose anagen syndrome. PMID: 39048559 - Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype. PMID: 40814173 - a single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition. In vitro functional assay showing the variant alters interaction with KRT82, however, only WT & the variant were assessed (no positive control). Sources: Literature |
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| Mendeliome v1.3020 | CCDC89 |
Bryony Thompson gene: CCDC89 was added gene: CCDC89 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC89 were set to 40591933 Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983 Review for gene: CCDC89 was set to AMBER Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile. Sources: Literature |
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| Mendeliome v1.3018 | TULP2 |
Bryony Thompson gene: TULP2 was added gene: TULP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TULP2 were set to 35619658: 33763418; 40613306 Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372 Review for gene: TULP2 was set to AMBER Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility. Sources: Literature |
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| Mendeliome v1.3009 | TMEM184B |
Lucy Spencer gene: TMEM184B was added gene: TMEM184B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TMEM184B were set to 39006436 Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related Review for gene: TMEM184B was set to GREEN Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication. A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function. The splice variant was shown to cause exon 7 skipping which is out of frame. Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels. Sources: Literature |
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| Mendeliome v1.2977 | CSMD2 |
Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. Phenotypic features - age of onset 1.5-10 years old - complex partial seizures (4), secondary GTCS (2) - Normal MRI-B (3), focal cortical dysplasia (1) - mild ID (1). The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter. CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. Phenotypic features - age of onset 1.5-10 years old - complex partial seizures (4), secondary GTCS (2) - Normal MRI-B (3), focal cortical dysplasia (1) - mild ID (1). The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter. CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association. |
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| Mendeliome v1.2977 | CSMD2 |
Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. Phenotypic features - age of onset 1.5-10 years old - complex partial seizures (4), secondary GTCS (2) - Normal MRI-B (3), focal cortical dysplasia (1) - mild ID (1). The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter. CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. Phenotypic features - age of onset 1.5-10 years old - complex partial seizures (4), secondary GTCS (2) - Normal MRI-B (3), focal cortical dysplasia (1) - mild ID (1). The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter. CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association. |
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| Mendeliome v1.2976 | CSMD2 |
Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1). The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter. CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence. Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1). The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter. CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence. Sources: Literature |
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| Mendeliome v1.2976 | CSMD2 |
Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1). The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter. CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos. Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence. Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1). The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter. CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos. Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence. Sources: Literature |
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| Mendeliome v1.2976 | CSMD2 |
Krithika Murali gene: CSMD2 was added gene: CSMD2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD2 were set to PMID: 40632521; 38649688; 31068362 Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD1-related Review for gene: CSMD2 was set to AMBER Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project. The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1). The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism. Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter. CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos. Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence. Sources: Literature |
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| Mendeliome v1.2973 | PTCH2 | Zornitza Stark edited their review of gene: PTCH2: Added comment: PMID 40803816: novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids identified in individual with duplication of the pituitary gland. Unclear how this relates to previously reported variants and phenotypes.; Changed publications: 30820324, 23479190, 18285427, 40803816; Changed phenotypes: Basal cell nevus syndrome, MIM#109400, Duplication of pituitary gland | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2964 | WDR18 |
Krithika Murali gene: WDR18 was added gene: WDR18 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WDR18 were set to PMID: 40677927 Phenotypes for gene: WDR18 were set to Cornelia de Lange syndrome (MONDO:0016033) Review for gene: WDR18 was set to RED Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing. In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals: - ARID3A (missense variant, REVEL 0.72) - PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS) - MCM7 (LoF variant, gene linked with cohesin complex) - MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60) - WDR18 (missense variant, weak in silico, REVEL 0.268) Sources: Literature |
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| Mendeliome v1.2963 | MIS18BP1 |
Krithika Murali gene: MIS18BP1 was added gene: MIS18BP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIS18BP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIS18BP1 were set to PMID: 40677927 Phenotypes for gene: MIS18BP1 were set to Cornelia de Lange syndrome (MONDO:0016033) Review for gene: MIS18BP1 was set to RED Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing. In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals: - ARID3A (missense variant, REVEL 0.72) - PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS) - MCM7 (LoF variant, gene linked with cohesin complex) - MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60) - WDR18 (missense variant, weak in silico, REVEL 0.268) Sources: Literature |
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| Mendeliome v1.2954 | ASAP2 |
Zornitza Stark gene: ASAP2 was added gene: ASAP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160 Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related Review for gene: ASAP2 was set to AMBER Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development. Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants. Sources: Literature |
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| Mendeliome v1.2953 | RTF1 |
Zornitza Stark changed review comment from: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Sources: Literature; to: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development. Sources: Literature |
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| Mendeliome v1.2952 | RTF1 |
Zornitza Stark gene: RTF1 was added gene: RTF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196 Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related Review for gene: RTF1 was set to GREEN Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Sources: Literature |
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| Mendeliome v1.2951 | PIK3C3 |
Krithika Murali gene: PIK3C3 was added gene: PIK3C3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PIK3C3 were set to PMID:40677927 Phenotypes for gene: PIK3C3 were set to Cornelia de Lange syndrome - MONDO:0016033 Review for gene: PIK3C3 was set to RED Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing. In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals: - ARID3A (missense variant, REVEL 0.72) - PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS) - MCM7 (LoF variant, gene linked with cohesin complex) - MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60) - WDR18 (missense variant, weak in silico, REVEL 0.268) Sources: Literature |
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| Mendeliome v1.2950 | ARID3A |
Krithika Murali gene: ARID3A was added gene: ARID3A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARID3A were set to PMID: 40677927 Phenotypes for gene: ARID3A were set to Cornelia de Lange syndrome - MONDO:0016033 Review for gene: ARID3A was set to RED Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing. In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals: - ARID3A (missense variant, REVEL 0.72) - PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS) - MCM7 (LoF variant, gene linked with cohesin complex) - MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60) - WDR18 (missense variant, weak in silico, REVEL 0.268) Sources: Literature |
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| Mendeliome v1.2948 | HYPK |
Krithika Murali gene: HYPK was added gene: HYPK was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HYPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HYPK were set to Clinical Genetics Early View Phenotypes for gene: HYPK were set to Neurodevelopmental disorder, MONDO:0700092, HYPK-related Review for gene: HYPK was set to RED Added comment: Single case report - Patel, R. et al 2025 Clinical Genetics Early View Male proband with developmental delay, autism and facial dysmorphism with a de novo missense HYPK variant (p. R70I). Variant-specific biochemical analyses demonstrates enhanced inhibitory activity of HYPK on NatA-mediated N-terminal protein acetylation. GestaltMatcher analysis indicates that the proband's facial phenotype closely resembles Ogden syndrome (NAA10) and some resemblance to NAA15-NDS - both associated genes are also involved in the N-terminal acetylation pathway. Sources: Literature |
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| Mendeliome v1.2945 | DLGAP5 |
Zornitza Stark gene: DLGAP5 was added gene: DLGAP5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DLGAP5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DLGAP5 were set to 40796344 Phenotypes for gene: DLGAP5 were set to Infertility disorder, MONDO:0005047, DLGAP5-related Review for gene: DLGAP5 was set to GREEN Added comment: 3 individuals with biallelic variants identified as part of a large cohort (N=488) of women experiencing recurrent early embryonic arrest. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3. Sources: Literature |
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| Mendeliome v1.2925 | CSMD3 |
Sarah Milton gene: CSMD3 was added gene: CSMD3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CSMD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD3 were set to PMID: 40632521 Phenotypes for gene: CSMD3 were set to Epilepsy, MONDO:0005027, CSMD3-related Review for gene: CSMD3 was set to GREEN Added comment: CSMD3 encodes a synaptic membrane proteins and play a role in neuronal maturation/growth dendrites. A related protein CSMD1 has been previously associated with a complex neurodevelopmental disorder. PMID: 40632521 describes 8 individuals with seizures. 4 with focal epilepsy, 3 with febrile seizures and 1 individual with infantile spasms. 1 individual described had a de novo missense variant with remainder having comp het/biallelic variants. Mild ID in 1 individual only. Variant type mostly missense variants with 1 nonsense, all appropriately rare in gnomAD v4 for recessive disorder. No variant specific functional studies performed, no clear discussion in paper about postulated mechanism for disease. No discussion around difference in mechanism for de novo monoallelic variant. Previous studies showed homozygous knockout mice display abnormal neuronal proliferation and growth retardation. Sources: Literature |
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| Mendeliome v1.2916 | PAX4 | Zornitza Stark edited their review of gene: PAX4: Changed phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2916 | PAX4 | Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225; Diabetes mellitus, type 2, MIM# 125853 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2888 | TMTC2 | Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2858 | SOD2 | Zornitza Stark Phenotypes for gene: SOD2 were changed from {Microvascular complications of diabetes 6} 612634; Lethal neonatal dilated cardiomyopathy to {Microvascular complications of diabetes 6} 612634; Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2841 | ARHGAP36 |
Zornitza Stark gene: ARHGAP36 was added gene: ARHGAP36 was added to Mendeliome. Sources: Expert Review SV/CNV, regulatory region tags were added to gene: ARHGAP36. Mode of inheritance for gene: ARHGAP36 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: ARHGAP36 were set to 35986704; 40015599 Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845 Mode of pathogenicity for gene: ARHGAP36 was set to Other Review for gene: ARHGAP36 was set to AMBER Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward. It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene. Genomic coordinates (GRCh38) : X:129,500,001-138,900,000. At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported. Sources: Expert Review |
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| Mendeliome v1.2817 | OGFRL1 |
Rylee Peters gene: OGFRL1 was added gene: OGFRL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OGFRL1 were set to PMID: 38699440 Phenotypes for gene: OGFRL1 were set to Cherubism (MONDO:0007315), OGFRL1-related Review for gene: OGFRL1 was set to RED Added comment: 3x individuals from 2 unrelated families with cherubism and homozygous NMD-predicted variants in OGFRL1. In one family, the NMD-predicted OGFRL1 variant was identified in 2x affected individuals and was either heterozygous or absent in 7x unaffected family members tested. OGFRL1 knockout mice and mice carrying a patient frameshift mutation were generated, however, neither mouse model recapitulated human cherubism. Absence of homozygous LoF variants in gnomAD v4. Sources: Literature |
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| Mendeliome v1.2817 | ST5 |
Rylee Peters gene: ST5 was added gene: ST5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ST5 were set to PMID: 40717498 Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related Review for gene: ST5 was set to GREEN Added comment: HGNC: DENND2B Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10. Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment). In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect. Sources: Literature |
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| Mendeliome v1.2817 | BLOC1S1 |
Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211 11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1. The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy. Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211 11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1. The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy. Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays. |
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| Mendeliome v1.2817 | BLOC1S1 |
Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211 11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1. The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy. Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211 11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1. The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy. Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays. |
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| Mendeliome v1.2811 | SNW1 |
Lucy Spencer gene: SNW1 was added gene: SNW1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SNW1 were set to 40608414 Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related Review for gene: SNW1 was set to GREEN Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation). 3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available). SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function. Sources: Literature |
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| Mendeliome v1.2787 | ZFP36L2 |
Zornitza Stark gene: ZFP36L2 was added gene: ZFP36L2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ZFP36L2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZFP36L2 were set to 34611029; 38829516; 37211617 Phenotypes for gene: ZFP36L2 were set to Oocyte/zygote/embryo maturation arrest 13, MIM# 620154 Review for gene: ZFP36L2 was set to GREEN Added comment: i) Literature in OMIM- PMID:34611029- x2 unrelated infertile Chinese women with defective oocyte maturation carrying different biallelic variants and functional analysis suggested that the variants cause maternal mRNA decay defects that result in female infertility. ii) New papers reporting biallelic variants in conjunction with female infertility due to oocyte maturation defect+/- embryonic development arrest - PMID: 38829516: Novel compound heterozygous variant (p.His62Gln and p.Pro290Leu) in a patient with oocyte maturation defect. These variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes. - PMID: 37211617: Novel homozygous variant c.853_861del (p.285_287del) in the affected individual with oocyte maturation defect from a consanguineous family. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs Sources: Expert list |
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| Mendeliome v1.2777 | TBPL2 |
Zornitza Stark gene: TBPL2 was added gene: TBPL2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TBPL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBPL2 were set to 37804378; 33966269; 33893736; 33541821 Phenotypes for gene: TBPL2 were set to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related Review for gene: TBPL2 was set to GREEN Added comment: New papers reporting biallelic variants in infertile women: i) PMID: 37804378- Compound heterozygous novel p.Arg268Ter and recurrent p.Arg233Ter in a female with impaired ovarian folliculogenesis. Structure prediction by molecular modeling demonstrated that three-dimensional structure of TBPL2 was destabilized in mutant proteins. ii) PMID: 33966269- Homozygous missense mutation p.C299R in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family. Functional assays showed that the transcriptional level of ZP3 was not completely blocked but severely reduced by the regulation of the mutant TBPL2, while the transcriptional level of H2Bc was significantly reduced but to a less severe extent compared with that of ZP3, suggesting that the missense had a damage to the transcription initiation function of TBPL2 and its downstream targeted genes got involved in different degrees. The mutant protein also has less stability, which contributes to the lower activity of transcription initiation in the mutant form. iii) PMID: 33893736- Homozygous splicing variant (c.788 + 3A>G) in two unrelated families characterized by oocyte maturation defects. Functional assays showed that the variant disrupted the integrity of TBPL2 mRNA and affected oocytes showed that vital genes for oocyte maturation and fertilization were widely and markedly downregulated, suggesting that a mutation in TBPL2, led to global gene alterations in oocytes; the same variant reported before in PMID: 33541821 in three affected females with diminished ovarian reserve from 3 independent families. Sources: Expert list |
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| Mendeliome v1.2775 | TACC3 |
Zornitza Stark gene: TACC3 was added gene: TACC3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TACC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TACC3 were set to 36395215 Phenotypes for gene: TACC3 were set to Female infertility due to oocyte meiotic arrest, MONDO:0044626 Review for gene: TACC3 was set to AMBER Added comment: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility. Sources: Expert list |
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| Mendeliome v1.2770 | PABPC1L |
Zornitza Stark gene: PABPC1L was added gene: PABPC1L was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PABPC1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PABPC1L were set to 37052235; 37723834; 38177974; 32172300 Phenotypes for gene: PABPC1L were set to Oocyte/zygote/embryo maturation arrest 22, #MIM 621093 Review for gene: PABPC1L was set to GREEN Added comment: i) Literature in OMIM (PMID: 37052235;37723834;38177974)- >3 unrelated infertile women (due to a mixed phenotype including oocyte maturation abnormalities, fertilization failure, and embryonic development arrest) with different biallelic variants ii) Additional paper (PMID: 32172300)- Homozygous likely deleterious variant in PABPC1L p.(Met26Lys) in a woman whose infertility phenotype resembles that of Pabpc1l−/− mouse. During her IVF cycles, 18 oocytes were retrieved and subjected to IVF and ICSI. Nine oocytes were assigned to ICSI, but eight were at germinal vesicle stage and only one showed polar body and failed to fertilize following ICSI. Similarly, nine oocytes were assigned to IVF, and only two showed polar body on the next day without any sign of fertilization. The remaining oocytes were at germinal vesicle stage. Sources: Expert list |
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| Mendeliome v1.2768 | NLRP14 |
Zornitza Stark gene: NLRP14 was added gene: NLRP14 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NLRP14 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NLRP14 were set to 38060382 Phenotypes for gene: NLRP14 were set to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest Review for gene: NLRP14 was set to AMBER Added comment: PMID: 38060382- Compound heterozygous variants (p.Cys428Profs∗28/p.Leu887delinsArgTyr) reported in an infertile woman with oocyte maturation defects and early embryo arrest (EEA). - Functional analysis showed comparable protein levels compared with the wild-type control, although a truncated band of the expected size (47 kDa) was observed for the p.Cys428Profs∗28 variant. -The truncated variant, p.Cys428Profs∗28, is lacking the LRR domain and, hence, completely loses the ability to bind with UHRF1. The p.Leu887delinsArgTyr variant results in significant alteration in binding modes with decreased binding area and binding free energy, which introduced regional instability in the NLRP14-UHRF1 interaction. The interaction of both variants and UHRF1 was disrupted and might lead to increased UHRF1 protein degradation in oocytes. Sources: Expert list |
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| Mendeliome v1.2766 | MEI1 |
Zornitza Stark gene: MEI1 was added gene: MEI1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MEI1 were set to 30388401; 38416203; 34037756; 36759719; 32741963; 36017582 Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia Review for gene: MEI1 was set to GREEN Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA) New papers (biallelic variants for OZEMA): i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles. ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. New papers (biallelic variants for NOA): i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. - others: PMID: 32741963;36017582 Note: Moderate evidence for OZEMA and HM in FeRGI database Sources: Expert list |
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| Mendeliome v1.2756 | FOXD1 |
Zornitza Stark gene: FOXD1 was added gene: FOXD1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: FOXD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOXD1 were set to 27805902; 31395028 Phenotypes for gene: FOXD1 were set to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related Review for gene: FOXD1 was set to GREEN Added comment: i) PMID: 27805902- 18 heterozygous (only 10 were nonsynonymous) variants were identified only in recurrent spontaneous abortion (RSA) patients (total of 33 patients) not seen in ctrl group, and only 3 variants had functional assays performed- p.Ala356Gly (x1 patient),p.Ile364Met (x2 patients), and p.Ins429AlaAla (x12 patients). In vitro assays revealed they had a functional effect as they led to perturbations in FOXD1 transactivation properties on promoters of the Placental Growth Factor (PGF) and the complement component gene (C3) having key roles during implantation/placentation. ii) PMID: 31395028- 9 heterozygous non-synonymous variants in patients affected by PE, IUGR, RPL and repeated implantation failure (RIF) , two of which (p.His267Tyr found in one RIF patient and p.Arg57del in one IUGR woman) represented novel and coherent candidates for in vitro testing. Functional experiments revealed that both led to an increased C3 (complement C3) promoter transcriptional activity. Also found increased FOXD1-p.Arg57del variant transactivation capacity on the PlGF (placental growth factor) promoter.The FOXD1 p.Ala356Gly and p.Ile364Met variants (previously found in RPL patients in PMID: 27805902) have also been identified in the present work in women with PE and IUGR and with isolated IUGR, respectively. Documented in FeRGI database- limited evidence for repeated implantation failure. Sources: Expert list |
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| Mendeliome v1.2752 | ELL3 |
Zornitza Stark gene: ELL3 was added gene: ELL3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ELL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ELL3 were set to 39820605 Phenotypes for gene: ELL3 were set to Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related Review for gene: ELL3 was set to GREEN Added comment: PMID:39820605- 8 different heterozygous variants (5 missense, 3 splicing) in 8 unrelated couples who experienced consecutive early miscarriages due to embryonic aneuploidy. For the three splice variants, mini-gene splicing assays revealed that all led to abnormal splicing, and consequently premature termination of translation or exon skipping, consistent with LOF effect. Findings from functional analysis on human oocytes and knockout mouse oocytes overall supporting that ELL3 depletion increases the incidence of meiotic spindle abnormality and oocyte aneuploidy. Sources: Expert list |
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| Mendeliome v1.2750 | CHEK1 |
Zornitza Stark gene: CHEK1 was added gene: CHEK1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CHEK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHEK1 were set to 33953335; 33948904 Phenotypes for gene: CHEK1 were set to Oocyte/zygote/embryo maturation arrest 21, MIM# 620610 Review for gene: CHEK1 was set to GREEN Added comment: Literature in OMIM- PMID: 33953335; 33948904 - >3 unrelated with infertility due to zygote/embryo cleavage arrest with three different missense variants and 1 1bp deletion. Functional studies using transfection studies showed that all mutant increased cytoplasmic localization significantly greater kinase activity. Injection of all mutant cRNA into mouse zygotes with 2 distinct pronuclei also resulted in significantly decreased cleavage rates compared to wildtype. Sources: Expert list |
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| Mendeliome v1.2748 | CDC25A |
Zornitza Stark gene: CDC25A was added gene: CDC25A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDC25A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDC25A were set to 40342881; 30009144; 16720623 Phenotypes for gene: CDC25A were set to Spermatogenic failure, MONDO:0004983, CDC25A-related Review for gene: CDC25A was set to GREEN Added comment: i) PMID: 40342881- Five novel heterozygous variants (Lys500Asn in 8 cases, His459Leu in 12 cases, Ser485Asp, Thr503Ser, c.1434 + 5G>C) and one previously identified SNP (in 7 cases) in azoospermic males from the Bengali-speaking Indian population. qPCR analysis indicated downregulation of CDC25A mRNA expression in azoospermic patients relative to fertile controls. Relative expression levels of CDC25A were about 2.5-fold lower in azoospermic testicular tissue and semen samples, reflecting diminished transcriptional activity in affected patients. This reduction in gene expression may reflect a potential functional deficiency of CDC25A, contributing to spermatogenic arrest. The decreased level of CDC25A mRNA levels corresponds with the findings of pathogenic variants identified in azoospermic patients, thus solidifying the evidence of CDC25A mutations contributing to male infertility. ii) PMID: 30009144,16720623- decreased expression of CDC25A observed in testicular biopsies from azoospermic men, suggesting association with meiotic arrest as the etiology of spermatogenic failure. Sources: Literature |
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| Mendeliome v1.2737 | BCORL1 |
Zornitza Stark edited their review of gene: BCORL1: Added comment: Association with spermatogenic failure: i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA). ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure. iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.; Changed rating: GREEN; Changed publications: 24123876, 30941876, 38342987, 32376790, 39267058, 39189935; Changed phenotypes: Shukla-Vernon syndrome, MIM#301029, Spermatogenic failure, MONDO:0004983, BCORL1-related |
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| Mendeliome v1.2718 | FASTKD5 |
chirag patel gene: FASTKD5 was added gene: FASTKD5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FASTKD5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FASTKD5 were set to PMID: 40499538 Phenotypes for gene: FASTKD5 were set to Leigh syndrome MONDO:0009723 Review for gene: FASTKD5 was set to GREEN Added comment: 3 unrelated individuals with Leigh syndrome (1 x severe/early-onset/fatal, 1 x milder/childhood-onset, 1 x adult-onset). WES identified compound heterozygous variants in FASTKD5 gene (3 x missense variants, 2 x frameshift variants leading to a premature stop codon). The FASTKD5 gene codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense variants, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. 2/3 missense variants resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. Sources: Literature |
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| Mendeliome v1.2698 | LONP1 |
Lauren Rogers changed review comment from: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301. - PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures. p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case) - PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly. - p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication). - p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case) - p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication) LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.; to: New reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301. - PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures. p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case) - PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly. - p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication). - p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case) - p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication) LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded. |
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| Mendeliome v1.2698 | LONP1 |
Lauren Rogers commented on gene: LONP1: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301. - PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures. p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case) - PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly. - p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication). - p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case) - p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication) LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded. |
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| Mendeliome v1.2667 | SREK1 |
