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DDG2P v6.17 TUBB3 Achchuthan Shanmugasundram edited their review of gene: TUBB3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TUBB3-related cortical dysplasia, complex, with other brain malformations are strong, monoallelic_autosomal and undetermined (PMIDs: 20074521, 20829227). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00755.; Changed publications to: 20829227, 20074521; Changed phenotypes to: MONDO:0013541, TUBB3-related cortical dysplasia, complex, with other brain malformations, CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 1, OMIM:614039.0
DDG2P v6.17 TUBB2A Achchuthan Shanmugasundram edited their review of gene: TUBB2A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TUBB2A-related cortical dysplasia, complex, with other brain malformations are definitive, monoallelic_autosomal and undetermined (PMID:24702957). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00402.; Changed phenotypes to: OMIM:615763.0, TUBB2A-related cortical dysplasia, complex, with other brain malformations, MONDO:0014337, CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5, OMIM:615763
DDG2P v6.17 TUBB Achchuthan Shanmugasundram edited their review of gene: TUBB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TUBB-related developmental disorder with cleft palate, cranial malformations and circumferential skin creases (Kunze type) are strong, monoallelic_autosomal and undetermined (PMIDs: 23246003, 23324645, 26637975, 34211110). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01654.; Changed publications to: 34211110, 23324645, 23246003, 26637975; Changed phenotypes to: MONDO:0020738, Circumferential Skin Creases Kunze Type, OMIM:156610, OMIM:156610.0, CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6, OMIM:615771, TUBB-related developmental disorder with cleft palate, cranial malformations and circumferential skin creases (Kunze type)
DDG2P v6.17 TTI2 Achchuthan Shanmugasundram edited their review of gene: TTI2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TTI2-related intellectual developmental disorder are strong, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01468.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, OMIM:615541.0, TTI2-related intellectual developmental disorder, MONDO:0014238
DDG2P v6.17 TTC12 Achchuthan Shanmugasundram edited their review of gene: TTC12: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TTC12-related primary ciliary dyskinesia are strong, biallelic_autosomal and loss of function (PMID:31978331). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02927.; Changed rating: GREEN; Changed phenotypes to: TTC12-related Primary Ciliary Dyskinesia, OMIM:618801.0, MONDO:0032924, TTC12-related primary ciliary dyskinesia
DDG2P v6.17 TSHR Achchuthan Shanmugasundram edited their review of gene: TSHR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TSHR-related hypothyroidism, congenital, nongoitrous are definitive, biallelic_autosomal and undetermined (PMIDs: 10720030, 11095460, 12050212, 7528344, 8954020, 9100579, 9185526, 9329388, 9589691). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01099. The DDG2P confidence category, allelic requirement and molecular mechanism for TSHR-related hyperthyroidism, familial gestational are definitive, monoallelic_autosomal and gain of function (PMID:9854118). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01423.; Changed publications to: 12050212, 10720030, 9100579, 9185526, 9329388, 8954020, 9854118, 11095460, 7528344, 9589691; Changed phenotypes to: TSHR-related hypothyroidism, congenital, nongoitrous, MONDO:0011309, OMIM:603373.0, HYPERTHYROIDISM, FAMILIAL GESTATIONAL, OMIM:603373, TSHR-related hyperthyroidism, familial gestational, HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1, OMIM:275200, MONDO:0010142, OMIM:275200.0
DDG2P v6.17 TSEN34 Achchuthan Shanmugasundram edited their review of gene: TSEN34: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TSEN34-related pontocerebellar hypoplasia are strong, biallelic_autosomal and undetermined (PMID:18711368). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00487.; Changed publications to: 18711368; Changed phenotypes to: PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4, OMIM:316970, MONDO:0012891, TSEN34-related pontocerebellar hypoplasia, OMIM:612390.0
DDG2P v6.17 TSEN2 Achchuthan Shanmugasundram edited their review of gene: TSEN2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TSEN2-related pontocerebellar hypoplasia are strong, biallelic_autosomal and undetermined (PMIDs: 18711368, 20952379, 23562994). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01310.; Changed publications to: 18711368, 20952379, 23562994; Changed phenotypes to: PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4, OMIM:316970, TSEN2-related pontocerebellar hypoplasia, MONDO:0012890, OMIM:612389.0
DDG2P v6.17 TSEN15 Achchuthan Shanmugasundram edited their review of gene: TSEN15: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TSEN15-related pontocerebellar hypoplasia and progressive microcephaly are strong, biallelic_autosomal and undetermined (PMID:27392077). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01755.; Changed phenotypes to: Pontocerebellar Hypoplasia and Progressive Microcephaly, MONDO:0014874, OMIM:617026.0, TSEN15-related pontocerebellar hypoplasia and progressive microcephaly
DDG2P v6.17 TRRAP Achchuthan Shanmugasundram edited their review of gene: TRRAP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRRAP-related autism and syndromic intellectual disability are strong, monoallelic_autosomal and undetermined (PMIDs: 30424743, 30827496). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02646.; Changed publications to: 30424743, 30827496; Changed phenotypes to: OMIM:618454.0, MONDO:0032760, Autism and Syndromic Intellectual Disability, TRRAP-related autism and syndromic intellectual disability
DDG2P v6.17 TRPV4 Achchuthan Shanmugasundram edited their review of gene: TRPV4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRPV4-related spondylometaphyseal dysplasia, Kozlowski type are definitive, monoallelic_autosomal and gain of function (PMIDs: 19232556, 20577006). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01027. The DDG2P confidence category, allelic requirement and molecular mechanism for TRPV4-related metatropic dysplasia are definitive, monoallelic_autosomal and undetermined (PMIDs: 19232556, 20425821, 20577006, 21964829). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01579.; Changed publications to: 20425821, 21964829, 20577006, 19232556; Changed phenotypes to: MONDO:0007986, SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE, OMIM:184252, METATROPIC DYSPLASIA, OMIM:156530, MONDO:0008477, OMIM:184252.0, TRPV4-related metatropic dysplasia, TRPV4-related spondylometaphyseal dysplasia, Kozlowski type, OMIM:156530.0
DDG2P v6.17 TRPV3 Achchuthan Shanmugasundram edited their review of gene: TRPV3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRPV3-related Olmsted syndrome are strong, monoallelic_autosomal and undetermined (PMID:22405088). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00500.; Changed phenotypes to: OLMSTED SYNDROME, OMIM:614594, TRPV3-related Olmsted syndrome, OMIM:614594.0, MONDO:0100296
DDG2P v6.17 TRPM3 Achchuthan Shanmugasundram edited their review of gene: TRPM3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRPM3-related developmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 31278393, 32439617, 34438093, 35146895, 36648066). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02899.; Changed publications to: 34438093, 31278393, 36648066, 35146895, 32439617; Changed phenotypes to: MONDO:0859365, TRPM3-related developmental disorder, OMIM:620224.0, TRPM3-related developmental disorder (monoallelic)
DDG2P v6.17 TRMT10C Achchuthan Shanmugasundram edited their review of gene: TRMT10C: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRMT10C-related mitochondrial RNA processing and multiple respiratory chain deficiencies are strong, biallelic_autosomal and undetermined (PMID:27132592). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01736.; Changed phenotypes to: OMIM:616974.0, MONDO:0014856, Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies, TRMT10C-related mitochondrial RNA processing and multiple respiratory chain deficiencies
DDG2P v6.17 TRIT1 Achchuthan Shanmugasundram edited their review of gene: TRIT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRIT1-related tRNA isopentenyltransferase deficiency are limited, biallelic_autosomal and undetermined (PMIDs: 24901367, 28185376, 31140736, 32088416, 32948376). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01848.; Changed rating: RED; Changed publications to: 24901367, 32088416, 32948376, 28185376, 31140736; Changed phenotypes to: MONDO:0054742, OMIM:617873.0, TRIT1-related tRNA isopentenyltransferase deficiency, tRNA isopentenyltransferase deficiency
DDG2P v6.17 TRIO Achchuthan Shanmugasundram edited their review of gene: TRIO: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRIO-related intellectual disability are strong, monoallelic_autosomal and undetermined (PMIDs: 26235986, 27418539, 28928363, 32109419). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01096.; Changed publications to: 26235986, 32109419, 27418539, 28928363; Changed phenotypes to: INTELLECTUAL DISABILITY, OMIM:601893, TRIO-related intellectual disability, MONDO:0032939, OMIM:618825.0
DDG2P v6.17 TRAPPC2L Achchuthan Shanmugasundram edited their review of gene: TRAPPC2L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRAPPC2L-related encephalopathy, progressive, early-onset, with episodic rhabdomyolysis are limited, biallelic_autosomal and undetermined (PMIDs: 30120216, 32843486). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03196.; Changed publications to: 30120216, 32843486; Changed phenotypes to: TRAPPC2L-related encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331.0, TRAPPC2L-related Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331, MONDO:0032681
DDG2P v6.17 TRAPPC10 Achchuthan Shanmugasundram edited their review of gene: TRAPPC10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRAPPC10-related intellectual disability are limited, biallelic_autosomal and undetermined (PMID:30167849). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03133.; Changed phenotypes to: OMIM:620027.0, TRAPPC10-related intellectual disability, TRAPPC10-associated intellectual disability, MONDO:0859285
DDG2P v6.17 TRAF7 Achchuthan Shanmugasundram edited their review of gene: TRAF7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRAF7-related developmental delay congenital anomalies and dysmorphic features are strong, monoallelic_autosomal and undetermined (PMIDs: 29961569, 32376980, 32459067, 33043583, 34247275, 34513876, 35684978, 35733823, 37067385). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02612.; Changed publications to: 33043583, 35684978, 37067385, 35733823, 32376980, 34247275, 29961569, 34513876, 32459067; Changed phenotypes to: MONDO:0032572, TRAF7-related developmental delay congenital anomalies and dysmorphic features, Developmental Delay Congenital Anomalies and Dysmorphic Features, OMIM:618164.0
DDG2P v6.17 TRA2B Achchuthan Shanmugasundram edited their review of gene: TRA2B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TRA2B-related neurodevelopmental syndrome are moderate, monoallelic_autosomal and undetermined (PMID:36549593). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03418.; Changed phenotypes to: MONDO:0700092, TRA2B-related neurodevelopmental syndrome, TRA2B-associated neurodevelopmental syndrome
DDG2P v6.17 TPRKB Achchuthan Shanmugasundram edited their review of gene: TPRKB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TPRKB-related Galloway-Mowat syndrome are limited, biallelic_autosomal and undetermined (PMID:28805828). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02820.; Changed phenotypes to: TPRKB-related Galloway-Mowat syndrome, MONDO:0033009, OMIM:617731.0, GALLOWAY-MOWAT SYNDROME 5, OMIM:617731
DDG2P v6.17 TPM3 Achchuthan Shanmugasundram edited their review of gene: TPM3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TPM3-related congenital myopathy are definitive, monoallelic_autosomal and undetermined (PMIDs: 24692096, 33768912). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03244.; Changed publications to: 24692096, 33768912; Changed phenotypes to: TPM3-related congenital myopathy, Nemaline/Cap myopathy, OMIM:255310.0, MONDO:0800341
DDG2P v6.17 TPM2 Achchuthan Shanmugasundram edited their review of gene: TPM2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TPM2-related arthrogryposis, distal are strong, monoallelic_autosomal and undetermined (PMID:12592607). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01665.; Changed phenotypes to: ARTHROGRYPOSIS, DISTAL, TYPE 1, OMIM:108120, MONDO:0007157, TPM2-related arthrogryposis, distal, OMIM:108120.0
DDG2P v6.17 TNPO2 Achchuthan Shanmugasundram edited their review of gene: TNPO2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TNPO2-related intellectual disability are limited, monoallelic_autosomal and undetermined (PMID:34314705). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03192.; Changed phenotypes to: TNPO2-related intellectual disability, OMIM:619556.0, MONDO:0859197
DDG2P v6.17 TMEM63A Achchuthan Shanmugasundram edited their review of gene: TMEM63A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TMEM63A-related transient hypomyelination during infancy are strong, monoallelic_autosomal and undetermined (PMID:31587869). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02831.; Changed phenotypes to: Transient Hypomyelination during Infancy, TMEM63A-related transient hypomyelination during infancy, OMIM:618688.0, MONDO:0032871
DDG2P v6.17 TMEM216 Achchuthan Shanmugasundram edited their review of gene: TMEM216: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TMEM216-related Joubert syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 20036350, 20512146). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00552.; Changed publications to: 20036350, 20512146; Changed phenotypes to: MONDO:0011963, TMEM216-related Joubert syndrome, JOUBERT SYNDROME 2, OMIM:608091, OMIM:608091.0
DDG2P v6.17 TMEM163 Achchuthan Shanmugasundram edited their review of gene: TMEM163: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TMEM163-related hypomyelinating leukodystrophy are moderate, monoallelic_autosomal and undetermined (PMIDs: 35455965, 35953447). The cross-cutting modifier is typified by incomplete penetrance. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03373.; Changed publications to: 35455965, 35953447; Changed phenotypes to: TMEM163-related hypomyelinating leukodystrophy, MONDO:0859378, OMIM:620243.0
DDG2P v6.17 TMEM135 Achchuthan Shanmugasundram edited their review of gene: TMEM135: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TMEM135-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01472.; Changed phenotypes to: MONDO:0700092, TMEM135-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 TMEM106B Achchuthan Shanmugasundram edited their review of gene: TMEM106B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TMEM106B related hypomyelinating leukodystrophy are strong, monoallelic_autosomal and undetermined (PMIDs: 29186371, 29444210). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02940.; Changed phenotypes to: TMEM106B related hypomyelinating leukodystrophy, OMIM:617964.0, MONDO:0054791
DDG2P v6.17 TLL1 Achchuthan Shanmugasundram edited their review of gene: TLL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TLL1-related atrial septal defect are limited, monoallelic_autosomal and undetermined (PMID:18830233). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00416.; Changed phenotypes to: OMIM:613087.0, TLL1-related atrial septal defect, ATRIAL SEPTAL DEFECT TYPE 6, OMIM:613087, MONDO:0013123
DDG2P v6.17 TK2 Achchuthan Shanmugasundram edited their review of gene: TK2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TK2-related mitochondrial DNA depletion syndrome, myopathic form are definitive, biallelic_autosomal and undetermined (PMIDs: 11687801, 12391347, 12873860, 35280287, 35750291). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01507.; Changed publications to: 35750291, 12873860, 35280287, 12391347, 11687801; Changed phenotypes to: MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC FORM, OMIM:258276, TK2-related mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301, OMIM:609560.0
DDG2P v6.17 THOC2 Achchuthan Shanmugasundram edited their review of gene: THOC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for THOC2-related intellectual developmental disorder are strong, monoallelic_X_hemizygous and undetermined (PMID:26166480). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01676.; Changed phenotypes to: MONDO:0010496, OMIM:300957.0, THOC2-related intellectual developmental disorder, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 12, OMIM:300957
DDG2P v6.17 THG1L Achchuthan Shanmugasundram edited their review of gene: THG1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for THG1L-related cerebellar ataxia are limited, biallelic_autosomal and undetermined (PMIDs: 27307223, 30214071, 31168944, 33682303, 37670026). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03161.; Changed publications to: 31168944, 37670026, 33682303, 30214071, 27307223; Changed phenotypes to: OMIM:618800.0, THG1L-related cerebellar ataxia, THG1L-associated cerebellar ataxia, OMIM:618800, MONDO:0032923
DDG2P v6.17 TGFB1 Achchuthan Shanmugasundram edited their review of gene: TGFB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TGFB1-related Camurati-Engelmann disease are definitive, monoallelic_autosomal and undetermined (PMIDs: 10973241, 11062463, 15103729). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00412.; Changed publications to: 15103729, 11062463, 10973241; Changed phenotypes to: TGFB1-related Camurati-Engelmann disease, CAMURATI-ENGELMANN DISEASE, OMIM:131300, OMIM:131300.0, MONDO:0007542
DDG2P v6.17 TFRC Achchuthan Shanmugasundram edited their review of gene: TFRC: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TFRC-related combined immunodeficiency are limited, biallelic_autosomal and undetermined (PMID:26642240). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01748.; Changed phenotypes to: Combined immunodeficiency, TFRC-related combined immunodeficiency, MONDO:0014760, OMIM:616740.0
DDG2P v6.17 TFE3 Achchuthan Shanmugasundram edited their review of gene: TFE3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TFE3-related intellectual disability with pigmentary mosaicism and coarse features are definitive, monoallelic_X_heterozygous and undetermined (PMIDs: 1672758, 30595499, 31833172, 32409512, 33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03013.; Changed publications to: 1672758, 33057194, 30595499, 32409512, 31833172; Changed phenotypes to: OMIM:301066.0, MONDO:0859080, Intellectual disability with pigmentary mosaicism and storage disorder, TFE3-related intellectual disability with pigmentary mosaicism, TFE3-related intellectual disability with pigmentary mosaicism and coarse features
DDG2P v6.17 TFAP2B Achchuthan Shanmugasundram edited their review of gene: TFAP2B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TFAP2B-related Char syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 10802654, 11505339, 7645594). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00497.; Changed publications to: 11505339, 7645594, 10802654; Changed phenotypes to: OMIM:169100.0, CHAR SYNDROME, OMIM:169100, MONDO:0008209, TFAP2B-related Char syndrome
DDG2P v6.17 TFAP2A Achchuthan Shanmugasundram edited their review of gene: TFAP2A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TFAP2A-related branchiooculofacial syndrome are definitive, monoallelic_autosomal and undetermined (PMID:31490282). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00703.; Changed phenotypes to: OMIM:113620.0, TFAP2A-related branchiooculofacial syndrome, BRANCHIOOCULOFACIAL SYNDROME, OMIM:113620, MONDO:0007235
DDG2P v6.17 TERT Achchuthan Shanmugasundram edited their review of gene: TERT: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TERT-related dyskeratosis congenita (biallelic) are strong, biallelic_autosomal and undetermined (PMIDs: 16247010, 17785587, 24628319, 25067791, 26546739, 30523342, 32315675, 34890115, 35477117, 35927969). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01663. The DDG2P confidence category, allelic requirement and molecular mechanism for TERT-related dyskeratosis congenita (monoallelic) are strong, monoallelic_autosomal and loss of function (PMIDs: 16247010, 25067791, 30523342, 35927969, 38641551). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03384.; Changed publications to: 32315675, 35477117, 35927969, 34890115, 25067791, 16247010, 26546739, 30523342, 24628319, 17785587, 38641551; Changed phenotypes to: OMIM:613989.0, Dyskeratosis Congenita, OMIM:613989, TERT-related dyskeratosis congenita (monoallelic), MONDO:0013521, TERT-related Dyskeratosis congenita, OMIM:613989, Dyskeratosis congenita, autosomal recessive 4, TERT-related dyskeratosis congenita (biallelic)
DDG2P v6.17 TELO2 Achchuthan Shanmugasundram edited their review of gene: TELO2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TELO2-related syndromic intellectual disability disorder are strong, biallelic_autosomal and undetermined (PMIDs: 27132593, 28944240, 36797513). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01733.; Changed publications to: 36797513, 28944240, 27132593; Changed phenotypes to: OMIM:616954.0, TELO2 Syndromic Intellectual Disability Disorder, TELO2-related syndromic intellectual disability disorder, MONDO:0014848
DDG2P v6.17 TDRD7 Achchuthan Shanmugasundram edited their review of gene: TDRD7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TDRD7-related cataract with or without azoospermia are moderate, biallelic_autosomal and loss of function (PMIDs: 21436445, 28418495, 31048812). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01467.; Changed publications to: 21436445, 31048812, 28418495; Changed phenotypes to: TDRD7-related cataract with or without azoospermia, CATARACT CONGENITAL AUTOSOMAL RECESSIVE TYPE 4, OMIM:613887, TDRD7-related cataract with or without azoospermia, OMIM:613887, OMIM:613887.0, MONDO:0013484
DDG2P v6.17 TCEAL1 Achchuthan Shanmugasundram edited their review of gene: TCEAL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TCEAL1-related neurodevelopmental disorder are moderate, monoallelic_X_hemizygous and undetermined (PMIDs: 36368327, 38200082). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03454.; Changed publications to: 38200082, 36368327; Changed phenotypes to: TCEAL1-related neurodevelopmental disorder, OMIM:301094.0, MONDO:0859085
DDG2P v6.17 TBXAS1 Achchuthan Shanmugasundram edited their review of gene: TBXAS1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TBXAS1-related ghosal hematodiaphyseal syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 18264100, 33595912, 35395429). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00704.; Changed publications to: 18264100, 33595912, 35395429; Changed phenotypes to: MONDO:0009274, GHOSAL HEMATODIAPHYSEAL SYNDROME, OMIM:231095, TBXAS1-related ghosal hematodiaphyseal syndrome, OMIM:231095.0
DDG2P v6.17 TAF2 Achchuthan Shanmugasundram edited their review of gene: TAF2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TAF2-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01319.; Changed phenotypes to: OMIM:615599.0, TAF2-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 TAF13 Achchuthan Shanmugasundram edited their review of gene: TAF13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TAF13-related intellectual disability and microcephaly are strong, biallelic_autosomal and undetermined (PMID:28257693). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02249.; Changed phenotypes to: MONDO:0044313, TAF13-related intellectual disability and microcephaly, OMIM:617432.0, Autosomal-Recessive Intellectual Disability and Microcephaly
DDG2P v6.17 TACR3 Achchuthan Shanmugasundram edited their review of gene: TACR3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TACR3-related hypogonadotropic hypogonadism are strong, biallelic_autosomal and undetermined (PMID:19079066). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00493.; Changed phenotypes to: HYPOGONADOTROPIC HYPOGONADISM, OMIM:146110, MONDO:0013913, OMIM:614840.0, TACR3-related hypogonadotropic hypogonadism