Sangavi Sivagnanasundram gene: SREK1 was added gene: SREK1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SREK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SREK1 were set to 40549565 Phenotypes for gene: SREK1 were set to Prader-Willi-like syndrome, SREK1-related MONDO:0008300 Review for gene: SREK1 was set to AMBER Added comment: Three Pakistani probands from three consanguineous families identified with biallelic variants in SREK1. Affected individuals presented with hyperphagic obesity and neurodevelopmental delay. They also presented with psychological and behavioural issues and were phenotypically similar to Prader-Willi affected individuals. Further testing was conducted using human induced pluripotent stem cell (iPSC) -derived neurons followed by RNA sequencing conducted on the neurons. The results of the assay was suggestive that variants located in the RNA recognition domain (residues 19–96 and 173–256) of SREK1 downregulation of SNORD115 and SNORD116 leading to Prader-Willi-like phenotype however proper validation and controls weren't used. No relevant mouse models were identified on IMPC (international mouse phenotype consortium) to further support gene-disease association there gene reviewed as Amber. Variants identified in SREK1 - AF's from gnomADv4.1 P95L - absent in gnomAD v4.1 T194M - EAS PopMax AF - 0.03787% (47 hets) E601K - SAS PopMax AF - 0.01319% (12 hets) Sources: Literature |
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| Mendeliome v1.2667 | ADAM23 |
Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain. 1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23. Also had a de novo missense variant in PRKD1. Knockout ADAM23 mice show early lethal epilepsy. Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 form a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain. 1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23. Also had a de novo missense variant in PRKD1. Knockout ADAM23 mice show early lethal epilepsy. Sources: Literature |
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| Mendeliome v1.2667 | ADAM23 |
Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain. 1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23. Also had a de novo missense variant in PRKD1. Knockout ADAM23 mice show early lethal epilepsy. Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain. 1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23. Also had a de novo missense variant in PRKD1. Knockout ADAM23 mice show early lethal epilepsy. Sources: Literature |
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| Mendeliome v1.2667 | ADAM23 |
Sarah Milton gene: ADAM23 was added gene: ADAM23 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADAM23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAM23 were set to (PMID: 40455867) Phenotypes for gene: ADAM23 were set to Neonatal-onset developmental and epileptic encephalopathy, MONDO:0100455, ADAM23-related Review for gene: ADAM23 was set to AMBER Added comment: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain. 1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23. Also had a de novo missense variant in PRKD1. Knockout ADAM23 mice show early lethal epilepsy. Sources: Literature |
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| Mendeliome v1.2655 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited (fathers listed as affected). Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient. |
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| Mendeliome v1.2655 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency is insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient. |
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| Mendeliome v1.2653 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient. |
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| Mendeliome v1.2643 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature gnomAD and dgv gold frequency in insufficient. |
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| Mendeliome v1.2643 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature |
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| Mendeliome v1.2643 | ANKS1B |
Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature |
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| Mendeliome v1.2643 | ANKS1B |
Monica Petica gene: ANKS1B was added gene: ANKS1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ANKS1B were set to PMID: 31388001; 38129387 Phenotypes for gene: ANKS1B were set to Neurodevelopmental syndrome; developmental delay; speech delay; motor delay; autism; intellectual disability Penetrance for gene: ANKS1B were set to unknown Review for gene: ANKS1B was set to GREEN Added comment: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene. Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies. Sources: Literature |
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| Mendeliome v1.2591 | ABCC8 | Zornitza Stark Phenotypes for gene: ABCC8 were changed from Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 to Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2558 | FBXO22 |
Sarah Milton gene: FBXO22 was added gene: FBXO22 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXO22 were set to PMID: 40215970 Phenotypes for gene: FBXO22 were set to Neurodevelopmental disorder, MONDO:0700092, FBXO22-related Review for gene: FBXO22 was set to GREEN Added comment: Encodes substrate recognition component of SCF E3 ubiquitin ligase complex. Has role in post translational ubiquitination and degradation of certain substrates e.g. histone demethylases. 14 cases from 12 families published with affected individuals noted to have homozygous frameshift variants (FBXO22:c.159_162del,c.8_36del,c.719_722del - all rare/absent gnomad v4). Phenotype included prenatal growth restriction/short stature, neurodevelopmental delay, microcephaly, hypotonia, seizures, craniofacial dysmorphisms (high forehead, depressed nasal bridge, hypertelorism), variable additional findings including cardiovascular and gastrointestinal anomalies. Supportive functional studies - FBXO22 is involved of degradation of KDM4B, KDM4B protein levels in one affected individual were found to be higher than control. Unique genome wide episignature identified for FBXO22 in 3 individuals with the disorder (given loss of this protein results in increased levels of various histone demethylases). Sources: Literature |
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| Mendeliome v1.2557 | SIRT1 | Zornitza Stark Phenotypes for gene: SIRT1 were changed from autoimmune disease, MONDO:0007179 to autoimmune disease, MONDO:0007179; monogenic diabetes MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2556 | SIRT1 | Zornitza Stark reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2543 | LSM1 |
Zornitza Stark edited their review of gene: LSM1: Added comment: LSM1 encodes a subunit of a complex composed of proteins LSM1-7 which is involved in mRNA stabilisation as well as degradation. Other proteins within the complex are yet to have a definitive disease association however LSM7 has been reported a candidate gene. 3 papers detail 10 affected individuals from 6 families with either a homozygous recurrent splice variant (LSM1:c.231+4A>C) or a homozygous missense variant (LSM1:p.Asn40Tyr in only 1 family). Both very rare in gnomad v4 with 0 homozygotes. The phenotype of the individuals encompassed severe intellectual disability/developmental delay, shared dysmorphic features (broad forehead, pointed chin, medially thickened arched eyebrows, hypertelorism, bulbous nasal tip), skeletal anomalies, cardiovascular (ASD/VSD/aortic valve) and genitourinary abnormalities (CAKUT/hypospadias), gastrointestinal manifestations, hypotonia and visual impairments. RT PCR of the splice variant demonstrated exon 3 skipping with a resultant truncated protein with presumed loss of function mechanism. It was noted by authors there are no biallelic loss of function variant in the gnomad v4, as such it was suggested complete loss of function is non viable. Variants outside of exon 3 have not yet been reported in affected individuals.; Changed rating: GREEN; Changed publications: 31010896, 36100156, 40204357; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, LSM1-related |
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| Mendeliome v1.2479 | SIRT1 | Sangavi Sivagnanasundram reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008794; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2452 | EFNA4 |
Bryony Thompson changed review comment from: Supporting animal models, but no compelling evidence in human cases. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease. PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent. PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls. PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4.; to: Supporting animal models, but no compelling evidence in human cases has been reported since 2006. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease. PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent. PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls. PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4. |
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| Mendeliome v1.2432 | CDC20 |
Zornitza Stark gene: CDC20 was added gene: CDC20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDC20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDC20 were set to 32666501; 33683667; 33898437; 34218387 Phenotypes for gene: CDC20 were set to Oocyte/zygote/embryo maturation arrest 14, MIM# 620276 Review for gene: CDC20 was set to GREEN Added comment: i) PMID: 32666501- Biallelic (homozygous/compound heterozygous) variants in 5 unrelated Chinese women with infertility due to oocyte maturation arrest. Knocked down mouse oocytes showed an metaphase I (MI) arrest phenotype that could be rescued by injection of wildtype human CDC20 cRNA; all of the variants significantly reduced the ability of CDC20 to rescue the phenotype. ii) PMID: 33683667- a compound heterozygous (missense and nonsense) variant in a Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest. iii) PMID: 33898437- 4 patients from 3 Chinese families with homozygous or compound heterozygous variants with infertility due to oocyte maturation arrest, fertilization failure, and early embryonic arrest. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that the homozygous and compound heterozygous variants significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest). iv) PMID: 34218387- homozygous missense variant in a Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of MII oocytes. Sources: Literature |
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| Mendeliome v1.2430 | CCNB3 |
Zornitza Stark gene: CCNB3 was added gene: CCNB3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CCNB3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCNB3 were set to 35722368; 32938693; 34021051; 30770433; 34850816 Phenotypes for gene: CCNB3 were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CCNB3-related Review for gene: CCNB3 was set to GREEN Added comment: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29) ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II. iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I. Supporting mouse evidence: iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos. v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development). Sources: Expert Review |
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| Mendeliome v1.2429 | CDKL1 |
Sarah Milton gene: CDKL1 was added gene: CDKL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CDKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDKL1 were set to PMID: 40088891 Phenotypes for gene: CDKL1 were set to Neurodevelopmental disorder, MONDO:0700092, CDKL1-related Mode of pathogenicity for gene: CDKL1 was set to Other Review for gene: CDKL1 was set to AMBER Added comment: CDKL1 encodes a cyclin dependent kinase of which there are CDKL1-5 in humans. (CDKL5 has been associated with a neurodevelopmental disorder previously.) Bereshneh et al describe 2 individuals with a neurodevelopmental disorder with de novo variants in CDKL1 sourced from databases containing individuals with neurodevelopmental disorders, no additional phenotypic information was provided. Both variants were missense and present in the population (c.505C>T - 13 heterozygotes in gnomad 4, c.344T>C - 2 heterozygotes gnomad 4). Both missense variants were located in the kinase domain and dominant negative mechanism was postulated based on drosophilia studies. Functional studies in drosphilia showed variants seen in probands partially rescued a loss of function model however overexpression of transcripts containing the variants resulted in a more severe phenotype suggesting dominant negative. Authors also noted the larger than expected number of LOF variants in gnomad for the disease to be caused by this mechanism. Sources: Literature |
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| Mendeliome v1.2428 | TEX11 |
Zornitza Stark gene: TEX11 was added gene: TEX11 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: TEX11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TEX11 were set to 25970010; 29661171; 34621296; 37124723 Phenotypes for gene: TEX11 were set to Spermatogenic failure, X-linked 2, MIM# 309120 Review for gene: TEX11 was set to GREEN Added comment: i) PMID:25970010- hemizygous variants in 7 out of of 289 azoospermic men, including a 90kb exonic deletion (Ex10-12) in 2 European men, 2 missense variants in 2 European/German men, and 3 splice variants in two white and one Arabic men. ii) PMID: 29661171 (2018)- a novel hemizygous missense variant (W856C) in two brothers with azoospermia (absent in the mother- ?can it be gonadal mosaicism). Their testicular biopsy revealed meiotic arrest and no post-meiotic round spermatids and mature spermatozoa were observed. iii) PMID: 34621296 (2021)- seven novel hemizygous variants in three familial (one missense, two splice) and four NOA-affected sporadic (three frameshift, one nonsense) cases iv) PMID: 37124723 (2023)- three novel hemizygous variants ( p.R105*, p.K143Q, and p.G859R) in three unrelated NOA males and their histological analysis of testicular biopsy specimens revealed thicker basement membrane of the seminiferous tubules and poorly developed spermatocytes. Sources: Expert Review |
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| Mendeliome v1.2422 | PLCZ1 |
Zornitza Stark gene: PLCZ1 was added gene: PLCZ1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLCZ1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLCZ1 were set to 26721930; 31463947; 36593593; 37004249 Phenotypes for gene: PLCZ1 were set to Spermatogenic failure 17, MIM# 617214 Review for gene: PLCZ1 was set to GREEN Added comment: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure. ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection. iii) PMID: 36593593- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure. iv) PMID: 37004249- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure Sources: Literature |
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| Mendeliome v1.2418 | DDX3Y |
Zornitza Stark gene: DDX3Y was added gene: DDX3Y was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: DDX3Y was set to Other Publications for gene: DDX3Y were set to 36997603 Phenotypes for gene: DDX3Y were set to Azoospermia, MONDO:0100459, DDX3Y-related Review for gene: DDX3Y was set to GREEN Added comment: PMID:36997603- Four (3 German, 1 Estonian) unrelated men with non-obstructive azoospermia carrying different LOF variants- absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain, and are predicted to lead to degradation of the transcripts by nonsense-mediated decay. All four patients shared histological phenotype of Sertoli cell-only (SCO), reduced testicular volume, and had elevated FSH upon primary or later presentation indicative of spermatogenic failure. Mode of inheritance: Y-linked Sources: Expert Review |
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| Mendeliome v1.2410 | TAX1BP3 |
Zornitza Stark gene: TAX1BP3 was added gene: TAX1BP3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TAX1BP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAX1BP3 were set to 39963794 Phenotypes for gene: TAX1BP3 were set to Familial cardiomyopathy, MONDO:0005217, TAX1BP3-related Review for gene: TAX1BP3 was set to AMBER Added comment: Biallelic variants (1 x del, 1 x missense) in TAX1BP3 cause a novel autosomal recessive form of arrhythmogenic cardiomyopathy. One family only, but 3 affected sibs had the bialleic variants which were absent in an unaffected sister. Carrier parents were normal. Experimental work on patient-derived induced pluripotent stem cell cardiac myocytes and a knockout mouse showed that show loss of TAX1BP3 causes calcium dysregulation in cardiomyocytes, a known mechanism for arrhythmia. AMBER until more case level data evolves. Sources: Literature |
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| Mendeliome v1.2368 | CFAP54 |
Zornitza Stark gene: CFAP54 was added gene: CFAP54 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP54 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP54 were set to 26224312; 36593121 Phenotypes for gene: CFAP54 were set to Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation Review for gene: CFAP54 was set to RED Added comment: PMID 36593121: Three men identified with bi-allelic variants and multiple morphologic abnormalities of the flagella or non-obstructive azoospermia. PMID: 26224312: Homozygous mice have PCD characterized by hydrocephalus, male infertility (spermatogenesis defects in flagella maturation), and mucus accumulation. Brain analysis showed mild dilatation of the lateral ventricles. Tracheal cilia beat frequency was significantly reduced. The gene was highest expressed in the testis and lungs Sources: Literature |
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| Mendeliome v1.2363 | SLC25A25 |
Zornitza Stark gene: SLC25A25 was added gene: SLC25A25 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC25A25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC25A25 were set to 34346195 Phenotypes for gene: SLC25A25 were set to Nephrolithiasis MONDO:0008171,SLC25A25 related Penetrance for gene: SLC25A25 were set to Incomplete Review for gene: SLC25A25 was set to RED Added comment: SLC25A25 encodes mitochondrial ATP-Mg/Pi carrier 3 A single missense variant was reported in 2 families with renal stones in 2021 by Jabalameli et al (PMID: 3436195). In family 1 there was 4 affected individuals who shared the same heterozygous variant NM_001330988.2 c.1083G>C|p.Gln361His, however this variant was also seen in 7 individuals in the family without stones In family 2 there were 7 affected individuals who also had p.Gln361His however this variant was also seen in 3 family members without stones. This variant is located within the mitochondrial carrier domain and functional studies were performed looking at uptake of radioactive ATP compared to wild type. These studies demonstrated the variant protein had approximately 21% activity compared to wild type. The variant was proposed to have incomplete penetrance and it should be noted there is 4352 heterozygotes in gnomad 4. At this time there is insufficient evidence for a gene disease association between SLC25A25 and nephrolithiasis. Sources: Literature |
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| Mendeliome v1.2352 | PPP2R5E |
chirag patel gene: PPP2R5E was added gene: PPP2R5E was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPP2R5E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PPP2R5E were set to PMID: 39284558 Phenotypes for gene: PPP2R5E were set to Mendelian neurodevelopmental disorder MONDO:0100500 Review for gene: PPP2R5E was set to RED Added comment: One 20yrs old individual with learning issues, motor coordination disorders, hypotonia (myopathy on EMG), and behavioural issues (mood and emotional dysregulation). WES testing identified a de novo heterozygous missense variant (Glu191Lys) in PPP2R5E gene. The variant was not found in the 4 healthy brothers of the individual. The variant is located within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation. Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures (e.g. PP2AR-1A, 2B, 3C, 5C, 5D). Sources: Literature |
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| Mendeliome v1.2351 | CFAP47 | chirag patel changed review comment from: 3 individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.; to: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2336 | GNA13 |
Bryony Thompson gene: GNA13 was added gene: GNA13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GNA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GNA13 were set to 39966435 Phenotypes for gene: GNA13 were set to Ito hypomelanosis MONDO:0010302 Mode of pathogenicity for gene: GNA13 was set to Other Review for gene: GNA13 was set to AMBER Added comment: 4 unrelated cases with a recurrent post-zygotic GNA13 variant (NM_006572.4:c.599G>A p.Arg200Lys) with a syndrome including hypomelanosis of Ito associated with developmental anomalies. The variant was identified in one patient via exome sequencing of paired tissue/blood and then targeted GNA13 testing of other cases. In vitro assays demonstrate a gain of function for the variant. Q226L was an artificial variant demonstrating a gain of function similar to R200K. The suggested mechanism of disease is through upregulation of the RHOA/ROCK pathway altering melanocyte function. Sources: Literature |
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| Mendeliome v1.2299 | CLCA2 |
Bryony Thompson gene: CLCA2 was added gene: CLCA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLCA2 were set to 31326550 Phenotypes for gene: CLCA2 were set to heart conduction disease MONDO:0000992 Review for gene: CLCA2 was set to AMBER Added comment: Only a single family reported. A missense (p.Trp575Cys) segregates with conduction disease in 5 individuals from a large Chinese family. Electrocardiogram monitoring of mice with missense introduced induced mild conduction block and ectopic pacemakers. Sources: Literature |
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| Mendeliome v1.2293 | HECTD1 |
chirag patel gene: HECTD1 was added gene: HECTD1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HECTD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HECTD1 were set to PMID: 39879987 Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder MONDO:0700092 Review for gene: HECTD1 was set to GREEN Added comment: 14 unrelated individuals (identified through GeneMatcher) with 15 variants of uncertain significance (VUS) in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant). Of the 15 different variants in HECTD1, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. All variants were absent in gnomAD, and HECTD1 is highly intolerant to loss-of-function variation (loss-of-function-intolerant score of 1). Clinical presentation was variable developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy. The one individual with compound heterozygous variants had growth impairment along with NDD. The variants were inherited from apparently healthy parents, suggesting that genetic or environmental modifiers may be required to develop the phenotype. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease. HECT-domain-containing protein 1 (HECTD1) mediates developmental pathways, including cell signalling, gene expression, and embryogenesis. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of 2 missense variants and 1 nonsense variant in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms. Sources: Literature |
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| Mendeliome v1.2291 | TAF11 |
Bryony Thompson gene: TAF11 was added gene: TAF11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TAF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TAF11 were set to 39727181 Phenotypes for gene: TAF11 were set to cleft lip MONDO:0004747 Review for gene: TAF11 was set to RED Added comment: 2 individuals in a single Chinese family with nonsyndromic cleft lip segregating with the missense p.Leu48Phe. The missense has an AF of 1.8% (including 15 homozygotes) in gnomAD v4 in the East Asian population, which is too common for an autosomal dominant disease—also, a supporting zebrafish model with craniofacial abnormalities (however the genetic evidence for this GDA is lacking). Sources: Literature |
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| Mendeliome v1.2279 | C1orf127 |
Zornitza Stark gene: C1orf127 was added gene: C1orf127 was added to Mendeliome. Sources: Literature new gene name tags were added to gene: C1orf127. Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1orf127 were set to 39753129 Phenotypes for gene: C1orf127 were set to Heterotaxy, visceral, MONDO:0018677, CIROZ-related Review for gene: C1orf127 was set to GREEN Added comment: 16 individuals from 10 families reported with bi-allelic variants in this gene and heterotaxy, including CHD. Supportive mouse model. CIROZ is absent or obsolete in select animals with motile cilia at their left-right organiser, including Carnivora, Atherinomorpha fish, or jawless vertebrates. Knockouts in zebrafish and Xenopus did not have observable LR anomalies. Approved HGNC name is CIROZ. Sources: Literature |
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| Mendeliome v1.2274 | PPA1 |
Zornitza Stark gene: PPA1 was added gene: PPA1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPA1 were set to 37999237 Phenotypes for gene: PPA1 were set to Galactosaemia, MONDO:0018116 Review for gene: PPA1 was set to RED Added comment: Homozygous missense variant detected in two siblings with increased galactose and galactose-related metabolites ascertained in neonatal screening. Some supportive functional data. Sources: Literature |
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| Mendeliome v1.2268 | MGA |
Zornitza Stark gene: MGA was added gene: MGA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MGA were set to 39600096; 20044811; 39545409 Phenotypes for gene: MGA were set to Syndromic disease, MONDO:0002254, MGA-related; Premature ovarian failure 26, MIM# 621065 Review for gene: MGA was set to AMBER Added comment: Association with syndromic disease: Three individuals with de novo LoF variants reported in individuals with ID and congenital anomalies. Zebrafish model supports role of this transcription factor in organogenesis. Note there are previous, less clear reports of association with NDD/CHD. Gene is constrained for LoF variants in gnomad v4; however, note there are ~30 individuals with LoF variants present. Borderline Green/Amber. Association with POF: LoF variants enriched in a large POF cohort. Familial testing in a small number of families performed. Mouse model supportive. Also borderline Amber/Green. Amber rating until phenotypes and mechanisms of disease for these two associations clarified. Sources: Literature |
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| Mendeliome v1.2224 | CRYL1 |
Andrew Fennell changed review comment from: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.; to: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2. See also PMID: 20301449 GeneReviews |
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| Mendeliome v1.2184 | HMGCS1 |
Zornitza Stark gene: HMGCS1 was added gene: HMGCS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HMGCS1 were set to 39531736 Phenotypes for gene: HMGCS1 were set to Rigid spine syndrome, MONDO:0019951, HMGCS1-related Review for gene: HMGCS1 was set to GREEN Added comment: Five individuals from four families reported. All individuals presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some; one individual died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. Four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays Sources: Literature |
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| Mendeliome v1.2166 | POLA2 |
Sangavi Sivagnanasundram gene: POLA2 was added gene: POLA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: POLA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLA2 were set to 39616267 Phenotypes for gene: POLA2 were set to Telomere biology disorders; Coats plus syndrome MONDO:0012815 Review for gene: POLA2 was set to GREEN Added comment: New gene-disease association. PMID: 39616267 - Five individuals from two unrelated swedish families presenting with clinical phenotype suggestive of a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Affected individuals also presented with shortened telomeres. Compound heterozygous variants were identified in both families. Family A (Ile96Thr;Pro424Leu) - Both variants are present in gnomAD v4.1 but FAF is rare enough for AR condition [c.287 T > C, p.(Ile96Thr) - FAF 0.002%; c.1271 C > T, p.(Pro424Leu) - FAF 0.0002 %] Family B (Ile96Thr; intragenic SNV resulting in the deletion of the 5’ terminal and exon 1) - same missense as the other family along with an SNV. In vitro assay using CRISPR/Cas9 genome engineering into HEK293T to assess whether the p.(Ile96Thr) would affect telomere length. The subclones carrying the missense variant showed telomeric shortening of ~4kb compared to the WT subclones. Sources: Literature |
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| Mendeliome v1.2153 | MRVI1 |
Bryony Thompson gene: MRVI1 was added gene: MRVI1 was added to Mendeliome. Sources: NHS GMS new gene name tags were added to gene: MRVI1. Mode of inheritance for gene: MRVI1 was set to Unknown Publications for gene: MRVI1 were set to 30001348 Phenotypes for gene: MRVI1 were set to moyamoya syndrome Review for gene: MRVI1 was set to RED Added comment: A single report of a variant as a possible modifier of NF1-related Moyamoya disease. The SNP rs35857561 segregates co-occurring with NF1 in 2 families and Moyamoya disease. rs35857561 is a common SNP and IRAG1 (new gene name) hasn't been reported in association with Mendelian disease. Sources: NHS GMS |
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| Mendeliome v1.2111 | TSHZ3 |
Bryony Thompson gene: TSHZ3 was added gene: TSHZ3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TSHZ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TSHZ3 were set to 27668656; 34919690; 36553458; 39420202 Phenotypes for gene: TSHZ3 were set to congenital anomaly of kidney and urinary tract MONDO:0019719 Review for gene: TSHZ3 was set to AMBER Added comment: More evidence for the gene-disease association is required PMID: 27668656 - TSHZ3 is included in the region deleted in chromosome 19q13.11 Deletion Syndrome, which includes intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT) PMID: 34919690 - haploinsufficient mouse model leads to kidney defects PMID: 36553458 - heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in a case with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis. PMID: 39420202 - 12 CAKUT patients from 9/301 (3%) families carried 5 different rare heterozygous TSHZ3 missense variants. However, 1 of the variants (p.Ser58Gly) present in 5 of the families is more common in gnomAD v4.1 than you would expect for a dominant disease including 5 homozygotes (1,408/1,612,114 alleles, 5 hom, AF=0.0008734). The authors state this is not unexpected in a condition, such as CAKUT. However, the different missense variants are inherited from unaffected parents in at least 2/9 families (there was no phenotype information available for an additional 3 parents). Sources: Literature |
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| Mendeliome v1.2108 | WDR83OS | Bryony Thompson changed review comment from: Now 14 cases from 9 unrelated families with homozygous LoF variants. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype.; to: Now 14 cases from 9 unrelated families with homozygous LoF variants, including the family reported in 2019. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2089 | IRAK2 |
chirag patel changed review comment from: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria. Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported. Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form. Sources: Literature; to: PMID: 39299377 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria. Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported. Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form. Preprint paper: 2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly. The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs. |
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| Mendeliome v1.2089 | IRAK2 |