DDG2P v6.17 TAC3 Achchuthan Shanmugasundram edited their review of gene: TAC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TAC3-related hypogonadotropic hypogonadism are strong, biallelic_autosomal and undetermined (PMID:19079066). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00444.; Changed phenotypes to: MONDO:0013912, TAC3-related hypogonadotropic hypogonadism, HYPOGONADOTROPIC HYPOGONADISM, OMIM:146110, OMIM:614839.0
DDG2P v6.17 TAB2 Achchuthan Shanmugasundram edited their review of gene: TAB2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for TAB2-related nonsyndromic congenital heart disease are definitive, monoallelic_autosomal and undetermined (PMIDs: 20493459, 27479907). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01246.; Changed phenotypes to: OMIM:612863.0, CONGENITAL HEART DISEASE, NONSYNDROMIC, 2, OMIM:612863, TAB2-related nonsyndromic congenital heart disease, MONDO:0013025
DDG2P v6.17 SYT1 Achchuthan Shanmugasundram edited their review of gene: SYT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SYT1-related intellectual disability are strong, monoallelic_autosomal and undetermined (PMIDs: 25705886, 30107533). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00305.; Changed phenotypes to: INTELLECTUAL DISABILITY, OMIM:616579, OMIM:618218.0, SYT1-related intellectual disability
DDG2P v6.17 SUPT16H Achchuthan Shanmugasundram edited their review of gene: SUPT16H: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SUPT16H-related neurodevelopmental disorder are limited, monoallelic_autosomal and undetermined (PMID:31924697). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03010.; Changed phenotypes to: OMIM:619480.0, MONDO:0859179, SUPT16H-related neurodevelopmental disorder
DDG2P v6.17 SUFU Achchuthan Shanmugasundram edited their review of gene: SUFU: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SUFU-related Joubert syndrome with cranio-facial and skeletal defects are strong, biallelic_autosomal and undetermined (PMID:28965847). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02372. The DDG2P confidence category, allelic requirement and molecular mechanism for SUFU-related Joubert and congenital ocular motor apraxia are strong, monoallelic_autosomal and undetermined (PMIDs: 33024317, 34675124). The cross-cutting modifier is typified by incomplete penetrance. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03224.; Changed phenotypes to: MONDO:0033309, SUFU-related Joubert and congenital ocular motor apraxia, OMIM:617757.0, SUFU-related Joubert syndrome with cranio-facial and skeletal defects, Joubert Syndrome with Cranio-facial and Skeletal Defects
DDG2P v6.17 STT3A Achchuthan Shanmugasundram edited their review of gene: STT3A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for STT3A-related congenital disorder of glycosylation are limited, biallelic_autosomal and undetermined (PMID:23842455). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01064. The DDG2P confidence category, allelic requirement and molecular mechanism for STT3A-related type I congenital disorder of glycosylation with neuromusculoskeletal disease are strong, monoallelic_autosomal and undetermined (PMID:34653363). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03226.; Changed phenotypes to: OMIM:615596.0, MONDO:0859223, STT3A-related congenital disorder of glycosylation, OMIM:619714.0, STT3A-related type I congenital disorder of glycosylation with neuromusculoskeletal disease, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IW, OMIM:615596
DDG2P v6.17 ST3GAL3 Achchuthan Shanmugasundram edited their review of gene: ST3GAL3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ST3GAL3-related intellectual developmental disorder are strong, biallelic_autosomal and undetermined (PMIDs: 17120046, 21907012). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01455.; Changed phenotypes to: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 12, OMIM:611090, OMIM:611090.0, MONDO:0012612, ST3GAL3-related intellectual developmental disorder
DDG2P v6.17 ST14 Achchuthan Shanmugasundram edited their review of gene: ST14: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ST14-related ichthyosis with hypotrichosis are strong, biallelic_autosomal and undetermined (PMIDs: 17273967, 18445049). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01285.; Changed publications to: 17273967, 18445049; Changed phenotypes to: OMIM:602400.0, MONDO:0011218, ST14-related ichthyosis with hypotrichosis, ICHTHYOSIS AUTOSOMAL RECESSIVE WITH HYPOTRICHOSIS, OMIM:610765
DDG2P v6.17 SRPX2 Achchuthan Shanmugasundram edited their review of gene: SRPX2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SRPX2-related bilateral perisylvian polymicrogyria are limited, monoallelic_X_hemizygous and undetermined (PMID:16497722). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01418.; Changed phenotypes to: SRPX2-related bilateral perisylvian polymicrogyria, OMIM:300388.0, BILATERAL PERISYLVIAN POLYMICROGYRIA, OMIM:300388, MONDO:0010314
DDG2P v6.17 SRP54 Achchuthan Shanmugasundram edited their review of gene: SRP54: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SRP54-related syndromic neutropenia with Shwachman-Diamond-like features are strong, monoallelic_autosomal and undetermined (PMID:28972538). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02416.; Changed phenotypes to: MONDO:0032899, SRP54-related syndromic neutropenia with Shwachman-Diamond-like features, OMIM:618752.0, Syndromic neutropenia with Shwachman-Diamond-like features
DDG2P v6.17 SRCAP Achchuthan Shanmugasundram edited their review of gene: SRCAP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SRCAP-related Floating-Harbor syndrome are definitive, monoallelic_autosomal and dominant negative (PMIDs: 22265015, 22965468, 23165645, 23621943, 23763483, 24375913, 25433523, 26788936, 30304910, 30425916, 32924116). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00246. The DDG2P confidence category, allelic requirement and molecular mechanism for SRCAP-related neurodevelopmental disorder are strong, monoallelic_autosomal and loss of function (PMIDs: 33909990, 34213696, 37340855). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03152.; Changed publications to: 32924116, 33909990, 26788936, 24375913, 30425916, 22265015, 30304910, 34213696, 22965468, 23165645, 25433523, 23621943, 23763483, 37340855; Changed phenotypes to: MONDO:0007621, SRCAP-related Neurodevelopmental Disorder, SRCAP-related Floating-Harbor syndrome, OMIM:136140.0, SRCAP-related neurodevelopmental disorder, FLOATING-HARBOR SYNDROME, OMIM:136140, MONDO:0859202, OMIM:619595.0
DDG2P v6.17 SPTLC2 Achchuthan Shanmugasundram edited their review of gene: SPTLC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPTLC2-related neuropathy, hereditary sensory and autonomic are strong, monoallelic_autosomal and undetermined (PMIDs: 20920666, 23658386, 25567748, 30866134, 31509666). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01537.; Changed publications to: 31509666, 25567748, 23658386, 30866134, 20920666; Changed phenotypes to: MONDO:0013337, NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC, OMIM:613640, SPTLC2-related neuropathy, hereditary sensory and autonomic, OMIM:613640.0
DDG2P v6.17 SPRY1 Achchuthan Shanmugasundram edited their review of gene: SPRY1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPRY1-related craniosynostosis with inner ear and renal anomalies are limited, biallelic_autosomal and undetermined (PMID:36543535). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03436.; Changed phenotypes to: SPRY1-related craniosynostosis with inner ear and renal anomalies, SPRY1-associated craniosynostosis with inner ear and renal anomalies
DDG2P v6.17 SPRTN Achchuthan Shanmugasundram edited their review of gene: SPRTN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPRTN-related progeria and hepatocellular carcinoma are limited, biallelic_autosomal and undetermined (PMID:25261934). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01584.; Changed publications to: 25261934; Changed phenotypes to: MONDO:0014527, PROGEROID SYNDROME, SPRTN-related progeria and hepatocellular carcinoma, OMIM:616200.0
DDG2P v6.17 SPECC1L Achchuthan Shanmugasundram edited their review of gene: SPECC1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPECC1L-related facial clefting, oblique are strong, monoallelic_autosomal and undetermined (PMIDs: 21703590, 2541274). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01400.; Changed publications to: 2541274, 21703590; Changed phenotypes to: SPECC1L-related facial clefting, oblique, FACIAL CLEFTING, OBLIQUE, 1, OMIM:600251, OMIM:600251.0
DDG2P v6.17 SPAST Achchuthan Shanmugasundram edited their review of gene: SPAST: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPAST-related developmental disorder are strong, monoallelic_autosomal and undetermined. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02859. The DDG2P confidence category, allelic requirement and molecular mechanism for SPAST-related spastic paraplegia are definitive, monoallelic_autosomal and loss of function (PMIDs: 10610178, 10699187, 11309678, 11843700, 16055926, 18701882, 36452170, 37251230, 37473796, 38145127, 40019011). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03840.; Changed publications to: 16055926, 37251230, 36452170, 11843700, 40019011, 10699187, 18701882, 11309678, 38145127, 10610178, 37473796; Changed phenotypes to: OMIM:182601.0, SPAST-related developmental disorder, MONDO:0700092, SPAST-related developmental disorder (monoallelic), SPAST-related spastic paraplegia, MONDO:0008438
DDG2P v6.17 SPARC Achchuthan Shanmugasundram edited their review of gene: SPARC: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SPARC-related osteogenesis imperfecta are strong, biallelic_autosomal and undetermined (PMID:26027498). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01673.; Changed phenotypes to: SPARC-related osteogenesis imperfecta, OSTEOGENESIS IMPERFECTA, TYPE XVII, OMIM:616507, OMIM:616507.0, MONDO:0014672
DDG2P v6.17 SOX4 Achchuthan Shanmugasundram edited their review of gene: SOX4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SOX4-related neurodevelopmental disease associated with mild dysmorphism are strong, monoallelic_autosomal and undetermined (PMIDs: 30661772, 35232796). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02643.; Changed publications to: 30661772, 35232796; Changed phenotypes to: Neurodevelopmental Disease Associated with Mild Dysmorphism, SOX4-related neurodevelopmental disease associated with mild dysmorphism, OMIM:618506.0, MONDO:0032791
DDG2P v6.17 SOX17 Achchuthan Shanmugasundram edited their review of gene: SOX17: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SOX17-related vesicoureteral reflux are definitive, monoallelic_autosomal and undetermined (PMID:20960469). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00585.; Changed phenotypes to: MONDO:0013356, OMIM:613674.0, VESICOURETERAL REFLUX TYPE 3, OMIM:613674, SOX17-related vesicoureteral reflux
DDG2P v6.17 SOX11 Achchuthan Shanmugasundram edited their review of gene: SOX11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SOX11-related neurodevelopmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 24886874, 26543203, 35341651). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00338.; Changed phenotypes to: MONDO:0014376, SOX11-related neurodevelopmental disorder, OMIM:615866, SOX11-related neurodevelopmental disorder, OMIM:615866.0
DDG2P v6.17 SOS2 Achchuthan Shanmugasundram edited their review of gene: SOS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SOS2-related Noonan syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 25795793, 26173643, 32788663). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03139.; Changed phenotypes to: SOS2-related Noonan syndrome, OMIM:616559.0, MONDO:0014691, SOS-2 associated Noonan syndrome, OMIM:616559
DDG2P v6.17 SNRPE Achchuthan Shanmugasundram edited their review of gene: SNRPE: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SNRPE-related hypotrichosis simplex are strong, monoallelic_autosomal and undetermined (PMIDs: 23246290, 33792916, 36814386, 9621144). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00962.; Changed publications to: 36814386, 9621144, 23246290, 33792916; Changed phenotypes to: AUTOSOMAL-DOMINANT HYPOTRICHOSIS SIMPLEX, OMIM:615059, OMIM:615059.0, MONDO:0014027, SNRPE-related hypotrichosis simplex
DDG2P v6.17 SNIP1 Achchuthan Shanmugasundram edited their review of gene: SNIP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SNIP1-related symptomatic epilepsy and skull dysplasia are limited, biallelic_autosomal and undetermined (PMID:22279524). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01312.; Changed phenotypes to: SYMPTOMATIC EPILEPSY AND SKULL DYSPLASIA, OMIM:614501, SNIP1-related symptomatic epilepsy and skull dysplasia, OMIM:614501.0
DDG2P v6.17 SNAP25 Achchuthan Shanmugasundram edited their review of gene: SNAP25: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SNAP25-related epilepsy and intellectual disability are definitive, monoallelic_autosomal and loss of function (PMIDs: 29100083, 33299146). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02378.; Changed phenotypes to: OMIM:616330.0, SNAP25-related epilepsy and intellectual disability, Epilepsy and intellectual disability, MONDO:0014590
DDG2P v6.17 SMO Achchuthan Shanmugasundram edited their review of gene: SMO: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMO-related Curry-Jones syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 27236920, 28386950, 31825089). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01746. The DDG2P confidence category, allelic requirement and molecular mechanism for SMO-related developmental disorder are strong, biallelic_autosomal and loss of function (PMID:32413283). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02966.; Changed publications to: 28386950, 32413283, 31825089, 27236920; Changed phenotypes to: Curry-Jones Syndrome, OMIM:601707, SMO-related developmental disorder, SMO-related Curry-Jones syndrome, MONDO:0011134, OMIM:601707.0, OMIM:241800.0, MONDO:0009436
DDG2P v6.17 SMCHD1 Achchuthan Shanmugasundram edited their review of gene: SMCHD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMCHD1-related isolated arhinia/Bosma arhinia syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 28067909, 28067911). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01773.; Changed publications to: 28067911, 28067909; Changed phenotypes to: SMCHD1-related isolated arhinia/Bosma arhinia syndrome, MONDO:0011323, Isolated Arhinia/Bosma Arhinia syndrome, OMIM:603457.0
DDG2P v6.17 SMC5 Achchuthan Shanmugasundram edited their review of gene: SMC5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMC5-related developmental disorder are moderate, biallelic_autosomal and undetermined (PMID:36333305). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03452.; Changed phenotypes to: SMC5-related developmental disorder, OMIM:620185.0, MONDO:0859576
DDG2P v6.17 SMC3 Achchuthan Shanmugasundram edited their review of gene: SMC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMC3-related Cornelia de Lange syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 17273969, 20358602, 25125236, 25655089). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00659.; Changed publications to: 17273969, 25655089, 20358602, 25125236; Changed phenotypes to: OMIM:610759.0, SMC3-related Cornelia de Lange syndrome, CORNELIA DE LANGE SYNDROME TYPE 3, OMIM:610759, MONDO:0012555
DDG2P v6.17 SMARCE1 Achchuthan Shanmugasundram edited their review of gene: SMARCE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMARCE1-related Coffin Siris are strong, monoallelic_autosomal and undetermined (PMID:22426308). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00174.; Changed phenotypes to: COFFIN SIRIS, OMIM:135900, MONDO:0014838, SMARCE1-related Coffin Siris, OMIM:616938.0
DDG2P v6.17 SMARCD1 Achchuthan Shanmugasundram edited their review of gene: SMARCD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMARCD1-related syndromic intellectual disability are moderate, monoallelic_autosomal and undetermined (PMIDs: 30879640, 38114583, 39389935). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02772.; Changed publications to: 39389935, 30879640, 38114583; Changed phenotypes to: SYNDROMIC INTELLECTUAL DISABILITY, OMIM:612100, SMARCD1-related syndromic intellectual disability, MONDO:0032912, OMIM:618779.0
DDG2P v6.17 SMARCA2 Achchuthan Shanmugasundram edited their review of gene: SMARCA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SMARCA2-related Nicolaides-Baraitser syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 22366787, 22426308, 22822383, 25169058, 27665729, 28948053, 31288860, 31813144, 32657847, 32694869, 34296532, 34521483, 35811451). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00849.; Changed publications to: 28948053, 22822383, 32694869, 34296532, 27665729, 22426308, 25169058, 31288860, 32657847, 31813144, 34521483, 35811451, 22366787; Changed phenotypes to: OMIM:601358.0, SMARCA2-related Nicolaides-Baraitser syndrome, MONDO:0011053, SMARCA2-related Nicolaides-Baraitser syndrome, OMIM:601358
DDG2P v6.17 SLF2 Achchuthan Shanmugasundram edited their review of gene: SLF2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLF2-related developmental disorder are moderate, biallelic_autosomal and undetermined (PMID:36333305). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03451.; Changed phenotypes to: MONDO:0859575, SLF2-related developmental disorder, OMIM:620184.0
DDG2P v6.17 SLC9A7 Achchuthan Shanmugasundram edited their review of gene: SLC9A7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC9A7-related intellectual developmental disorder are limited, monoallelic_X_hemizygous and undetermined (PMID:30335141). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03038.; Changed phenotypes to: Intellectual developmental disorder, X-linked 108, OMIM:301024, MONDO:0026723, OMIM:301024.0, SLC9A7-related intellectual developmental disorder
DDG2P v6.17 SLC6A17 Achchuthan Shanmugasundram edited their review of gene: SLC6A17: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC6A17-related intellectual developmental disorder are strong, biallelic_autosomal and undetermined (PMID:25704603). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00656.; Changed phenotypes to: OMIM:616269.0, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 48, OMIM:616269, SLC6A17-related intellectual developmental disorder, MONDO:0014559
DDG2P v6.17 SLC5A7 Achchuthan Shanmugasundram edited their review of gene: SLC5A7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC5A7-related congenital myasthenic syndrome with episodic apnea are strong, biallelic_autosomal and undetermined (PMID:27569547). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01876.; Changed phenotypes to: SLC5A7-related congenital myasthenic syndrome with episodic apnea, Congenital Myasthenic Syndrome with Episodic Apnea, MONDO:0014939, OMIM:617143.0
DDG2P v6.17 SLC4A1 Achchuthan Shanmugasundram edited their review of gene: SLC4A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC4A1-related renal tubular acidosis, distal (monoallelic) are strong, monoallelic_autosomal and undetermined (PMIDs: 37775346, 9312167, 9600966). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00171. The DDG2P confidence category, allelic requirement and molecular mechanism for SLC4A1-related renal tubular acidosis, distal (biallelic) are strong, biallelic_autosomal and undetermined (PMIDs: 10926824, 31933135, 9854053). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00185.; Changed publications to: 9600966, 37775346, 31933135, 9312167, 9854053, 10926824; Changed phenotypes to: SLC4A1-related renal tubular acidosis, distal (monoallelic), RENAL TUBULAR ACIDOSIS, DISTAL, AR, OMIM:611590, OMIM:179800.0, SLC4A1-related renal tubular acidosis, distal (biallelic), MONDO:0008368, RENAL TUBULAR ACIDOSIS, DISTAL, AD, OMIM:179800
DDG2P v6.17 SLC45A1 Achchuthan Shanmugasundram edited their review of gene: SLC45A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC45A1-related intellectual disability and epilepsy are strong, biallelic_autosomal and undetermined (PMID:28434495). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02234.; Changed phenotypes to: MONDO:0044322, OMIM:617532.0, Intellectual disability and epilepsy, SLC45A1-related intellectual disability and epilepsy
DDG2P v6.17 SLC39A8 Achchuthan Shanmugasundram edited their review of gene: SLC39A8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC39A8-related intellectual disability with cerebellar atrophy are definitive, biallelic_autosomal and undetermined (PMIDs: 26637978, 26637979). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01660.; Changed publications to: 26637979, 26637978; Changed phenotypes to: OMIM:616721.0, Intellectual Disability with Cerebellar Atrophy, SLC39A8-related intellectual disability with cerebellar atrophy, MONDO:0014746
DDG2P v6.17 SLC35B2 Achchuthan Shanmugasundram edited their review of gene: SLC35B2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC35B2-related chondrodysplasia with hypomyelinating leukodystrophy are limited, biallelic_autosomal and undetermined (PMID:35325049). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03411.; Changed phenotypes to: MONDO:0859518, SLC35B2-related chondrodysplasia with hypomyelinating leukodystrophy, OMIM:620269.0
DDG2P v6.17 SLC32A1 Achchuthan Shanmugasundram edited their review of gene: SLC32A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC32A1-related developmental and epileptic encephalopathy are moderate, monoallelic_autosomal and undetermined (PMIDs: 34038384, 36073542). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03331.; Changed publications to: 36073542, 34038384; Changed phenotypes to: SLC32A1-related developmental and epileptic encephalopathy, MONDO:0958331, OMIM:620774.0, SLC32A1-associated developmental and epileptic encephalopathy
DDG2P v6.17 SLC31A1 Achchuthan Shanmugasundram edited their review of gene: SLC31A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC31A1-related congenital copper transport disorder are moderate, biallelic_autosomal and undetermined (PMIDs: 21937992, 35913762, 36562171). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01558.; Changed publications to: 21937992, 36562171, 35913762; Changed phenotypes to: SLC31A1-associated congenital copper transport disorder, OMIM:620306.0, MONDO:0957211, SLC31A1-related congenital copper transport disorder
DDG2P v6.17 SLC30A7 Achchuthan Shanmugasundram edited their review of gene: SLC30A7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC30A7-related Joubert syndrome are limited, monoallelic_autosomal and undetermined (PMID:35751429). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03423.; Changed phenotypes to: SLC30A7-related Joubert syndrome, SLC30A7-associated Joubert syndrome, MONDO:0018772
DDG2P v6.17 SLC25A4 Achchuthan Shanmugasundram edited their review of gene: SLC25A4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC25A4-related severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number are strong, monoallelic_autosomal and undetermined (PMIDs: 27693233, 30046662). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01880. The DDG2P confidence category, allelic requirement and molecular mechanism for SLC25A4-related Fontaine progeroid syndrome are strong, monoallelic_autosomal and undetermined (PMID:30329211). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02572.; Changed publications to: 30329211, 27693233, 30046662; Changed phenotypes to: Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number, SLC25A4-related severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number, SLC25A4-related Fontaine progeroid syndrome, MONDO:0014959, Fontaine progeroid syndrome, OMIM:617184.0, MONDO:0012853
DDG2P v6.17 SLC25A24 Achchuthan Shanmugasundram edited their review of gene: SLC25A24: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC25A24-related hypertrichosis, progeroid appearance, and mitochondrial dysfunction (Gorlin-Chaudhry-Moss syndrome ) are definitive, monoallelic_autosomal and undetermined (PMIDs: 29100093, 29100094). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02383.; Changed publications to: 29100093, 29100094; Changed phenotypes to: SLC25A24-related hypertrichosis, progeroid appearance, and mitochondrial dysfunction (Gorlin-Chaudhry-Moss syndrome ), OMIM:612289.0, Gorlin-Chaudhry-Moss syndrome (GCMS), MONDO:0012853, Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction
DDG2P v6.17 SLC25A22 Achchuthan Shanmugasundram edited their review of gene: SLC25A22: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC25A22-related epileptic encephalopathy, early infantile are strong, biallelic_autosomal and undetermined (PMIDs: 15592994, 19780765, 24596948, 31279168, 33821742). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00635.; Changed publications to: 33821742, 15592994, 19780765, 31279168, 24596948; Changed phenotypes to: OMIM:609304.0, SLC25A22-related epileptic encephalopathy, early infantile, MONDO:0012245, EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 3, OMIM:609304
DDG2P v6.17 SLC25A19 Achchuthan Shanmugasundram edited their review of gene: SLC25A19: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC25A19-related Amish lethal microcephaly are strong, biallelic_autosomal and undetermined (PMID:12185364). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00311.; Changed phenotypes to: AMISH LETHAL MICROCEPHALY, OMIM:607196, OMIM:607196.0, SLC25A19-related Amish lethal microcephaly, MONDO:0011790
DDG2P v6.17 SLC1A2 Achchuthan Shanmugasundram edited their review of gene: SLC1A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC1A2-related epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMIDs: 27476654, 28777935). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01865.; Changed phenotypes to: EPILEPTIC ENCEPHALOPATHY, SLC1A2-related epileptic encephalopathy, MONDO:0014916, OMIM:617105.0
DDG2P v6.17 SLC13A1 Achchuthan Shanmugasundram edited their review of gene: SLC13A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC13A1-related hypersulfaturia and hyposulfatemia are moderate, biallelic_autosomal and loss of function (PMIDs: 36175384, 39925707). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03395.; Changed rating: GREEN; Changed publications to: 39925707, 36175384; Changed phenotypes to: SLC13A1-associated hypersulfaturia and hyposulfatemia, SLC13A1-related hypersulfaturia and hyposulfatemia
DDG2P v6.17 SLC12A9 Achchuthan Shanmugasundram edited their review of gene: SLC12A9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects are moderate, biallelic_autosomal and loss of function (PMID:38334070). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03558.; Changed phenotypes to: SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects, MONDO:0100038
DDG2P v6.17 SLC12A5 Achchuthan Shanmugasundram edited their review of gene: SLC12A5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SLC12A5-related epilepsy of infancy with migrating focal seizures are strong, biallelic_autosomal and undetermined (PMIDs: 26333769, 27436767, 28477354). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00696.; Changed publications to: 27436767, 28477354, 26333769; Changed phenotypes to: SLC12A5-related epilepsy of infancy with migrating focal seizures, MONDO:0100025
DDG2P v6.17 SKI Achchuthan Shanmugasundram edited their review of gene: SKI: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SKI-related Shprintzen-Goldberg craniosynostosis syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 23023332, 23103230, 24736733, 33628537). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01276.; Changed publications to: 33628537, 24736733, 23103230, 23023332; Changed phenotypes to: SKI-related Shprintzen-Goldberg craniosynostosis syndrome, SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME, OMIM:182212, MONDO:0008426, OMIM:182212.0
DDG2P v6.17 SIX6 Achchuthan Shanmugasundram edited their review of gene: SIX6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SIX6-related microphthalmia, isolated, with cataract are limited, monoallelic_autosomal and undetermined (PMID:15266624). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00986.; Changed phenotypes to: MICROPHTHALMIA, ISOLATED, WITH CATARACT 2, OMIM:212550, SIX6-related microphthalmia, isolated, with cataract, OMIM:212550.0
DDG2P v6.17 SIX5 Achchuthan Shanmugasundram edited their review of gene: SIX5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SIX5-related branchiootorenal syndrome are definitive, monoallelic_autosomal and undetermined (PMID:17357085). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00803.; Changed phenotypes to: BRANCHIOOTORENAL SYNDROME TYPE 2, OMIM:610896, OMIM:610896.0, SIX5-related branchiootorenal syndrome, MONDO:0012575
DDG2P v6.17 SIAH1 Achchuthan Shanmugasundram edited their review of gene: SIAH1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SIAH1-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMID:32430360). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02959.; Changed phenotypes to: SIAH1-related neurodevelopmental disorder, MONDO:0859144, OMIM:619314.0, SIAH1-associated neurodevelopmental disorder
DDG2P v6.17 SHOX Achchuthan Shanmugasundram edited their review of gene: SHOX: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SHOX-related Langer mesomelic dysplasia are definitive, monoallelic_X_hemizygous and loss of function (PMIDs: 11889214, 12116254, 17935511, 9590292). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00460. The DDG2P confidence category, allelic requirement and molecular mechanism for SHOX-related Leri-Weill dyschondrosteosis are definitive, monoallelic_X_heterozygous and loss of function (PMIDs: 11030412, 11403039, 15356038, 21712857, 9590293). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01278.; Changed publications to: 9590293, 11030412, 9590292, 17935511, 12116254, 11889214, 11403039, 15356038, 21712857; Changed phenotypes to: OMIM:127300.0, SHOX-related Leri-Weill dyschondrosteosis, LERI-WEILL DYSCHONDROSTEOSIS, OMIM:127300, OMIM:249700.0, LANGER MESOMELIC DYSPLASIA, OMIM:249700, MONDO:0009588, MONDO:0007481, SHOX-related Langer mesomelic dysplasia; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v6.17 SHMT2 Achchuthan Shanmugasundram edited their review of gene: SHMT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SHMT2-related neurodevelopmental syndrome are strong, biallelic_autosomal and undetermined (PMID:33015733). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03048.; Changed phenotypes to: OMIM:619121.0, MONDO:0030866, SHMT2-related neurodevelopmental syndrome
DDG2P v6.17 SEMA6B Achchuthan Shanmugasundram edited their review of gene: SEMA6B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SEMA6B-related neurodevelopmental disorder are moderate, monoallelic_autosomal and undetermined (PMIDs: 32169168, 33798445, 34017830, 34092044, 34110594, 34218423, 35604360). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02945.; Changed publications to: 32169168, 35604360, 34017830, 34218423, 33798445, 34110594, 34092044; Changed phenotypes to: SEMA6B-related neurodevelopmental disorder, MONDO:0030034, OMIM:618876.0
DDG2P v6.17 SEC61A1 Achchuthan Shanmugasundram edited their review of gene: SEC61A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SEC61A1-related tubulo-interstitial and glomerulocystic kidney disease with anemia are limited, monoallelic_autosomal and undetermined (PMIDs: 27392076, 33185949, 39976632). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01752.; Changed publications to: 39976632, 27392076, 33185949; Changed phenotypes to: SEC61A1-related tubulo-interstitial and glomerulocystic kidney disease with anemia, Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia, MONDO:0100337, OMIM:617056.0
DDG2P v6.17 SEC23A Achchuthan Shanmugasundram edited their review of gene: SEC23A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SEC23A-related craniolenticulosutural dysplasia are limited, biallelic_autosomal and undetermined (PMID:16980979). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01060.; Changed phenotypes to: SEC23A-related craniolenticulosutural dysplasia, CRANIOLENTICULOSUTURAL DYSPLASIA, OMIM:607812, OMIM:607812.0, MONDO:0011911
DDG2P v6.17 SDHAF1 Achchuthan Shanmugasundram edited their review of gene: SDHAF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SDHAF1-related mitochondrial complex II deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 19465911, 22995659). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01012.; Changed publications to: 22995659, 19465911; Changed phenotypes to: MONDO:0030935, OMIM:619166.0, MITOCHONDRIAL COMPLEX II DEFICIENCY, OMIM:252011, SDHAF1-related mitochondrial complex II deficiency
DDG2P v6.17 SDHA Achchuthan Shanmugasundram edited their review of gene: SDHA: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SDHA-related Leigh syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 16361598, 24781757, 35014173). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01098.; Changed publications to: 16361598, 35014173, 24781757; Changed phenotypes to: MONDO:0100294, LEIGH SYNDROME, OMIM:256000, OMIM:252011.0, SDHA-related Leigh syndrome
DDG2P v6.17 SCN4A Achchuthan Shanmugasundram edited their review of gene: SCN4A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SCN4A-related hypokalemic periodic paralysis are definitive, monoallelic_autosomal and undetermined (PMIDs: 10599760, 10851391, 10944223, 11591859, 16890191). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00228. The DDG2P confidence category, allelic requirement and molecular mechanism for SCN4A-related hyperkalemic periodic paralysis are definitive, monoallelic_autosomal and gain of function (PMIDs: 15596759, 1659668, 1659948). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00392. The DDG2P confidence category, allelic requirement and molecular mechanism for SCN4A-related paramyotonia congenita of von Eulenburg are definitive, monoallelic_autosomal and undetermined (PMIDs: 10369308, 1310898, 1316765, 1338909, 17998485, 18203179, 19015483, 19015492, 8388676, 8580427). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00709.; Changed publications to: 1310898, 10369308, 16890191, 11591859, 19015492, 17998485, 1659668, 10851391, 18203179, 10944223, 19015483, 10599760, 8580427, 1338909, 1316765, 1659948, 15596759, 8388676; Changed phenotypes to: SCN4A-related paramyotonia congenita of von Eulenburg, SCN4A-related hypokalemic periodic paralysis, SCN4A-related hyperkalemic periodic paralysis, OMIM:613345.0, PARAMYOTONIA CONGENITA OF VON EULENBURG, OMIM:168300, HYPOKALEMIC PERIODIC PARALYSIS, OMIM:170400, HYPERKALEMIC PERIODIC PARALYSIS TYPE 1, OMIM:170500, OMIM:170500.0, MONDO:0013234, MONDO:0008224, OMIM:168300.0, MONDO:0008195
DDG2P v6.17 SCN3A Achchuthan Shanmugasundram edited their review of gene: SCN3A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SCN3A-related focal epilepsy are strong, monoallelic_autosomal and undetermined (PMIDs: 18242854, 24157691). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01652.; Changed phenotypes to: SCN3A-related focal epilepsy, OMIM:617935.0, MONDO:0054776, Focal epilepsy
DDG2P v6.17 SCN1B Achchuthan Shanmugasundram edited their review of gene: SCN1B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SCN1B-related generalized epilepsy with febrile seizures plus or temporal lobe epilepsy are definitive, monoallelic_autosomal and undetermined (PMIDs: 12011299, 14504340, 17020904, 19522081, 21040232, 27277800, 29992740, 30660056, 36291443, 9697698). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01480. The DDG2P confidence category, allelic requirement and molecular mechanism for SCN1B-related developmental and epileptic encephalopathy are definitive, biallelic_autosomal and undetermined non-loss-of-function (PMIDs: 19710327, 23148524, 28218389, 31465153, 31709768, 33901312). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03722.; Changed publications to: 12011299, 36291443, 21040232, 33901312, 31465153, 23148524, 19522081, 17020904, 9697698, 31709768, 28218389, 14504340, 29992740, 30660056, 18464934, 27277800, 19710327; Changed phenotypes to: SCN1B-related developmental and epileptic encephalopathy, MONDO:0033361, SCN1B-related generalized epilepsy with febrile seizures plus or temporal lobe epilepsy, MONDO:0011416, BRUGADA SYNDROME 5, OMIM:612838, OMIM:604233.0, OMIM:617350.0; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.17 SC5D Achchuthan Shanmugasundram edited their review of gene: SC5D: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SC5D-related lathosterolosis are definitive, biallelic_autosomal and undetermined (PMIDs: 12189593, 12812989). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00878.; Changed phenotypes to: MONDO:0011816, SC5D-related lathosterolosis, LATHOSTEROLOSIS, OMIM:607330, OMIM:607330.0
DDG2P v6.17 SASS6 Achchuthan Shanmugasundram edited their review of gene: SASS6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SASS6-related severe microcephaly with brain abnormalities are moderate, biallelic_autosomal and undetermined (PMIDs: 24951542, 30639237, 36739862, 38501757). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03564.; Changed publications to: 24951542, 38501757, 36739862, 30639237; Changed phenotypes to: MONDO:0014623, SASS6-related severe microcephaly with brain abnormalities, OMIM:616402.0
DDG2P v6.17 SART3 Achchuthan Shanmugasundram edited their review of gene: SART3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SART3-related neurodevelopmental disorder with 46,XY gonadal dysgenesis (INDYGON) are moderate, biallelic_autosomal and loss of function (PMID:37296101). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03514.; Changed phenotypes to: MONDO:0100038, SART3-related neurodevelopmental disorder with 46,XY gonadal dysgenesis (INDYGON)
DDG2P v6.17 SARS2 Achchuthan Shanmugasundram edited their review of gene: SARS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SARS2-related hyperuricemia, pulmonary hypertension, renal failure and alkalosis are strong, biallelic_autosomal and undetermined (PMIDs: 21255763, 24034276, 33751860). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03113.; Changed phenotypes to: SARS2-related hyperuricemia, pulmonary hypertension, renal failure and alkalosis, OMIM:613845, SARS2-related hyperuricemia, pulmonary hypertension, renal failure and alkalosis, OMIM:613845.0, MONDO:0013458
DDG2P v6.17 SARS Achchuthan Shanmugasundram edited their review of gene: SARS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SARS1-related neurodevelopmental disorder with microcephaly, ataxia, and seizures are moderate, biallelic_autosomal and undetermined (PMIDs: 28236339, 34570399). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03234. The DDG2P confidence category, allelic requirement and molecular mechanism for SARS1-related neurodevelopmental disorder are limited, monoallelic_autosomal and dominant negative (PMID:36041817). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03434.; Changed phenotypes to: OMIM:617709.0, MONDO:0060577, SARS1-related neurodevelopmental disorder with microcephaly, ataxia, and seizures, Autosomal dominant SARS1-related neurodevelopmental disorder, MONDO:0700092, SARS1-related neurodevelopmental disorder, SARS1-related neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
DDG2P v6.17 SAMD9L Achchuthan Shanmugasundram edited their review of gene: SAMD9L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for SAMD9L-related ataxia-pancytopenia syndrome are limited, monoallelic_autosomal and undetermined (PMID:27259050). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01741.; Changed phenotypes to: Ataxia-Pancytopenia Syndrome, OMIM:159550, OMIM:159550.0, MONDO:0008038, SAMD9L-related ataxia-pancytopenia syndrome
DDG2P v6.17 RYR2 Achchuthan Shanmugasundram edited their review of gene: RYR2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RYR2-related catecholaminergic polymorphic ventricular tachycardia and intellectual disability are limited, monoallelic_autosomal and undetermined (PMIDs: 11157710, 15544013, 15544015, 15720454, 16084945, 16188589, 16272262, 17875969, 19781797, 19926015, 21126784, 21652165, 22222782, 22334434, 22519458, 30170228). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03201.; Changed publications to: 16188589, 30170228, 15544013, 16084945, 22222782, 15544015, 22334434, 19926015, 15720454, 17875969, 19781797, 21126784, 16272262, 21652165, 22519458, 11157710; Changed phenotypes to: RYR2-related catecholaminergic polymorphic ventricular tachycardia and intellectual disability, RYR2-related Catecholaminergic polymorphic ventricular tachycardia and intellectual disability
DDG2P v6.17 RUBCN Achchuthan Shanmugasundram edited their review of gene: RUBCN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RUBCN-related syndromic intellectual disability with ataxia, dysarthria and epilepsy are limited, biallelic_autosomal and undetermined (PMIDs: 20826435, 32450808). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00613.; Changed publications to: 32450808, 20826435; Changed phenotypes to: OMIM:615705.0, RUBCN-related syndromic intellectual disability with ataxia, dysarthria and epilepsy, SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY, MONDO:0014311
DDG2P v6.17 RTTN Achchuthan Shanmugasundram edited their review of gene: RTTN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RTTN-related bilateral diffuse polymicrogyria are definitive, biallelic_autosomal and undetermined (PMIDs: 22939636, 26608784, 29883675). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01577.; Changed phenotypes to: RTTN-related bilateral diffuse polymicrogyria, MONDO:0018764, BILATERAL DIFFUSE POLYMICROGYRIA, OMIM:614833, OMIM:614833.0
DDG2P v6.17 RTEL1 Achchuthan Shanmugasundram edited their review of gene: RTEL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RTEL1-related dyskeratosis congenita are moderate, monoallelic_autosomal and loss of function (PMIDs: 23329068, 23453664). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03361. The DDG2P confidence category, allelic requirement and molecular mechanism for RTEL1-related dyskeratosis congenita are definitive, biallelic_autosomal and loss of function (PMIDs: 23329068, 23453664, 23591994, 23959892). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03386.; Changed publications to: 23453664, 23959892, 23329068, 23591994; Changed phenotypes to: OMIM:615190.0, RTEL1-related dyskeratosis congenita, DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 4, OMIM:615190, MONDO:0014076; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.17 RRM1 Achchuthan Shanmugasundram edited their review of gene: RRM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RRM1-related mitochondrial DNA depletion/deletions syndrome are limited, biallelic_autosomal and undetermined (PMID:35617047). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03370. The DDG2P confidence category, allelic requirement and molecular mechanism for RRM1-related mitochondrial DNA depletion/deletions syndrome are limited, monoallelic_autosomal and undetermined (PMID:35617047). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03371.; Changed phenotypes to: MONDO:0957993, RRM1-related mitochondrial DNA depletion/deletions syndrome, OMIM:620647.0
DDG2P v6.17 RPS23 Achchuthan Shanmugasundram edited their review of gene: RPS23: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RPS23-related microcephaly, hearing loss, and dysmorphic features are strong, monoallelic_autosomal and undetermined (PMID:28257692). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02247.; Changed phenotypes to: RPS23-related microcephaly, hearing loss, and dysmorphic features, Microcephaly, hearing loss, and dysmorphic features, OMIM:617412.0, MONDO:0044311
DDG2P v6.17 RPL13 Achchuthan Shanmugasundram edited their review of gene: RPL13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RPL13-related spondyloepimetaphyseal dysplasia with severe short stature are limited, monoallelic_autosomal and undetermined (PMID:31630789). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02835.; Changed phenotypes to: Spondyloepimetaphyseal Dysplasia with Severe Short Stature, OMIM:618728.0, RPL13-related spondyloepimetaphyseal dysplasia with severe short stature, MONDO:0032885
DDG2P v6.17 RPL10 Achchuthan Shanmugasundram edited their review of gene: RPL10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RPL10-related syndromic intellectual developmental disorder are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 25316788, 25846674, 26290468, 29066376, 35876338). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03002.; Changed publications to: 26290468, 35876338, 25846674, 29066376, 25316788; Changed phenotypes to: RPL10-related syndromic intellectual developmental disorder, MONDO:0030908, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, 35, OMIM:300998, OMIM:300998.0
DDG2P v6.17 RNU4ATAC Achchuthan Shanmugasundram edited their review of gene: RNU4ATAC: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RNU4ATAC-related microcephalic osteodysplastic primordial dwarfism are definitive, biallelic_autosomal and undetermined (PMIDs: 17666473, 21474760, 21474761, 22581640). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00669.; Changed publications to: 21474760, 21474761, 22581640, 17666473; Changed phenotypes to: OMIM:210710.0, RNU4ATAC-related microcephalic osteodysplastic primordial dwarfism, MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I, OMIM:210710, MONDO:0008871
DDG2P v6.17 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RNU4-2 related neurodevelopmental disorder with microcephaly and seizures (ReNU syndrome) are strong, monoallelic_autosomal and loss of function (PMIDs: 38821540, 38991538, 39369315, 39434505, 40011755, 40379786). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03537.; Changed publications to: 38991538, 39369315, 40011755, 39434505, 38821540, 40379786; Changed phenotypes to: RNU4-2 related neurodevelopmental disorder with microcephaly and seizures (ReNU syndrome), OMIM:620851.0, MONDO:0971172, RNU4-2 related neurodevelopmental disorder with microcephaly and seizures
DDG2P v6.17 RNU12 Achchuthan Shanmugasundram edited their review of gene: RNU12: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RNU12-related CDAGS syndrome are limited, biallelic_autosomal and undetermined (PMIDs: 27863452, 34085356). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03197.; Changed publications to: 34085356, 27863452; Changed phenotypes to: MONDO:0011287, RNU12-related CDAGS syndrome, OMIM:603116.0
DDG2P v6.17 RNF125 Achchuthan Shanmugasundram edited their review of gene: RNF125: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RNF125-related intellectual disability and macrocephaly are limited, monoallelic_autosomal and undetermined (PMIDs: 25196541, 34196401). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03221.; Changed phenotypes to: RNF125-related intellectual disability and macrocephaly, OMIM:616260, OMIM:616260.0, RNF125-related intellectual disability and macrocephaly, MONDO:0014553
DDG2P v6.17 RMND1 Achchuthan Shanmugasundram edited their review of gene: RMND1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RMND1-related encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect are strong, biallelic_autosomal and undetermined (PMID:23022099). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00870.; Changed phenotypes to: ENCEPHALOPATHY ASSOCIATED WITH MULTIPLE OXIDATIVE PHOSPHORYLATION COMPLEX DEFICIENCIES AND A MITOCHONDRIAL TRANSLATION DEFECT, OMIM:614922, MONDO:0013969, RMND1-related encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect, OMIM:614922.0
DDG2P v6.17 RLIM Achchuthan Shanmugasundram edited their review of gene: RLIM: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RLIM-related intellectual disability are strong, monoallelic_X_hemizygous and undetermined (PMID:25644381). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02011.; Changed phenotypes to: RLIM-related intellectual disability, OMIM:300978.0, INTELLECTUAL DISABILITY, OMIM:616579, MONDO:0010506
DDG2P v6.17 DDX58 Achchuthan Shanmugasundram edited their review of gene: DDX58: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RIGI-related Singleton-Merten syndrome are limited, monoallelic_autosomal and undetermined (PMIDs: 25620203, 30574673). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01163.; Changed publications to: 30574673, 25620203; Changed phenotypes to: RIGI-related Singleton-Merten syndrome, MONDO:0014575, SINGLETON-MERTEN SYNDROME, OMIM:182250, OMIM:616298.0
DDG2P v6.17 RHOBTB2 Achchuthan Shanmugasundram edited their review of gene: RHOBTB2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RHOBTB2-related developmental and epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMID:29276004). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02589.; Changed phenotypes to: OMIM:618004.0, MONDO:0033373, Developmental and Epileptic Encephalopathy, RHOBTB2-related developmental and epileptic encephalopathy
DDG2P v6.17 REST Achchuthan Shanmugasundram commented on gene: REST: The DDG2P confidence category, allelic requirement and molecular mechanism for REST-related gingival fibromatosis and sensorineural hearing loss are moderate, monoallelic_autosomal and undetermined (PMID:36509837). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03456.