chirag patel gene: IRAK2 was added gene: IRAK2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IRAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IRAK2 were set to PMID: 39299377 Phenotypes for gene: IRAK2 were set to Immunodeficiency, no OMIM # Review for gene: IRAK2 was set to RED Added comment: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria. Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported. Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form. Sources: Literature |
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| Mendeliome v1.2087 | MARK2 |
chirag patel gene: MARK2 was added gene: MARK2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MARK2 were set to PMID: 39419027, 39436150 Phenotypes for gene: MARK2 were set to Neurodevelopmental disorder MONDO:0700092 Mode of pathogenicity for gene: MARK2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MARK2 was set to GREEN Added comment: 31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears). WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains. The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD. Sources: Literature |
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| Mendeliome v1.2071 | ZNF808 | Zornitza Stark Phenotypes for gene: ZNF808 were changed from non-syndromic neonatal diabetes; MONDO:0016391 to Pancreatic agenesis 3, MIM# 620991 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.2063 | DHRSX |
Achchuthan Shanmugasundram gene: DHRSX was added gene: DHRSX was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHRSX were set to 38821050 Phenotypes for gene: DHRSX were set to congenital disorder of glycosylation, MONDO:0015286 Review for gene: DHRSX was set to GREEN Added comment: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs. This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature |
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| Mendeliome v1.1980 | LARP1 |
Sangavi Sivagnanasundram gene: LARP1 was added gene: LARP1 was added to Mendeliome. Sources: Other Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LARP1 were set to 39182167 Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092 Review for gene: LARP1 was set to GREEN Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency. Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis. Sources: Other |
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| Mendeliome v1.1980 | MED22 |
Mark Cleghorn gene: MED22 was added gene: MED22 was added to Mendeliome. Sources: Other Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: MED22 were set to unknown Review for gene: MED22 was set to AMBER Added comment: ESHG talk 2/6/24, unpublished Elisa Cali, UCL Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures Rare in gnomad v4.1 (9 het alleles, no homozygotes) Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed) Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size Sources: Other |
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| Mendeliome v1.1978 | TMEM216 |
Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively. This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296, Retinitis pigmentosa, MONDO:0019200, TMEM216-related |
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| Mendeliome v1.1972 | PLEKHM2 |
Bryony Thompson gene: PLEKHM2 was added gene: PLEKHM2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842 Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021 Review for gene: PLEKHM2 was set to AMBER Added comment: 2 unrelated families reported with DCM and supporting functional evidence PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models Sources: Literature |
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| Mendeliome v1.1952 | REXO2 |
Zornitza Stark gene: REXO2 was added gene: REXO2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: REXO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: REXO2 were set to 39107301 Phenotypes for gene: REXO2 were set to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related Review for gene: REXO2 was set to AMBER Added comment: Female infant of Chinese ancestry, presented at 2 years of age with whole-body rash with histological features of hyperkeratosis, parakeratosis and acanthosis with elongated rete ridges, focal liquefaction and degeneration of the basal layers of epidermis, vascular proliferation in the superficial dermis, infiltration of lymphocytes and eosinophils around small blood vessels in the dermis. She has recurrent infections (frequent and severe pneumonia). Extensive functional validation demonstrating heterozygous de novo mutation (p.T132A) impairs REXO2’s ability to cleave RNA leading to activation of the dsRNA sensor MDA5 leading to a Type 1 interferonopathy. Sources: Literature |
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| Mendeliome v1.1950 | TMEFF1 |
Zornitza Stark gene: TMEFF1 was added gene: TMEFF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEFF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEFF1 were set to 39048830 Phenotypes for gene: TMEFF1 were set to Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; HSV encephalitis Review for gene: TMEFF1 was set to GREEN Added comment: 2 unrelated patients with severe HSV encephalitis. Functional validation showing that human TMEFF1 encodes a type I IFN-independent, cortical neuron- and CNS-intrinsic restriction factor that is effective against HSV-1 that operates by impairing the entry of HSV-1 into cortical neurons. Sources: Literature |
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| Mendeliome v1.1906 | KCNJ10 | Zornitza Stark edited their review of gene: KCNJ10: Added comment: PMID 38979912: 11 individuals from 8 unrelated families reported with variants in this gene and paroxysmal dyskinesia. Notably one was the parent of a child with recessive SeSAME syndrome (established gene-disease association). Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes.; Changed publications: 19289823, 19420365, 21849804, 11466414, 38979912; Changed phenotypes: SESAME syndrome, MIM# 612780, Paroxysmal dyskinesia, MONDO:0015427, KCNJ10-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1884 | MYZAP |
Zornitza Stark changed review comment from: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. Note the MYZAP and GCOM1 genes are part of the GRINL1A complex transcription unit. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly. Sources: Literature; to: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. The MYZAP gene is part of the GRINL1A complex transcription unit (CTU), or GCOM1, which also includes the downstream POLR2M gene, or GRINL1A.. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly. Transcription from an upstream promoter within the GRINL1A CTU produces 2 types of alternatively spliced transcripts: MYZAP transcripts, also called GRINL1A upstream (GUP) transcripts, which include only exons from the MYZAP gene, and GRINL1A combined (GCOM) transcripts, which include exons from both the MYZAP gene and the downstream POLR2M gene. Transcription of the POLR2M gene initiates at a downstream promoter within the GRINL1A CTU and produces alternatively spliced POLR2M transcripts, also called GRINL1A downstream (GDOWN) transcripts, which include only exons from the POLR2M gene 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 v1.1795 | TAP2 | Zornitza Stark Phenotypes for gene: TAP2 were changed from Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis to MHC class I deficiency 2, MIM# 620813; Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1786 | AVPR1A |
Zornitza Stark gene: AVPR1A was added gene: AVPR1A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: AVPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AVPR1A were set to 24924430 Phenotypes for gene: AVPR1A were set to Autism spectrum disorder MONDO:0005258 Review for gene: AVPR1A was set to RED Added comment: DISPUTED by ClinGen: The Arginine Vasopressin Receptor 1A (AVPR1A) was considered a candidate gene in autism spectrum disorder (ASD) based on reports focused on linkage intervals and animal models. Additionally, experimental evidence showed that AVPR1A is possibly involved in social behaviors, including affiliation and attachment (PMID: 24924430). However, these association studies were underpowered—sequencing more individuals may have identified variants of functional significance. In two studies, transmission disequilibrium between AVPR1A microsatellites and autism were found but most were not statistically significant (PMID: 12082568, 16520824). In another study, investigators screened AVPR1A exons in 125 independent autistic probands (PMID: 15098001). However, the study did not demonstrate a disease-causing variant in the coding sequence, and the authors noted that differences in AVPR1A at the amino-acid level are unlikely to confer genetic vulnerability to autism. Experimental evidence is available, but, in the absence of human genetic evidence, such data were not utilized in the scoring. In summary, there is no valid genetic evidence to support an association between AVPR1A and autism spectrum disorder. Sources: Expert list |
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| Mendeliome v1.1758 | RAB32 |
Bryony Thompson gene: RAB32 was added gene: RAB32 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RAB32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB32 were set to 38614108 Phenotypes for gene: RAB32 were set to Parkinson disease MONDO:0005180 Mode of pathogenicity for gene: RAB32 was set to Other Review for gene: RAB32 was set to RED Added comment: A single variant in RAB32 - c.213C>G p.(Ser71Arg) with a significant association with PD (odds ratio [OR] 13.17, 95% CI 2.15-87.23; p=0.0055, 6,043 PD cases and 62,549 controls). The variant cosegregated with autosomal dominant PD in 3 families (9 affected individuals), with incomplete penetrance. In vitro studies demonstrate that RAB32 Ser71Arg activates LRRK2 kinase. The variant is reported as a novel reduced penetrance PD risk factor. The 95% CI for the OR estimate are very wide. A confirmatory study is required for this variant. Sources: Literature |
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| Mendeliome v1.1756 | CCDC91 |
Bryony Thompson gene: CCDC91 was added gene: CCDC91 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC91 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CCDC91 were set to 38627542 Phenotypes for gene: CCDC91 were set to Punctate palmoplantar keratoderma type III MONDO:0007047 Review for gene: CCDC91 was set to AMBER Added comment: A single 3-generation Chinese acrokeratoelastoidosis family segregates c.1101 + 1 G > A (causes exon 11 skipping). In vitro knockdown experiments in cell lines demonstrated distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-human skin fibroblasts cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates Sources: Literature |
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| Mendeliome v1.1696 | PTCRA |
Achchuthan Shanmugasundram gene: PTCRA was added gene: PTCRA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTCRA were set to 38422122 Phenotypes for gene: PTCRA were set to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783 Review for gene: PTCRA was set to GREEN Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds). Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons. Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available. Sources: Literature |
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| Mendeliome v1.1656 | FRYL |
Ain Roesley gene: FRYL was added gene: FRYL was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FRYL were set to 38479391 Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related Review for gene: FRYL was set to GREEN gene: FRYL was marked as current diagnostic Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father) 5x missense + 8x fs/stopgain + 1x canonical splice 13/13 with ID/DD (1x deceased) 4/14 seizures 7/14 with cardiac anomalies such as PDA, TOF, VSD, dextrocardia 1x also has a de novo fs variant in SF3B4 1x also has a de novo stop gain variant in SDHA functional studies using flies were performed Sources: Literature |
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| Mendeliome v1.1638 | TCN1 |
Bryony Thompson gene: TCN1 was added gene: TCN1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TCN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TCN1 were set to 29764838; 19686235 Phenotypes for gene: TCN1 were set to transcobalamin I deficiency MONDO:0008659 Review for gene: TCN1 was set to AMBER Added comment: Unclear if TC1 deficiency is associated with a clinical phenotype and only found 2 families with genetic findings. 1 confirmed chet (2 truncating variants) with severe TC 1 deficiency (depression and anxiety only reported symptoms, had sickle cell trait) & another family with 2 siblings that are presumed homozygous for a truncating variant (no plasma or serum TC 1 levels but no DNA available for genetic testing) which was found heterozygous in multiple first-degree relatives. Unclear if there is a clinical phenotype. Heterozygous individuals displayed mildly low or low-normal TC 1 serum levels. Also, 4 homozygotes were identified in a study of a loss-of-function variant associated with lower vitamin B12 concentration in African Americans but there was limited ability to assess the clinical impact of the recessive disease Sources: Literature |
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| Mendeliome v1.1589 | UBAP1L |
Ee Ming Wong changed review comment from: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy - Reported variants included splice, nonsense, frameshift and in-frame del variants - Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Sources: Literature; to: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy - Reported variants included splice, nonsense, frameshift and in-frame del variants - Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Sources: Literature |
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| Mendeliome v1.1588 | UBAP1L |
Ee Ming Wong gene: UBAP1L was added gene: UBAP1L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UBAP1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBAP1L were set to PMID: 38293907; 38420906 Phenotypes for gene: UBAP1L were set to Cone-rod dystrophy (MONDO:0015993), UBAP1L-related Review for gene: UBAP1L was set to GREEN gene: UBAP1L was marked as current diagnostic Added comment: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy - Reported variants included splice, nonsense, frameshift and in-frame del variants - Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Sources: Literature |
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| Mendeliome v1.1584 | RGS6 |
Seb Lunke gene: RGS6 was added gene: RGS6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RGS6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RGS6 were set to 38332109; 25525169 Phenotypes for gene: RGS6 were set to Cataract,MONDO:0005129; intellectual disability, MONDO:0001071; microcephaly, MONDO:0001149 Review for gene: RGS6 was set to RED Added comment: Original paper from 2015 describes single consanguineous with two siblings affected by cataract, developmental delay, and microcephaly >3SD. A homozygous canonical splice variant predicted to lead to NMD in RGS6 was identified by WGS and linkage (rather than full WGS analysis). The 2024 paper speculates that the phenotype is driven by a change in RGS6 isoform balance rather than LoF using a knock-out mouse model. It is noted that the mice did not have microcephaly, and ID was assessed using social interaction. No mention of cataract in the mice. Sources: Literature |
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| Mendeliome v1.1581 | TUBA4A |
Sarah Pantaleo gene: TUBA4A was added gene: TUBA4A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TUBA4A were set to PMID: 38413182 Phenotypes for gene: TUBA4A were set to Congenital myopathy MONDO:0019952 Review for gene: TUBA4A was set to AMBER Added comment: One novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. Identified candidate genes using laser capture micro dissection, proteomics, WES, clinical data, myopathological changes, electrophysiological exams and thigh muscle MRIs. The variant is de novo in both patients, c.679C>T, p.(Leu227Phe). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiqution-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of Leu227Phe resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model. Patient 1 is 14yo and had delayed motor development milestones since infancy. Myopathic face, high-arched palate, waddling gait, winged scapula and muscle weakness in four limbs with lower extremities and proximal muscle more severely affected. Follow up at 14yo showed slight improvement in motor function compared with 3yo. Patient 2 is 6yo and presented with motor retardation since birth. At 3yo, presented with mild ptosis and ophthalmoparesis, high-arched palate and muscle weakness involving both proximal and distal in all limbs. No likely pathogenic variants in 116 other protein-encoding genes. Variants confirmed by Sanger sequencing and absent from gnomAD. ACMG predicts likely pathogenic classification. Sources: Literature |
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| Mendeliome v1.1566 | APPL1 | Bryony Thompson edited their review of gene: APPL1: Added comment: PMID: 36208030 - a study using the UK Biobank comparing individuals with and without diabetes found LoF variants in APPL1 were ‘Inconsistent’ with being high penetrant for diabetes (failed both statistical criteria - enrichment & comparison to maximum credible allele frequency). Refutes previous study.; Changed rating: RED; Changed publications: 26073777, 36208030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1565 | KLF11 |
Bryony Thompson Added comment: Comment on list classification: Association with monogenic diabetes now Refuted Classification - 02/08/2023. ClinGen Monogenic Diabetes GCEP - https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b1e38a49-7c12-4514-a2a1-109e04da146f-2023-02-08T170000.000Z?page=1&size=25&search= |
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| Mendeliome v1.1564 | KLF14 |
Hali Van Niel changed review comment from: PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other; to: Cannot find any evidence of association with mendelian disease PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other |
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| Mendeliome v1.1564 | KLF14 |
Hali Van Niel gene: KLF14 was added gene: KLF14 was added to Mendeliome. Sources: Other Mode of inheritance for gene: KLF14 was set to Unknown Publications for gene: KLF14 were set to 33389382; 35081256; 24486580 Phenotypes for gene: KLF14 were set to diabetes mellitus MONDO:0005015 Review for gene: KLF14 was set to RED Added comment: PMID: 33389382 Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes PMID: 35081256 Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity PMID: 24486580 Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population) Sources: Other |
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| Mendeliome v1.1564 | PCSK2 |
Hali Van Niel gene: PCSK2 was added gene: PCSK2 was added to Mendeliome. Sources: Other Mode of inheritance for gene: PCSK2 was set to Unknown Publications for gene: PCSK2 were set to 26607656; 7698505; 17618154 Phenotypes for gene: PCSK2 were set to diabetes mellitus MONDO:0005015 Review for gene: PCSK2 was set to RED Added comment: Cannot find any evidence of association with mendelian disease PMID: 26607656 10 SNPs genotyped, genetic polymorphisms responsible for glucose homeostasis and incidental diabetes PMID: 7698505 DNA polymorphism found in 11% of non insulin dependent diabetes patients (out of 152 japanese patients) vs 4% in health population (out of 102 japanese patients). PMID: 17618154 29 SNPS analysed across PCSK2, 4 SNPS associated type 2 diabetes in african american population Sources: Other |
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| Mendeliome v1.1543 | ONECUT1 |
Bryony Thompson gene: ONECUT1 was added gene: ONECUT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ONECUT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ONECUT1 were set to 37639628; 34663987; 10825208 Phenotypes for gene: ONECUT1 were set to Neonatal diabetes mellitus MONDO:0016391 Review for gene: ONECUT1 was set to GREEN Added comment: 3 unrelated neonatal diabetes cases with homozygous variants & supporting iPSC/mouse models PMID: 37639628 - UK biobank study of ONECUT1 variants in neonatal diabetes mellitus (NDM), MODY, and type 2 diabetes. Identified a case with syndromic NDM with a homozygous frameshift (p.Met289Argfs*8). Rare heterozygous variants were not enriched in individuals with suspected MODY (n=484). Heterozygous null variants were significantly associated with type 2 diabetes (p=0.006) as a potential susceptibility gene. PMID: 34663987 - 2 consanguineous families with homozygous variants (Glu231Ter or Glu231Asp) in cases with syndromic ND. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation. PMID: 10825208 - Hnf6 (old gene name) null mice have diabetes Sources: Literature |
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| Mendeliome v1.1538 | SIRT1 |
Achchuthan Shanmugasundram gene: SIRT1 was added gene: SIRT1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SIRT1 were set to 23473037 Phenotypes for gene: SIRT1 were set to autoimmune disease, MONDO:0007179 Review for gene: SIRT1 was set to RED Added comment: PMID:23473037 reported the identification of a missense SIRT1 variant (p.Leu107Pro) in five members of a single family and all five of them had autoimmune disorder, four had type I diabetes and one had ulcerative colitis. Sources: Literature |
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| Mendeliome v1.1529 | NDUFB9 |
Zornitza Stark edited their review of gene: NDUFB9: Added comment: PMID: 38129218: Thr144Met, listed as ACMG-P, hom in 1x pt with mito complex I deficiency and leukodystrophy, no functional studies, both parents are het. However, this variant has 2 homozygotes in gnomADv4 so unlikely pathogenic.; Changed publications: 22200994, 38129218 |
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| Mendeliome v1.1516 | ANO1 | Zornitza Stark Phenotypes for gene: ANO1 were changed from Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease, MONDO:0016820, ANO1 related to Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease 7, MIM# 620687 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1515 | ANO1 | Zornitza Stark edited their review of gene: ANO1: Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease 7, MIM# 620687 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1513 | NUP160 |
Melanie Marty changed review comment from: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes. PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria. PMID: 33456446 1 x family (2 sibs) with steroid-resistant nephrotic syndrome and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy. PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse mode using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS.; to: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes. PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria. PMID: 33456446 1 x family (2 sibs) with SRNS and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy. PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS. |
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| Mendeliome v1.1510 | RHOXF1 |
Chris Ciotta gene: RHOXF1 was added gene: RHOXF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RHOXF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: RHOXF1 were set to PMID: 38258527 Phenotypes for gene: RHOXF1 were set to Spermatogenic failure, MONDO:0004983, RHOXF1-related Review for gene: RHOXF1 was set to AMBER Added comment: In a cohort of 1,201 men from China with oligozoospermia and azoospermia, hemizygous RHOXF1 variants were identified in 4 unrelated individuals. Three of these variants were missense variants (V130M, A91V & A156V), all were absent from gnomAD (including version 4) and had deleterious in silicos. The one other variant was a nonsense variant (R160X) which is predicted to escape NMD and truncate the protein. This is seen in gnomAD version 4 in 1 heterozygote female, and absent in other versions. In vitro functional evidence for these variants was provided, the V130M, A156V and R160X mutants demonstrated impaired protein localisation with an increase in the protein in the cytoplasm and impaired nuclear entry, the A91V mutant protein did not share these localisation defects. Further, The V130M mutant protein decreased DMRT1 promotor activity, DMRT1 is considered essential for testicular development and spermatogenesis. However, the R160X variant demonstrated increased activation, three times higher than WT. The two other missense variants had no effect. Sources: Literature |
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| Mendeliome v1.1506 | WDR44 |
Andrew Fennell gene: WDR44 was added gene: WDR44 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WDR44 were set to PMID: 38191484 Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related Review for gene: WDR44 was set to GREEN Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development. WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model. The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients. Sources: Literature |
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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 v1.1431 | MANF |
Zornitza Stark gene: MANF was added gene: MANF was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: MANF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MANF were set to 26077850; 33500254; 34815294 Phenotypes for gene: MANF were set to Diabetes, deafness, developmental delay, and short stature syndrome, MIM# 620651 Review for gene: MANF was set to AMBER Added comment: Two individuals reported with homozygous variants. Mouse model recapitulates deafness phenotype. Sources: Expert Review |
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| Mendeliome v1.1408 | CEP192 |
Chern Lim gene: CEP192 was added gene: CEP192 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP192 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CEP192 were set to 37981762 Phenotypes for gene: CEP192 were set to microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size Review for gene: CEP192 was set to RED gene: CEP192 was marked as current diagnostic Added comment: PMID: 37981762: - In one family, chet missense p.His638Tyr and p.Asn1917Ser segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size in two affected siblings. Both sibs also fulfilled dx for mosaic variegated aneuploidy (MVA) syndrome and have tetraploidy. - A lower but substantial proportion of MVA/tetraploidy cells was observed in II-1, II-2, and II-4 (who are het for one of the variants). - In the same family, each variants in heterozygous state segregated with infertility and/or reduced testicular size in the proband’s father and maternal uncle. - Variant screening of CEP192 coding regions performed for 1264 unrelated males with idiopathic infertility. - Asn1917Ser was also detected in three additional unrelated infertile males with reduced testicular volumes. - Two other missense and two synonymous variants were repeatedly detected in infertile males. - qPCR showed CEP192 expression was decreased in individuals with c.1912C>T His638Tyr, mini-gene assay showed that c.1912C>T His638Tyr led to the skipping of exon 14, predicted to result in NMD. - Epithelial cells cultured in vitro from patients with biallelic variants showed the number of cells arrested during the prophase increased because of the failure of spindle formation. - Embyronic mouse lethality in Cep192-/- (hom for His638Tyr), Cep192M/M (hom for Asn1917Ser) and Cep192-/M (chet). - Embryos of Cep192M/M mice had significant increase of MVA and tetraploidy cells. - Number of apoptotic cells increased in Cep192M/M embryos compared with that of Cep192+/+, similar result in Cep192-/- embryos. - Male mice with Cep192 heterozygous variants replicated infertility Conclusions: - Association of this gene with autosomal recessive disease has not been established. - Association of monoallelic variants in this gene with infertility is not well established: - Two variants with some supportive evidence from mouse model. Sources: Literature |
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| Mendeliome v1.1401 | FOXL1 |
Lilian Rudd gene: FOXL1 was added gene: FOXL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FOXL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOXL1 were set to PMID: 34633540 Phenotypes for gene: FOXL1 were set to Otosclerosis 11 #MIM620576 Review for gene: FOXL1 was set to RED Added comment: Single paper with variant in large AD family from Newfoundland with otosclerosis, hearing loss onset varied from late teens onwards. Segregation not completely convincing, 1 person with the deletion without otosclerosis. Conductive HL, sometimes mixed, not isolated SNHL. Second family with common haplotype and same 15bp deletion with otosclerosis. Functional studies. High population frequency and 3x homozygotes. Sources: Literature |
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| Mendeliome v1.1378 | UNC119 |
Zornitza Stark changed review comment from: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association. Borderline Green for association with cone-rod dystrophy.; to: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association. Cone-rod dystrophy: one of the reported variants is missense with no other supporting evidence. |
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| Mendeliome v1.1357 | FYB1 |
Zornitza Stark gene: FYB1 was added gene: FYB1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: FYB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FYB1 were set to 25516138; 25876182 Phenotypes for gene: FYB1 were set to Thrombocytopenia 3, MIM# 273900 Review for gene: FYB1 was set to GREEN Added comment: Two families with LoF variants and segregation reported in the literature. Aware of two additional cases through clinical testing (Prevention Genetics). Good functional evidence, including mouse models. Moderate by ClinGen, though note score was in 'Strong' range and downgraded due to two families in the literature only. Sources: Expert Review |
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| Mendeliome v1.1338 | SGSM3 |
Dean Phelan gene: SGSM3 was added gene: SGSM3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SGSM3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SGSM3 were set to PMID: 37833060 Phenotypes for gene: SGSM3 were set to Neurodevelopmental disorder (MONDO:0700092), SGSM3-related Review for gene: SGSM3 was set to AMBER Added comment: PMID: 37833060 - 13 patients from 8 families of Ashkenazi Jewish origin all had the same homozygous frameshift variant (c.981dup). Predicted to cause NMD. The variant co-segregated with disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. Considered a founder variant (1 in 52 Ashkenazi Jews carry the variant). Also present in other populations but no homozygotes in gnomAD. Sources: Literature |
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| Mendeliome v1.1335 | AGPAT3 |
Ee Ming Wong gene: AGPAT3 was added gene: AGPAT3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGPAT3 were set to 37821758 Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related Review for gene: AGPAT3 was set to GREEN gene: AGPAT3 was marked as current diagnostic Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa - All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant - Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis - KO AGPAT3 mouse demonstrated impaired neuronal migration Sources: Literature |
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| Mendeliome v1.1335 | HEPHL1 |
Naomi Baker gene: HEPHL1 was added gene: HEPHL1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: HEPHL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEPHL1 were set to PMID: 31125343; 31293895 Phenotypes for gene: HEPHL1 were set to Abnormal hair, joint laxity, and developmental delay (MIM#261990) Review for gene: HEPHL1 was set to RED Added comment: PMID: 31125343 - Single patient reported with biallelic variants (missense and splice) that presented with abnormal hair and early cognitive delays. Authors also created a knockout mouse, with homozygotes having short, curled whiskers while heterozygotes did not have this phenotype. PMID: 31293895 - Report of curly whiskers (cw) mouse model that has a spontaneous variant (frame shifting single base insertion) in Hephl1. Sources: Literature |
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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 v1.1330 | CASP2 |
Lisa Norbart gene: CASP2 was added gene: CASP2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CASP2 were set to 37880421 Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related Penetrance for gene: CASP2 were set to Complete Review for gene: CASP2 was set to GREEN gene: CASP2 was marked as current diagnostic Added comment: 7 patients from 5 families 4 families hom for PTCs, 1 family Chet for splice+PTC RNA studies done for the splice to indicate usage of two cryptic splice donor sites 5/5 have ID/dev delay 1/5 has seizures 2/5 hypotonia 3/5 lissencephaly (pachygyria and cortical thickening) Sources: Literature |
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| Mendeliome v1.1318 | ZFHX3 | Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1279 | EPHX1 | Zornitza Stark Phenotypes for gene: EPHX1 were changed from Lipoatrophic diabetes to Hereditary lipodystrophy, MONDO:0020087, EPHX1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1263 | PLS3 | Zornitza Stark edited their review of gene: PLS3: Added comment: PMID 37751738: 8 unrelated families with affected males with an X-linked condition characterised by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. All were missense variants. A mouse knock in model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Gain-of-function is a suggested mechanism.; Changed publications: 32655496, 25209159, 29736964, 29884797, 28777485, 24088043, 37751738; Changed phenotypes: Bone mineral density QTL18, osteoporosis - MIM#300910, congenital diaphragmatic hernia MONDO:0005711, PLS3-related; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1254 | 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 v1.1117 | APOL1 |
Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021 Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2. PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance. PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN rs73885319 (G1) OR 9.66, p=9.97E-25 rs60910145 (G1) OR 9.75, p=9.04E-24 rs71785313 (G2) OR 5.69, p=3.39E-06 2 APOL1 risk alleles OR 18.31, p=3.31E-58 PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease G1: p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes) p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes) G2: p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER |
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| Mendeliome v1.1071 | SMARCA4 |
Paul De Fazio changed review comment from: Additional phenotype reported: A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested. A mouse CRISPR model with the orthologous variant had a similar phenotype.; to: Additional phenotype reported: A single missense variant E1610K (M_001128849.3) was reported in 7 affected members of a family with progressive hearing loss due to otosclerosis and no other clinical features. Variant is absent from gnomAD. Note that unaffected members of the family were not tested - some obligate carriers were apparently unaffected, reflecting incomplete penetrance. A mouse CRISPR model with the orthologous variant had a similar phenotype. |
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| Mendeliome v1.1071 | AQP4 |
Lucy Spencer gene: AQP4 was added gene: AQP4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AQP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AQP4 were set to 37143309 Phenotypes for gene: AQP4 were set to ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448 Review for gene: AQP4 was set to AMBER Added comment: PMID: 37143309 Cohort of patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Missense variant in AQP4 seen homozygous in 2 siblings and het in the parents. Patients had macrocephaly, developmental delay, hypotonia, epilepsy, and cognitive deficit. Western blots on generated MDCK cell lines showed no detectable expression of AQP4 protein from the cells with the patients variant. Immunofluorescence also showed no membrane expression. Overexpression studies in HEK293T cells showed WT was seen as mainly monomers or dimers where as variant protein formed large aggregates- likely due to the saturation of protein degradation pathways because of the overexpression. Sources: Literature |
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| Mendeliome v1.1064 | STAB1 |
Chern Lim gene: STAB1 was added gene: STAB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STAB1 were set to 37490907; 28052375 Phenotypes for gene: STAB1 were set to Iron metabolism disease (MONDO:0002279), STAB1-related Review for gene: STAB1 was set to GREEN gene: STAB1 was marked as current diagnostic Added comment: PMID: 37490907 - Biallelic variants identified in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies. - Homozygous/compound heterozygous variants: missense, frameshift, stopgain, inframe del of 3 AAs, one synonymous. - Samples from three of the patients from two families showed no immunoreactivity with anti-stabilin-1 compared to control liver where high signal was detected in the liver sinusoids (immunohistochemistry analysis). - Patients’ peripheral monocytes and monocyte-derived macrophages showed very little expression of stabilin-1 on CD14+ monocytes and macrophages compared to control subjects (flow cytometry analysis). - These families have also been published in PMID: 28052375. Sources: Literature |
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| Mendeliome v1.1063 | PTPA |
Ee Ming Wong changed review comment from: - Six individuals with later-onset Parkinson disease with no atypical features eg intellectual disability or early cognitive dysfunction - All were heterozygous for missense variants, a second hit not identified: authors suggests these are monoallelic cases - Three of the 5 missense variants have multiple heterozygotes in gnomAD, two of the missense variants have homozygotes in gnomAD, including one with 7 homozygotes.; to: - Six individuals with later-onset Parkinson disease with no atypical features eg intellectual disability or early cognitive dysfunction - All were heterozygous for missense variants, a second hit not identified: authors suggests these are monoallelic cases - Three of the 5 missense variants have multiple heterozygotes in gnomAD, two of the missense variants have homozygotes in gnomAD, including one with 7 homozygotes. |
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| Mendeliome v1.1060 | SENP7 |
Elena Savva gene: SENP7 was added gene: SENP7 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SENP7 were set to PMID: 37460201 Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related Review for gene: SENP7 was set to AMBER Added comment: PMID: 37460201 - 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically. - Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome. - Additional studies performed supporting downstream proteins expression being affected - Neutropenia observed in 2/3 patients Sources: Literature |
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| Mendeliome v1.1013 | PLCG1 |
Zornitza Stark gene: PLCG1 was added gene: PLCG1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLCG1 were set to 37422272 Phenotypes for gene: PLCG1 were set to Autoinflammatory syndrome, MONDO:0019751, PLCG1-related; Immune dysregulation Mode of pathogenicity for gene: PLCG1 was set to Other Review for gene: PLCG1 was set to AMBER Added comment: Single 7yo proband presented with thrombocytopaenia and lymphadenopathy. De Novo , c.3062C>T, p.S1021F with functional testing supportive of GOF mechanism of disease Sources: Expert Review |
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| Mendeliome v1.1009 | WBP4 |
chirag patel gene: WBP4 was added gene: WBP4 was added to Mendeliome. Sources: Other Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: WBP4 were set to Neurodevelopmental disorder Review for gene: WBP4 was set to GREEN gene: WBP4 was marked as current diagnostic Added comment: ESHG 2023: 11 individuals from 8 families with homozygous LOF variants in WBP4 gene (4 different variants). Presentation of severe DD and ID, hypotonia, abnormal outer ears, and varying congenital anomalies. WBP4 is spliceosome protein which binds/interacts with SNRNP200. In vivo and in vitro studies previously showed WBP4 enhances splicing and regulates alternative splicing. Patient fibroblasts showed loss of expression of WBP4. RNA sequencing analysis showed abnormal splicing patterns. Proposed spliceosomopathy. Sources: Other |
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| Mendeliome v1.1003 | INTS13 |
chirag patel gene: INTS13 was added gene: INTS13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS13 were set to PMID: 36229431 Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome Review for gene: INTS13 was set to GREEN gene: INTS13 was marked as current diagnostic Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies. Sources: Literature |
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| Mendeliome v1.1001 | DCAF15 |
chirag patel gene: DCAF15 was added gene: DCAF15 was added to Mendeliome. Sources: Other Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome Review for gene: DCAF15 was set to AMBER Added comment: ESHG 2023: 3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child) Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment. WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3). Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli. Sources: Other |
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| Mendeliome v1.995 | ANO1 | Zornitza Stark Phenotypes for gene: ANO1 were changed from Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease, MONDO:0016820, ANO1 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.992 | ANO1 | Zornitza Stark edited their review of gene: ANO1: Added comment: PMID 37253099: screening analysis of Moyamoya disease (MMD) cohort revealed 8 individuals with variants in the ANO1 gene. Two families had the same rare variant p.Met658Val. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Amber rating due to somewhat conflicting segregation and functional data presented.; Changed publications: 37253099; Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease, MONDO:0016820, ANO1 related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.987 | 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 v1.967 | ZNF808 | Krithika Murali Added comment: Comment on list classification: Green in Genomics England PanelApp neonatal diabetes panel with both of these papers cited in their review. Note that De Franco et al has not been peer-reviewed, however, the evidence provided is strong and from a reputable source. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.966 | ZNF808 |
Hazel Phillimore gene: ZNF808 was added gene: ZNF808 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF808 were set to PMID: 37308312 Phenotypes for gene: ZNF808 were set to non-syndromic neonatal diabetes; MONDO:0016391 Review for gene: ZNF808 was set to GREEN Added comment: PMID: 37308312; Alqahtani, MA. et al. (2023) Clin Genet. doi: 10.1111/cge.14389. Three siblings in one consanguineous Saudi Arabian family with non-syndromic neonatal diabetes, all with a homozygous frameshift variant, NM_001321425.2:c.1448dupA, p.(Tyr483*), in ZNF808. (Same nucleotide and amino acid numbering as for the MANE SELECT transcript, NM_001039886.4). This variant has been entered as likely pathogenic in ClinVar by this group. This variant occurs in the last exon of the gene and is therefore not NMD-predicted. Instead it is predicted to cause a truncated protein. This paper shows a diagram with several other truncating variants in this exon, which were reported in the paper by De Franco, E. et al. (2021). (These patients also had low vitamin D levels, suggesting an association, and is consistent with other studies looking into loci that are associated with vitamin D). De Franco, E. et al. (2021) medRxiv 08.23.21262262. (Exeter, UK): Firstly, this group found a homozygous variant NM_001039886.3:c.637del, p.(Leu213*) that is predicted to cause a truncated protein, and also a homozygous CNV Chr19(GRCh37):g.53057128_53100968del (predicted to cause a deletion of exons 4 and 5) in two unrelated affected individuals. These patients had pancreatic agenesis, defined as insulin-dependent diabetes in the first 6 months of life (neonatal diabetes) and exocrine pancreatic insufficiency. Both were from consanguineous families. Parents were subsequently tested and shown to be heterozygous carriers. They then investigated 232 additional patients who had been diagnosed with neonatal diabetes before the age of 6 months and found ten more homozygous ZNF808 variants. Six were nonsense: p.(Gln194*), p.(Cys233*), p.(Tyr427*), p.(Lys458*), p.(Tyr528*) and p.(Arg727*), and three were frameshift variants: p.(Ala379Valfs*157), p.(Leu588Profs*118), p.(Asn770Ilefs*98) and one was a whole-gene deletion. All the frameshift and nonsense variants occurred in the last exon of the gene, which contains all 23 zinc finger domains; and therefore all of these variants are predicted to result in truncated proteins, and removal of some, if not all, those domains. This group also carried out functional studies using an in vitro model of pancreas development and showed an aberrant activation of many transposable elements (mostly MER11 elements) that would be normally be repressed during early pancreas development. Sources: Literature |
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| Mendeliome v1.956 | RPH3A |
Lucy Spencer gene: RPH3A was added gene: RPH3A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPH3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPH3A were set to 37403762; 29441694 Phenotypes for gene: RPH3A were set to Neurodevelopmental disorder (MONDO#0700092), RPH3A-related Review for gene: RPH3A was set to GREEN Added comment: PMID: 37403762- 6 patients with RPH3A variant. All 6 have ID, 4 have epilepsy, 2 with obesity, 1 with dysmorphic features. All 6 have missense variants, 3 shown to be de novo, the other 3 parents were not available for testing. I patient also had language and motor impairment, breathing issues and mixed hypo/hypertonia- he also had variants in CUL4B, PRKAG2, SCN4A, none of these genes cause seizures (which he had). Patch clamp studies on 2 of the missense showed they increased either the number of NMDA receptors on neuron membrane surface or increased their conductance. Study suggests that the variants interrupt the normal role of RPH3A activity at the synaptic NMDAR complex which is needed for the induction of synaptic plasticity and NMDAR-dependant behaviours Previously this gene was reported in PMID: 29441694- 1 girl with learning disabilities, tremors, ataxia, hyperglycemia and muscle fatigability. Chet for 2 RPH3A missense. Functional analysis showed strong and marginal impairment of protein binding for each variant. this is the only biallelic report currently. Sources: Literature |
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| Mendeliome v1.956 | MIR204 |
Chern Lim gene: MIR204 was added gene: MIR204 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIR204 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIR204 were set to 26056285; 37321975 Phenotypes for gene: MIR204 were set to Retinal dystrophy and iris coloboma with or without cataract (MIM#616722) Mode of pathogenicity for gene: MIR204 was set to Other Review for gene: MIR204 was set to GREEN gene: MIR204 was marked as current diagnostic Added comment: PMID: 26056285 - Bilateral coloboma and rod-cone dystrophy with or without cataract in nine individuals of a five-generation family. - Heterozygous n.37C>T segregates with the disease in all affected individuals. - Functional analysis including transcriptome analysis showed this variant resulted in significant alterations of miR-204 targeting capabilities. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family. - Authors suggested gain of function is the likely disease mechanism. PMID: 37321975 - Four members of a three-generation family with early-onset chorioretinal dystrophy, heterozygous for n.37C>T. - Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants. - Haplotype analysis excluded relatedness with the family reported in PMID: 26056285. - In silico analysis of the MIR204 n.37C>T variant reveals profound changes to its target mRNAs and suggests a gain-of-function mechanism of miR 204 variant. Sources: Literature |
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| Mendeliome v1.936 | MYMX |
Bryony Thompson gene: MYMX was added gene: MYMX was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYMX was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYMX were set to 35642635 Phenotypes for gene: MYMX were set to Carey-Fineman-Ziter syndrome MONDO:0009700 Review for gene: MYMX was set to AMBER Added comment: Single family, two siblings with weakness of the facial musculature, hypomimic face, increased overbite, micrognathia, and facial dysmorphism with homozygous p.Arg46*. The phenotype resembles CFZ syndrome. The variant prevents fusion of myoblasts from patient-derived iPSCs. Mouse model recapitulates a lethal CFZS-like phenotype. Sources: Literature |
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| Mendeliome v1.915 | MOS |
Melanie Marty gene: MOS was added gene: MOS was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MOS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MOS were set to PMID: 34779126; PMID: 34997960; PMID: 36403623; PMID: 35670744 Phenotypes for gene: MOS were set to Early embryonic arrest and fragmentation; infertility Review for gene: MOS was set to GREEN Added comment: PMID: 34779126: 3 x females with infertility with biallelic MOS variants identified. Using oocyte-specific Erk1/2 knockout mice, they verified that MOS-ERK signal pathway inactivation in oocytes caused early embryonic arrest and fragmentation. PMID: 34997960: 2 x females with biallelic MOS variants. Functional studies showed a reduction of protein for two of these variants (missense and frameshift). Functional studies also showed these variants reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase 1/2. PMID: 35670744 1 x additional family (twins) with infertility and abnormal oocyte morphology with large first polar body. Functional studies showed the MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, functional studies also showed when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1. PMID: 36403623 1 x female with primary infertility, patient’s oocytes had a large polar body and poor embryonic development, hom missense variant in MOS identified. Sources: Literature |
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| Mendeliome v1.908 | PRSS8 |
Lucy Spencer gene: PRSS8 was added gene: PRSS8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PRSS8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRSS8 were set to 36715754 Phenotypes for gene: PRSS8 were set to ichthyosis MONDO:0019269, PRSS8-related Review for gene: PRSS8 was set to AMBER Added comment: PMID: 36715754 1 family with 3 affected sons with congenital ichthyosis, consanguineous parents. All 3 affected members are homozygous for a canonical splice in PRSS8, quantitative RT-PCR showed a significant reduction in normal PRSS8 transcript. A second family with 4 affected members (proband and 3 cousins) with ichthyosis (3 also had autism), also consanguineous. Only the proband was tested who is homozygous for a missense in PTSS8. However this patient also had a TAAR1 missense (no disease association, but the paper suggests this could be responsible for the autism phenotype- KO mice have abnormal learning behaviour). Sources: Literature |
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| Mendeliome v1.906 | NSUN6 |
Michelle Torres gene: NSUN6 was added gene: NSUN6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSUN6 were set to 37226891 Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related Review for gene: NSUN6 was set to AMBER Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants: - p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested. - p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers. - p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers. Sources: Literature |
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| Mendeliome v1.906 | UNC79 |
Krithika Murali gene: UNC79 was added gene: UNC79 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UNC79 were set to PMID:37183800 Phenotypes for gene: UNC79 were set to Neurodevelopmental disorderMONDO:0700092 Review for gene: UNC79 was set to AMBER Added comment: PMID:37183800 Bayat et al 2023 report 6 unrelated patients with heterozygous NMD-predicted LoF variants in UNC79 - x1 canonical splice site variant, x5 nonsense/frameshift. 5 were confirmed de novo, 1 not identified in mother - father unavailable for testing. All variants absent in gnomAD and v2 pLI score for UNC79 is 1. Patients with UNC79 variants were identified through GeneMatcher or an international network of Epilepsy and Genetics departments. x1 patient underwent duo exome sequencing, remaining had trio exome sequencing - no other causative variants identified. Phenotypic features included: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal to bilateral tonic-clonic seizures) - 5/6 hypotonia unc79 knockdown drosophila flies exhibited significantly higher rate of seizure-like behaviour than controls. unc79 haploinsufficiency shown to lead to significant reduction in protein levels of both unc79 and unc80 in mouse brains. Unc79 haploinsufficiency associated with deficiency in hippocampal-dependent learning and memory in mice. Authors have reviewed their own evidence in relation to the gene-disease criteria detailed by Strande et al 2017 and note that their clinical and experimental data provides moderate-level evidence supporting the association between UNC79 and a neurodevelopment disorder including ASD. Amber association favoured due to clinical phenotypic range reported between affected individuals and their lack of specificity. Sources: Literature |
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| Mendeliome v1.898 | NPR1 |
Lilian Rudd gene: NPR1 was added gene: NPR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPR1 were set to PMID: 37080586 Phenotypes for gene: NPR1 were set to Genetic hypertension MONDO:0015512 Review for gene: NPR1 was set to GREEN Added comment: 4 sibs with systemic hypertension in the neonatal period - presenting with cardiogenic shock, with homozygous variants (consanguineous parents), parents confirmed heterozygotes. 3/4 infants had increased NT (>3.5) in utero RT-PCR shows dramatic reduction of RNA levels 2 sibs in a second family, normal NT and pregnancy, neonatal systematic hypertension presenting with cardiogenic shock, Sources: Literature |
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| Mendeliome v1.898 | POU3F2 |
Sarah Pantaleo gene: POU3F2 was added gene: POU3F2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: POU3F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POU3F2 were set to PMID: 37207645 Phenotypes for gene: POU3F2 were set to Autism spectrum disorder, NDD, and adolescent-onset obesity Penetrance for gene: POU3F2 were set to unknown Mode of pathogenicity for gene: POU3F2 was set to Other Review for gene: POU3F2 was set to GREEN Added comment: We associate ultra-rare variants in POU3F2, encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopment delay in 12 individuals. Demonstrate variant pathogenicity through in vitro analysis. Used exome sequencing, GeneMatcher and Genomics England 100,000 Genomes Project rare disease database. Both truncating and missense variants in over 10 individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity (may have had other features eg. CAKUT in 2 individuals, diabetes in two) . Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperplasia during childhood. With the exception of an early truncating variant, the variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promoter activation. Variants absent from population and clinical databases. Almost all constituted putatively non-inherited de novo variants (8/10). Functional studies provide evidence for loss of function in eight and gain of function in one obesity-associated POU3F2 variant. One variant did not impact POU3F2-promoter activation, leaving the possibility for further path-mechanisms. Sources: Literature |
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| Mendeliome v1.897 | ACBD6 |
Lucy Spencer gene: ACBD6 was added gene: ACBD6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACBD6 were set to 36457943; 21937992; 35446914 Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder (MONDO#0700092), ACBD6-related Review for gene: ACBD6 was set to GREEN Added comment: PMID: 36457943 2 siblings with a neurodevelopmental disorder: severely delayed development, obesity, pancytopenia, diabetes, liver cirrhosis, intravertebral disc herniation, mild brain atrophy. Consanguineous family both siblings found to have a homozygous frameshift. This paper also mentioned 3 other reported variants in 6 individuals (only 3 unrelated) all homozygous, 2 frameshift, 1 canonical splice. All reported to have a neurodevelopmental disorder, some with limited information but one family also has obesity, spasticity, and dysmorphism. PMIDs: 21937992, 35446914 Sources: Literature |
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| Mendeliome v1.879 | GATAD2A |
Bryony Thompson changed review comment from: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature; to: PMID: 37181331 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature |
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| Mendeliome v1.847 | PMEPA1 |
Hazel Phillimore changed review comment from: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688. A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes . Eight families with truncating variants affecting the same stretch of cytosines in this gene. In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group. Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family. Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3). Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome. Sources: Literature; to: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688. A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes . Eight families with truncating variants affecting the same stretch of cytosines in this gene. In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group. (Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.). Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family. Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3). Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome. Sources: Literature |
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| Mendeliome v1.837 | MRPL39 |
Lilian Rudd changed review comment from: AR 3 unrelated individuals, confirmed variants in trans Functional studies on patient fibroblasts Multisystem disease, variable onset 2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading to early death (< 1 year of age)) Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD Sources: Literature; to: AR 3 unrelated individuals, confirmed variants in trans Functional studies on patient fibroblasts Multisystem disease, variable onset 2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading to early death (< 1 year of age)) Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD Sources: Literature |
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| Mendeliome v1.836 | SRSF1 |
Paul De Fazio gene: SRSF1 was added gene: SRSF1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SRSF1 were set to 37071997 Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092 Review for gene: SRSF1 was set to GREEN gene: SRSF1 was marked as current diagnostic Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism. Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS. Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms. Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17). Sources: Literature |
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| Mendeliome v1.834 | MRPL39 |
Lilian Rudd changed review comment from: AR 3 unrelated individuals, confirmed variants in trans Functional studies on patient fibroblasts Multisystem disease, variable onset 2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000) Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD Sources: Literature; to: AR 3 unrelated individuals, confirmed variants in trans Functional studies on patient fibroblasts Multisystem disease, variable onset 2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading to early death (< 1 year of age)) Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD Sources: Literature |
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| Mendeliome v1.830 | GATAD2A |
Bryony Thompson gene: GATAD2A was added gene: GATAD2A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372 Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related Review for gene: GATAD2A was set to GREEN Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature |
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| Mendeliome v1.793 | MAP3K3 |
Zornitza Stark gene: MAP3K3 was added gene: MAP3K3 was added to Mendeliome. Sources: Literature somatic tags were added to gene: MAP3K3. Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774 Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related Mode of pathogenicity for gene: MAP3K3 was set to Other Review for gene: MAP3K3 was set to GREEN Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies). Sources: Literature |
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| Mendeliome v1.776 | CEP162 |
Paul De Fazio gene: CEP162 was added gene: CEP162 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP162 were set to 36862503 Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related Penetrance for gene: CEP162 were set to unknown Review for gene: CEP162 was set to AMBER gene: CEP162 was marked as current diagnostic Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior. Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation. Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients. Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background). Sources: Literature |
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| Mendeliome v1.774 | DOCK11 |
Lucy Spencer gene: DOCK11 was added gene: DOCK11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: DOCK11 were set to 36952639 Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related Review for gene: DOCK11 was set to GREEN Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. 6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild. Sources: Literature |
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| Mendeliome v1.765 | NPPA |
Chern Lim changed review comment from: PMID: 36303204: - 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP. PMID: 19646991: - NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has 195 hets in gnomADv3. PMID: 23275345: - Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD. ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).; to: PMID: 36303204: - 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP. PMID: 19646991: - NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has >200 hets in gnomADv3. PMID: 23275345: - Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD. ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020). |
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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 v1.738 | MNX1 | Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.736 | MNX1 | Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.698 | MCF2L |
Michelle Torres gene: MCF2L was added gene: MCF2L was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MCF2L was set to Unknown Publications for gene: MCF2L were set to 36760094 Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related Review for gene: MCF2L was set to RED Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7). Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery). Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery). Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested. Sources: Literature |
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| Mendeliome v1.689 | LGR4 |
Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes). |
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| Mendeliome v1.689 | LGR4 |
Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein. Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation gnomAD: no hom PTCs PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.664 | ATP9A | Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.635 | MIR145 |