DDG2P v6.17 RBPJ Achchuthan Shanmugasundram edited their review of gene: RBPJ: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RBPJ-related Adams-Oliver syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 22883147, 28160419). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01131.; Changed publications to: 22883147, 28160419; Changed phenotypes to: OMIM:614814.0, ADAMS OLIVER SYNDROME, MONDO:0013895, RBPJ-related Adams-Oliver syndrome
DDG2P v6.17 RBM28 Achchuthan Shanmugasundram edited their review of gene: RBM28: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RBM28-related alopecia, neurologic defects, and endocrinopathy syndrome are limited, biallelic_autosomal and undetermined (PMID:18439547). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00449.; Changed phenotypes to: RBM28-related alopecia, neurologic defects, and endocrinopathy syndrome, OMIM:612079.0, MONDO:0012794, ALOPECIA NEUROLOGIC DEFECTS AND ENDOCRINOPATHY SYNDROME, OMIM:612079
DDG2P v6.17 RAP1B Achchuthan Shanmugasundram edited their review of gene: RAP1B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAP1B-related developmental disorder are limited, monoallelic_autosomal and undetermined (PMIDs: 26280580, 32627184). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03053.; Changed publications to: 26280580, 32627184; Changed phenotypes to: OMIM:620654.0, RAP1B-related developmental disorder, MONDO:0958000
DDG2P v6.17 RANBP2 Achchuthan Shanmugasundram edited their review of gene: RANBP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RANBP2-related acute necrotizing encephalopathy, susceptibility to are limited, monoallelic_autosomal and undetermined (PMID:19118815). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01534.; Changed phenotypes to: RANBP2-related acute necrotizing encephalopathy, susceptibility to, OMIM:608033.0, ACUTE NECROTIZING ENCEPHALOPATHY 1, SUSCEPTIBILITY TO, OMIM:285648, MONDO:0011953
DDG2P v6.17 RALGDS Achchuthan Shanmugasundram edited their review of gene: RALGDS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RALGDS-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00643.; Changed phenotypes to: MONDO:0700092, RALGDS-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 RALA Achchuthan Shanmugasundram edited their review of gene: RALA: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RALA-related neurodevelopmental syndrome are strong, monoallelic_autosomal and undetermined (PMID:30500825). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02934.; Changed phenotypes to: OMIM:619311.0, MONDO:0859142, RALA-related Neurodevelopmental Syndrome, RALA-related neurodevelopmental syndrome
DDG2P v6.17 RAD51C Achchuthan Shanmugasundram edited their review of gene: RAD51C: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAD51C-related Fanconi anemia are strong, biallelic_autosomal and undetermined (PMID:20400963). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01017.; Changed phenotypes to: RAD51C-related Fanconi anemia, OMIM:613390.0, MONDO:0013248, FANCONI ANEMIA, COMPLEMENTATION GROUP 0, OMIM:613390
DDG2P v6.17 RAC3 Achchuthan Shanmugasundram edited their review of gene: RAC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAC3-related neurodevelopment disorder are strong, monoallelic_autosomal and undetermined (PMID:30293988). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02570.; Changed phenotypes to: Neurodevelopment disorder, RAC3-related neurodevelopment disorder, MONDO:0032820, OMIM:618577.0
DDG2P v6.17 RAC1 Achchuthan Shanmugasundram edited their review of gene: RAC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAC1-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 28886345, 35139179). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02367.; Changed phenotypes to: OMIM:617751.0, MONDO:0030913, RAC1-related neurodevelopmental disorder
DDG2P v6.17 RABL6 Achchuthan Shanmugasundram edited their review of gene: RABL6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RABL6-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00176.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0700092, RABL6-related intellectual developmental disorder
DDG2P v6.17 RAB34 Achchuthan Shanmugasundram edited their review of gene: RAB34: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAB34-related orofaciodigital syndrome are moderate, biallelic_autosomal and loss of function (PMIDs: 37384395, 37619988). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03529.; Changed publications to: 37384395, 37619988; Changed phenotypes to: RAB34-related orofaciodigital syndrome, OMIM:620718.0, MONDO:0958230
DDG2P v6.17 RAB14 Achchuthan Shanmugasundram edited their review of gene: RAB14: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAB14-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02880.; Changed phenotypes to: MONDO:0700092, RAB14-related developmental disorder (monoallelic), RAB14-related developmental disorder
DDG2P v6.17 RAB11B Achchuthan Shanmugasundram edited their review of gene: RAB11B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAB11B-related intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:29106825). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01972.; Changed phenotypes to: RAB11B-related intellectual disability, OMIM:617807.0, MONDO:0060624, INTELLECTUAL DISABILITY, OMIM:616579
DDG2P v6.17 RAB11A Achchuthan Shanmugasundram edited their review of gene: RAB11A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for RAB11A-related epilepsy and intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:29100083). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02376.; Changed phenotypes to: Epilepsy and intellectual disability, MONDO:0700092, RAB11A-related epilepsy and intellectual disability
DDG2P v6.17 QARS Achchuthan Shanmugasundram edited their review of gene: QARS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for QARS1-related microcephaly, progressive, seizures, and cerebral and cerebellar atrophy are strong, biallelic_autosomal and undetermined (PMID:24656866). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00574.; Changed phenotypes to: MONDO:0014335, OMIM:615760.0, QARS1-related microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MICROCEPHALY, PROGRESSIVE, SEIZURES, AND CEREBRAL AND CEREBELLAR ATROPHY, OMIM:615760
DDG2P v6.17 PYCR2 Achchuthan Shanmugasundram edited their review of gene: PYCR2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PYCR2-related postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume are strong, biallelic_autosomal and undetermined (PMID:25865492). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01573.; Changed phenotypes to: MONDO:0014632, OMIM:616420.0, PYCR2-related postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume, POSTNATAL MICROCEPHALY, HYPOMYELINATION, AND REDUCED CEREBRAL WHITE-MATTER VOLUME
DDG2P v6.17 PTPN11 Achchuthan Shanmugasundram edited their review of gene: PTPN11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PTPN11-related Noonan syndrome with multiple lentigines are definitive, monoallelic_autosomal and undetermined (PMIDs: 11992261, 12058348, 12161596, 14634749, 14961557, 14991917, 15121796, 15389709, 15520399, 16172598, 16358218, 16377799, 16679933, 16733669, 17697839, 17875892, 17927788, 19054014, 19659470, 19768645, 19864201, 21365175, 21677813, 21747628, 21910226, 22822385, 23799168, 24790373, 24820750, 25884655, 25917897, 26377839, 27484170, 33354767). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00841. The DDG2P confidence category, allelic requirement and molecular mechanism for PTPN11-related Noonan syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 11704759, 11992261, 12161469, 12325025, 12357036, 12522798, 12529711, 12872825, 14974085, 15211660, 15240615, 15248152, 15384080, 15521065, 15889278, 15929108, 15956085, 15985475, 16078230, 16188759, 16358218, 16804314, 17052965, 17184563, 17194341, 17339163, 17361219, 17497712, 17515436, 18348260, 19449407, 19760651, 21269411, 21533187, 23312968, 24739123, 25974318, 30681346). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03310.; Changed publications to: 12325025, 21677813, 24790373, 14991917, 19054014, 17927788, 12161469, 12529711, 15889278, 16804314, 15985475, 17194341, 16679933, 17361219, 16188759, 15929108, 16358218, 15389709, 17339163, 15248152, 26377839, 24820750, 33354767, 21910226, 11704759, 23312968, 25917897, 19659470, 24739123, 11992261, 22822385, 12357036, 14961557, 12872825, 17184563, 12058348, 12161596, 15240615, 15520399, 14634749, 21365175, 15211660, 15521065, 15956085, 25974318, 17697839, 16733669, 19864201, 18348260, 23799168, 15121796, 19449407, 14974085, 21747628, 16172598, 27484170, 17515436, 21269411, 15384080, 12522798, 16078230, 17052965, 17875892, 19760651, 21533187, 30681346, 25884655, 19768645, 16377799, 17497712; Changed phenotypes to: MONDO:0100082, LEOPARD SYNDROME TYPE 1, OMIM:151100, PTPN11-related Noonan syndrome, PTPN11-related Noonan syndrome with multiple lentigines, OMIM:151100.0, MONDO:0008104, NOONAN SYNDROME 1, OMIM:163950
DDG2P v6.17 PTDSS1 Achchuthan Shanmugasundram edited their review of gene: PTDSS1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PTDSS1-related Lenz-Majewski hyperostotic dwarfism are definitive, monoallelic_autosomal and gain of function (PMID:24241535). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00360. The DDG2P confidence category, allelic requirement and molecular mechanism for PTDSS1-related developmental delay are limited, monoallelic_autosomal and undetermined (PMID:35224839). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03416.; Changed phenotypes to: LENZ-MAJEWSKI HYPEROSTOTIC DWARFISM, OMIM:151050, PTDSS1-related Lenz-Majewski hyperostotic dwarfism, MONDO:0007892, PTDSS1-related developmental delay, Developmental delay, OMIM:151050.0
DDG2P v6.17 PSMC5 Achchuthan Shanmugasundram edited their review of gene: PSMC5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PSMC5-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02898.; Changed phenotypes to: PSMC5-related developmental disorder (monoallelic), MONDO:0700092, PSMC5-related developmental disorder
DDG2P v6.17 PSMC3 Achchuthan Shanmugasundram edited their review of gene: PSMC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PSMC3-related neurodevelopmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:37256937). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03496.; Changed phenotypes to: MONDO:0700092, PSMC3-related neurodevelopmental disorder
DDG2P v6.17 PSMC1 Achchuthan Shanmugasundram edited their review of gene: PSMC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PSMC1-related neurodevelopmental disorder are limited, monoallelic_autosomal and undetermined (PMID:35861243). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03337.; Changed phenotypes to: MONDO:0700092, PSMC1-related neurodevelopmental disorder
DDG2P v6.17 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PSMB8-related Nakajo syndrome are definitive, biallelic_autosomal and loss of function (PMIDs: 21129723, 21852578, 21881205, 21953331, 26524591, 37600812). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00131.; Changed publications to: 26524591, 21129723, 21881205, 37600812, 21852578, 21953331; Changed phenotypes to: NAKAJO SYNDROME, OMIM:256040, OMIM:256040.0, PSMB8-related Nakajo syndrome, MONDO:0054698
DDG2P v6.17 PRRX1 Achchuthan Shanmugasundram edited their review of gene: PRRX1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRRX1-related agnathia-otocephaly complex are limited, monoallelic_autosomal and dominant negative (PMIDs: 21294718, 22211708, 22674740, 23444262, 37154149). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00249. The DDG2P confidence category, allelic requirement and molecular mechanism for PRRX1-related craniosynostosis are moderate, monoallelic_autosomal and undetermined (PMID:37154149). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02554. The DDG2P confidence category, allelic requirement and molecular mechanism for PRRX1-related agnathia-otocephaly complex are limited, biallelic_autosomal and undetermined (PMIDs: 22211708, 23444262). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02581.; Changed publications to: 22211708, 37154149, 22674740, 21294718, 23444262; Changed phenotypes to: AGNATHIA-OTOCEPHALY COMPLEX monoallelic, MONDO:0008740, AGNATHIA-OTOCEPHALY COMPLEX biallelic, OMIM:202650.0, PRRX1-related craniosynostosis, MONDO:0015469, PRRX1-related agnathia-otocephaly complex
DDG2P v6.17 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRMT9-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01462.; Changed phenotypes to: PRMT9-related intellectual developmental disorder, MONDO:0700092, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 PRKD1 Achchuthan Shanmugasundram edited their review of gene: PRKD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRKD1-related syndromic congenital heart defects are definitive, monoallelic_autosomal and undetermined (PMIDs: 27479907, 32817298, 36308391, 38677542). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01768.; Changed publications to: 27479907, 36308391, 32817298, 38677542; Changed phenotypes to: PRKD1-related syndromic congenital heart defects, Syndromic congenital heart defects, OMIM:617364.0, MONDO:0044303
DDG2P v6.17 PRKAR1B Achchuthan Shanmugasundram commented on gene: PRKAR1B: The DDG2P confidence category, allelic requirement and molecular mechanism for PRKAR1B-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMIDs: 33057194, 33833410). The cross-cutting modifiers are potential secondary finding and restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03017.
DDG2P v6.17 PRKACB Achchuthan Shanmugasundram edited their review of gene: PRKACB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRKACB-related multiple congenital malformation syndrome are strong, monoallelic_autosomal and undetermined (PMID:33058759). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03064.; Changed phenotypes to: MONDO:0030877, OMIM:619143.0, PRKACB-related multiple congenital malformation syndrome, PRKACB-related Multiple Congenital Malformation Syndrome
DDG2P v6.17 PRKACA Achchuthan Shanmugasundram edited their review of gene: PRKACA: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRKACA-related multiple congenital malformation syndrome are strong, monoallelic_autosomal and undetermined (PMID:33058759). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03063.; Changed phenotypes to: PRKACA-related multiple congenital malformation syndrome, PRKACA-related Multiple Congenital Malformation Syndrome, OMIM:619142.0, MONDO:0030876
DDG2P v6.17 PRDM6 Achchuthan Shanmugasundram edited their review of gene: PRDM6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PRDM6-related isolated nonsyndromic patent ductus arteriosus are limited, monoallelic_autosomal and undetermined (PMID:27181681). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01739.; Changed phenotypes to: OMIM:617039.0, PRDM6-related isolated nonsyndromic patent ductus arteriosus, MONDO:0024266, Isolated Nonsyndromic Patent Ductus Arteriosus.
DDG2P v6.17 PRDM15 Achchuthan Shanmugasundram commented on gene: PRDM15: The DDG2P confidence category, allelic requirement and molecular mechanism for PRDM15-related renal and neurodevelopmental disorder are limited, biallelic_autosomal and undetermined (PMID:33593823). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03106.
DDG2P v6.17 PPP3CA Achchuthan Shanmugasundram edited their review of gene: PPP3CA: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PPP3CA-related severe neurodevelopmental disease with seizures are strong, monoallelic_autosomal and undetermined (PMID:28942967). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02370.; Changed phenotypes to: MONDO:0700092, Severe Neurodevelopmental Disease with Seizures, PPP3CA-related severe neurodevelopmental disease with seizures
DDG2P v6.17 PPP1CB Achchuthan Shanmugasundram edited their review of gene: PPP1CB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PPP1CB-related rasopathy with developmental delay, short stature, and sparse slow-growing hair are definitive, monoallelic_autosomal and undetermined (PMID:27264673). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01758.; Changed phenotypes to: MONDO:0054588, Rasopathy with developmental delay, short stature and sparse slow-growing hair, OMIM:617506.0, PPP1CB-related rasopathy with developmental delay, short stature, and sparse slow-growing hair
DDG2P v6.17 PPFIA3 Achchuthan Shanmugasundram edited their review of gene: PPFIA3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PPFIA3-related neurodevelopmental disorder are moderate, monoallelic_autosomal and loss of function (PMID:38181735). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03539.; Changed phenotypes to: Paul-Chao neurodevelopmental syndrome, OMIM:621122, MONDO:1040014, PPFIA3-related neurodevelopmental disorder
DDG2P v6.17 PPA2 Achchuthan Shanmugasundram edited their review of gene: PPA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PPA2-related sudden arrhythmic cardiac death after infectious or alcohol trigger are definitive, biallelic_autosomal and undetermined (PMIDs: 27523597, 27523598, 34400813). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01771.; Changed publications to: 27523597, 27523598, 34400813; Changed phenotypes to: Sudden arrhythmic cardiac death after infectious or alcohol trigger, PPA2-related sudden arrhythmic cardiac death after infectious or alcohol trigger, OMIM:617223.0, MONDO:0014974
DDG2P v6.17 POU3F3 Achchuthan Shanmugasundram edited their review of gene: POU3F3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POU3F3-related intellectual disability are definitive, monoallelic_autosomal and undetermined (PMID:31303265). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02759.; Changed phenotypes to: OMIM:618604.0, POU3F3-related intellectual disability, MONDO:0032830, INTELLECTUAL DISABILITY, OMIM:616579
DDG2P v6.17 POT1 Achchuthan Shanmugasundram edited their review of gene: POT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POT1-related Coats plus are limited, biallelic_autosomal and undetermined (PMID:27013236). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01756.; Changed phenotypes to: POT1-related Coats plus, MONDO:0957264, Coats Plus, OMIM:620368.0
DDG2P v6.17 POMP Achchuthan Shanmugasundram edited their review of gene: POMP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POMP-related keratosis linearis with ichthyosis congenita and sclerosing keratoderma are limited, biallelic_autosomal and undetermined (PMID:20226437). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01501.; Changed phenotypes to: MONDO:0011169, POMP-related keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952.0, KERATOSIS LINEARIS WITH ICHTHYOSIS CONGENITA AND SCLEROSING KERATODERMA, OMIM:601952
DDG2P v6.17 POLR2A Achchuthan Shanmugasundram edited their review of gene: POLR2A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POLR2A-related syndromic intellectual disability are definitive, monoallelic_autosomal and undetermined (PMIDs: 31353023, 33665635, 35461703). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02762.; Changed publications to: 33665635, 31353023, 35461703; Changed phenotypes to: OMIM:618603.0, MONDO:0032829, POLR2A-related syndromic intellectual disability, SYNDROMIC INTELLECTUAL DISABILITY, OMIM:612100
DDG2P v6.17 POLG Achchuthan Shanmugasundram edited their review of gene: POLG: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POLG-related mitochondrial DNA depletion syndrome, Alpers type are definitive, biallelic_autosomal and undetermined (PMIDs: 15122711, 15929042, 16130100, 32391929). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01327.; Changed publications to: 32391929, 16130100, 15122711, 15929042; Changed phenotypes to: OMIM:203700.0, MITOCHONDRIAL DNA DEPLETION SYNDROME 4A, OMIM:203700, MONDO:0008758, POLG-related mitochondrial DNA depletion syndrome, Alpers type
DDG2P v6.17 POLD1 Achchuthan Shanmugasundram edited their review of gene: POLD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for POLD1-related subcutaneous lipodystrophy, deafness, mandibular hypoplasia and male hypogonadism are definitive, monoallelic_autosomal and undetermined (PMIDs: 23770608, 26172944, 28521875, 28791128, 29199204, 30023403, 32826474, 36280868). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00218.; Changed publications to: 23770608, 30023403, 28791128, 36280868, 26172944, 32826474, 28521875, 29199204; Changed phenotypes to: OMIM:615381.0, POLD1-related subcutaneous lipodystrophy, deafness, mandibular hypoplasia and male hypogonadism, MONDO:0014157, SUBCUTANEOUS LIPODYSTROPHY, DEAFNESS, MANDIBULAR HYPOPLASIA AND MALE HYPOGONADISM
DDG2P v6.17 PNPLA1 Achchuthan Shanmugasundram edited their review of gene: PNPLA1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PNPLA1-related congenital ichthyosis are strong, biallelic_autosomal and undetermined (PMIDs: 22246504, 24344921, 26691440, 28403545, 31120544, 31833240, 33786896, 34899144, 36647593). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00829.; Changed publications to: 36647593, 24344921, 26691440, 22246504, 28403545, 34899144, 33786896, 31120544, 31833240; Changed phenotypes to: CONGENITAL ICHTHYOSIS, PNPLA1-related congenital ichthyosis, MONDO:0014011, OMIM:615024.0
DDG2P v6.17 PMPCB Achchuthan Shanmugasundram edited their review of gene: PMPCB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PMPCB-related neurodegeneration in early childhood are strong, biallelic_autosomal and undetermined (PMID:29576218). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02600.; Changed phenotypes to: OMIM:617954.0, Neurodegeneration in Early Childhood, PMPCB-related neurodegeneration in early childhood, MONDO:0054785
DDG2P v6.17 PLXND1 Achchuthan Shanmugasundram edited their review of gene: PLXND1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PLXND1-related Moebius syndrome are limited, monoallelic_autosomal and undetermined (PMID:26068067). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00327. The DDG2P confidence category, allelic requirement and molecular mechanism for PLXND1-related cardiac malformation syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 24254849, 35396997). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01509.; Changed phenotypes to: PLXND1-related Moebius syndrome, OMIM:157900.0, MONDO:0008006, PLXND1-related cardiac malformation syndrome, MOEBIUS SYNDROME, OMIM:620294.0, MONDO:0859532
DDG2P v6.17 PLCH1 Achchuthan Shanmugasundram edited their review of gene: PLCH1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PLCH1-related holoprosencephaly are limited, biallelic_autosomal and undetermined (PMID:33820834). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03315.; Changed phenotypes to: MONDO:0030886, PLCH1-related holoprosencephaly, HPE-related disorder, OMIM:619895.0
DDG2P v6.17 PLCB4 Achchuthan Shanmugasundram edited their review of gene: PLCB4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PLCB4-related auriculocondylar syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 22560091, 23315542, 28328130, 35170830). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00070.; Changed publications to: 23315542, 35170830, 28328130, 22560091; Changed phenotypes to: AURICULOCONDYLAR SYNDROME, OMIM:602483, PLCB4-related auriculocondylar syndrome, MONDO:0013845, OMIM:614669.0
DDG2P v6.17 PIP5K1C Achchuthan Shanmugasundram edited their review of gene: PIP5K1C: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIP5K1C-related lethal congenital contracture syndrome are limited, biallelic_autosomal and undetermined (PMID:17701898). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00274. The DDG2P confidence category, allelic requirement and molecular mechanism for PIP5K1C-related neurodevelopmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:37451268). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03467.; Changed publications to: 37451268, 17701898; Changed phenotypes to: PIP5K1C-related neurodevelopmental disorder, OMIM:611369.0, PIP5K1C-associated neurodevelopmental disorder, MONDO:0012656, MONDO:0700092, PIP5K1C-related lethal congenital contracture syndrome, LETHAL CONGENITAL CONTRACTURE SYNDROME TYPE 3, OMIM:611369
DDG2P v6.17 PIK3R1 Achchuthan Shanmugasundram edited their review of gene: PIK3R1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIK3R1-related SHORT syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 23810378, 23810379, 28472977). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00179. The DDG2P confidence category, allelic requirement and molecular mechanism for PIK3R1-related agammaglobulinemia are limited, biallelic_autosomal and loss of function (PMID:22351933). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00858.; Changed publications to: 23810378, 22351933, 28472977, 23810379; Changed phenotypes to: SHORT SYNDROME, OMIM:269880, MONDO:0010026, MONDO:0014083, OMIM:615214.0, OMIM:269880.0, PIK3R1-related SHORT syndrome, AGAMMAGLOBULINEMIA 7, AUTOSOMAL RECESSIVE, OMIM:615214, PIK3R1-related agammaglobulinemia; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v6.17 PIGY Achchuthan Shanmugasundram edited their review of gene: PIGY: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGY-related glycosylphosphatidylinositol deficiency are strong, biallelic_autosomal and undetermined (PMID:26293662). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01784.; Changed phenotypes to: OMIM:616809.0, MONDO:0014780, Glycosylphosphatidylinositol deficiency, OMIM:610293, PIGY-related glycosylphosphatidylinositol deficiency
DDG2P v6.17 PIGW Achchuthan Shanmugasundram edited their review of gene: PIGW: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGW-related hyperphosphatasia with intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:24367057). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01699.; Changed phenotypes to: OMIM:616025.0, PIGW-related hyperphosphatasia with intellectual developmental disorder, HYPERPHOSPHATASIA WITH INTELLECTUAL DEVELOPMENTAL DISORDER SYNDROME 5, OMIM:616025
DDG2P v6.17 PIGV Achchuthan Shanmugasundram edited their review of gene: PIGV: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGV-related hyperphosphatasia with intellectual developmental disorder are definitive, biallelic_autosomal and loss of function (PMIDs: 17351347, 20802478, 22228761, 33402532, 40799153). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00078.; Changed publications to: 17351347, 33402532, 20802478, 40799153, 22228761; Changed phenotypes to: OMIM:239300.0, HYPERPHOSPHATASIA WITH INTELLECTUAL DEVELOPMENTAL DISORDER, OMIM:239300, PIGV-related hyperphosphatasia with intellectual developmental disorder, MONDO:0009398
DDG2P v6.17 PIGU Achchuthan Shanmugasundram edited their review of gene: PIGU: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGU-related intellectual disability, central nervous system anomalies and scoliosis are strong, biallelic_autosomal and undetermined (PMID:31353022). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02761.; Changed phenotypes to: OMIM:618590.0, Intellectual Disability, Central Nervous System anomalies and Scoliosis, PIGU-related intellectual disability, central nervous system anomalies and scoliosis, MONDO:0032824
DDG2P v6.17 PIGT Achchuthan Shanmugasundram edited their review of gene: PIGT: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGT-related multiple congenital anomalies-hypotonia-seizures syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 23636107, 24906948). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01110.; Changed publications to: 24906948, 23636107; Changed phenotypes to: PIGT-related multiple congenital anomalies-hypotonia-seizures syndrome, MONDO:0014165, OMIM:615398.0, MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 3, OMIM:615398
DDG2P v6.17 PIGN Achchuthan Shanmugasundram edited their review of gene: PIGN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGN-related multiple congenital anomalies-hypotonia-seizures syndrome are definitive, biallelic_autosomal and loss of function (PMIDs: 21493957, 24253414, 24852103, 26364997, 26394714, 26419326, 27038415, 27300081, 29096607, 29330547, 32585529, 33193741, 33966742, 34051595, 35468813, 35812661, 36322149, 36363484). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01414.; Changed publications to: 29096607, 34051595, 35812661, 27038415, 24253414, 26419326, 26394714, 27300081, 24852103, 35468813, 33966742, 26364997, 36363484, 29330547, 36322149, 21493957, 32585529, 33193741; Changed phenotypes to: PIGN-related multiple congenital anomalies-hypotonia-seizures syndrome, MONDO:0013563, OMIM:614080.0, PIGN-related multiple congenital anomalies-hypotonia-seizures syndrome, OMIM:614080
DDG2P v6.17 PIGM Achchuthan Shanmugasundram edited their review of gene: PIGM: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PIGM-related glycosylphosphatidylinositol deficiency are limited, biallelic_autosomal and undetermined (PMID:16767100). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02424.; Changed phenotypes to: MONDO:0012465, OMIM:610293.0, PIGM-related glycosylphosphatidylinositol deficiency, Glycosylphosphatidylinositol deficiency, OMIM:610293
DDG2P v6.17 PHF5A Achchuthan Shanmugasundram edited their review of gene: PHF5A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PHF5A-related neurodevelopmental disorder with congenital malformations are moderate, monoallelic_autosomal and undetermined (PMIDs: 33811463, 37422718). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03487.; Changed phenotypes to: PHF5A-related neurodevelopmental disorder with congenital malformations, MONDO:0100038
DDG2P v6.17 PHC1 Achchuthan Shanmugasundram edited their review of gene: PHC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PHC1-related primary microcephaly are limited, biallelic_autosomal and undetermined (PMID:23418308). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00227.; Changed phenotypes to: PHC1-related primary microcephaly, MONDO:0014173, PRIMARY MICROCEPHALY, OMIM:615414, OMIM:615414.0
DDG2P v6.17 PGAP2 Achchuthan Shanmugasundram edited their review of gene: PGAP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PGAP2-related intellectual disability are definitive, biallelic_autosomal and undetermined (PMIDs: 23561846, 23561847, 29119105). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00290.; Changed publications to: 23561847, 23561846, 29119105; Changed phenotypes to: OMIM:614207.0, PGAP2-related intellectual disability, INTELLECTUAL DISABILITY, OMIM:616579, MONDO:0013628
DDG2P v6.17 PECR Achchuthan Shanmugasundram edited their review of gene: PECR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PECR-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00315.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0700092, PECR-related intellectual developmental disorder
DDG2P v6.17 PDSS1 Achchuthan Shanmugasundram edited their review of gene: PDSS1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PDSS1-related coenzyme Q10 deficiency, primary are strong, biallelic_autosomal and undetermined (PMID:17332895). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00213.; Changed phenotypes to: OMIM:614651.0, COENZYME Q10 DEFICIENCY, PRIMARY, 2, OMIM:614651, PDSS1-related coenzyme Q10 deficiency, primary
DDG2P v6.17 PDE10A Achchuthan Shanmugasundram edited their review of gene: PDE10A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PDE10A-related childhood-onset chorea with bilateral striatal lesions are strong, monoallelic_autosomal and undetermined (PMID:27058447). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01729.; Changed phenotypes to: PDE10A-related childhood-onset chorea with bilateral striatal lesions, Childhood-Onset Chorea with Bilateral Striatal Lesions, OMIM:616922.0, MONDO:0014835
DDG2P v6.17 PARP1 Achchuthan Shanmugasundram edited their review of gene: PARP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PARP1-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00254.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0700092, PARP1-related intellectual developmental disorder
DDG2P v6.17 PACS2 Achchuthan Shanmugasundram edited their review of gene: PACS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for PACS2-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 28867141, 30290155). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02368.; Changed publications to: 30290155, 28867141; Changed phenotypes to: Unspecified Neurodevelopmental Disorder, PACS2-related neurodevelopmental disorder, OMIM:618067.0, MONDO:0054845
DDG2P v6.17 PABPC1 Achchuthan Shanmugasundram commented on gene: PABPC1: The DDG2P confidence category, allelic requirement and molecular mechanism for PABPC1-related developmental delay are limited, monoallelic_autosomal and undetermined (PMID:35511136). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03484.
DDG2P v6.17 P4HB Achchuthan Shanmugasundram edited their review of gene: P4HB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for P4HB-related Cole-Carpenter syndrome are strong, monoallelic_autosomal and undetermined (PMID:25683117). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00895.; Changed phenotypes to: COLE-CARPENTER SYNDROME, OMIM:112240, OMIM:112240.0, MONDO:0007204, P4HB-related Cole-Carpenter syndrome
DDG2P v6.17 OTUD5 Achchuthan Shanmugasundram edited their review of gene: OTUD5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for OTUD5-related neurodevelopmental disorder are strong, monoallelic_X_hemizygous and undetermined (PMIDs: 33131077, 33523931, 33748114). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03438.; Changed publications to: 33523931, 33748114, 33131077; Changed phenotypes to: OTUD5-related neurodevelopmental disorder, OMIM:301056.0, MONDO:0025351, OTUD5-associated neurodevelopmental disorder
DDG2P v6.17 OSGEP Achchuthan Shanmugasundram edited their review of gene: OSGEP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for OSGEP-related nephrotic syndrome with primary microcephaly are strong, biallelic_autosomal and undetermined (PMID:28805828). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02386.; Changed phenotypes to: Nephrotic syndrome with primary microcephaly, MONDO:0033007, OSGEP-related nephrotic syndrome with primary microcephaly, OMIM:617729.0
DDG2P v6.17 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for OGDH-related neurodevelopmental disorder are moderate, biallelic_autosomal and undetermined (PMIDs: 32383294, 36520152). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03200.; Changed publications to: 32383294, 36520152; Changed phenotypes to: MONDO:0008759, OGDH-related neurodevelopmental disorder, OMIM:203740.0
DDG2P v6.17 NUP62 Achchuthan Shanmugasundram edited their review of gene: NUP62: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NUP62-related infantile striatonigral degeneration are strong, biallelic_autosomal and undetermined (PMID:16786527). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00243.; Changed phenotypes to: NUP62-related infantile striatonigral degeneration, INFANTILE STRIATONIGRAL DEGENERATION, OMIM:271930, OMIM:271930.0
DDG2P v6.17 NUP54 Achchuthan Shanmugasundram commented on gene: NUP54: The DDG2P confidence category, allelic requirement and molecular mechanism for NUP54-related early-onset dystonia with striatal lesions are moderate, biallelic_autosomal and undetermined (PMID:36333996). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03415.