Lucy Spencer gene: MIR145 was added gene: MIR145 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MIR145 were set to 36649075 Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related Review for gene: MIR145 was set to RED Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p. Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts. Sources: Literature |
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| Mendeliome v1.614 | LY96 |
Zornitza Stark gene: LY96 was added gene: LY96 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LY96 were set to 36462957 Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related Review for gene: LY96 was set to RED Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation. Sources: Expert Review |
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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 v1.601 | BSN |
Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865 Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature |
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| Mendeliome v1.593 | UHRF1 |
Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022 - One patient with compound het missense and nonsense variants, both parents are carriers (hets). - The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical. - Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. - Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v1.588 | BSN |
Krithika Murali gene: BSN was added gene: BSN was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027 Review for gene: BSN was set to GREEN Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development. In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected. Association between biallelic variants and epilepsy stronger than for monoallelic. Sources: Literature |
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| Mendeliome v1.563 | SLC26A6 |
Arina Puzriakova gene: SLC26A6 was added gene: SLC26A6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969 Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969) SLC26A6 is currently not associated with any human phenotype in OMIM or G2P. Sources: Literature |
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| Mendeliome v1.538 | CHUK | Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.530 | MPC2 |
Zornitza Stark gene: MPC2 was added gene: MPC2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MPC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPC2 were set to 36417180 Phenotypes for gene: MPC2 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related Review for gene: MPC2 was set to AMBER Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels. Sources: Literature |
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| Mendeliome v1.511 | NPC1 |
Naomi Baker gene: NPC1 was added gene: NPC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPC1 were set to 36417180 Phenotypes for gene: NPC1 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related Review for gene: NPC1 was set to AMBER Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels. Sources: Literature |
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| Mendeliome v1.507 | GABRA3 |
Sarah Pantaleo gene: GABRA3 was added gene: GABRA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: GABRA3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GABRA3 were set to PMID: 29053855 Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features, Penetrance for gene: GABRA3 were set to Incomplete Review for gene: GABRA3 was set to GREEN Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor. Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. Sources: Literature |
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| Mendeliome v1.504 | UQCRH |
Chern Lim gene: UQCRH was added gene: UQCRH was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UQCRH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UQCRH were set to 34750991 Phenotypes for gene: UQCRH were set to Mitochondrial complex III deficiency, nuclear type 11, MIM#620137 Review for gene: UQCRH was set to AMBER gene: UQCRH was marked as current diagnostic Added comment: PMID: 34750991: - Two affected cousins, presented with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. - Both have a 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH, predicted to culminate in an in-frame deletion exons 2 and 3 of the four-exon UQCRH gene, resulting in a shortened product. - Mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/-) also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. - Patient fibroblasts and Uqcrh-/- mouse tissues showed a CIII defect. - Expression of wild-type UQCRH in patient fibroblasts ameliorates the CIII defect. Sources: Literature |
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| Mendeliome v1.476 | PDIA6 | chirag patel edited their review of gene: PDIA6: Added comment: 2nd patient with large polycystic kidneys, death and end stage renal failure at 18 months, microcephaly, bilateral inguinal hernias, umbilical hernia, developmental delay, bilateral sensorineural hearing loss, visual impairment, steatorrhea, fibrotic changes in liver, and insulin-dependent diabetes. WGS found homozygous stop-gain variant (Tyr368*) in PDIA6. Segregation not performed.; Changed rating: AMBER; Changed publications: PMID: 35856135; Changed phenotypes: Polycystic kidney disease, infancy-onset diabetes, and microcephaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.459 | RPS6KB1 |
Arina Puzriakova gene: RPS6KB1 was added gene: RPS6KB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RPS6KB1 were set to 34916228 Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy Review for gene: RPS6KB1 was set to GREEN Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640) Sources: Literature |
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| Mendeliome v1.442 | THAP1 |
Michelle Torres commented on gene: THAP1: Monoallelic is well established with reduced penetrance. Biallelic was seen in 3 families generally with severe and early onset dystonia: PMID: 36205328: consanguineous family (gene panel), proband homozygous for p.Lys162Asn with early onset multifocal dystonia with severe oromandibular/laryngeal dysfunction; both parents were confirmed carriers with milder features (47 yo father with tightness and difficulty with fine motor tasks, 41 yo mother with tightness). PMID: 21425335: 3 siblings are homozygous for the p.Leu32His with early-onset generalized dystonia. Carriers were unaffected. PMID: 20211909: a homozygous variant was identified in an individual with with writer's dystonia initially and then developing segmental dystonia, onset at 57 yo, parents could not be tested. |
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| Mendeliome v1.440 | FICD |
Alison Yeung gene: FICD was added gene: FICD was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FICD were set to 36136088 Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257 Review for gene: FICD was set to GREEN Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53 Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy. Sources: Literature |
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| Mendeliome v1.421 | PAX4 | Krithika Murali reviewed gene: PAX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Maturity-onset diabetes of the young, type IX - MIM#612225; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.411 | PSMC1 | Zornitza Stark Phenotypes for gene: PSMC1 were changed from 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.390 | FAM20B |
Bryony Thompson gene: FAM20B was added gene: FAM20B was added to Mendeliome. Sources: Other Mode of inheritance for gene: FAM20B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM20B were set to 30847897; 30105814; 22732358; 27405802 Phenotypes for gene: FAM20B were set to Desbuquois dysplasia MONDO:0015426 Review for gene: FAM20B was set to AMBER Added comment: Two siblings from a single family with neonatal short limb dysplasia resembling Desbuquois dysplasia. One of the siblings underwent genetic testing and compound heterozygous variants were identified in FAM20B ((NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). Multiple mouse models reported with skeletal abnormalities. Sources: Other |
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| Mendeliome v1.385 | VPS33A |
Bryony Thompson changed review comment from: PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells. PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts; to: Now two missense variants reported with disease in at least 15 probands/families PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells. PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts |
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| Mendeliome v1.369 | DUT |
Daniel Flanagan gene: DUT was added gene: DUT was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DUT were set to 28073829; 35611808 Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome (MIM#620044) Review for gene: DUT was set to GREEN Added comment: Homozygous missense (p.(Tyr142Cys)) identified in eight affected individuals from four unrelated consanguineous families (French, Egyptian, two Libyan) with diabetes and bone marrow failure. DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway. p.(Tyr142Cys) has 11 heterozygotes and no homozygotes in gnomAD. Sources: Expert list |
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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 v1.357 | DAW1 |
Alison Yeung gene: DAW1 was added gene: DAW1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DAW1 were set to 36074124 Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, MONDO:0016575; Visceral heterotaxy, MONDO:0018677 Review for gene: DAW1 was set to GREEN Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype Sources: Literature |
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| Mendeliome v1.338 | AVPR2 | Zornitza Stark reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic 304800, Nephrogenic syndrome of inappropriate antidiuresis 300539; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.338 | AVP | Zornitza Stark reviewed gene: AVP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, neurohypophyseal MIM#125700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.338 | ANO1 | Zornitza Stark Phenotypes for gene: ANO1 were changed from Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.337 | ANO1 | Zornitza Stark reviewed gene: ANO1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intestinal dysmotility syndrome, MIM# 620045; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.332 | PTPA |
Zornitza Stark gene: PTPA was added gene: PTPA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPA were set to 36073231 Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related Review for gene: PTPA was set to AMBER Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below. There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID. Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports. ------ Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants. These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation. Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies. Role of the gene: As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders. Variant studies: Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt. Drosophila / animal models: Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment. Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice. Sources: Literature |
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| Mendeliome v1.289 | TMEM147 |
Naomi Baker gene: TMEM147 was added gene: TMEM147 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM147 were set to PMID: 36044892 Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related Review for gene: TMEM147 was set to GREEN Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction. Sources: Literature |
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| Mendeliome v1.285 | HNRNPH1 |
Hazel Phillimore changed review comment from: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2). In gnomAD, there are very few LOF variants. (LOF shows pLI = 1). The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.; to: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2. In gnomAD, there are very few LOF variants. (LOF shows pLI = 1). The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma. |
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| Mendeliome v1.285 | TMEM163 |
Teresa Zhao changed review comment from: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. All have global developmental delay, three of them have seizures and two have ID. Sources: Literature; to: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. All have global developmental delay, three of them have seizures. Sources: Literature |
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| Mendeliome v1.283 | TMEM163 |
Teresa Zhao gene: TMEM163 was added gene: TMEM163 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TMEM163 were set to PMID: 35953447 Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy Review for gene: TMEM163 was set to GREEN Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. All have global developmental delay, three of them have seizures and two have ID. Sources: Literature |
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| Mendeliome v1.221 | PSMC1 | Zornitza Stark Phenotypes for gene: PSMC1 were changed from spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.212 | PSMC1 |
Hazel Phillimore gene: PSMC1 was added gene: PSMC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMC1 were set to PMID: 35861243 Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes Mode of pathogenicity for gene: PSMC1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PSMC1 was set to AMBER Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr). Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1. Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low. Sources: Literature |
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| Mendeliome v1.190 | EIF2B1 | Zornitza Stark Phenotypes for gene: EIF2B1 were changed from leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.187 | EIF2B1 | Zornitza Stark reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal diabetes mellitus, MONDO:0016391, EIF2B1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.179 | EIF2B1 | Elena Savva reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31882561; Phenotypes: Leukoencephalopathy with vanishing white matter MIM#603896, permanent neonatal/early onset diabetes and transient liver dysfunction; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.171 | SLCO2A1 | Zornitza Stark edited their review of gene: SLCO2A1: Added comment: PMID 29313109: Over 40 Japanese individuals reported with bi-allelic variants in this gene and multiple small intestinal ulcers of nonspecific histology. Some overlap with the hypertrophic osteoarthropathy also associated with bi-allelic variants in this gene. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO.; Changed publications: 23509104, 27134495, 33852188, 22331663, 27134495, 29313109; Changed phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441, Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.158 | C9orf84 |
Zornitza Stark changed review comment from: 8 families reported with bi-allelic variants in this gene and spermatogenic failure. Sources: Literature; to: 8 families reported with bi-allelic variants in this gene and spermatogenic failure. A male germ cell-specific Shoc1 knockout mouse model recapitulates the phenotype (germline knockout: early lethality). HGNC approved name is SHOC1. Sources: Literature |
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| Mendeliome v1.157 | HIST1H4E | Zornitza Stark Phenotypes for gene: HIST1H4E were changed from Neurodevelopmental disorder, HIST1H4E-related MONDO:0700092 to Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.156 | HIST1H4E | Zornitza Stark reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 3, MIM# 619950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.134 | CCDC155 |
Melanie Marty gene: CCDC155 was added gene: CCDC155 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC155 were set to 35674372; 35708642; 29790874; 35587281 Phenotypes for gene: CCDC155 were set to Non-obstructive azoospermia; Premature ovarian insufficiency Review for gene: CCDC155 was set to GREEN Added comment: Current HGNC name is KASH5 Summary: 4 families reported with non-obstructive azoospermia or premature ovarian insufficiency. Functional studies have been performed and mouse models recapitulate the phenotype. PMID: 35674372 CNV and frameshift variants in KASH5 were identified in a non-obstructive azoospermia affected patient and in his infertile sister by whole-exome sequencing and CNV array. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis. PMID: 35708642 Hom splice identified in KASH5 in 2 sisters with premature ovarian insufficiency. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes. PMID: 29790874 2 brothers with non-obstructive azoospermia with hom missense in CCDC155 35587281 2 siblings with hom missense in CCDC155 non-obstructive azoospermia and premature ovarian insufficiency. Sources: Literature |
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| Mendeliome v1.108 | CD28 |
Zornitza Stark changed review comment from: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data. Sources: Expert Review; to: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. Sources: Expert Review |
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| Mendeliome v1.108 | CD28 |
Zornitza Stark gene: CD28 was added gene: CD28 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CD28 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD28 were set to 34214472 Phenotypes for gene: CD28 were set to Hereditary predisposition to infections, MONDO:0015979, CD28-related; isolated susceptibility to cutaneous α- and γ-HPVs Review for gene: CD28 was set to RED Added comment: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data. Sources: Expert Review |
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| Mendeliome v1.44 | BUB1 |
Paul De Fazio gene: BUB1 was added gene: BUB1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BUB1 were set to 35044816; 19772675; 19117986; 23209306 Phenotypes for gene: BUB1 were set to Intellectual disability and microcephaly Review for gene: BUB1 was set to GREEN gene: BUB1 was marked as current diagnostic Added comment: 2 unrelated patients with ID, microcephaly, short stature, dysmorphic features reported with biallelic variants: P1 (3yo male): homozygous start-loss variant (2 hets and 0 hom in gnomAD). Functional testing showed a small amount of full-length protein was translated, and BUB1 recruitment to kinetochores was nearly undetectable. P2 (16yo female): compound heterozygous for a canonical splice variant (1 het and no hom in gnomAD) and an NMD-predicted frameshift variant (absent from gnomAD). The splice variant was shown to result in an in-frame deletion of 54 amino acids in the kinase domain. P2 cells have reduced protein levels but essentially no kinase activity. BUB1 patient cells have impaired mitotic fidelity. Homozygous Bub1 disruption in mice is embryonic lethal (PMID:19772675). A hypomorphic mouse is viable with increased tumourigenesis with ageing and aneuploidy (PMID:19117986). A kinase-dead mouse does not show increased tumourigenesis but does have a high frequency of aneuploid cells (PMID:23209306) Sources: Literature |
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| Mendeliome v1.32 | HIST1H4J | Zornitza Stark Phenotypes for gene: HIST1H4J were changed from microcephaly; intellectual disability; dysmorphic features to Tessadori-van Haaften neurodevelopmental syndrome 2 , MIM# 619759 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.31 | HIST1H4J | Zornitza Stark edited their review of gene: HIST1H4J: Changed phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 2 , MIM# 619759 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.14 | MYO9A | Zornitza Stark edited their review of gene: MYO9A: Added comment: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14784 | DNAJC3 | Zornitza Stark Phenotypes for gene: DNAJC3 were changed from to Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus - MIM#616192 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14773 | AVP | Zornitza Stark Phenotypes for gene: AVP were changed from to Diabetes insipidus, neurohypophyseal MIM#125700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14704 | GCK | Zornitza Stark Phenotypes for gene: GCK were changed from to Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853); Diabetes mellitus, permanent neonatal 1, AR (MIM#606176); Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485); MODY, type II, AD (MIM#125851) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14649 | AVP | chirag patel reviewed gene: AVP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 6526016, 1840604, 8554046; Phenotypes: Diabetes insipidus, neurohypophyseal MIM#125700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14625 | GLIS3 | Zornitza Stark Phenotypes for gene: GLIS3 were changed from to Diabetes mellitus, neonatal, with congenital hypothyroidism, MIM#610199 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14622 | GLIS3 | Zornitza Stark reviewed gene: GLIS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21139041, 35410112, 35394098, 34093443; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism, MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14592 | GCK | chirag patel reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19790256; Phenotypes: Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853), Diabetes mellitus, permanent neonatal 1, AR (MIM#606176), Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485), MODY, type II, AD (MIM#125851); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14572 | GREM1 | Zornitza Stark Phenotypes for gene: GREM1 were changed from to Genetic intestinal polyposis MONDO:0018188 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14291 | DNAJC3 | Krithika Murali changed review comment from: Well-established association with monogenic diabetes with growth restriction, hypothyroidism, neuropathy, sensorineural hearing loss and cerebellar ataxia also reported affected individuals (PMID 33486469 Lytrvi et al 2021 report 2 additional families and summarise the phenotypic features of 4 previously reported families).; to: Well-established association with monogenic diabetes. Growth restriction, hypothyroidism, neuropathy, sensorineural hearing loss and cerebellar ataxia also reported in affected individuals (PMID 33486469 Lytrvi et al 2021 report 2 additional families and summarise the phenotypic features of 4 previously reported families). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14291 | DNAJC3 | Krithika Murali reviewed gene: DNAJC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33486469, 34630333, 34654017, 32738013; Phenotypes: ?Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus - MIM#616192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.14064 | GSN |
Zornitza Stark changed review comment from: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported. Multiple families with same founder variant.; to: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported. Multiple families with same founder variant, p.Asp187Asn, though other variants also reported. |
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| Mendeliome v0.13885 | APPL1 | Elena Savva Phenotypes for gene: APPL1 were changed from Maturity-onset diabetes of the young, type 14 MIM#616511 to Maturity-onset diabetes of the young, type 14 MIM#616511 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13885 | APPL1 | Elena Savva Phenotypes for gene: APPL1 were changed from Maturity-onset diabetes of the young, type 14 MIM#616511 to Maturity-onset diabetes of the young, type 14 MIM#616511 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13880 | APPL1 | Elena Savva Phenotypes for gene: APPL1 were changed from to Maturity-onset diabetes of the young, type 14 MIM#616511 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13795 | PDGFRA | Ain Roesley Phenotypes for gene: PDGFRA were changed from Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial - MIM#175510 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial - MIM#175510; coloboma MONDO#0001476, PDGFRA-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.13696 | HNF4A | Zornitza Stark Phenotypes for gene: HNF4A were changed from to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026; MODY, type I, OMIM # 125850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13693 | HNF4A | Zornitza Stark reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31875549, 24285859, 22802087, 30005691, 28458902; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026, MODY, type I, OMIM # 125850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13693 | HNF1A | Zornitza Stark Phenotypes for gene: HNF1A were changed from to Diabetes mellitus, insulin-dependent, 20, MIM# 612520; MODY, type III , MIM#600496 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13690 | HNF1A | Zornitza Stark reviewed gene: HNF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9097962, 9112026; Phenotypes: Diabetes mellitus, insulin-dependent, 20, MIM# 612520, MODY, type III , MIM#600496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13683 | DUSP6 |
Krithika Murali changed review comment from: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted. |
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| Mendeliome v0.13683 | DUSP6 |
Krithika Murali changed review comment from: 1 study cited by OMIM (Miraoui et al 2013) - heterozygous variants in 5 unrelated individuals with congenital hypogonadotrophic hypogonadism (CHH). 4/5 variants highly prevalent in healthy population and/or in conjunction with variants in other genes either known to be associated with CHH or possibly associated. No additional studies published since this paper. PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing. Summary of DUSP6 variants identified in this study c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3 c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant) c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant No segregation information provided. PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted. PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted. |
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| Mendeliome v0.13525 | BMPR1A | Zornitza Stark Phenotypes for gene: BMPR1A were changed from to Polyposis, juvenile intestinal, MIM# 174900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13522 | BMPR1A | Zornitza Stark reviewed gene: BMPR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11381269; Phenotypes: Polyposis, juvenile intestinal, MIM# 174900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13384 | BSCL2 |
Zornitza Stark edited their review of gene: BSCL2: Added comment: Multiple families reported with bi-allelic variants and isolated or syndromic lipodystrophy. Mono-allelic variants and DEE: Two families reported with de novo variants in PMIDs 31369919 and 35290466. We are aware of further three individuals identified as a result of clinical testing, so a total of 4 with a change at position p.Pro149; Changed publications: 14981520, 15732094, 11479539, 15181077, 15126564, 23564749, 31369919, 35290466 |
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| Mendeliome v0.13343 | PDGFRA | Zornitza Stark Phenotypes for gene: PDGFRA were changed from to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial - MIM#175510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13297 | PDGFRA |
Krithika Murali changed review comment from: ?Suitability for Incidentalome versus Mendeliome based on adult age of diagnosis in reported cases. --- Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility. --- PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006. PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues. PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease. PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported. PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35. PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease. -- Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome.; to: Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility. --- PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006. PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues. PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease. PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported. PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35. PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease. -- Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome. |
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| Mendeliome v0.13292 | PDGFRA | Krithika Murali reviewed gene: PDGFRA: Rating: GREEN; Mode of pathogenicity: None; Publications: 14699510, 17087943, 25975287, 29486293, 33449152, 34107389, 17566086, 18670346; Phenotypes: Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial - MIM#175510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13289 | HSPG2 |
Zornitza Stark changed review comment from: Allelic disorders with some phenotypic overlap. Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia; blepharophimosis is a key feature. More than 20 families reported. Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. Two families reported.; to: Allelic disorders with some phenotypic overlap. Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia; blepharophimosis is a key feature. More than 20 families reported. Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. Two families reported. Appears associated with null variants. |
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| Mendeliome v0.13285 | PKLR | Zornitza Stark Phenotypes for gene: PKLR were changed from to Pyruvate kinase deficiency, MIM# 266200; Adenosine triphosphate, elevated, of erythrocytes, MIM# 102900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13282 | PKLR | Zornitza Stark reviewed gene: PKLR: Rating: GREEN; Mode of pathogenicity: None; Publications: 1896471, 9160692, 9057665, 16704447, 9090535; Phenotypes: Pyruvate kinase deficiency, MIM# 266200, Adenosine triphosphate, elevated, of erythrocytes, MIM# 102900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.13263 | RSPH4A |
Belinda Chong changed review comment from: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523) 9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)): - In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene. - In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene - Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD. Common founder mutation: - Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry. Multiple individuals in ClinVar with primary ciliary dyskinesia; to: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523) 9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)): - In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene. - In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene - Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD. Common founder mutation: - Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry. Multiple individuals in ClinVar with primary ciliary dyskinesia PMID: 25789548; Frommer 2015: 8 PCD families reported, only 4 different variants identified. Functional studies performed. PMID: 22448264; Ziętkiewicz 2012: 4 additional families/variants reported. |
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| Mendeliome v0.12855 | PDCD1 |
Krithika Murali changed review comment from: No OMIM gene disease association. 1 individual from a consanguineous family reported with PDCD1 deficiency. PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis.; to: No OMIM gene disease association. 1 individual from a consanguineous family reported with PDCD1 deficiency. PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis. |
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| Mendeliome v0.12714 | AHSG |