DDG2P v6.17 NTRK2 Achchuthan Shanmugasundram edited their review of gene: NTRK2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NTRK2-related epilepsy and intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:29100083). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02374.; Changed phenotypes to: NTRK2-related epilepsy and intellectual disability, OMIM:617830.0, Epilepsy and intellectual disability, MONDO:0033367
DDG2P v6.17 NSUN2 Achchuthan Shanmugasundram edited their review of gene: NSUN2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NSUN2-related intellectual disability are strong, biallelic_autosomal and undetermined (PMIDs: 21063731, 22541559, 22541562, 22577224). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00298.; Changed publications to: 21063731, 22541562, 22541559, 22577224; Changed phenotypes to: NSUN2-related intellectual disability, MONDO:0012613, AUTOSOMAL- RECESSIVE INTELLECTUAL DISABILITY MRT5, OMIM:611091, OMIM:611091.0
DDG2P v6.17 NSMCE3 Achchuthan Shanmugasundram edited their review of gene: NSMCE3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NSMCE3-related distinct DNA breakage syndrome are limited, biallelic_autosomal and undetermined (PMIDs: 27427983, 33741030, 40728043). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01140.; Changed publications to: 40728043, 33741030, 27427983; Changed phenotypes to: NSMCE3-related distinct DNA breakage syndrome, DISTINCT DNA BREAKAGE SYNDROME
DDG2P v6.17 NRXN2 Achchuthan Shanmugasundram edited their review of gene: NRXN2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NRXN2-related autism are limited, monoallelic_autosomal and loss of function (PMIDs: 21424692, 36923655, 38739110). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00534.; Changed publications to: 38739110, 21424692, 36923655; Changed phenotypes to: AUTISM, OMIM:209850, OMIM:209850.0, NRXN2-related autism, MONDO:0005260
DDG2P v6.17 NR1I3 Achchuthan Shanmugasundram edited their review of gene: NR1I3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NR1I3-related intellectual disability are limited, monoallelic_autosomal and undetermined (PMID:22726846). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00508.; Changed publications to: 22726846; Changed phenotypes to: EHMT1-LIKE INTELLECTUAL DISABILITY, NR1I3-related intellectual disability, MONDO:0001071
DDG2P v6.17 NPM1 Achchuthan Shanmugasundram edited their review of gene: NPM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NPM1-related dyskeratosis congenita are strong, monoallelic_autosomal and undetermined (PMID:31570891). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02813.; Changed phenotypes to: Dyskeratosis Congenita, MONDO:0015780, NPM1-related dyskeratosis congenita
DDG2P v6.17 NOVA2 Achchuthan Shanmugasundram edited their review of gene: NOVA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NOVA2-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 32197073, 35607920). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02446.; Changed phenotypes to: Intellectual disability with ataxia/spasticity, NOVA2-related neurodevelopmental disorder, OMIM:618859.0, MONDO:0030024, NOVA2-associated neurodevelopmental disorder
DDG2P v6.17 NOP10 Achchuthan Shanmugasundram edited their review of gene: NOP10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NOP10-related dyskeratosis congenita are moderate, biallelic_autosomal and loss of function (PMID:17507419). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00165.; Changed phenotypes to: MONDO:0009136, NOP10-related dyskeratosis congenita, OMIM:224230, OMIM:224230.0, NOP10-related dyskeratosis congenita
DDG2P v6.17 NKAP Achchuthan Shanmugasundram edited their review of gene: NKAP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NKAP-related marfanoid habitus and cognitive impairment are strong, monoallelic_X_hemizygous and undetermined (PMID:31587868). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02830.; Changed phenotypes to: MONDO:0026733, NKAP-related marfanoid habitus and cognitive impairment, Marfanoid Habitus and Cognitive Impairment, OMIM:301039.0
DDG2P v6.17 NHP2 Achchuthan Shanmugasundram edited their review of gene: NHP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NHP2-related dyskeratosis congenita are moderate, biallelic_autosomal and loss of function (PMIDs: 18523010, 30472699, 31985013, 37440454). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01207.; Changed publications to: 31985013, 18523010, 37440454, 30472699; Changed phenotypes to: NHP2-related dyskeratosis congenita, NHP2-related dyskeratosis congenita, OMIM:613987, MONDO:0009136, OMIM:613987.0
DDG2P v6.17 NFU1 Achchuthan Shanmugasundram edited their review of gene: NFU1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NFU1-related multiple mitochondrial dysfunctions syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 11156534, 22077971). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00303.; Changed publications to: 22077971, 11156534; Changed phenotypes to: MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1, OMIM:605711, MONDO:0011582, NFU1-related multiple mitochondrial dysfunctions syndrome, OMIM:605711.0
DDG2P v6.17 NEDD4L Achchuthan Shanmugasundram edited their review of gene: NEDD4L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NEDD4L-related periventricular nodular heterotopia with intellectual disability, cleft palate, and 2-3 toe syndactyly are strong, monoallelic_autosomal and undetermined (PMIDs: 23934111, 27694961, 28515470). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00563.; Changed publications to: 23934111, 27694961, 28515470; Changed phenotypes to: NEDD4L-related periventricular nodular heterotopia with intellectual disability, cleft palate, and 2-3 toe syndactyly, OMIM:617201.0, MONDO:0014966, Periventricular nodular heterotopia with ID, cleft palate and 2.3 toe syndactyly
DDG2P v6.17 NDUFV2 Achchuthan Shanmugasundram edited their review of gene: NDUFV2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDUFV2-related mitochondrial complex I deficiency, nuclear are moderate, biallelic_autosomal and undetermined (PMIDs: 12754703, 26008862, 33811136, 34405929). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03314.; Changed publications to: 12754703, 33811136, 26008862, 34405929; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229, MONDO:0032612, NDUFV2-related mitochondrial complex I deficiency, nuclear, OMIM:618229.0
DDG2P v6.17 NDUFV1 Achchuthan Shanmugasundram edited their review of gene: NDUFV1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDUFV1-related mitochondrial complex I deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 10080174, 11349233, 35482246, 38626668, 39525154, 40207266). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00512.; Changed publications to: 39525154, 11349233, 40207266, 35482246, 10080174, 38626668; Changed phenotypes to: MITOCHONDRIAL COMPLEX I DEFICIENCY, OMIM:252010, NDUFV1-related mitochondrial complex I deficiency, OMIM:618225.0, MONDO:0032609
DDG2P v6.17 NDUFS8 Achchuthan Shanmugasundram edited their review of gene: NDUFS8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDUFS8-related mitochondrial respiratory chain complex I deficiency are definitive, biallelic_autosomal and loss of function (PMIDs: 15159508, 22499348, 36101822, 38229652, 9837812). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00224.; Changed publications to: 15159508, 22499348, 38229652, 36101822, 9837812; Changed phenotypes to: MONDO:0032606, NDUFS8-related mitochondrial respiratory chain complex I deficiency, MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY, OMIM:252010, OMIM:618222.0
DDG2P v6.17 NDUFA9 Achchuthan Shanmugasundram edited their review of gene: NDUFA9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDUFA9-related Leigh syndrome are limited, biallelic_autosomal and undetermined (PMIDs: 22114105, 28671271, 28853723). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01698.; Changed publications to: 22114105, 28671271, 28853723; Changed phenotypes to: NDUFA9-related Leigh syndrome, LEIGH SYNDROME, OMIM:256000, OMIM:256000.0, MONDO:0009723
DDG2P v6.17 NDUFA10 Achchuthan Shanmugasundram edited their review of gene: NDUFA10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDUFA10-related Leigh syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 21150889, 26741492, 28247337, 36270260). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01697.; Changed publications to: 28247337, 36270260, 21150889, 26741492; Changed phenotypes to: OMIM:618243.0, NDUFA10-related Leigh syndrome, LEIGH SYNDROME DUP, OMIM:256000, MONDO:0032626
DDG2P v6.17 NDST1 Achchuthan Shanmugasundram edited their review of gene: NDST1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NDST1-related intellectual disability with or without seizures are moderate, biallelic_autosomal and undetermined (PMIDs: 21937992, 25125150, 27620904, 28211985, 28600779, 31164858, 32878022, 38129107). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00677.; Changed publications to: 31164858, 28211985, 32878022, 28600779, 21937992, 38129107, 25125150, 27620904; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, NDST1-related intellectual disability with or without seizures
DDG2P v6.17 NCDN Achchuthan Shanmugasundram edited their review of gene: NCDN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NCDN-related neurodevelopmental disorder with seizures (biallelic) are limited, biallelic_autosomal and undetermined (PMID:33711248). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03115. The DDG2P confidence category, allelic requirement and molecular mechanism for NCDN-related neurodevelopmental disorder with seizures (monoallelic) are strong, monoallelic_autosomal and undetermined (PMID:33711248). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03116.; Changed phenotypes to: NCDN-related neurodevelopmental disorder with seizures (biallelic), NCDN-associated neurodevelopmental disorder with seizures (monoallelic), MONDO:0859162, NCDN-associated neurodevelopmental disorder with seizures (biallelic), NCDN-related neurodevelopmental disorder with seizures (monoallelic), OMIM:619373.0
DDG2P v6.17 NCAPG2 Achchuthan Shanmugasundram edited their review of gene: NCAPG2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NCAPG2-related severe neurodevelopmental syndrome are strong, biallelic_autosomal and undetermined (PMID:30609410). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02637.; Changed phenotypes to: MONDO:0032764, OMIM:618460.0, Severe Neurodevelopmental Syndrome, NCAPG2-related severe neurodevelopmental syndrome
DDG2P v6.17 NAE1 Achchuthan Shanmugasundram edited their review of gene: NAE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NAE1-related neurodevelopmental disorder with intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia, and neurodegeneration are moderate, biallelic_autosomal and undetermined (PMID:36608681). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03425.; Changed phenotypes to: OMIM:620210.0, NAE1-associated neurodevelopmental disorder with intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration, NAE1-related neurodevelopmental disorder with intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia, and neurodegeneration, MONDO:0859361
DDG2P v6.17 NAA20 Achchuthan Shanmugasundram edited their review of gene: NAA20: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for NAA20-related developmental delay and microcephaly are limited, biallelic_autosomal and undetermined (PMIDs: 34230638, 37191084). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03179.; Changed publications to: 34230638, 37191084; Changed phenotypes to: NAA20-related developmental delay and microcephaly, MONDO:0030533, OMIM:619717.0, NAA20-associated developmental delay and microcephaly
DDG2P v6.17 MYLPF Achchuthan Shanmugasundram edited their review of gene: MYLPF: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MYL11-related arthrogryposis, distal are strong, biallelic_autosomal and undetermined (PMID:32707087). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03032. The DDG2P confidence category, allelic requirement and molecular mechanism for MYL11-related arthrogryposis, distal are limited, monoallelic_autosomal and undetermined (PMID:32707087). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03033.; Changed phenotypes to: MYL11-related arthrogryposis, distal, MYLPF arthrogryposis (biallelic), OMIM:619110.0, MYLPF arthrogryposis (monoallelic), MONDO:0030847
DDG2P v6.17 MYH9 Achchuthan Shanmugasundram edited their review of gene: MYH9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MYH9-related macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss are definitive, monoallelic_autosomal and loss of function (PMIDs: 10973259, 25077172). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01498.; Changed publications to: 10973259, 25077172; Changed phenotypes to: MYH9-related macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, OMIM:155100, MYH9-related macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, OMIM:155100.0, MONDO:0015912
DDG2P v6.17 MYH6 Achchuthan Shanmugasundram edited their review of gene: MYH6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MYH6-related atrial septal defect are limited, monoallelic_autosomal and loss of function (PMIDs: 15735645, 20656787, 29505555, 29536580, 29969989, 31638415, 34481090). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00379.; Changed publications to: 15735645, 31638415, 29505555, 29536580, 34481090, 20656787, 29969989; Changed phenotypes to: ATRIAL SEPTAL DEFECT TYPE 3, OMIM:614089, MYH6-related atrial septal defect, OMIM:614089.0, MONDO:0013567
DDG2P v6.17 MYH3 Achchuthan Shanmugasundram edited their review of gene: MYH3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MYH3-related distal arthrogryposis are definitive, monoallelic_autosomal and undetermined (PMIDs: 16642020, 18695058). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01341. The DDG2P confidence category, allelic requirement and molecular mechanism for MYH3-related spondylocarpotarsal synostosis syndrome are strong, biallelic_autosomal and loss of function (PMID:29805041). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02609.; Changed phenotypes to: OMIM:618469.0, MONDO:0020746, OMIM:193700.0, DISTAL ARTHROGRYPOSIS TYPE 2A, OMIM:193700, MYH3-related spondylocarpotarsal synostosis syndrome, Recessive Spondylocarpotarsal Synostosis Syndrome, MYH3-related distal arthrogryposis
DDG2P v6.17 MYH10 Achchuthan Shanmugasundram edited their review of gene: MYH10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MYH10-related multiple congenital anomalies are moderate, monoallelic_autosomal and dominant negative (PMIDs: 25003005, 25356899, 35980381). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01930.; Changed mode of pathogenicity: Other; Changed publications to: 35980381, 25356899, 25003005; Changed phenotypes to: MYH10-related Multiple congenital anomalies, MYH10-related multiple congenital anomalies, MONDO:0700281
DDG2P v6.17 MTSS1L Achchuthan Shanmugasundram edited their review of gene: MTSS1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MTSS2-related syndromic intellectual disability are moderate, monoallelic_autosomal and undetermined (PMID:36067766). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03349.; Changed phenotypes to: MTSS2-related syndromic intellectual disability, MTSS2-associated syndromic intellectual disability, OMIM:620086.0, MONDO:0859303
DDG2P v6.17 MTOR Achchuthan Shanmugasundram edited their review of gene: MTOR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MTOR-related Smith-Kingsmore syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 23934111, 28892148). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01220.; Changed phenotypes to: MTOR-related Smith-Kingsmore syndrome, OMIM:616638.0, MONDO:0014716, Smith-Kingsmore syndrome, OMIM:616638
DDG2P v6.17 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MT-TL1-related mitochondrial disorder are limited, mitochondrial and undetermined (PMID:34075211). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03132.; Changed phenotypes to: MONDO:0044970, MT-TL1-related mitochondrial disorder, MT-TL1-associated mitochondrial disorder
DDG2P v6.17 MSI1 Achchuthan Shanmugasundram edited their review of gene: MSI1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MSI1-related microcephaly are limited, biallelic_autosomal and undetermined (PMID:28572454). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02422.; Changed phenotypes to: MSI1-related microcephaly, MSI1-associated Microcephaly, MONDO:0001149
DDG2P v6.17 MRPS22 Achchuthan Shanmugasundram edited their review of gene: MRPS22: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MRPS22-related combined oxidative phosphorylation deficiency are strong, biallelic_autosomal and undetermined (PMID:17873122). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00122.; Changed phenotypes to: COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 5, OMIM:611719, MRPS22-related combined oxidative phosphorylation deficiency, OMIM:611719.0
DDG2P v6.17 MRPS2 Achchuthan Shanmugasundram edited their review of gene: MRPS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MRPS2-related sensorineural hearing loss, hypoglycemia and multiple oxphos complex deficiencies are strong, biallelic_autosomal and undetermined (PMID:29576219). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02599.; Changed phenotypes to: MONDO:0054781, Sensorineural Hearing Loss Hypoglycemia and Multiple OXPHOS Complex Deficiencies, OMIM:617950.0, MRPS2-related sensorineural hearing loss, hypoglycemia and multiple oxphos complex deficiencies
DDG2P v6.17 MPZ Achchuthan Shanmugasundram edited their review of gene: MPZ: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MPZ-related neuropathy, congenital hypomyelinating are definitive, monoallelic_autosomal and undetermined (PMIDs: 12953275, 15184631, 26310628, 8816708). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02972.; Changed publications to: 26310628, 15184631, 8816708, 12953275; Changed phenotypes to: OMIM:618184.0, MONDO:0020765, NEUROPATHY, CONGENITAL HYPOMYELINATING, 2, OMIM:618184, MPZ-related neuropathy, congenital hypomyelinating
DDG2P v6.17 MPC2 Achchuthan Shanmugasundram edited their review of gene: MPC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MPC2-related metabolic disorder are limited, biallelic_autosomal and undetermined (PMID:36417180). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03458.; Changed phenotypes to: MPC2-related metabolic disorder, MONDO:0005066
DDG2P v6.17 MORC2 Achchuthan Shanmugasundram edited their review of gene: MORC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MORC2-related axonal neuropathy and neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 26497905, 26659848, 26912637, 27105897, 27329773, 27794525, 28334961, 28402445, 28771897, 30624633, 32693025, 33762496, 33844363, 34059105, 34189813, 34630290, 34664855, 35332768, 35904125). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01894.; Changed publications to: 33762496, 28771897, 26912637, 27105897, 28334961, 34664855, 28402445, 34189813, 27794525, 30624633, 35332768, 35904125, 26497905, 34059105, 26659848, 34630290, 27329773, 32693025, 33844363; Changed phenotypes to: MORC2 - axonal neuropathy and neurodevelopmental disorder, OMIM:619090.0, MORC2-related axonal neuropathy and neurodevelopmental disorder, MONDO:0030835
DDG2P v6.17 MOGS Achchuthan Shanmugasundram edited their review of gene: MOGS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MOGS-related congenital disorder of glycosylation are strong, biallelic_autosomal and undetermined (PMIDs: 10788335, 24716661, 35790351). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00017.; Changed publications to: 10788335, 35790351, 24716661; Changed phenotypes to: MOGS-related congenital disorder of glycosylation, OMIM:606056.0, CONGENITAL DISORDERS OF GLYCOSYLATION, OMIM:612379, MONDO:0011629
DDG2P v6.17 MMP14 Achchuthan Shanmugasundram edited their review of gene: MMP14: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MMP14-related Winchester syndrome are limited, biallelic_autosomal and undetermined (PMID:22922033). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01317.; Changed phenotypes to: OMIM:277950.0, MMP14-related Winchester syndrome, MONDO:0010201, WINCHESTER SYNDROME, OMIM:277950
DDG2P v6.17 MMP13 Achchuthan Shanmugasundram edited their review of gene: MMP13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MMP13-related spondyloepimetaphyseal dysplasia, Missouri type are definitive, monoallelic_autosomal and undetermined (PMIDs: 19615667, 8412645). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00762. The DDG2P confidence category, allelic requirement and molecular mechanism for MMP13-related metaphyseal anadysplasia are definitive, biallelic_autosomal and undetermined (PMIDs: 19615667, 8412645). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01239.; Changed publications to: 19615667, 8412645; Changed phenotypes to: MMP13-related metaphyseal anadysplasia, METAPHYSEAL ANADYSPLASIA TYPE 1, OMIM:602111, OMIM:250400.0, MONDO:0009597, SPONDYLOEPIMETAPHYSEAL DYSPLASIA MISSOURI TYPE, OMIM:602111, OMIM:602111.0, MMP13-related spondyloepimetaphyseal dysplasia, Missouri type, MONDO:0011198
DDG2P v6.17 MMGT1 Achchuthan Shanmugasundram commented on gene: MMGT1: The DDG2P confidence category, allelic requirement and molecular mechanism for MMGT1-related developmental disorder are moderate, monoallelic_X_hemizygous and undetermined (PMID:33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03016.
DDG2P v6.17 MIR184 Achchuthan Shanmugasundram edited their review of gene: MIR184: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MIR184-related keratoconus with cataract (EDICT syndrome) are definitive, monoallelic_autosomal and undetermined (PMIDs: 21996275, 23833072, 24138095, 25373792, 27195078). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01111.; Changed rating: GREEN; Changed publications to: 27195078, 21996275, 25373792, 24138095, 23833072; Changed phenotypes to: MONDO:0013678, KERATOCONUS WITH CATARACT, EDICT SYNDROME, OMIM:614303, OMIM:614303.0, MIR184-related keratoconus with cataract (EDICT syndrome)
DDG2P v6.17 MFSD2A Achchuthan Shanmugasundram edited their review of gene: MFSD2A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MFSD2A-related primary microcephaly are definitive, biallelic_autosomal and undetermined (PMID:26005865). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01689.; Changed phenotypes to: MICROCEPHALY 15, PRIMARY, AUTOSOMAL RECESSIVE, OMIM:616486, OMIM:616486.0, MFSD2A-related primary microcephaly
DDG2P v6.17 MFN2 Achchuthan Shanmugasundram commented on gene: MFN2: The DDG2P confidence category, allelic requirement and molecular mechanism for MFN2-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03015.
DDG2P v6.17 MED25 Achchuthan Shanmugasundram edited their review of gene: MED25: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED25-related Basel-Vanagaite-Smirin-Yosef syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 25527630, 25792360, 31602195, 32324310). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02957.; Changed publications to: 25792360, 25527630, 31602195, 32324310; Changed phenotypes to: MONDO:0014643, MED25-related Basel-Vanagaite-Smirin-Yosef syndrome, Basel-Vanagaite-Smirin-Yosef Syndrome, OMIM:616449, OMIM:616449.0
DDG2P v6.17 MED23 Achchuthan Shanmugasundram edited their review of gene: MED23: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED23-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMIDs: 21868677, 25845469, 30847200, 31164858). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00707.; Changed publications to: 31164858, 25845469, 30847200, 21868677; Changed phenotypes to: MED23-related intellectual developmental disorder, MONDO:0013651, INTELLECTUAL DEVELOPMENTAL DISORDER AUTOSOMAL RECESSIVE TYPE 18, OMIM:614249, OMIM:614249.0
DDG2P v6.17 MED17 Achchuthan Shanmugasundram edited their review of gene: MED17: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED17-related microcephaly, postnatal progressive, with seizures and brain atrophy are strong, biallelic_autosomal and undetermined (PMID:20950787). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00395.; Changed phenotypes to: MICROCEPHALY, POSTNATAL PROGRESSIVE, WITH SEIZURES AND BRAIN ATROPHY, OMIM:613668, MONDO:0013351, MED17-related microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668.0
DDG2P v6.17 MED12 Achchuthan Shanmugasundram edited their review of gene: MED12: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related Opitz-Kaveggia syndrome are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 17334363, 18973276, 20507344, 24039113, 26273451, 27081531, 27286923, 27312080). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00747. The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related Lujan-Fryns syndrome are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 17369503, 24123922, 24715367, 27286923, 27312080, 27500536, 27980443, 28544239, 30006928, 31536828, 6711603). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00913. The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related developmental disorder are definitive, monoallelic_X_heterozygous and loss of function (PMIDs: 33244165, 33244166, 35385210). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03071.; Changed publications to: 17369503, 35385210, 27980443, 18973276, 20507344, 27286923, 24039113, 30006928, 6711603, 27312080, 33244166, 27500536, 24715367, 24123922, 28544239, 33244165, 27081531, 17334363, 31536828, 26273451; Changed phenotypes to: OMIM:305450.0, LUJAN-FRYNS SYNDROME, OMIM:309520, OMIM:309520.0, OPITZ-KAVEGGIA SYNDROME, OMIM:305450, MED12-related Lujan-Fryns syndrome, MONDO:0700092, MED12-related developmental disorder, MED12-related Opitz-Kaveggia syndrome
DDG2P v6.17 MED11 Achchuthan Shanmugasundram edited their review of gene: MED11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED11-related neurodevelopmental disorder are moderate, biallelic_autosomal and undetermined (PMID:36001086). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03343.; Changed phenotypes to: MED11-associated neurodevelopmental disorder, MONDO:0957225, OMIM:620327.0, MED11-related neurodevelopmental disorder
DDG2P v6.17 MATN3 Achchuthan Shanmugasundram edited their review of gene: MATN3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MATN3-related multiple epiphyseal dysplasia are definitive, monoallelic_autosomal and undetermined (PMIDs: 11479597, 13849708, 14729835, 15948199). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00889.; Changed publications to: 15948199, 11479597, 13849708, 14729835; Changed phenotypes to: MATN3-related multiple epiphyseal dysplasia, MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 5, OMIM:607078, MONDO:0011765, OMIM:607078.0
DDG2P v6.17 MAST1 Achchuthan Shanmugasundram edited their review of gene: MAST1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAST1-related developmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 30449657, 33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02878.; Changed publications to: 33057194, 30449657; Changed phenotypes to: MAST1-related developmental disorder (monoallelic), MONDO:0032648, OMIM:618273.0, MAST1-related developmental disorder
DDG2P v6.17 MAPRE2 Achchuthan Shanmugasundram edited their review of gene: MAPRE2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAPRE2-related circumferential skin creases, Kunze type are definitive, biallelic_autosomal and undetermined (PMID:26637975). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01655.; Changed phenotypes to: MONDO:0014755, MAPRE2-related circumferential skin creases, Kunze type, Circumferential Skin Creases Kunze Type, OMIM:156610, OMIM:616734.0
DDG2P v6.17 MAP4K4 Achchuthan Shanmugasundram edited their review of gene: MAP4K4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAP4K4-related neurodevelopmental disorder with or without congenital anomalies are moderate, monoallelic_autosomal and loss of function (PMIDs: 28518170, 36469137, 37126546). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03550. The DDG2P confidence category, allelic requirement and molecular mechanism for MAP4K4-related neurodevelopmental disorder with or without congenital anomalies are moderate, monoallelic_autosomal and dominant negative (PMID:37126546). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03716.; Changed publications to: 28518170, 36469137, 37126546; Changed phenotypes to: MAP4K4-related neurodevelopmental disorder with/without congenital anomalies, MONDO:0100038, MAP4K4-related neurodevelopmental disorder with or without congenital anomalies
DDG2P v6.17 MAP3K7 Achchuthan Shanmugasundram edited their review of gene: MAP3K7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAP3K7-related frontometaphyseal dysplasia are strong, monoallelic_autosomal and undetermined (PMIDs: 27426733, 27426734). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01776.; Changed publications to: 27426734, 27426733; Changed phenotypes to: MONDO:0014935, OMIM:617137.0, FRONTOMETAPHYSEAL DYSPLASIA, OMIM:617137, MAP3K7-related frontometaphyseal dysplasia
DDG2P v6.17 MAN2A2 Achchuthan Shanmugasundram edited their review of gene: MAN2A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAN2A2-related disorder of glycosylation are limited, biallelic_autosomal and undetermined (PMID:36357165). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03421.; Changed phenotypes to: MONDO:0024322, MAN2A2-related disorder of glycosylation
DDG2P v6.17 MAN1B1 Achchuthan Shanmugasundram edited their review of gene: MAN1B1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAN1B1-related intellectual developmental disorder are definitive, biallelic_autosomal and undetermined (PMIDs: 21763484, 21937992, 24348268, 24566669, 26279649, 26577042). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01138.; Changed publications to: 26279649, 26577042, 24348268, 21937992, 21763484, 24566669; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0013624, MAN1B1-related intellectual developmental disorder, OMIM:614202.0
DDG2P v6.17 MAF Achchuthan Shanmugasundram edited their review of gene: MAF: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MAF-related cataract are definitive, monoallelic_autosomal and undetermined (PMIDs: 11772997, 16470690, 24664492, 29314435, 30659945). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01427. The DDG2P confidence category, allelic requirement and molecular mechanism for MAF-related cataracts, congenital, with sensorineural deafness, down syndrome-like facial appearance, short stature, and mental retardation are definitive, monoallelic_autosomal and undetermined (PMID:25865493). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01853.; Changed publications to: 24664492, 25865493, 29314435, 11772997, 16470690, 30659945; Changed phenotypes to: MAF-related cataract, MONDO:0012437, OMIM:610202.0, MAF-related cataracts, congenital, with sensorineural deafness, down syndrome-like facial appearance, short stature, and mental retardation, OMIM:601088.0, MONDO:0010992, MAF-related cataract, OMIM:610202, MAF-related cataracts, congenital, with sensorineural deafness, down syndrome-like facial appearance, short stature, and mental retardation, OMIM:601088
DDG2P v6.17 MACF1 Achchuthan Shanmugasundram edited their review of gene: MACF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MACF1-related defects in neuronal migration and axon guidance are strong, monoallelic_autosomal and undetermined (PMID:30471716). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02631.; Changed phenotypes to: Defects in Neuronal Migration and Axon Guidance, MACF1-related defects in neuronal migration and axon guidance, MONDO:0032677, OMIM:618325.0
DDG2P v6.17 LZTR1 Achchuthan Shanmugasundram edited their review of gene: LZTR1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LZTR1-related Noonan syndrome (biallelic) are strong, biallelic_autosomal and undetermined (PMIDs: 29469822, 29959388, 30368668, 31182298, 37936555, 38135892). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02571. The DDG2P confidence category, allelic requirement and molecular mechanism for LZTR1-related Noonan syndrome (monoallelic) are definitive, monoallelic_autosomal and undetermined (PMIDs: 25795793, 30368668, 30664951, 30859559, 31533111, 31825158, 33407364, 35656879, 35840934, 36304179). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02988.; Changed publications to: 38135892, 33407364, 30859559, 35840934, 29959388, 29469822, 35656879, 37936555, 31182298, 36304179, 30368668, 31825158, 25795793, 30664951, 31533111; Changed phenotypes to: MONDO:0014693, NOONAN SYNDROME 10, OMIM:616564, LZTR1-related Noonan syndrome (monoallelic), LZTR1-related Noonan syndrome (biallelic), Noonan syndrome, OMIM:616564.0
DDG2P v6.17 LSM11 Achchuthan Shanmugasundram commented on gene: LSM11: The DDG2P confidence category, allelic requirement and molecular mechanism for LSM11-related Aicardi-Goutieres syndrome are limited, biallelic_autosomal and loss of function (PMID:33230297). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03531.
DDG2P v6.17 LRPAP1 Achchuthan Shanmugasundram edited their review of gene: LRPAP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LRPAP1-related myopia, extreme are definitive, biallelic_autosomal and loss of function (PMID:23830514). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00056.; Changed rating: GREEN; Changed phenotypes to: MYOPIA 23, AUTOSOMAL RECESSIVE, OMIM:615431, EXTREME MYOPIA, MONDO:0014183, OMIM:615431.0, LRPAP1-related myopia, extreme
DDG2P v6.17 LONP1 Achchuthan Shanmugasundram edited their review of gene: LONP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LONP1-related CODAS syndrome are strong, biallelic_autosomal and loss of function (PMIDs: 25574826, 25808063, 28148925, 29408517, 30997404, 31169704, 36684615, 36685982). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01139. The DDG2P confidence category, allelic requirement and molecular mechanism for LONP1-related congenital diaphragmatic hernia are limited, monoallelic_autosomal and loss of function (PMID:34547244). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03209.; Changed publications to: 29408517, 28148925, 30997404, 31169704, 36684615, 36685982, 25574826, 25808063, 34547244; Changed phenotypes to: MONDO:0010879, OMIM:600373.0, LONP1-associated congenital diaphragmatic hernia, MONDO:0005711, CODAS SYNDROME, OMIM:600373, LONP1-related CODAS syndrome, LONP1-related congenital diaphragmatic hernia
DDG2P v6.17 LMNB2 Achchuthan Shanmugasundram edited their review of gene: LMNB2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LMNB2-related primary microcephaly are strong, monoallelic_autosomal and undetermined (PMID:33033404). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03056.; Changed phenotypes to: LMNB2-related primary microcephaly, OMIM:619180.0, MONDO:0030929, LMNB2-related Primary Microcephaly
DDG2P v6.17 LMNB1 Achchuthan Shanmugasundram edited their review of gene: LMNB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LMNB1-related developmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 32910914, 33033404). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03049.; Changed publications to: 33033404, 32910914; Changed phenotypes to: MONDO:0030928, OMIM:619179.0, LMNB1-associated developmental disorder, LMNB1-related developmental disorder
DDG2P v6.17 LMBRD2 Achchuthan Shanmugasundram edited their review of gene: LMBRD2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LMBRD2-related intellectual disability are limited, monoallelic_autosomal and undetermined (PMID:32820033). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03212.; Changed phenotypes to: OMIM:619694.0, LMBRD2-associated intellectual disability, LMBRD2-related intellectual disability, MONDO:0859218
DDG2P v6.17 LIPT2 Achchuthan Shanmugasundram edited their review of gene: LIPT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LIPT2-related mitochondrial lipoylation defect associated with severe neonatal encephalopathy are strong, biallelic_autosomal and undetermined (PMID:28757203). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02219.; Changed phenotypes to: Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy, MONDO:0060562, OMIM:617668.0, LIPT2-related mitochondrial lipoylation defect associated with severe neonatal encephalopathy
DDG2P v6.17 LIPT1 Achchuthan Shanmugasundram edited their review of gene: LIPT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LIPT1-related Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase are strong, biallelic_autosomal and undetermined (PMIDs: 24256811, 24341803, 27247813). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02224.; Changed publications to: 24256811, 27247813, 24341803; Changed phenotypes to: MONDO:0014576, LIPT1-related Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase, OMIM:616299.0, Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.
DDG2P v6.17 LIAS Achchuthan Shanmugasundram edited their review of gene: LIAS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LIAS-related neonatal-onset epilepsy, defective mitochondrial energy metabolism and glycine elevation are strong, biallelic_autosomal and undetermined (PMIDs: 22152680, 26108146). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02223.; Changed phenotypes to: OMIM:614462.0, MONDO:0013762, Neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation, LIAS-related neonatal-onset epilepsy, defective mitochondrial energy metabolism and glycine elevation
DDG2P v6.17 LFNG Achchuthan Shanmugasundram edited their review of gene: LFNG: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LFNG-related spondylocostal dysostosis are definitive, biallelic_autosomal and undetermined (PMIDs: 16385447, 22822384, 30531807, 37038048, 38565611). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01136.; Changed publications to: 30531807, 22822384, 37038048, 38565611, 16385447; Changed phenotypes to: LFNG-related spondylocostal dysostosis, MONDO:0012349, SPONDYLOCOSTAL DYSOSTOSIS TYPE 3, OMIM:609813, OMIM:609813.0
DDG2P v6.17 LETM1 Achchuthan Shanmugasundram edited their review of gene: LETM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LETM1-related neurodevelopmental disorder are moderate, biallelic_autosomal and undetermined (PMID:36055214). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03409.; Changed phenotypes to: OMIM:620089.0, MONDO:0859304, LETM1-related neurodevelopmental disorder
DDG2P v6.17 LEMD2 Achchuthan Shanmugasundram edited their review of gene: LEMD2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LEMD2-related early progeroid syndrome are moderate, monoallelic_autosomal and undetermined (PMIDs: 30905398, 37867468, 38757373). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02782.; Changed publications to: 37867468, 38757373, 30905398; Changed phenotypes to: Nuclear Envelopathy with Early Progeroid Appearance, LEMD2-related early progeroid syndrome, OMIM:619322.0, MONDO:0859147
DDG2P v6.17 LDB3 Achchuthan Shanmugasundram edited their review of gene: LDB3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LDB3-related myopathy myofibrillar are limited, monoallelic_autosomal and undetermined (PMIDs: 15668942, 17337483). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00544.; Changed publications to: 15668942, 17337483; Changed phenotypes to: OMIM:609452.0, MYOPATHY MYOFIBRILLAR TYPE 4, OMIM:609452, MONDO:0012277, LDB3-related myopathy myofibrillar
DDG2P v6.17 LAS1L Achchuthan Shanmugasundram edited their review of gene: LAS1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LAS1L-related intellectual disability are limited, monoallelic_X_hemizygous and undetermined (PMIDs: 25644381, 34653234). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02010.; Changed phenotypes to: LAS1L-related intellectual disability, OMIM:309585.0, INTELLECTUAL DISABILITY, OMIM:616579
DDG2P v6.17 LARS2 Achchuthan Shanmugasundram edited their review of gene: LARS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LARS2-related Perrault syndrome are strong, biallelic_autosomal and undetermined (PMID:23541342). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00856.; Changed phenotypes to: LARS2-related Perrault syndrome, PERRAULT SYNDROME, MONDO:0014126, OMIM:615300.0
DDG2P v6.17 LAGE3 Achchuthan Shanmugasundram edited their review of gene: LAGE3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for LAGE3-related Galloway-Mowat syndrome are limited, monoallelic_X_hemizygous and undetermined (PMID:28805828). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02821.; Changed phenotypes to: OMIM:301006.0, GALLOWAY-MOWAT SYNDROME 2, OMIM:301006, MONDO:0033006, LAGE3-related Galloway-Mowat syndrome
DDG2P v6.17 KRT74 Achchuthan Shanmugasundram edited their review of gene: KRT74: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KRT74-related hypotrichosis and/or woolly hair are moderate, monoallelic_autosomal and undetermined (PMIDs: 20346438, 21188418, 24714551). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00610.; Changed publications to: 24714551, 20346438, 21188418; Changed phenotypes to: HYPOTRICHOSIS SIMPLEX OF THE SCALP 2, OMIM:613981, OMIM:613981.0, KRT74-related hypotrichosis and/or woolly hair, MONDO:0013514
DDG2P v6.17 KPNA7 Achchuthan Shanmugasundram edited their review of gene: KPNA7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KPNA7-related Gomez-Lopez-Fernandes syndrome are limited, biallelic_autosomal and undetermined (PMID:24045845). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01769.; Changed phenotypes to: KPNA7-related Gomez-Lopez-Fernandes syndrome, Gomez-Lopez-Fernandes syndrome
DDG2P v6.17 KLHL7 Achchuthan Shanmugasundram edited their review of gene: KLHL7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KLHL7-related PERCHING syndrome (developmental delay, dysmorphism, feeding and respiratory difficulties, hypotonia, and joint contractures) are strong, biallelic_autosomal and loss of function (PMIDs: 27392078, 29074562, 30142437, 30300710, 30997404, 31953236, 35670385, 35699517, 37076692, 38333279). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02566.; Changed publications to: 35670385, 27392078, 31953236, 35699517, 30142437, 29074562, 38333279, 30300710, 30997404, 37076692; Changed phenotypes to: MONDO:0014890, Crisponi/CISS1-like phenotype associated with early-onset retinitis pigmentosa, Cold-induced sweating syndrome type 1 (CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa), OMIM:617055.0, KLHL7-related PERCHING syndrome (developmental delay, dysmorphism, feeding and respiratory difficulties, hypotonia, and joint contractures)
DDG2P v6.17 KLHL20 Achchuthan Shanmugasundram edited their review of gene: KLHL20: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KLHL20-related developmental disorder with seizures are moderate, monoallelic_autosomal and undetermined (PMID:36214804). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03488.; Changed phenotypes to: KLHL20-related developmental disorder with seizures, MONDO:0100038
DDG2P v6.17 KLF7 Achchuthan Shanmugasundram edited their review of gene: KLF7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KLF7-related developmental disorder are definitive, monoallelic_autosomal and undetermined (PMID:29251763). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02987.; Changed phenotypes to: MONDO:0700092, KLF7-related developmental disorder
DDG2P v6.17 KIRREL3 Achchuthan Shanmugasundram edited their review of gene: KIRREL3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KIRREL3-related intellectual developmental disorder are limited, monoallelic_autosomal and undetermined (PMID:19012874). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00765.; Changed phenotypes to: INTELLECTUAL DEVELOPMENTAL DISORDER AUTOSOMAL DOMINANT TYPE 4, OMIM:612581, KIRREL3-related intellectual developmental disorder, MONDO:0012947, OMIM:612581.0
DDG2P v6.17 KIF5C Achchuthan Shanmugasundram edited their review of gene: KIF5C: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KIF5C-related cortical dysplasia, complex, with other brain malformations are strong, monoallelic_autosomal and undetermined (PMID:23603762). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00729.; Changed phenotypes to: OMIM:615282.0, KIF5C-related cortical dysplasia, complex, with other brain malformations, MONDO:0014116, CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 2, OMIM:615282
DDG2P v6.17 KIF5B Achchuthan Shanmugasundram commented on gene: KIF5B: The DDG2P confidence category, allelic requirement and molecular mechanism for KIF5B-related disease are moderate, monoallelic_autosomal and undetermined (PMIDs: 35342932, 36018820). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03463.
DDG2P v6.17 KIF3B Achchuthan Shanmugasundram edited their review of gene: KIF3B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KIF3B-related ciliopathy are limited, monoallelic_autosomal and undetermined (PMID:32386558). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02969.; Changed phenotypes to: MONDO:0005308, KIF3B-related ciliopathy
DDG2P v6.17 KDM5A Achchuthan Shanmugasundram edited their review of gene: KDM5A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KDM5A-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01352.; Changed phenotypes to: KDM5A-related intellectual developmental disorder, MONDO:0700092, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 KDM1A Achchuthan Shanmugasundram edited their review of gene: KDM1A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KDM1A-related developmental delay and distinctive facial features are strong, monoallelic_autosomal and undetermined (PMIDs: 26656649, 29559475). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02308.; Changed publications to: 26656649, 29559475; Changed phenotypes to: MONDO:0014751, OMIM:616728.0, Developmental delay and distinctive facial features, KDM1A-related developmental delay and distinctive facial features
DDG2P v6.17 KCTD1 Achchuthan Shanmugasundram edited their review of gene: KCTD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCTD1-related scalp-ear-nipple syndrome are limited, monoallelic_autosomal and gain of function (PMIDs: 23541344, 33000225, 34456244). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00769.; Changed rating: RED; Changed publications to: 23541344, 33000225, 34456244; Changed phenotypes to: KCTD1-related scalp-ear-nipple syndrome, SCALP-EAR-NIPPLE SYNDROME, OMIM:181270, OMIM:181270.0, MONDO:0008404
DDG2P v6.17 KCNT1 Achchuthan Shanmugasundram edited their review of gene: KCNT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNT1-related malignant migrating partial seizures of infancy are definitive, monoallelic_autosomal and gain of function (PMIDs: 23086396, 23086397, 23278465, 24029078, 24120652, 25120433, 26122718, 26140313, 26740507, 26748457, 27081515, 28081520, 28366665, 28987752, 29037447, 29196578, 29291456, 29870100, 30112700, 30525185, 30782581, 30804880, 30847371, 30903923, 31388363, 31560846, 31872048, 31926846, 32883383, 33650128, 34147500, 34567798, 36279596, 36297665, 36746065). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00887. The DDG2P confidence category, allelic requirement and molecular mechanism for KCNT1-related epilepsy are definitive, monoallelic_autosomal and undetermined (PMIDs: 23086396, 23086397). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00927.; Changed publications to: 30525185, 30782581, 30847371, 28987752, 34567798, 31560846, 23278465, 26122718, 24029078, 23086397, 26740507, 29870100, 31926846, 36746065, 26140313, 30903923, 36279596, 34147500, 28366665, 27081515, 28081520, 29037447, 30804880, 23086396, 36297665, 33650128, 25120433, 29291456, 24120652, 29196578, 32883383, 30112700, 31872048, 26748457, 31388363; Changed phenotypes to: OMIM:614959.0, MONDO:0017385, KCNT1-related epilepsy, MALIGNANT MIGRATING PARTIAL SEIZURES OF INFANCY, SEVERE AUTOSOMAL DOMINANT NOCTURNAL FRONTAL LOBE EPILEPSY, OMIM:614959, MONDO:0013989, KCNT1-related malignant migrating partial seizures of infancy
DDG2P v6.17 KCNQ3 Achchuthan Shanmugasundram edited their review of gene: KCNQ3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNQ3-related syndrome are definitive, monoallelic_autosomal and undetermined. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01704.; Changed phenotypes to: MONDO:0700092, KCNQ3 syndrome, KCNQ3-related syndrome
DDG2P v6.17 KCNMA1 Achchuthan Shanmugasundram edited their review of gene: KCNMA1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNMA1-related generalized epilepsy and paroxysmal dyskinesia are definitive, monoallelic_autosomal and gain of function (PMIDs: 15937479, 26195193, 28728269, 29330545, 31152168, 31427379, 32132200, 32633875, 33043086, 33178487, 34224328, 34499417, 34563042, 34674900, 35095492, 35141357, 35156297, 35730691, 36127141, 36252966). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00511. The DDG2P confidence category, allelic requirement and molecular mechanism for KCNMA1-related developmental delay, seizures and cerebellar atrophy are strong, biallelic_autosomal and loss of function (PMIDs: 27567911, 29545233, 31152168). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03175.; Changed publications to: 31152168, 15937479, 34563042, 36252966, 34499417, 35095492, 32132200, 33043086, 35156297, 35141357, 32633875, 34224328, 26195193, 34674900, 29545233, 33178487, 28728269, 35730691, 29330545, 31427379, 36127141, 27567911; Changed phenotypes to: KCNMA1-related developmental delay, seizures and cerebellar atrophy, OMIM:609446.0, MONDO:0060551, OMIM:617643.0, GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA, OMIM:609446, MONDO:0012276, KCNMA1-related generalized epilepsy and paroxysmal dyskinesia
DDG2P v6.17 KCNK3 Achchuthan Shanmugasundram edited their review of gene: KCNK3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNK3-related developmental delay with sleep apnea are strong, monoallelic_autosomal and undetermined (PMIDs: 33057194, 36195757). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02892.; Changed phenotypes to: KCNK3-related developmental disorder (monoallelic), KCNK3-associated developmental delay with sleep apnea, KCNK3-related developmental delay with sleep apnea, MONDO:0700360
DDG2P v6.17 KCNJ6 Achchuthan Shanmugasundram edited their review of gene: KCNJ6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNJ6-related Keppen-Lubinsky syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 25620207, 36071510). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00759.; Changed publications to: 36071510, 25620207; Changed phenotypes to: OMIM:614098.0, KEPPEN-LUBINSKY SYNDROME, OMIM:614098, KCNJ6-related Keppen-Lubinsky syndrome, MONDO:0013572
DDG2P v6.17 KCNH5 Achchuthan Shanmugasundram edited their review of gene: KCNH5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNH5-related epilepsy and epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMIDs: 23647072, 36307226). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00923.; Changed publications to: 23647072, 36307226; Changed phenotypes to: KCNH5-related epilepsy and epileptic encephalopathy, MONDO:0957812, OMIM:620537.0
DDG2P v6.17 KCNE1 Achchuthan Shanmugasundram edited their review of gene: KCNE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNE1-related Jervell and Lange-Nielsen syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 10973849, 16461811, 19716085, 30461122, 31941373, 9328483, 9354783, 9445165). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00124. The DDG2P confidence category, allelic requirement and molecular mechanism for KCNE1-related long QT syndrome are limited, monoallelic_autosomal and undetermined (PMIDs: 10973849, 31941373, 9354802). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00931.; Changed publications to: 30461122, 19716085, 9354802, 10973849, 9354783, 9328483, 31941373, 16461811, 9445165; Changed phenotypes to: LONG QT SYNDROME-5, OMIM:613695, KCNE1-related long QT syndrome, OMIM:612347.0, MONDO:0013372, JERVELL AND LANGE-NIELSEN SYNDROME TYPE 2, OMIM:612347, MONDO:0012871, KCNE1-related Jervell and Lange-Nielsen syndrome, OMIM:613695.0
DDG2P v6.17 KCND2 Achchuthan Shanmugasundram edited their review of gene: KCND2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCND2-related neurodevelopmental disorder with or without seizures are moderate, monoallelic_autosomal and undetermined (PMIDs: 24501278, 34245260). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03544.; Changed publications to: 24501278, 34245260; Changed phenotypes to: MONDO:1040003, KCND2-related neurodevelopmental disorder with or without seizures
DDG2P v6.17 KCNC3 Achchuthan Shanmugasundram edited their review of gene: KCNC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNC3-related spinocerebellar ataxia are strong, monoallelic_autosomal and undetermined (PMIDs: 16501573, 25497598, 25981959, 37365508). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00208.; Changed publications to: 16501573, 25497598, 25981959, 37365508; Changed phenotypes to: SPINOCEREBELLAR ATAXIA TYPE 13, OMIM:605259, OMIM:605259.0, MONDO:0011529, KCNC3-related spinocerebellar ataxia
DDG2P v6.17 KCNB1 Achchuthan Shanmugasundram edited their review of gene: KCNB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNB1-related epileptic encephalopathy, early infantile are definitive, monoallelic_autosomal and undetermined (PMID:25164438). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01597.; Changed phenotypes to: KCNB1-related epileptic encephalopathy, early infantile, OMIM:616056.0, EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 26, OMIM:616056, MONDO:0014477
DDG2P v6.17 KCNA4 Achchuthan Shanmugasundram edited their review of gene: KCNA4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNA4-related abnormal striatum, congenital cataract and intellectual disability are limited, biallelic_autosomal and undetermined (PMID:27582084). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02801.; Changed phenotypes to: MONDO:0032656, OMIM:618284.0, KCN4 related abnormal striatum, congenital cataract and intellectual disability., KCNA4-related abnormal striatum, congenital cataract and intellectual disability