Elena Savva gene: AHSG was added gene: AHSG was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AHSG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AHSG were set to PMID: 28054173; 9395485; 31288248; 17389622 Phenotypes for gene: AHSG were set to ?Alopecia-intellectual disability syndrome 1 MIM#203650; infantile cortical hyperostosis Review for gene: AHSG was set to RED Added comment: PMID: 28054173 - 7 relatives within a large consanguinous fam w/ alopecia and ID, and a hom missense (p.Arg317His). Modelling predicts this variant to be a phosphorylation site, functional studies show a difference in protein size. Unclear biological significance. Alt change with stronger GS (p.(Arg317Cys)) is a common poly with 19 homozygotes in gnomAD. No hom PTCs in gnomAD PMID: 9395485 - K/O mouse model shows no gross anatomical abnormalities, were fertile and "healthy". No mentioned of ID, alopecia PMID: 17389622 - K/O mouse model on the calcification resistant genetic background C57BL/6, shows uraemia and phosphate challenge. No mentioned of ID, alopecia PMID: 31288248 - 1 hom infant (p.K2*, within 5' NMD escape region) with infantile cortical hyperostosis, loss of enzyme in patient serum shown by ELISA. No mentioned of ID, alopecia Sources: Literature |
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| Mendeliome v0.12711 | MDFIC |
Belinda Chong gene: MDFIC was added gene: MDFIC was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MDFIC were set to 35235341 Phenotypes for gene: MDFIC were set to Central conducting lymphatic anomaly with lymphedema Review for gene: MDFIC was set to GREEN Added comment: Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. Sources: Literature |
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| Mendeliome v0.12534 | CATSPER1 |
Ain Roesley changed review comment from: 2 consanguineous families; to: 2 consanguineous families KO mice models had reduced sperm motility and fertilisation rates |
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| Mendeliome v0.12519 | TSPAN7 |
Zornitza Stark changed review comment from: The P172H missense, which is reported in two families, is present at a high frequency in gnomad, including 66 hemizygotes.; to: The P172H missense, which is reported in two families, is present at a high frequency in gnomad, including 66 hemizygotes. Most variants in ClinVar are either VOUS or LB. |
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| Mendeliome v0.12500 | CASQ1 | Ain Roesley Phenotypes for gene: CASQ1 were changed from to Myopathy, vacuolar, with CASQ1 aggregates MIM#616231 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12498 | CASQ1 | Ain Roesley reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26136523, 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates MIM#616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12449 | SLC30A8 | Zornitza Stark Phenotypes for gene: SLC30A8 were changed from to {Diabetes mellitus, noninsulin-dependent, susceptibility to}, MIM# 125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12445 | SLC30A8 | Zornitza Stark reviewed gene: SLC30A8: Rating: RED; Mode of pathogenicity: None; Publications: 17293876; Phenotypes: {Diabetes mellitus, noninsulin-dependent, susceptibility to}, MIM# 125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12296 | EIF2AK3 | Bryony Thompson Phenotypes for gene: EIF2AK3 were changed from to Wolcott-Rallison syndrome MONDO:0009192; neonatal diabetes mellitus; epiphyseal dysplasia/osteopenia; hepatic/renal dysfunction; intellectual disability/developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.12289 | EIF2AK3 | Bryony Thompson reviewed gene: EIF2AK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932183, 12960215, 16813601, 11997520, 20202148; Phenotypes: Wolcott-Rallison syndrome MONDO:0009192, neonatal diabetes mellitus, epiphyseal dysplasia/osteopenia, hepatic/renal dysfunction, intellectual disability/developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11802 | SUMO4 | Zornitza Stark Phenotypes for gene: SUMO4 were changed from to {Diabetes mellitus, insulin-dependent, 5} 600320 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11798 | SUMO4 | Zornitza Stark reviewed gene: SUMO4: Rating: RED; Mode of pathogenicity: None; Publications: 15123604; Phenotypes: {Diabetes mellitus, insulin-dependent, 5} 600320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11691 | UNC119 |
Zornitza Stark changed review comment from: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association. Amber for association with cone-rod dystrophy.; to: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association. Borderline Green for association with cone-rod dystrophy. |
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| Mendeliome v0.11686 | UCP3 | Zornitza Stark Phenotypes for gene: UCP3 were changed from to {Obesity, severe, and type II diabetes}, MIM#601665 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11680 | USH2A |
Belinda Chong edited their review of gene: USH2A: Added comment: Well established gene-disease association - Usher syndrome, DEFINITIVE by ClinGen. PMID 20507924: Screened the long isoform of USH2A in 80 patients with nonsyndromic autosomal recessive RP and identified at least 1 deleterious mutation in 19% of cases. The authors stated that their findings supported USH2A as the most common known cause of RP in the United States. https://www.ncbi.nlm.nih.gov/books/NBK1341/, PMID 17296898, ClinVar Reports of cosegregation of Usher Syndrome and Retinitis Pigmentosa; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Mendeliome v0.11674 | C4A |
Ain Roesley changed review comment from: Associated with increased risk for systemic lupus erythematosus (SLE). This is mostly involving haplotypes, gene copy number, gene conversions with/without C4B; to: Associated with increased risk for systemic lupus erythematosus (SLE). This is mostly involving haplotypes, gene copy number, gene conversions with/without C4B There are no LP/P SNV in clinvar PMID: 32048120; 2019 Update of the IUIS Phenotypical Classification indicates that complete C4 deficiency requires both C4A+C4B and C4A alone leads to partial deficiency |
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| Mendeliome v0.11668 | C4B |
Ain Roesley changed review comment from: Associated with increased risk for systemic lupus erythematosus (SLE). This is mostly involving haplotypes, gene copy number, gene conversions with/without C4A; to: Associated with increased risk for systemic lupus erythematosus (SLE). This is mostly involving haplotypes, gene copy number, gene conversions with/without C4A no LP/P SNVs in clinvar. (1 LP but evidence provided indicates that it was classified as a VUS) PMID: 32048120; 2019 Update of the IUIS Phenotypical Classification indicates that complete C4 deficiency requires both C4A+C4B and C4A alone leads to partial deficiency |
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| Mendeliome v0.11659 | UCP3 | Belinda Chong reviewed gene: UCP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 10618503, 11238538, 21544083; Phenotypes: {Obesity, severe, and type II diabetes}; Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11636 | SMAD4 | Zornitza Stark Phenotypes for gene: SMAD4 were changed from to Juvenile polyposis/hereditary haemorrhagic telangiectasia syndrome, MIM# 175050; Polyposis, juvenile intestinal, MIM# 174900; Myhre syndrome, MIM# 139210 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11633 | SMAD4 | Zornitza Stark reviewed gene: SMAD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30809044, 15235019, 16613914, 20101697, 22158539, 22243968; Phenotypes: Juvenile polyposis/hereditary haemorrhagic telangiectasia syndrome, MIM# 175050, Polyposis, juvenile intestinal, MIM# 174900, Myhre syndrome, MIM# 139210; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11583 | VEGFA | Zornitza Stark Phenotypes for gene: VEGFA were changed from to {Microvascular complications of diabetes 1} 603933 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11581 | VEGFA | Zornitza Stark reviewed gene: VEGFA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Microvascular complications of diabetes 1} 603933; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11492 | IL6 | Zornitza Stark Phenotypes for gene: IL6 were changed from to {Crohn disease-associated growth failure} 266600; {Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to} 108010; {Rheumatoid arthritis, systemic juvenile} 604302; {Kaposi sarcoma, susceptibility to} 148000; {Type 1 diabetes mellitus} 222100; {Type 2 diabetes mellitus} 125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11490 | IL6 | Zornitza Stark reviewed gene: IL6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: {Crohn disease-associated growth failure} 266600, {Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to} 108010, {Rheumatoid arthritis, systemic juvenile} 604302, {Kaposi sarcoma, susceptibility to} 148000, {Type 1 diabetes mellitus} 222100, {Type 2 diabetes mellitus} 125853; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11468 | IRS1 | Zornitza Stark Phenotypes for gene: IRS1 were changed from to {Coronary artery disease, susceptibility to}; {Type 2 diabetes mellitus, susceptibility to}, MIM# 125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11466 | IRS1 | Zornitza Stark reviewed gene: IRS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Coronary artery disease, susceptibility to}, {Type 2 diabetes mellitus, susceptibility to}, MIM# 125853; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11433 | INS | Zornitza Stark Phenotypes for gene: INS were changed from to Diabetes mellitus, insulin-dependent, 2, MIM# 125852; Diabetes mellitus, permanent neonatal 4, MIM# 618858; Maturity-onset diabetes of the young, type 10, MIM# 613370 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11430 | INS | Zornitza Stark reviewed gene: INS: Rating: GREEN; Mode of pathogenicity: None; Publications: 18162506; Phenotypes: Diabetes mellitus, insulin-dependent, 2, MIM# 125852, Diabetes mellitus, permanent neonatal 4, MIM# 618858, Maturity-onset diabetes of the young, type 10, MIM# 613370; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11386 | ABCC8 | Elena Savva Phenotypes for gene: ABCC8 were changed from to Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11384 | ABCC8 | Elena Savva reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21054355, 32027066, 32376986; Phenotypes: Diabetes mellitus, noninsulin-dependent MIM#125853, Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857, Diabetes mellitus, transient neonatal 2 MIM#610374, Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450, Hypoglycemia of infancy, leucine-sensitive MIM#240800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11286 | KIT | Zornitza Stark Phenotypes for gene: KIT were changed from to Piebaldism, MIM# 172800; Gastrointestinal stromal tumor, familial, MIM# 606764; Mastocytosis, cutaneous, MIM# 154800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11284 | KIT | Zornitza Stark reviewed gene: KIT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Piebaldism, MIM# 172800, Gastrointestinal stromal tumor, familial, MIM# 606764, Mastocytosis, cutaneous, MIM# 154800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11281 | KLF11 | Zornitza Stark Phenotypes for gene: KLF11 were changed from to Maturity-onset diabetes of the young, type VII MIM#610508 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11255 | TSR1 |
Bryony Thompson gene: TSR1 was added gene: TSR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TSR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TSR1 were set to 31296288; 31296287 Phenotypes for gene: TSR1 were set to idiopathic spontaneous coronary artery dissection MONDO:0007385 Review for gene: TSR1 was set to RED Added comment: A single case-control study with 85 SCAD cases and 296 non-SCAD controls from the Chinese Han population that underwent exome sequencing. TSR1 was the top hit in association analyses (p < 5.41 × 10-5 in both the optimal sequence kernel association and mixed effects score tests), with 5 variants identified in 8 SCAD cases. Sources: Literature |
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| Mendeliome v0.11131 | ZFP57 | Zornitza Stark Phenotypes for gene: ZFP57 were changed from to IUGR; Diabetes mellitus, transient neonatal 1 OMIM:601410; Multi Locus Imprinting Disturbance; diabetes mellitus, transient neonatal, 1, MONDO:0011073 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11128 | ZFP57 | Zornitza Stark reviewed gene: ZFP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 18622393, 27075368, 23150280, 30315371, 31399135, 33053156; Phenotypes: IUGR, Diabetes mellitus, transient neonatal 1 OMIM:601410, Multi Locus Imprinting Disturbance, diabetes mellitus, transient neonatal, 1MONDO:0011073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11109 | HIST1H4C | Zornitza Stark Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11107 | AL117258.1 |
Melanie Marty changed review comment from: Gene also known as CIROP Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature; to: Gene also known as CIROP and LMLN2 Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature |
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| Mendeliome v0.11103 | HIST1H4C | Paul De Fazio edited their review of gene: HIST1H4C: Changed phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758, Neurodevelopmental disorder, HIST1H4C related MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11103 | HIST1H4C | Paul De Fazio edited their review of gene: HIST1H4C: Changed phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758, Neurodevelopmental disorder,HIST1H4C related MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11101 | HIST1H4C | Paul De Fazio reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1 MIM#619758, Neurodevelopmental disorder MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11099 | CPSF3 |
Belinda Chong gene: CPSF3 was added gene: CPSF3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CPSF3 were set to 35121750 Phenotypes for gene: CPSF3 were set to Intellectual disability syndrome Review for gene: CPSF3 was set to GREEN Added comment: study of a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes Six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. - Four identified through Icelandic geneology (p.Gly468Glu), three carrier couples total of four children who had died prematurely. Tested archival samples for two of these children, and confirm a homozygous genotype. - Two of Mexican descent (p.Ile354Thr), first-degree cousins Sources: Literature |
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| Mendeliome v0.11097 | AL117258.1 |
Melanie Marty gene: AL117258.1 was added gene: AL117258.1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AL117258.1 were set to 34903892 Phenotypes for gene: AL117258.1 were set to Heterotaxy, congenital heart defects Review for gene: AL117258.1 was set to GREEN Added comment: Gene also known as CIROP Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature |
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| Mendeliome v0.11092 | CRLS1 |
Michelle Torres gene: CRLS1 was added gene: CRLS1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CRLS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRLS1 were set to 35147173 Phenotypes for gene: CRLS1 were set to Mitochondrial disease MONDO:0044970 CRLS1-related Added comment: - Three families (4 individuals) with cardiolipin deficiency. - Two families (one consanguineous with 2 affected siblings) with homozygous the p.(Ile109Asn) had infantile progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. - The fourth individual cHet p.(Ala172Asp) and p.(Leu217Phe) presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. - Functional studies on patient cells showed increased levels of the substrate of CRLS1 and impaired mitochondrial morphology and biogenesis Sources: Literature |
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| Mendeliome v0.11078 | AP3D1 | Zornitza Stark edited their review of gene: AP3D1: Added comment: Now four affected individuals from two unrelated families, with a mouse model that recapitulates the human phenotype.; Changed rating: GREEN; Changed publications: 26744459, 9697856, 30472485; Changed phenotypes: Hermansky-Pudlak syndrome 10, MIM# 617050, Oculocutaneous albinism, Severe neutropaenia, Recurrent infections, Seizures, Hearing loss, Neurodevelopmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.11028 | MAPK8IP1 | Zornitza Stark Phenotypes for gene: MAPK8IP1 were changed from to Susceptibility to diabetes mellitus, noninsulin-dependent MIM#125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.11010 | DLC1 |
Bryony Thompson gene: DLC1 was added gene: DLC1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: DLC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DLC1 were set to 29773874 Phenotypes for gene: DLC1 were set to Nephrotic syndrome MONDO:0005377 Review for gene: DLC1 was set to GREEN Added comment: Biallelic variants in 4 families, and knockdown of DLC1 in cultured podocytes reduces migration rate and treatment with dexamethasone abolishes RhoA activation. Sources: Expert list |
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| Mendeliome v0.11004 | MAPK8IP1 | Paul De Fazio reviewed gene: MAPK8IP1: Rating: RED; Mode of pathogenicity: None; Publications: 10700186; Phenotypes: Susceptibility to diabetes mellitus, noninsulin-dependent MIM#125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10796 | KIF26B |
Zornitza Stark gene: KIF26B was added gene: KIF26B was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: KIF26B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF26B were set to 30151950 Phenotypes for gene: KIF26B were set to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis Review for gene: KIF26B was set to RED Added comment: 1 report only of infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. Whole exome sequencing on the trio identified a de novo KIF26B missense variant (p.Gly546Ser). Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Sources: Expert Review |
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| Mendeliome v0.10793 | CHP1 |
Zornitza Stark gene: CHP1 was added gene: CHP1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CHP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHP1 were set to 29379881; 32787936 Phenotypes for gene: CHP1 were set to Spastic ataxia 9, autosomal recessive, MIM #618438 Review for gene: CHP1 was set to GREEN Added comment: 2 different consanguineous families with 2 affected siblings with ataxia (1 paediatric onset, 1 adult onset). 3 of the patients had cerebellar atrophy. WES identified homozygous variants in CHP1 gene in both families (K19del and Arg91Cys), which segregated with the disorder in the family. Decreased CHP1 protein on IHC of cerebellar tissue in family with Arg91Cys variant. In vitro functional expression studies in HEK293 cells showed that the K19del mutation resulted in decreased protein expression, with normal levels of transcript, suggesting defects in protein stability. The mutant protein formed massive protein aggregates in transfected neuronal cell bodies and neurite-like projections, whereas the wildtype protein showed a more uniform distribution. The mutant protein altered CHP1 association into functional complexes and impaired membrane localization of the Na+/H+ transporter NHE1. The findings indicated that the CHP1 mutation likely causes ataxia in an NHE1-dependent manner, resembling the mechanism observed in the Chp1 vacillator mutant mouse. Sources: Expert Review |
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| Mendeliome v0.10792 | PI4KA | Zornitza Stark Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531; Neurodevelopmental syndrome with hypomyelinating leukodystrophy; Spastic paraplegia 84, autosomal recessive, MIM# 619621 to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531; Neurodevelopmental syndrome with hypomyelinating leukodystrophy; Spastic paraplegia 84, autosomal recessive, MIM# 619621; Gastrointestinal defects and immunodeficiency syndrome 2, MIM# 619708 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10791 | PI4KA | Zornitza Stark edited their review of gene: PI4KA: Changed phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531, Neurodevelopmental syndrome with hypomyelinating leukodystrophy, Spastic paraplegia 84, autosomal recessive, MIM# 619621, Gastrointestinal defects and immunodeficiency syndrome 2, MIM# 619708 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10669 | CAPN10 | Zornitza Stark Phenotypes for gene: CAPN10 were changed from to {Diabetes mellitus, noninsulin-dependent 1} 601283 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10640 | MYL9 | Ain Roesley reviewed gene: MYL9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33264186; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10554 | PPIA |
Naomi Baker gene: PPIA was added gene: PPIA was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PPIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PPIA were set to PMID: 34972208 Phenotypes for gene: PPIA were set to amyotrophic lateral sclerosis, MONDO:0004976 Review for gene: PPIA was set to RED Added comment: Paper characterizes a knockout mouse model that recapitulates key features of ALS-FTD. Also identified a heterozygous missense variant in one patient with sporadic amyotrophic lateral sclerosis. Functional studies of the missense variant suggest loss-of-function. Sources: Literature |
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| Mendeliome v0.10553 | DNHD1 |
Daniel Flanagan gene: DNHD1 was added gene: DNHD1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DNHD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNHD1 were set to 34932939 Phenotypes for gene: DNHD1 were set to Male infertility due to sperm motility disorder (MONDO:0018395) Review for gene: DNHD1 was set to GREEN Added comment: Biallelic DNHD1 variants identified in 8 unrelated probands with asthenoteratozoospermia, reduced sperm motility and abnormal sperm morphology. DNHD1 knockout mice were infertile and had significantly reduced sperm concentration and motility rates, consistent with human individuals. Sources: Literature |
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| Mendeliome v0.10510 | NAA20 |
Zornitza Stark gene: NAA20 was added gene: NAA20 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAA20 were set to 34230638 Phenotypes for gene: NAA20 were set to Intellectual disability; Microcephaly; Neurodevelopmental disorder MONDO:0700092 Review for gene: NAA20 was set to GREEN Added comment: 2 consanguineous families with 5 affected individuals with developmental delay, intellectual disability, and microcephaly (-2-4SD). Exome and genome sequencing identified 2 different homozygous variants in NAA20 gene (p.Met54Val and p.Ala80Val), and segregated with affected individuals. N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Sources: Literature |
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| Mendeliome v0.10250 | REL |
Zornitza Stark changed review comment from: Second unrelated individual reported, homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets.; to: Second unrelated individual reported, with a different homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets. |
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| Mendeliome v0.10250 | REL |
Zornitza Stark edited their review of gene: REL: Added comment: Second unrelated individual reported, homozygous splice site variant. Immunodeficiency-92 (IMD92) is an autosomal recessive primary immunodeficiency characterized by the onset of recurrent infections in infancy or early childhood. Infectious agents are broad, including bacterial, viral, fungal, and parasitic, including Cryptosporidium and Mycobacteria. Patient lymphocytes show defects in both T- and B-cell proliferation, cytokine secretion, and overall function, and there is also evidence of dysfunction of NK, certain antigen-presenting cells, and myeloid subsets.; Changed rating: AMBER; Changed publications: 31103457, 34623332; Changed phenotypes: Immunodeficiency 92, MIM# 619652, 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 |
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| Mendeliome v0.10204 | KCND2 |
Eleanor Williams gene: KCND2 was added gene: KCND2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KCND2 were set to 24501278; 16934482; 29581270; 34245260 Phenotypes for gene: KCND2 were set to global developmental delay, HP:0001263; seizure, HP:0001250 Mode of pathogenicity for gene: KCND2 was set to Other Review for gene: KCND2 was set to GREEN Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype. PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M. PMID: 29581270 - Lin et al, 2018 - performed functional work that shows V404M enhances inactivation of channels that have not yet opened and dramatically impairs the inactivation of channels that have opened. PMID:16934482 - Singh et al, 2006 - reports a patient with cognative impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant. Sources: Literature |
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| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10100 | MSH5 |
Bryony Thompson changed review comment from: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature; to: 4 unrelated male azoospermia cases with 3 different homozygous frameshift/missense variants. A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.10096 | MSH4 |
Bryony Thompson gene: MSH4 was added gene: MSH4 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MSH4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MSH4 were set to 34794894; 10809667; 12478991; 28541421; 32741963; 33437391; 34755185; 33448284 Phenotypes for gene: MSH4 were set to Primary ovarian insufficiency; azoospermia Review for gene: MSH4 was set to GREEN Added comment: PMID: 34755185 - 2 siblings, 1 with non-obstructive azoospermia and 1 with POI, both homozygous for a stopgain variant. 1 male with non-obstructive azoospermia and biallelic variants. PMID: 33448284 - 2 sisters with POI and 3 brothers with azoospermia in a consanguineous family with a homozygous missense variant (p.Ser754Leu) PMID: 33437391 - 1 case with non-obstructive azoospermia with a homozygous stopgain variant PMID: 32741963 - 2 unrelated cases with spermatogenic arrest with homozygous missense variants (p.Pro638Leu; p. Ser754Leu) PMID: 28541421 - 2 sisters with POI and homozygous for a splice site variant PMID: 10809667 - Msh4-/- male mice are infertile and Msh4-/- female mice lacked most oocytes in the ovaries. Sources: Literature |
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| Mendeliome v0.10046 | ATP9A | Zornitza Stark reviewed gene: ATP9A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34379057, 34764295; Phenotypes: Neurodevelopmental delay, Postnatal microcephaly, Failure to thrive, Gastrointestinal symptoms; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.10018 | OGDH |
Zornitza Stark gene: OGDH was added gene: OGDH was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OGDH were set to 32383294 Phenotypes for gene: OGDH were set to Developmental delay; ataxia; seizure; raised lactate Review for gene: OGDH was set to AMBER Added comment: Two siblings reported with homozygous missense variant in this gene and global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Note previous report of an individual with developmental delay, hypotonia, and movement disorders and metabolic decompensation and biochemical evidence of OGDH deficiency but genetic testing not done. Sources: Literature |
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| Mendeliome v0.10017 | FAAH2 |
Ain Roesley changed review comment from: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature; to: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomAD Sources: Literature |
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| Mendeliome v0.10017 | FAAH2 |
Ain Roesley gene: FAAH2 was added gene: FAAH2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FAAH2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FAAH2 were set to PMID: 34645488 Penetrance for gene: FAAH2 were set to unknown Review for gene: FAAH2 was set to RED gene: FAAH2 was marked as current diagnostic Added comment: PMID: 34645488; - 1x nonsense variant inherited from normal mother - proband presented with a classical Zellweger syndrome phenotype including global developmental delay, seizure disorder, severe hypotonia, failure to thrive, adrenal insufficiency and elevated very long-chain fatty acids and liver enzymes - this variant has 2 hemizygotes in gnomAD PMID: 25885783; - 1x missense inherited from normal mother and absent in normal brother - presented with autistic features, anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities - biochemical studies on patient fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. - BUT this variant has 30 hemizygotes in gnomoad Sources: Literature |
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| Mendeliome v0.9950 | DMC1 |
Bryony Thompson gene: DMC1 was added gene: DMC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: DMC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DMC1 were set to 34794894; 29331980; 9660954; 9660953; 18166824 Phenotypes for gene: DMC1 were set to Primary ovarian insufficiency; non-obstructive azoospermia Review for gene: DMC1 was set to GREEN Added comment: PMID: 34515795 - a homozygous frameshift (p. Glu10Asnfs*31) cosegregated with non-obstructive azoospermia in 1 brother and diminished ovarian reserve (not primary ovarian insufficiency) in 2 sisters in a non-consanguineous family. Further homozygous knockout mice study demonstrated total failure of follicle development and spermatogenesis in male mice. PMID: 29331980 - a homozygous missense (p.Asp36Asn) cosegregated with non-obstructive azoospermia and POI phenotypes in a single family. PMID: 18166824 - a POI case identified with a homozygous missense (p.Met200Val, 185 homozygotes in gnomAD v2.1), which is too common for a recessive Mendelian disease PMID: 9660954, 9660953 - both male and female knockout mice are sterile Sources: Literature |
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| Mendeliome v0.9948 | CPEB1 |
Bryony Thompson gene: CPEB1 was added gene: CPEB1 was added to Mendeliome. Sources: Literature SV/CNV tags were added to gene: CPEB1. Mode of inheritance for gene: CPEB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CPEB1 were set to 34794894; 33095795; 32354341; 30689869; 11702780 Phenotypes for gene: CPEB1 were set to Primary ovarian insufficiency Review for gene: CPEB1 was set to AMBER Added comment: Large CNVs including CPEB1 mainly reported, but also include BNC1. PMID: 33095795 - 1 POI case with missense variant p.R87C, which has 101 hets in gnomAD v2.1 (too common for a Mendelian dominantly inherited disease). Also another POI case with an 83.8Kb deletion including CPEB1. PMID: 32354341 - 1 primary amenorrhea case heterozygous deletion of exons 8-12 of CPEB1 PMID: 30689869 - 6 POI cases (including previously reported) with a 15q25.2 deletion including CPEB1, but also including POI gene BNC1. Also, a homozygous microdeletion involving CPEB1 intron 1 in one case. PMID: 11702780 - knockout mouse model had vestigial ovaries devoid of oocytes Sources: Literature |
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| Mendeliome v0.9936 | AKT2 | Zornitza Stark Phenotypes for gene: AKT2 were changed from to Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; Hypoinsulinemic hypoglycemia with hemihypertrophy, OMIM:240900; Diabetes mellitus, type II , MIM#125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9932 | BNC1 |
Bryony Thompson gene: BNC1 was added gene: BNC1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: BNC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BNC1 were set to 34794894; 30010909; 16624857; 32962729; 32894148; 30689869; 27301361 Phenotypes for gene: BNC1 were set to Premature ovarian failure 16 MIM#618723 Review for gene: BNC1 was set to GREEN Added comment: PMID: 30010909 - a heterozygous frameshift variant segregates with POF in 6 affected females in a Chinese family. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility. PMID: 32962729 - 1 POF case with p.Asp575Val (which has 89 hets in gnomAD v2.1) and 1 POF case with biallelic missense variants (p.Asp568Val & p.Leu525Pro). SCV001364363.1 - 1 POF case submitted by Medical Cytogenetics and Molecular Genetics Laboratory,IRCCS Istituto Auxologico Italiano to ClinVar with NM_001717.4(BNC1):c.2273C>T (p.Thr758Ile) PMID: 32894148, 30689869, 27301361 - large CNVs involving BNC1 reported in POF cases PMID: 16624857 - knockdown of the gene in mouse oocytes lead to subfertility Sources: Literature |
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| Mendeliome v0.9776 | NEBL | Bryony Thompson Added comment: Comment on list classification: Limited gene-disease vailidity, Classification - 09/25/2020 by ClinGen Dilated Cardiomyopathy GCEP. Evidence Summary: NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of NEBL and autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9607 | COG6 | Zornitza Stark changed review comment from: More than 5 unrelated families reported. Key features include growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. Ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies are prominent. Note Shaheen syndrome, MIM#615328 is an allelic disorder, with overlapping clinical features, but normal transferring isoforms recorded creating confusion about whether it represents a distinct entity.; to: More than 5 unrelated families reported. Key features include growth retardation, developmental delay, microcephaly, liver and gastrointestinal disease, joint contractures and episodic fever. Ectodermal signs such as hypohidrosis/hyperthermia, hyperkeratosis and tooth anomalies are prominent. Note Shaheen syndrome, MIM#615328 is an allelic disorder, with overlapping clinical features, but normal transferrin isoforms recorded creating confusion about whether it represents a distinct entity. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9392 | KCNAB3 |
Daniel Flanagan gene: KCNAB3 was added gene: KCNAB3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: KCNAB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNAB3 were set to PMID: 32990398 Phenotypes for gene: KCNAB3 were set to febrile seizures; afebrile seizure; genetic epilepsy with febrile seizures plus Review for gene: KCNAB3 was set to RED Added comment: Missense variant identified in a single Han Chinese family with febrile seizures plus. Three affected carriers and one unaffected carrier. Patch clamp functional studies indicates that the variant accelerates the inactivation of the potassium channels. Sources: Expert list |
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| Mendeliome v0.9388 | UHRF1 |
Zornitza Stark gene: UHRF1 was added gene: UHRF1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: UHRF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UHRF1 were set to 29574422; 28976982 Phenotypes for gene: UHRF1 were set to Multi locus imprinting disturbance in offspring Review for gene: UHRF1 was set to RED Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and Silver Russell Syndrome phenotype. Maenohara et al demonstrate functions of UHRF1 during the global epigenetic reprogramming of oocytes and early embryos. Sources: Expert Review |
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| Mendeliome v0.9379 | OOEP |
Zornitza Stark gene: OOEP was added gene: OOEP was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OOEP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OOEP were set to 29574422 Phenotypes for gene: OOEP were set to Multi locus imprinting disturbance in offspring Review for gene: OOEP was set to RED Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and a transient neonatal diabetes mellitus phenotype. This gene encodes part of the subcortical maternal complex (SCMC). Other genes in this group act as 'maternal effect' genes and are associated with early embryonic arrest, recurrent hydatiform mole and MLID in offspring. As is the case for other genes encoding components of the SCMC, the pathogenicity of variants can be difficult to establish as reproductive outcomes are not recorded in genomic databases and variants may be listed in population databases as they are not classed as pathogenic in males or women with no reproductive history. Functional studies of genes encoding components of the SCMC are limited as their expression is restricted to the oocyte and early embryo. Sources: Literature |
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| Mendeliome v0.9355 | SLC4A3 |
Daniel Flanagan gene: SLC4A3 was added gene: SLC4A3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: SLC4A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC4A3 were set to PMID: 29167417; 34557911 Phenotypes for gene: SLC4A3 were set to Short QT syndrome Review for gene: SLC4A3 was set to AMBER Added comment: Moderate evidence for autosomal dominant short QT syndrome 1 by ClinGen /gene curation expert panel (PMID: 34557911). A single missense variant (absent gnomAD) identified in two SQTS families. In family 1, it segregated with SQTS (QTc<370ms) in 23 carriers, and 19 non-carriers had a QTc>370ms. In family 2, it segregated in 4 individuals. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration. ClinGen expert panel was divided between strong (4 votes) and moderate (5 votes). Sources: Expert Review |
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| Mendeliome v0.9351 | MARS | Zornitza Stark changed review comment from: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT and mono-allelic variants: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9351 | MARS | Zornitza Stark changed review comment from: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease.; to: Association with CMT: Two families reported. One mutation positive family member was asymptomatic. Second case is proband only testing with no segregation or functional data. Note one of the variants identified in dominant MARS1-associated neuropathy, p.Arg618Cys, has also been reported in AR MARS1-related pulmonary interstiatial/liver disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9347 | USP48 |
Eleanor Williams gene: USP48 was added gene: USP48 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: USP48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: USP48 were set to 34059922 Phenotypes for gene: USP48 were set to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 Penetrance for gene: USP48 were set to Incomplete Review for gene: USP48 was set to GREEN Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance. In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis. In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein. In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens. In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths. Sources: Literature |
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| Mendeliome v0.9338 | AIP |
Paul De Fazio changed review comment from: Germline variants in AIP cause predisposition to pituitary adenomas which may result in acromegaly. A 2015 cohort study of 143 patients with pituitary gigantism who consented to genetic testing found 29% had variants in AIP. Age at first symptoms was 9-13 years, age at diagnosis 14-20 years.; to: Germline variants in AIP cause predisposition to pituitary adenomas which may result in acromegaly. A 2015 cohort study of 143 patients with pituitary gigantism who consented to genetic testing found 29% had variants in AIP. Age at first symptoms was 9-13 years, age at diagnosis 14-20 years. Many patients have no family history, suggesting low penetrance. |
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| Mendeliome v0.9285 | EIF3F | Zornitza Stark edited their review of gene: EIF3F: Added comment: Hüffmeier et al (2021) reported 21 patients who were homozygous/compound heterozygous for Phe232Val variant in EIF3F. All affected individuals had developmental delay and speech delay. About half had behavioural problems, altered muscular tone, hearing loss, and short stature. The study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum.; Changed publications: 30409806, 33736665; Changed phenotypes: Mental retardation, autosomal recessive 67, MIM# 618295 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.9274 | CDH15 |
Zornitza Stark commented on gene: CDH15: PMID: 19012874 - 4 unrelated patients with missense variants and mild-severe ID. Only two genes checked. All variants are common in gnomAD (>20 hets each) and classified as VUS or likely benign in ClinVar (paper is from 2008, pre-dates gnomAD). Functional studies were performed showing a LOF effect, where cell adhesion was reduced. However NMD PTCs are present in gnomAD (many >=6 hets each) PMID: 12052883 - null mouse model were viable, showed no gross developmental defects. In particular, the skeletal musculature appeared essentially normal. In the cerebellum of M-cadherin-lacking mutants, typical contactus adherens junctions were present and similar in size and numbers to the equivalent junctions in wild-type animals. However, the adhesion plaques in the cerebellum of these mutants appeared to contain elevated levels of N-cadherin compared to wild-type animals. PMID: 28422132 - reviewed microdeletions spanning multiple genes including CDH15, suggests it may contribute to a more severe neurological phenotype, with particular regard to brain malformations. PMID: 26506440 - speculates low penetrance for PTCs in this gene. Acknowledges variants in ExAC, describes them as benign Note no P/LP variants in ClinVar |
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| Mendeliome v0.9250 | ATP6V0C |
Zornitza Stark gene: ATP6V0C was added gene: ATP6V0C was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP6V0C were set to 33190975; 33090716 Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly Review for gene: ATP6V0C was set to AMBER Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures. Sources: Literature |
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| Mendeliome v0.9088 | IFIH1 |
Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified. Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant. Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis. |
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| Mendeliome v0.9068 | CACNA1I |
Kristin Rigbye gene: CACNA1I was added gene: CACNA1I was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CACNA1I were set to 33704440 Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CACNA1I was set to Other Review for gene: CACNA1I was set to GREEN Added comment: 4 different missense variants identified and shown to result in a gain of function. 2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy. 1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases. Sources: Literature |
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| Mendeliome v0.8953 | RMRP | Zornitza Stark reviewed gene: RMRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16244706, 21396580, 22420014; Phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities, CID, impaired lymphocyte proliferation, low Ig levels, antibodies variably decreased, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8910 | 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 v0.8889 | ZNF699 |
Zornitza Stark gene: ZNF699 was added gene: ZNF699 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF699 were set to 33875846 Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488 Review for gene: ZNF699 was set to GREEN Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections. 12 unrelated families reported, 5 different homozygous frameshift variants. Sources: Literature |
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| Mendeliome v0.8853 | PLAG1 |
Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green. Silver-Russell syndrome-4 (SRS4) is characterised by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed. So far 4 families have been reported with some functional studies of the role of the gene in the growth pathway. Abi Habib et al. (2018) reported 1 family (child, sister and mother) patient with Silver-Russell syndrome (with normal methylation on chromosomes 7, 11, and 14, and exclusion of maternal UPD and chromosomal rearrangements). Using WES they identified a heterozygous 1-bp deletion in the PLAG1 gene. The variant segregated with disease, and was not present in polymorphism databases or ExAC. They also reported another patient with a different heterozygous 1-bp deletion in the PLAG1 gene. This was not found in her unaffected twin brother, older brother, or parents. Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 promoter P3, independently and via the HMGA2-PLAG1-IGF2 pathway. Disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus. Inoue et al. (2020) reported 1 family with 2 affected people with Silver-Russell syndrome with a nonsense variant in the PLAG1 gene, which segregated with disease. Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215 |
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| Mendeliome v0.8851 | WIPF1 | Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2 MIM# 614493; Reduced T cells; defective lymphocyte responses to anti-CD3; high IgE; Thrombocytopenia with or without small platelets; recurrent bacterial and viral Infections; eczema; bloody diarrhoea; gastrointestinal bleeding; WAS protein absent | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8844 | TAP2 | Zornitza Stark Phenotypes for gene: TAP2 were changed from to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8841 | TAP1 | Zornitza Stark Phenotypes for gene: TAP1 were changed from to Bare lymphocyte syndrome, type I MIM#604571; Low CD8; absent MHC I on lymphocytes; vasculitis; pyoderma gangrenosum; skin lesions; recurrent respiratory tract infections; bronchiectasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8836 | WIPF1 | Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8835 | TAP2 | Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8835 | TAP1 | Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8834 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
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| Mendeliome v0.8824 | PLXNA2 |
Zornitza Stark gene: PLXNA2 was added gene: PLXNA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLXNA2 were set to 34327814 Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology Review for gene: PLXNA2 was set to AMBER Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants. The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members. Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)). Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed). The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed). Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved. Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele. As the authors discuss: *PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration. *Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch. *Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD. *Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus. Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg: - Cyanotic heart disease explaining discordance in cognitive outcome among sibs - Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or - Additional pathogenic variants possibly explaining the CHD in the first subject. There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes. Sources: Literature |
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| Mendeliome v0.8823 | SLC51A |
Zornitza Stark gene: SLC51A was added gene: SLC51A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC51A were set to 31863603 Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484 Review for gene: SLC51A was set to RED Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated. Sources: Literature |
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| Mendeliome v0.8807 | VPS50 |
Zornitza Stark gene: VPS50 was added gene: VPS50 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Sources: Literature |
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| Mendeliome v0.8792 | RELT |
Zornitza Stark gene: RELT was added gene: RELT was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: RELT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RELT were set to 30506946 Phenotypes for gene: RELT were set to Amelogenesis imperfecta, type IIIC, MIM# 618386 Review for gene: RELT was set to GREEN Added comment: Amelogenesis imperfecta type IIIC is characterized by hypocalcified enamel in both the primary and secondary dentition. The enamel is rough and yellow-brown; under normal use, the enamel disintegrates from occlusal surfaces of the molars, leaving a ring of intact enamel remaining on the sides. At least 3 families and a mouse model. Sources: Expert Review |
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| Mendeliome v0.8741 | TCF7L2 |
Zornitza Stark changed review comment from: 2 reviews Konstantinos Varvagiannis (Other) I don't know Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants. Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11). One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury. TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts. Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development. Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1]. The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA). No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism. There are no variant or other studies performed, nor any animal models discussed. In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs). Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm. There is no other associated phenotype (notably NDD) in OMIM. G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF). SysID includes this gene within the autism candidate genes and current primary ID genes. |
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| Mendeliome v0.8722 | RFXAP | Zornitza Stark Phenotypes for gene: RFXAP were changed from to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8719 | RFXANK | Zornitza Stark Phenotypes for gene: RFXANK were changed from to MHC class II deficiency, complementation group B MIM# 209920; Bare Lymphocyte Syndrome, type II, complementation group B; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8713 | RFXANK | Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8713 | RFXAP | Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8657 | NFKBIA | Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8651 | NFKB1 | Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKBIA | Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | NFKB1 | Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8638 | AQP2 | Zornitza Stark Phenotypes for gene: AQP2 were changed from to Diabetes insipidus, nephrogenic, MIM#125800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8635 | AQP2 | Zornitza Stark reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7537761, 11536078; Phenotypes: Diabetes insipidus, nephrogenic, MIM#125800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8601 | CLCN3 |
Kristin Rigbye gene: CLCN3 was added gene: CLCN3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CLCN3 were set to PMID: 34186028 Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CLCN3 was set to Other Review for gene: CLCN3 was set to GREEN Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available. The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities: - Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures. - Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants. - Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals. - Six have mood or behavioural disorders, particularly anxiety (3/6). - Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia. The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal. Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers. Both loss and gain of function in this gene resulted in the same phenotype. Sources: Literature |
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| Mendeliome v0.8601 | TNPO2 |
Elena Savva gene: TNPO2 was added gene: TNPO2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TNPO2 were set to PMID: 34314705 Phenotypes for gene: TNPO2 were set to Developmental delays, neurologic deficits and dysmorphic features Mode of pathogenicity for gene: TNPO2 was set to Other Review for gene: TNPO2 was set to GREEN Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present Sources: Literature |
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| Mendeliome v0.8600 | SEMA3D | Ain Roesley edited their review of gene: SEMA3D: Added comment: Reported as a common susceptibility loci. No reported evidence for an association with Mendelian disease. Sema3d null heterozygote and homozygote mouse model had normal intestinal innervation.; Changed publications: 28334784, 25839327; Changed phenotypes: Hirschsprung disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8591 | UBA2 |
Ain Roesley changed review comment from: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available) 1x proband with unilateral split-hand malformation. Her daughter and grandson reported to have ectrofactyly but were unavailable for testing; to: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available) 1x proband with unilateral split-hand malformation (missense). Her daughter and grandson reported to have ectrofactyly but were unavailable for testing |
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| Mendeliome v0.8570 | PDCL3 |
Zornitza Stark gene: PDCL3 was added gene: PDCL3 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: PDCL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDCL3 were set to 32621347 Phenotypes for gene: PDCL3 were set to Megacystis-microcolon Review for gene: PDCL3 was set to AMBER Added comment: Single publication (PMID 32621347): one family with two affected fetuses - one with megacystis and microcolon, and the other with megacystisis and bilateral diaphragmatic hernia (prune-belly phenotype). Compound het LOF variants in PDCL3 (one frameshift and one missense). Complete absence of PDLC3 expression demonstrated in one of the affected fetuses. No homozygous LOF PDCL3 variants in gnomAD. PCDL3 negatively modulates actin folding and is strongly expressed in smooth muscle of bladder and colon. Sources: Expert Review |
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| Mendeliome v0.8569 | SGO1 | Zornitza Stark Phenotypes for gene: SGO1 were changed from to Chronic atrial and intestinal dysrhythmia, MIM# 616201 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8565 | SGO1 | Zornitza Stark reviewed gene: SGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8511 | CAMK4 |
Zornitza Stark gene: CAMK4 was added gene: CAMK4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350 Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus Review for gene: CAMK4 was set to GREEN Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018). The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below]. Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function. Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported. Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below). Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID. --- The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein. Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect. To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV. Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect. ---- Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20]. ---- Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). Sources: Expert Review |
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| Mendeliome v0.8485 | STX3 |
Zornitza Stark changed review comment from: At least 5 unrelated families reported.; to: At least 5 unrelated families reported. STX3 isoform B (STX3B) predominates in the retina, so mutations in the STX3 gene that affect both isoform A (STX3A) and STX3B cause both retinal and gastrointestinal disease (RDMVID), whereas mutations in STX3 affecting only the STX3A transcript cause only diarrhoea. |
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| Mendeliome v0.8475 | CD3G | Zornitza Stark Phenotypes for gene: CD3G were changed from to Immunodeficiency 17, CD3 gamma deficient MIM# 615607; immune deficiency; autoimmunity; failure to thrive; recurrent gastrointestinal infections; recurrent respiratory infections; autoimmune haemolytic anaemia; bronchiolitis obliterans; low CD3 complex; partial T lymphocytopenia; intractable diarrhoea. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8468 | CD3G | Danielle Ariti reviewed gene: CD3G: Rating: GREEN; Mode of pathogenicity: None; Publications: 2872416, 1635567, 17277165, 23590417, 24910257, 18482219, 31921117, 11160319; Phenotypes: Immunodeficiency 17, CD3 gamma deficient MIM# 615607, immune deficiency, autoimmunity, failure to thrive, recurrent gastrointestinal infections, recurrent respiratory infections, autoimmune haemolytic anaemia, bronchiolitis obliterans, low CD3 complex, partial T lymphocytopenia, intractable diarrhoea.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8381 | HNF1B | Zornitza Stark Phenotypes for gene: HNF1B were changed from to Renal cysts and diabetes syndrome, MIM# 137920 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8335 | IMPDH2 |
Laura Raiti gene: IMPDH2 was added gene: IMPDH2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IMPDH2 were set to PMID: 33098801 Phenotypes for gene: IMPDH2 were set to Dystonia Review for gene: IMPDH2 was set to GREEN Added comment: 6 unrelated individuals 1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein. IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition. 1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified: 3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg) 1 x deletion: c.478_480delTCC (p.Ser160del) The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair. The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1. The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2. Sources: Literature |
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| Mendeliome v0.8332 | ACTG2 | Zornitza Stark Phenotypes for gene: ACTG2 were changed from Visceral myopathy, MIM#155310 to Visceral myopathy, MIM#155310; Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, MIM# 619431 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8331 | ACTG2 | Zornitza Stark edited their review of gene: ACTG2: Changed phenotypes: Visceral myopathy, MIM#155310, Megacystis-microcolon-intestinal hypoperistalsis syndrome 5, MIM# 619431 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8292 | RING1 |
Eleanor Williams gene: RING1 was added gene: RING1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RING1 were set to 29386386 Phenotypes for gene: RING1 were set to microcephaly; intellectual disability Review for gene: RING1 was set to RED Added comment: Not associated with any phenotype in OMIM. PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Sources: Literature |
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| Mendeliome v0.8229 | ATP9A |
Arina Puzriakova gene: ATP9A was added gene: ATP9A was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843 Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms Review for gene: ATP9A was set to AMBER Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3. Sources: Literature |
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| Mendeliome v0.8130 | C21orf2 |
Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. 7 families also reported with isolated retinal dystrophy.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. 7 families also reported with isolated retinal dystrophy. New HGNC approved name is CFAP410. |
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| Mendeliome v0.8050 | MYL9 | Zornitza Stark Phenotypes for gene: MYL9 were changed from Megacystis-microcolon-intestinal hypoperistalsis syndrome to Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8049 | MYL9 | Zornitza Stark edited their review of gene: MYL9: Changed phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#619365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8011 | ADA2 | Zornitza Stark commented on gene: ADA2: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits. Some affected individuals have immunodeficiency. At least 10 unrelated families reported, the p.Gly47Arg variant is a common founder variant in the Jewish population. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8002 | SEMA3F |
Zornitza Stark gene: SEMA3F was added gene: SEMA3F was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEMA3F were set to 33495532 Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism Review for gene: SEMA3F was set to GREEN Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates. Sources: Literature |
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| Mendeliome v0.7986 | RELN |
Ee Ming Wong edited their review of gene: RELN: Added comment: - Six affected individuals carrying missense variants in RELN including 1. Two individuals with compound heterozygous variants - One of the variants has 26 homozygotes in gnomAD and therefore pathogenicity of this variant is in question - LoF demonstrated for three of the variants (reduced RELN secretion), except for p.Y1821H which demonstrated an apparently increased RELN secretion (GoF) 2. Two brothers carrying the maternally inherited variant (mother apparently healthy) - LoF demonstrated for these variants 3. Two individuals de novo for RELN variants - Dominant negative demonstrated for these variants where secretion of WT-RELN was impaired when co-transfected with mutant constructs in HEK293T cells; Changed rating: AMBER; Changed publications: Riva et al bioRxiv (pre-print, not peer-reviewed); Changed phenotypes: Pachygyria, Polymicrogyria, Heterotopia; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v0.7983 | TRPM6 | Zornitza Stark Phenotypes for gene: TRPM6 were changed from to Hypomagnesaemia 1, intestinal (MIM#602014) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7967 | TRPM6 | Kristin Rigbye reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal (MIM#602014), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7891 | PGM2L1 |
Chern Lim gene: PGM2L1 was added gene: PGM2L1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PGM2L1 were set to 33979636 Phenotypes for gene: PGM2L1 were set to severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris Review for gene: PGM2L1 was set to GREEN gene: PGM2L1 was marked as current diagnostic Added comment: PMID: 33979636: - Hom/chet PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. - Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect. Sources: Literature |
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| Mendeliome v0.7801 | LMOD1 | Zornitza Stark Phenotypes for gene: LMOD1 were changed from to Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, MIM# 619362 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7797 | LMOD1 | Zornitza Stark reviewed gene: LMOD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28292896; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, MIM# 619362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7767 | FGB |
Zornitza Stark changed review comment from: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both. Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder. Well established gene-disease association.; to: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both. Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder. Well established gene-disease association. |
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| Mendeliome v0.7599 | ZPR1 |
Zornitza Stark gene: ZPR1 was added gene: ZPR1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZPR1 were set to 29851065 Phenotypes for gene: ZPR1 were set to Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies 619321 Review for gene: ZPR1 was set to RED Added comment: 3 families reported with growth restriction, hypoplastic kidneys, alopecia, and distinctive facies (GKAF). All were Hispanic families from the middle Rio Grande Valley. Homozygous missense identified in one family, p. Ile196Thr. Others unavailable for testing, founder effect postulated. Sources: Literature |
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| Mendeliome v0.7561 | CAPN15 | Zornitza Stark Phenotypes for gene: CAPN15 were changed from microphthalmia HP:0000568; coloboma HP:0000589 to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318; microphthalmia HP:0000568; coloboma HP:0000589 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7559 | CAPN15 | Zornitza Stark reviewed gene: CAPN15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33410501; Phenotypes: Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318, microphthalmia HP:0000568, coloboma HP:0000589; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7464 | VPS41 |
Kristin Rigbye changed review comment from: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."; to: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function." "Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay. Two siblings further presented with therapy-resistant epilepsy. No major dysmorphic features were found. In two individuals, retinal pigment alterations were noticed. Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals while in one case (Subject 9) bilateral hyperintensities at the nucleus caudatus area were noted. No hearing or vision problems were noted and in cases where nerve conduction studies were performed, these were normal. Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells." |
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| Mendeliome v0.7209 | YIPF5 | Zornitza Stark Phenotypes for gene: YIPF5 were changed from Neonatal diabetes; microcephaly; seizures to Microcephaly, epilepsy, and diabetes syndrome 2 , MIM#619278 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7208 | YIPF5 | Zornitza Stark edited their review of gene: YIPF5: Changed phenotypes: Microcephaly, epilepsy, and diabetes syndrome 2 , MIM#619278 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7191 | UNC50 |
Arina Puzriakova gene: UNC50 was added gene: UNC50 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC50 were set to 29016857; 33820833 Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita Review for gene: UNC50 was set to AMBER Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype. - PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle. - PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally. -- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity. Sources: Literature |
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| Mendeliome v0.7187 | PDIA6 |
Zornitza Stark gene: PDIA6 was added gene: PDIA6 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes Review for gene: PDIA6 was set to AMBER Added comment: Amber in view of the good quality functional data. 1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. Sources: Literature |
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| Mendeliome v0.7147 | MIA3 |
Zornitza Stark changed review comment from: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported. Mouse model has absence of bone mineralization. Sources: Expert list; to: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization. Sources: Expert list |
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| Mendeliome v0.7147 | MIA3 |
Zornitza Stark gene: MIA3 was added gene: MIA3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIA3 were set to 32101163; 33778321 Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269 Review for gene: MIA3 was set to AMBER Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported. Mouse model has absence of bone mineralization. Sources: Expert list |
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| Mendeliome v0.7113 | MESP1 |
Zornitza Stark gene: MESP1 was added gene: MESP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203 Phenotypes for gene: MESP1 were set to Congenital heart disease Review for gene: MESP1 was set to AMBER Added comment: Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development. Sources: Expert list |
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| Mendeliome v0.7075 | CELA3B |
Bryony Thompson gene: CELA3B was added gene: CELA3B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CELA3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELA3B were set to 31369399; 33565216 Phenotypes for gene: CELA3B were set to Chronic pancreatitis Mode of pathogenicity for gene: CELA3B was set to Other Review for gene: CELA3B was set to AMBER Added comment: PMID: 33565216 - p.Arg90Cys (c.268C>T) identified in a chronic pancreatitis (also diabetes and pancreatic adenocarcinoma present in some individuals) pedigree. Variant was present in 2 affected individuals and not present in 7 healthy relatives. Also, supporting in vitro functional assays demonstrating gain of function mechanism for R90C and R90L, and supporting mouse model. PMID: 31369399 - p.Arg90Leu (c.269G>T) identified in 4 French chronic pancreatitis cases and 0 controls. However, there are 229 hets in gnomAD v2.1 with this variant. Sources: Literature |
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| Mendeliome v0.7073 | SLC10A1 |
Zornitza Stark gene: SLC10A1 was added gene: SLC10A1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: SLC10A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC10A1 were set to 24867799; 27882152; 28835676; 29290974; 31201272 Phenotypes for gene: SLC10A1 were set to Familial hypercholanemia-2, MIM#619256 Review for gene: SLC10A1 was set to GREEN Added comment: IEM characterised by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT). Some variants are recurrent (founder effect likely) but at least 3 different variants reported, mouse model. Sources: Expert list |
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| Mendeliome v0.6940 | IER3IP1 | Zornitza Stark Phenotypes for gene: IER3IP1 were changed from to Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231; Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6937 | IER3IP1 | Zornitza Stark reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21835305, 22991235, 24138066, 28711742; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231, Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6901 | SPINT2 | Zornitza Stark changed review comment from: More than 15 unrelated families reported.; to: Well established gene-disease association. PMID 30445423 reviews 34 patients from 26 families: 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation. Choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhoea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhoea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6825 | SCA31 |
Bryony Thompson STR: SCA31 was added STR: SCA31 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA31 were set to 19878914; 31755042 Phenotypes for STR: SCA31 were set to Spinocerebellar ataxia 31 MIM#117210 Review for STR: SCA31 was set to GREEN STR: SCA31 was marked as clinically relevant Added comment: Complex repeat insertion (TGGAA)n, (TAGAA)n, (TAAAA)n, (TAAAATAGAA)n, TGGAA is present only in affected cases. Sequencing showed that the insertion consisted of a preceding TCAC sequence, and 3 pentanucleotide repeat components (TGGAA)n, (TAGAA)n, and (TAAAA)n in all patients tested. 2.5-3.8 KB insertion is associated with disease and RNA toxicity expected to be mechanism of disease Normal and pathogenic cut-offs are based on animal model experiments (PMID: 31755042) Sources: Expert list |
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| Mendeliome v0.6808 | SATB1 | Zornitza Stark commented on gene: SATB1: Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present. 12 individuals from 11 families reported (one inherited variant, affected parent). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6754 | ZCCHC8 |
Bryony Thompson gene: ZCCHC8 was added gene: ZCCHC8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZCCHC8 were set to 31488579 Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis Review for gene: ZCCHC8 was set to AMBER Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model. Sources: Literature |
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| Mendeliome v0.6742 | UBAP1 |
Zornitza Stark changed review comment from: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.; to: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex. PMID 32934340: additional 7 families. Median age of onset 10yrs. |
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| Mendeliome v0.6668 | WBP11 | Zornitza Stark Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227; malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6574 | TTC7A | Zornitza Stark Phenotypes for gene: TTC7A were changed from Gastrointestinal defects and immunodeficiency syndrome, 243150 to Gastrointestinal defects and immunodeficiency syndrome, 243150; Very Early Onset Inflammatory Bowel Disease (VEOIBD) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6519 | PAX4 | Zornitza Stark Phenotypes for gene: PAX4 were changed from to Maturity-onset diabetes of the young, type IX MIM#612225; Diabetes mellitus, type 2, MIM# 125853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6516 | PAX4 | Zornitza Stark reviewed gene: PAX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 17426099, 14561778, 25951767, 21263211; Phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Diabetes mellitus, type 2, MIM# 125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6501 | PCBD1 |
Michelle Torres edited their review of gene: PCBD1: Added comment: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; Changed phenotypes: MODY, Hyperphenylalaninemia, BH4-deficient, D 264070 |
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| Mendeliome v0.6494 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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| Mendeliome v0.6490 | PCBD1 |
Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes. PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY |
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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 v0.6326 | IGSF1 | Zornitza Stark Phenotypes for gene: IGSF1 were changed from to Hypothyroidism, central, and testicular enlargement, MIM# 300888 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6323 | IGSF1 | Zornitza Stark reviewed gene: IGSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27310681, 30086211, 24108313, 26840047, 27762734, 23143598; Phenotypes: Hypothyroidism, central, and testicular enlargement, MIM# 300888; 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 v0.6228 | SLC46A1 | Zornitza Stark changed review comment from: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.; to: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhoea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6207 | WBP11 |
Eleanor Williams gene: WBP11 was added gene: WBP11 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WBP11 were set to 33276377 Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems Review for gene: WBP11 was set to GREEN Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies. Sources: Literature |
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| Mendeliome v0.6179 | EYA3 |
Paul De Fazio gene: EYA3 was added gene: EYA3 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: EYA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: EYA3 were set to 33475861 Phenotypes for gene: EYA3 were set to Oculo-auriculo-vertebral spectrum (OAVS) Review for gene: EYA3 was set to RED gene: EYA3 was marked as current diagnostic Added comment: 3 individuals with OAVS from two unrelated families with the same missense variant, p.(Asn358Ser). Variant has 20 heterozygotes in gnomAD. Unaffected carriers in both families were also identified - unknown if incomplete penetrance or nonsegregation. Functional studies indicate the variant increases protein half life, and gene knockdown in zebrafish had an effect on craniofacial development. Rated Red due to both families sharing the variant and uncertainty about incomplete penetrance versus nonsegregation. Sources: Literature |
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| Mendeliome v0.6174 | OTUD5 |
Zornitza Stark gene: OTUD5 was added gene: OTUD5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: OTUD5 were set to 33131077 Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality Review for gene: OTUD5 was set to RED Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies. Sources: Literature |
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| Mendeliome v0.6171 | CLRN2 |
Paul De Fazio gene: CLRN2 was added gene: CLRN2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLRN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLRN2 were set to 33496845 Phenotypes for gene: CLRN2 were set to Non-syndromic hearing loss Review for gene: CLRN2 was set to AMBER gene: CLRN2 was marked as current diagnostic Added comment: Missense variant segregates with non-syndromic hearing loss in 3 members of a consanguineous family, two from one nuclear family and one from another. The variant was also shown to result in some transcripts being abnormally spliced, resulting in a premature stop codon. Functional studies in zebrafish and mice show the gene plays an essential role in normal organization and maintenance of the auditory hair bundles, and for hearing function. Rated Amber due to supporting functional studies in mice. Sources: Literature |
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| Mendeliome v0.6119 | FOXF1 |
Zornitza Stark changed review comment from: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.; to: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs. Over 50 families reported. |
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| Mendeliome v0.6107 | CREB3L3 |
Bryony Thompson gene: CREB3L3 was added gene: CREB3L3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: CREB3L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CREB3L3 were set to 32580631; 29954705; 27982131; 27291420; 26427795; 21666694 Phenotypes for gene: CREB3L3 were set to Hyperlipidaemia; hypertriglyceridemia Review for gene: CREB3L3 was set to AMBER Added comment: PMID: 26427795 - a loss of function variant (c.359delG p.K120fsX20) was identified in 2 affected adult siblings and a 13 yo normotriglyceridemic daughter of one of the siblings. PMID: 21666694 - Lipoprotein profiles of the families of 4 individuals with CREB3L3 nonsense mutations showed a significantly elevated mean plasma TG level in 11 mutation carriers compared with 5 non-carrier first-degree relatives (9.67 ± 4.70 vs. 1.66 ± 0.55 mM, P = 0.021, Wilcoxon test). 3 of those families have the same variant - Lys245GlufsTer130, which has 126 (281,946 alleles) hets in gnomAD v2.1. PMID: 32580631 - case-control analysis of nonmonogenic severe hypertriglyceridemia cases (N=265) vs normolipidemic controls (N=477), identified 5 cases with LoF variants (3 of whom had the Lys245GlufsTer130 frameshift) and none in controls. OR 20.2 (95% CI 1.11–366.1) p = 0.002, adjusted p = 0.03. The frequency of Lys245GlufsTer130 is higher than expected for a dominant disorder, but other loss of function variants have been identified. The gene may be associated with variable penetrance. There are multiple supporting null mouse models with hyperlipidaemia. Sources: Expert list |
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| Mendeliome v0.6100 | ZMYND15 |
Bryony Thompson gene: ZMYND15 was added gene: ZMYND15 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ZMYND15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZMYND15 were set to 24431330; 33169450; 20675388 Phenotypes for gene: ZMYND15 were set to Severe oligozoospermia Review for gene: ZMYND15 was set to GREEN Added comment: 4 unrelated consanguineous cases with homozygous loss of function variants. Zmynd15-null male mice display reduced testis weight and azoospermia Sources: Literature |
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| Mendeliome v0.6095 | TMEM251 |
Bryony Thompson gene: TMEM251 was added gene: TMEM251 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM251 were set to 33252156 Phenotypes for gene: TMEM251 were set to Dysostosis multiplex‐like skeletal dysplasia; severe short stature Review for gene: TMEM251 was set to AMBER Added comment: Two unrelated consanguineous families with homozygous variants (c.133C>T; p.Arg45Trp and c.215dupA; p.Tyr72Ter), with co-segregation data in one family. Preliminary in vitro functional assays conducted - Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Sources: Literature |
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| Mendeliome v0.6035 | TSPYL1 | Zornitza Stark Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome (MIM#608800) to Sudden infant death with dysgenesis of the testes syndrome (MIM#608800); sudden infant death-dysgenesis of the testes syndrome MONDO:0012124 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6026 | TSPYL1 | Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6016 | FGF13 |
Zornitza Stark gene: FGF13 was added gene: FGF13 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FGF13 were set to 33245860 Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy Mode of pathogenicity for gene: FGF13 was set to Other Review for gene: FGF13 was set to GREEN Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Sources: Literature |
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| Mendeliome v0.5687 | DPAGT1 | Zornitza Stark Phenotypes for gene: DPAGT1 were changed from to Congenital disorder of glycosylation, type Ij, MIM# 608093; DPAGT1-CDG MONDO:0011964; Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM# 614750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5684 | DPAGT1 |
Zornitza Stark changed review comment from: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder.; to: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder. More than 5 unrelated families reported with this presentation. |
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| Mendeliome v0.5684 | DPAGT1 | Zornitza Stark reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111; Phenotypes: Congenital disorder of glycosylation, type Ij, MIM# 608093, DPAGT1-CDG MONDO:0011964, Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM# 614750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5644 | MSH5 |
Bryony Thompson gene: MSH5 was added gene: MSH5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MSH5 were set to 28175301; 9916805; 24970489 Phenotypes for gene: MSH5 were set to Premature ovarian failure 13 MIM#617442 Review for gene: MSH5 was set to AMBER Added comment: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5. Sources: Literature |
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| Mendeliome v0.5526 | YIPF5 |
Zornitza Stark gene: YIPF5 was added gene: YIPF5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YIPF5 were set to 33164986 Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures Review for gene: YIPF5 was set to GREEN Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association. Sources: Literature |
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| Mendeliome v0.5449 | ALG8 | Zornitza Stark changed review comment from: Review of 15 reported individuals in PMID: 26066342: multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13.; to: Bi-allelic variants and CDG: Review of 15 reported individuals in PMID: 26066342. Multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5408 | MYL9 |
Zornitza Stark gene: MYL9 was added gene: MYL9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: MYL9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYL9 were set to 29453416; 33031641 Phenotypes for gene: MYL9 were set to Megacystis-microcolon-intestinal hypoperistalsis syndrome Review for gene: MYL9 was set to AMBER Added comment: Two unrelated families reported. Sources: Literature |
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| Mendeliome v0.5349 | SLC12A2 | Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Delpire-McNeill syndrome, MIM#619083, Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies, Deafness, autosomal dominant 78, MIM# 619081 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5348 | SLC12A2 | Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies, Deafness, autosomal dominant 78, MIM# 619081 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.5347 | SLC12A2 | Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.5254 | 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). |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.5079 | 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 v0.4998 | 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 |
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| Mendeliome v0.4885 | NEUROD1 | Zornitza Stark Phenotypes for gene: NEUROD1 were changed from to Maturity-onset diabetes of the young 6, MIM#606394; Retinitis pigmentosa, retinopathy, permanent neonatal diabetes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.4882 | NEUROD1 | Zornitza Stark reviewed gene: NEUROD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25477324, 25684977, 22784109, 29521454; Phenotypes: Maturity-onset diabetes of the young 6, MIM#606394, Retinitis pigmentosa, retinopathy, permanent neonatal diabetes; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 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 v0.4796 | AP1S1 | Zornitza Stark Phenotypes for gene: AP1S1 were changed from to MEDNIK syndrome 609313; non-syndromic congenital intestinal failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| Mendeliome v0.4786 | AP1S1 | Ee Ming Wong reviewed gene: AP1S1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32306098; Phenotypes: non-syndromic congenital intestinal failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 v0.4525 | 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 |
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| 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). --- 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. ----- 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 |
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| 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 v0.4091 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| Mendeliome v0.3785 | PLA2G4A |
Zornitza Stark gene: PLA2G4A was added gene: PLA2G4A was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PLA2G4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLA2G4A were set to 18451993; 25102815; 23268370 Phenotypes for gene: PLA2G4A were set to Gastrointestinal ulceration, recurrent, with dysfunctional platelets, MIM# 618372 Review for gene: PLA2G4A was set to GREEN Added comment: At least three unrelated individuals reported. Sources: Expert list |
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| 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 |
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| 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 Phenotypes for gene: ANO1 were changed from to Impaired intestinal peristalsis; dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Mendeliome v0.3363 | TSPYL1 | Zornitza Stark Phenotypes for gene: TSPYL1 were changed from to Sudden infant death with dysgenesis of the testes syndrome (MIM#608800) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3359 | TSPYL1 | Zornitza Stark reviewed gene: TSPYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 15273283, 19463995, 22137496, 25449952, 16418600; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome (MIM#608800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.2723 | 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 v0.2630 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 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 v0.2556 | 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 |
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| 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 |
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| Mendeliome v0.2440 | ATOH7 | Paul De Fazio changed review comment from: Segregates with disease in 3 consanguineous families from Pakistan/Turkey and one non-consanguineous family of Swiss origin. Functional effect was demonstrated in the latter family. The mouse homolog is required for retinal ganglion cell and optic nerve formation.; to: Segregates with disease in 3 consanguineous families from Pakistan/Turkey with global eye abnormalities, and one non-consanguineous family of Swiss origin with optic nerve hypoplasia. Functional effect was demonstrated in the latter family. The mouse homolog is required for retinal ganglion cell and optic nerve formation (in mice). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 v0.2304 | 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 |
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| Mendeliome v0.2286 | KCNJ11 | Zornitza Stark Phenotypes for gene: KCNJ11 were changed from to {Diabetes mellitus, type 2, susceptibility to} 125853; Diabetes mellitus, transient neonatal, 3 610582; Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820; Maturity-onset diabetes of the young, type 13 616329 AD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| Mendeliome v0.2280 | KCNJ11 | Elena Savva reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: {Diabetes mellitus, type 2, susceptibility to} 125853, Diabetes mellitus, transient neonatal, 3 610582, Diabetes, permanent neonatal, with or without neurologic features 606176, Hyperinsulinemic hypoglycemia, familial, 2 601820, Maturity-onset diabetes of the young, type 13 616329 AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 v0.1590 | 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 v0.1471 | COX4I2 | Zornitza Stark edited their review of gene: COX4I2: Added comment: Glu138Lys present in 3 homozygotes in gnomad, wich is out of keeping for this rare metabolic disorder. Note no other variants reported in this gene since original report in 2009. All variants submitted to ClinVar are VOUS/LB/B.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1450 | CEL | Zornitza Stark Phenotypes for gene: CEL were changed from to Maturity-onset diabetes of the young, type VIII | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1446 | CEL | Zornitza Stark reviewed gene: CEL: Rating: AMBER; Mode of pathogenicity: None; Publications: 24062244, 21784842, 19760265, 18544793, 17989309, 16369531, 29233499, 27650499; Phenotypes: Maturity-onset diabetes of the young, type VIII; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1242 | TTC7A | Zornitza Stark Phenotypes for gene: TTC7A were changed from to Gastrointestinal defects and immunodeficiency syndrome, 243150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1239 | TTC7A | Melanie Marty reviewed gene: TTC7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30553809, 28936210; Phenotypes: Gastrointestinal defects and immunodeficiency syndrome, 243150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1164 | SOD2 | Zornitza Stark Phenotypes for gene: SOD2 were changed from to {Microvascular complications of diabetes 6} 612634 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1161 | SOD2 | Zornitza Stark reviewed gene: SOD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Microvascular complications of diabetes 6} 612634; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1111 | FLNA | Zornitza Stark Phenotypes for gene: FLNA were changed from to ?FG syndrome 2, XL; Cardiac valvular dysplasia, X-linked; Congenital short bowel syndrome; Frontometaphyseal dysplasia 1; Heterotopia, periventricular, 1; Intestinal pseudoobstruction, neuronal Melnick-Needles syndrome; Otopalatodigital syndrome, type I; Otopalatodigital syndrome, type II; Terminal osseous dysplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1069 | FLNA | Elena Savva reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30089473; Phenotypes: ?FG syndrome 2, XL, Cardiac valvular dysplasia, X-linked, Congenital short bowel syndrome, Frontometaphyseal dysplasia 1, Heterotopia, periventricular, 1, Intestinal pseudoobstruction, neuronal Melnick-Needles syndrome, Otopalatodigital syndrome, type I, Otopalatodigital syndrome, type II, Terminal osseous dysplasia; 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 v0.831 | NKX2-2 |
Zornitza Stark gene: NKX2-2 was added gene: NKX2-2 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: NKX2-2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NKX2-2 were set to 24411943; 9584121 Phenotypes for gene: NKX2-2 were set to Syndromic neonatal diabetes, with severe developmental delay, hypotonia, cortical blindness, hearing impairment Review for gene: NKX2-2 was set to GREEN Added comment: Sources: Expert list |
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| Mendeliome v0.788 | TDP2 |
Zornitza Stark gene: TDP2 was added gene: TDP2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: TDP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TDP2 were set to 31410782; 30109272; 24658003 Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23; OMIM #616949 Review for gene: TDP2 was set to GREEN Added comment: ID is part of the phenotype: 4 families with 6 affected patients, with functional evidence. 1 family with 3 affected sibs with homozygous splice site mutation in the TDP2 gene. Patient cell extracts showed absence of the full-length TDP2 protein and absence of 5-prime TDP activity, consistent with a loss of function, although 3-prime TDP activity, conferred by TDP1, was normal. In addition, patient lymphoblastoid cells were hypersensitive to the TOP2 poison etoposide. The findings indicated impaired capacity for double-strand break repair. 1 unrelated Egyptian patient with a similar disorder was homozygous for a truncating mutation in the TDP2 gene 1 unrelated Caucasian patient with same homozygous splice site mutation in the TDP2 gene. Western blot analysis did not detect TDP2 protein in patient primary skin fibroblasts. Patient fibroblasts showed an inability to rapidly repair topoisomerase-induced DNA double-strand breaks in the nucleus and also showed a profound hypersensitivity to this type of DNA damage. Complementation of patient cells with recombinant human TDP2 restored normal rates of nuclear DSB repair. Sources: Expert list |
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| Mendeliome v0.760 | AVPR2 | Zornitza Stark Phenotypes for gene: AVPR2 were changed from to Diabetes insipidus, nephrogenic 304800; Nephrogenic syndrome of inappropriate antidiuresis 300539 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.749 | AVPR2 | Belinda Chong reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 9127330, PubMed: 15872203; Phenotypes: Diabetes insipidus, nephrogenic 304800, Nephrogenic syndrome of inappropriate antidiuresis 300539; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.652 | H3F3B | Zornitza Stark commented on gene: H3F3B: Elizabeth J Bhoj, H3F3A/B Consortium, Hakon H. Hakonarson.: Mutations In H3f3a And H3f3b Encoding Histone 3.3: Report Of 26 Patients With Neurodevelopmental And Congenital Manifestations. American Society of Human Genetics, Orlando, FL October 2017 Notes: Platform Presentation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.644 | EIF3F |
Zornitza Stark gene: EIF3F was added gene: EIF3F was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EIF3F were set to 30409806 Phenotypes for gene: EIF3F were set to Mental retardation, autosomal recessive 67, MIM# 618295 Review for gene: EIF3F was set to GREEN Added comment: Nine individuals from 7 families reported, all homozygous for the same missense variant, p.(Phe232Val). This variant is present at 0.12% frequency in non-Finnish Europeans in gnomad (no homozygotes). Sources: Expert list |
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| Mendeliome v0.425 | FAT2 |
Zornitza Stark gene: FAT2 was added gene: FAT2 was added to Mendeliome_VCGS. Sources: Expert list Mode of inheritance for gene: FAT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FAT2 were set to 29053796 Phenotypes for gene: FAT2 were set to Spinocerebellar ataxia 45, MIM#617769 Review for gene: FAT2 was set to AMBER Added comment: Segregates in one family, and identified in one apparently sporadic case. In vitro functional evidence. Sources: Expert list |
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| Mendeliome v0.307 | PIGB |
Zornitza Stark gene: PIGB was added gene: PIGB was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGB were set to 31256876 Phenotypes for gene: PIGB were set to Epileptic encephalopathy, early infantile, 80; OMIM #618580 Review for gene: PIGB was set to GREEN Added comment: 10 unrelated families with biallelic mutations in PIGB, with global DD and/or ID, and seizures. Two had polymicrogyria, 4 had a peripheral neuropathy, and 2 had a clinical diagnosis of DOORS syndrome. Patient lymphocytes and fibroblasts showed variably decreased levels of cell surface GPI-anchored proteins, including CD16 and CD59. In vitro functional expression studies performed with some of the mutations in PIGB-null CHO cells showed that the mutant proteins were unable to fully restore expression of GPI-anchored surface proteins, consistent with a loss of function, although the mutations had variable effects. Sources: Literature |
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| Mendeliome v0.282 | LMAN2L |
Zornitza Stark gene: LMAN2L was added gene: LMAN2L was added to Mendeliome_VCGS. Sources: Literature Mode of inheritance for gene: LMAN2L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: LMAN2L were set to 31020005; 26566883 Phenotypes for gene: LMAN2L were set to Mental retardation, autosomal recessive, 52; OMIM #616887 Review for gene: LMAN2L was set to AMBER Added comment: 1 consanguineous family with 7 individuals with ID and epilepsy, with homozygous LMAN2L missense mutation. Segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies. 1 non-consanguineous family with 4 affected with heterozygous frameshift LMAN2L mutation. Segregates in family. Mutation eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane. Sources: Literature |
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