DDG2P v6.17 KCNA1 Achchuthan Shanmugasundram edited their review of gene: KCNA1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KCNA1-related epileptic encephalopathy are limited, biallelic_autosomal and undetermined (PMID:31586945). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03173. The DDG2P confidence category, allelic requirement and molecular mechanism for KCNA1-related epileptic encephalopathy are limited, monoallelic_autosomal and undetermined (PMIDs: 19205071, 30055040, 32705822, 33355533, 34778950, 36793218). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03174.; Changed publications to: 34778950, 30055040, 19205071, 33355533, 36793218, 31586945, 32705822; Changed phenotypes to: KCNA1-related epileptic encephalopathy, monoallelic, MONDO:0100062, KCNA1-related epileptic encephalopathy, KCNA1-related epileptic encephalopathy, biallelic
DDG2P v6.17 KBTBD13 Achchuthan Shanmugasundram edited their review of gene: KBTBD13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KBTBD13-related nemaline myopathy are definitive, monoallelic_autosomal and undetermined (PMIDs: 12805120, 21104864, 21109227). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00067.; Changed publications to: 21104864, 12805120, 21109227; Changed phenotypes to: OMIM:609273.0, KBTBD13-related nemaline myopathy, NEMALINE MYOPATHY 6, OMIM:609273, MONDO:0012237
DDG2P v6.17 KAT5 Achchuthan Shanmugasundram edited their review of gene: KAT5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for KAT5-related neurodevelopmental syndrome are strong, monoallelic_autosomal and undetermined (PMID:32822602). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03041.; Changed phenotypes to: OMIM:619103.0, KAT5-related Neurodevelopmental Syndrome, MONDO:0030852, KAT5-related neurodevelopmental syndrome
DDG2P v6.17 ITGA6 Achchuthan Shanmugasundram edited their review of gene: ITGA6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ITGA6-related epidermolysis bullosa with pyloric atresia are limited, biallelic_autosomal and loss of function (PMID:9185503). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03906.; Changed phenotypes to: EPIDERMOLYSIS BULLOSA WITH PYLORIC ATRESIA, OMIM:226730, MONDO:0859233, ITGA6-related epidermolysis bullosa with pyloric atresia, OMIM:619817.0; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.17 IRX5 Achchuthan Shanmugasundram edited their review of gene: IRX5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IRX5-related hypertelorism, severe, with midface prominence, myopia, intellectual developmental disorder, and bone fragility are strong, biallelic_autosomal and undetermined (PMIDs: 22581230, 34899143). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00994.; Changed publications to: 34899143, 22581230; Changed phenotypes to: HYPERTELORISM, SEVERE, WITH MIDFACE PROMINENCE, MYOPIA, INTELLECTUAL DEVELOPMENTAL DISORDER, AND BONE FRAGILITY, OMIM:611174, OMIM:611174.0, IRX5-related hypertelorism, severe, with midface prominence, myopia, intellectual developmental disorder, and bone fragility
DDG2P v6.17 IQSEC2 Achchuthan Shanmugasundram edited their review of gene: IQSEC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IQSEC2-related intellectual developmental disorder are definitive, monoallelic_X_heterozygous and loss of function (PMIDs: 20473311, 21686261, 23674175, 24306141, 26733290, 26793055, 27665735, 28295038, 28815955, 29026562, 30206421, 30666632, 30842726, 31415821, 31439632, 31490346, 31829726, 32529990, 32564198, 32761587, 33494955, 34484768, 35347702, 35446980, 36012761, 36267700, 36444437, 36684544, 37761403). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00063.; Changed publications to: 33494955, 28815955, 36684544, 30842726, 30666632, 26733290, 34484768, 26793055, 31490346, 30206421, 23674175, 28295038, 32529990, 37761403, 32761587, 36444437, 31415821, 24306141, 27665735, 20473311, 29026562, 31439632, 31829726, 35446980, 21686261, 36012761, 35347702, 32564198, 36267700; Changed phenotypes to: MONDO:0010656, INTELLECTUAL DEVELOPMENTAL DISORDER X-LINKED TYPE 1, OMIM:309530, OMIM:309530.0, IQSEC2-related intellectual developmental disorder
DDG2P v6.17 IQSEC1 Achchuthan Shanmugasundram edited their review of gene: IQSEC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IQSEC1-related intellectual disability, developmental delay, and short stature are strong, biallelic_autosomal and undetermined (PMID:31607425). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02832.; Changed phenotypes to: IQSEC1-related intellectual disability, developmental delay, and short stature, OMIM:618687.0, Intellectual Disability, Developmental Delay, and Short Stature, MONDO:0032870
DDG2P v6.17 INTS11 Achchuthan Shanmugasundram edited their review of gene: INTS11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for INTS11-related neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities are moderate, biallelic_autosomal and loss of function (PMIDs: 37054711, 37980560). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03549.; Changed phenotypes to: MONDO:0957386, INTS11-related neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428, INTS11-related neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428.0
DDG2P v6.17 INPP5K Achchuthan Shanmugasundram edited their review of gene: INPP5K: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for INPP5K-related muscular dystrophy, congenital, with cataracts, and intellectual disability are strong, biallelic_autosomal and undetermined (PMIDs: 28190456, 28190459, 28940338). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01962.; Changed publications to: 28940338, 28190456, 28190459; Changed phenotypes to: INPP5K-related muscular dystrophy, congenital, with cataracts, and intellectual disability, Muscular dystrophy, congenital, with cataracts and intellectual disability, OMIM:617404, OMIM:617404.0, MONDO:0024607
DDG2P v6.17 INPP4A Achchuthan Shanmugasundram edited their review of gene: INPP4A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for INPP4A-related neurodevelopmental disorder with spasticity, epilepsy and cerebellar hypoplasia are moderate, biallelic_autosomal and loss of function (PMIDs: 21937992, 25338135, 31978615, 36653678, 36759255, 39315527). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01556.; Changed rating: GREEN; Changed publications to: 39315527, 36653678, 21937992, 25338135, 36759255, 31978615; Changed phenotypes to: MONDO:0100038, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, INPP4A-related neurodevelopmental disorder with spasticity, epilepsy and cerebellar hypoplasia
DDG2P v6.17 IL11 Achchuthan Shanmugasundram edited their review of gene: IL11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IL11-related craniosynostosis are limited, biallelic_autosomal and undetermined (PMID:21741611). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01476.; Changed phenotypes to: IL11-related craniosynostosis, CRANIOSYNOSTOSIS AND DENTAL ANOMALIES, OMIM:614188
DDG2P v6.17 IHH Achchuthan Shanmugasundram edited their review of gene: IHH: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IHH-related brachydactyly are definitive, monoallelic_autosomal and undetermined (PMIDs: 11455389, 12384778, 12525541, 16871364, 18629882, 19277064). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00942. The DDG2P confidence category, allelic requirement and molecular mechanism for IHH-related acrocapitofemoral dysplasia are definitive, biallelic_autosomal and undetermined (PMID:12632327). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01359.; Changed publications to: 11455389, 12632327, 16871364, 12525541, 18629882, 12384778, 19277064; Changed phenotypes to: MONDO:0011907, MONDO:0007215, BRACHYDACTYLY, TYPE A1, OMIM:112500, ACROCAPITOFEMORAL DYSPLASIA, OMIM:607778, OMIM:607778.0, OMIM:112500.0, IHH-related brachydactyly, IHH-related acrocapitofemoral dysplasia
DDG2P v6.17 IGBP1 Achchuthan Shanmugasundram edited their review of gene: IGBP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IGBP1-related agenesis of the corpus callosum with intellectual developmental disorder-ocular coloboma-micrognathia are limited, monoallelic_X_hemizygous and undetermined (PMID:23871722). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01025.; Changed phenotypes to: OMIM:300472.0, MONDO:0010333, IGBP1-related agenesis of the corpus callosum with intellectual developmental disorder-ocular coloboma-micrognathia, AGENESIS OF THE CORPUS CALLOSUM WITH INTELLECTUAL DEVELOPMENTAL DISORDER-OCULAR COLOBOMA-MICROGNATHIA, OMIM:300472
DDG2P v6.17 IFT80 Achchuthan Shanmugasundram edited their review of gene: IFT80: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IFT80-related asphyxiating thoracic dystrophy are definitive, biallelic_autosomal and undetermined (PMID:17468754). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01252.; Changed phenotypes to: IFT80-related asphyxiating thoracic dystrophy, ASPHYXIATING THORACIC DYSTROPHY 2, OMIM:611263, MONDO:0012644, OMIM:611263.0
DDG2P v6.17 IFT43 Achchuthan Shanmugasundram edited their review of gene: IFT43: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IFT43-related cranioectodermal dysplasia are definitive, biallelic_autosomal and undetermined (PMID:21378380). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00347.; Changed phenotypes to: OMIM:614099.0, CRANIOECTODERMAL DYSPLASIA TYPE 3, OMIM:614099, IFT43-related cranioectodermal dysplasia, MONDO:0013573
DDG2P v6.17 IFT122 Achchuthan Shanmugasundram edited their review of gene: IFT122: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IFT122-related cranioectodermal dysplasia are definitive, biallelic_autosomal and undetermined (PMIDs: 17022080, 19760620, 20493458). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00514.; Changed publications to: 19760620, 20493458, 17022080; Changed phenotypes to: IFT122-related cranioectodermal dysplasia, MONDO:0021093, CRANIOECTODERMAL DYSPLASIA, OMIM:218330, OMIM:218330.0
DDG2P v6.17 IFITM5 Achchuthan Shanmugasundram edited their review of gene: IFITM5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IFITM5-related osteogenesis imperfecta are definitive, monoallelic_autosomal and undetermined (PMIDs: 22863190, 22863195). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01448.; Changed phenotypes to: OMIM:610967.0, IFITM5-related osteogenesis imperfecta, MONDO:0012591, OSTEOGENESIS IMPERFECTA TYPE V, OMIM:610967
DDG2P v6.17 IFIH1 Achchuthan Shanmugasundram edited their review of gene: IFIH1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IFIH1-related Aicardi-Goutieres syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 24686847, 24995871, 25080300, 25620204, 26833990, 27658362, 28319323, 28716935, 29018476, 29270977, 29782060, 31427910, 31898846, 32042913, 32202700, 34189822, 34453469, 36685504). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01033. The DDG2P confidence category, allelic requirement and molecular mechanism for IFIH1-related Singleton-Merten syndrome are strong, monoallelic_autosomal and gain of function (PMIDs: 25620204, 28319323). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01514.; Changed publications to: 25080300, 27658362, 29018476, 31898846, 29270977, 32202700, 34453469, 24995871, 24686847, 25620204, 29782060, 28716935, 32042913, 34189822, 36685504, 31427910, 26833990, 28319323; Changed phenotypes to: IFIH1-related Aicardi-Goutieres syndrome, OMIM:182250.0, IFIH1-related Singleton-Merten syndrome, AICARDI-GOUTIERES SYNDROME 7, OMIM:615846, MONDO:0014367, MONDO:0024535, SINGLETON-MERTEN SYNDROME, OMIM:182250, OMIM:615846.0
DDG2P v6.17 IER3IP1 Achchuthan Shanmugasundram edited their review of gene: IER3IP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for IER3IP1-related microcephaly with simplified gyral pattern, epilepsy, and neonatal diabetes are strong, biallelic_autosomal and undetermined (PMIDs: 21835305, 22991235, 24138066, 28711742, 36416459). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03485.; Changed publications to: 36416459, 22991235, 21835305, 28711742, 24138066; Changed phenotypes to: IER3IP1-related microcephaly with simplified gyral pattern, epilepsy, and neonatal diabetes, OMIM:614231.0, MONDO:0031481
DDG2P v6.17 HYLS1 Achchuthan Shanmugasundram edited their review of gene: HYLS1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HYLS1-related hydrolethalus syndrome are definitive, biallelic_autosomal and undetermined (PMID:15843405). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00504.; Changed phenotypes to: MONDO:0009365, OMIM:236680.0, HYLS1-related hydrolethalus syndrome, HYDROLETHALUS SYNDROME TYPE 1, OMIM:236680
DDG2P v6.17 HUWE1 Achchuthan Shanmugasundram edited their review of gene: HUWE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HUWE1-related syndromic intellectual developmental disorder, Turner type are definitive, monoallelic_X_heterozygous and undetermined (PMIDs: 18252223, 23721686, 27130160, 29180823, 30797980). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00191.; Changed publications to: 23721686, 30797980, 27130160, 18252223, 29180823; Changed phenotypes to: HUWE1-related syndromic intellectual developmental disorder, Turner type, MONDO:0010407, OMIM:309590.0, INTELLECTUAL DEVELOPMENTAL DISORDER SYNDROMIC X-LINKED TURNER TYPE, OMIM:300706
DDG2P v6.17 HSF4 Achchuthan Shanmugasundram edited their review of gene: HSF4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HSF4-related cataract (monoallelic) are definitive, monoallelic_autosomal and undetermined (PMIDs: 12089525, 16876512, 19014451, 24045990, 24637349, 26490182, 29243736, 30143024). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00619.; Changed publications to: 29243736, 12089525, 24637349, 26490182, 19014451, 16876512, 30143024, 24045990; Changed phenotypes to: HSF4-related cataract (monoallelic), MONDO:0007290, OMIM:116800.0, CATARACT 5, MULTIPLE TYPES, OMIM:116800
DDG2P v6.17 HOXD13 Achchuthan Shanmugasundram edited their review of gene: HOXD13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HOXD13-related brachydactyly-syndactyly syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 12414828, 12649808, 12900906, 17236141, 19060004, 8817328, 9758628). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00949.; Changed publications to: 8817328, 17236141, 19060004, 12900906, 12414828, 9758628, 12649808; Changed phenotypes to: OMIM:610713.0, MONDO:0012544, HOXD13-related brachydactyly-syndactyly syndrome, BRACHYDACTYLY-SYNDACTYLY SYNDROME, OMIM:610713
DDG2P v6.17 HOXB1 Achchuthan Shanmugasundram edited their review of gene: HOXB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HOXB1-related facial paresis, congenital are strong, biallelic_autosomal and undetermined (PMID:22770981). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00821.; Changed phenotypes to: FACIAL PARESIS, HEREDITARY CONGENITAL, 3, OMIM:614744, MONDO:0013880, HOXB1-related facial paresis, congenital, OMIM:614744.0
DDG2P v6.17 HNRNPH2 Achchuthan Shanmugasundram edited their review of gene: HNRNPH2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HNRNPH2-related neurodevelopmental disorder are strong, monoallelic_X_heterozygous and undetermined (PMID:27545675). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01875.; Changed phenotypes to: HNRNPH2-related neurodevelopmental disorder, Neurodevelopmental Disorder in Females, OMIM:300986.0
DDG2P v6.17 HMGCS2 Achchuthan Shanmugasundram edited their review of gene: HMGCS2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HMGCS2-related 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 11228257, 11479731, 12647205, 9337379, 9727719). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01325.; Changed publications to: 11479731, 9337379, 11228257, 12647205, 9727719; Changed phenotypes to: OMIM:605911.0, MONDO:0011614, 3-HYDROXY-3-METHYLGLUTARYL-COA SYNTHASE 2 DEFICIENCY, OMIM:605911, HMGCS2-related 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency
DDG2P v6.17 HMGCR Achchuthan Shanmugasundram edited their review of gene: HMGCR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HMGCR-related limb-girdle muscular dystrophy are moderate, biallelic_autosomal and loss of function (PMIDs: 36745799, 37167966). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03528.; Changed phenotypes to: HMGCR-related limb-girdle muscular dystrophy, MONDO:0957270, OMIM:620375.0
DDG2P v6.17 HK1 Achchuthan Shanmugasundram edited their review of gene: HK1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HK1-related neurodevelopmental disorder with visual defects and brain anomalies are strong, monoallelic_autosomal and undetermined non-loss-of-function (PMIDs: 30778173, 33057194, 36639056, 38617198, 40469904). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02858.; Changed mode of pathogenicity: Other; Changed publications to: 36639056, 33057194, 40469904, 30778173, 38617198; Changed phenotypes to: HK1-related neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807, HK1-related developmental disorder (monoallelic), OMIM:618547.0
DDG2P v6.17 HECW2 Achchuthan Shanmugasundram edited their review of gene: HECW2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HECW2-related neurodevelopmental disorder (monoallelic) are definitive, monoallelic_autosomal and undetermined (PMIDs: 27334371, 27389779, 29395664, 29807643, 32814609, 33205896, 34047014, 34321324, 34327820, 35987951, 37280227). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01893. The DDG2P confidence category, allelic requirement and molecular mechanism for HECW2-related neurodevelopmental disorder (biallelic) are limited, biallelic_autosomal and undetermined (PMIDs: 35487419, 35753050). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03392.; Changed publications to: 29395664, 29807643, 35987951, 33205896, 35753050, 34327820, 27334371, 27389779, 34321324, 37280227, 35487419, 34047014, 32814609; Changed phenotypes to: HECW2-related neurodevelopmental disorder (monoallelic), HECW2-associated neurodevelopmental disorder, HECW2-related neurodevelopmental disorder, OMIM:617268, HECW2-related neurodevelopmental disorder (biallelic), OMIM:617268.0, MONDO:0014995
DDG2P v6.17 HECTD4 Achchuthan Shanmugasundram edited their review of gene: HECTD4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HECTD4-related neurodevelopmental disorder with seizures, hypotonia, spasticity, and agenesis of the corpus callosum are moderate, biallelic_autosomal and undetermined (PMID:36401616). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03490.; Changed phenotypes to: HECTD4-related neurodevelopmental disorder with seizures, hypotonia, spasticity, and agenesis of the corpus callosum, MONDO:0859516, OMIM:620250.0
DDG2P v6.17 HDAC3 Achchuthan Shanmugasundram edited their review of gene: HDAC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HDAC3-related neurodevelopmental disorder are moderate, monoallelic_autosomal and loss of function (PMID:39047730). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03596.; Changed phenotypes to: MONDO:0700092, HDAC3-related neurodevelopmental disorder
DDG2P v6.17 HCN1 Achchuthan Shanmugasundram edited their review of gene: HCN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HCN1-related epileptic encephalopathy, early infantile are definitive, monoallelic_autosomal and undetermined (PMID:24747641). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00411.; Changed phenotypes to: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 24, OMIM:615871, OMIM:615871.0, MONDO:0014377, HCN1-related epileptic encephalopathy, early infantile
DDG2P v6.17 HARS Achchuthan Shanmugasundram edited their review of gene: HARS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for HARS1-related Usher syndrome are limited, biallelic_autosomal and undetermined (PMID:22279524). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00615.; Changed phenotypes to: MONDO:0013788, USHER SYNDROME, OMIM:614504, OMIM:614504.0, HARS1-related Usher syndrome
DDG2P v6.17 HIST1H4C Achchuthan Shanmugasundram edited their review of gene: HIST1H4C: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for H4C3-related Tessadori-Bicknell-van Haaften neurodevelopmental syndrome are strong, monoallelic_autosomal and undetermined (PMID:28920961). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01969.; Changed phenotypes to: HIST1H4C, OMIM:619758.0, MONDO:0030729, H4C3-related Tessadori-Bicknell-van Haaften neurodevelopmental syndrome
DDG2P v6.17 HIST1H4J Achchuthan Shanmugasundram edited their review of gene: HIST1H4J: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for H4C11-related intellectual disability with facial dysmorphism are moderate, monoallelic_autosomal and undetermined (PMIDs: 31804630, 35202563). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02441.; Changed publications to: 31804630, 35202563; Changed phenotypes to: MONDO:0030730, Intellectual disability with facial dysmorphism, OMIM:619759.0, H4C11-related intellectual disability with facial dysmorphism
DDG2P v6.17 HIST3H3 Achchuthan Shanmugasundram edited their review of gene: HIST3H3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for H3-4-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00751.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0700092, H3-4-related intellectual developmental disorder
DDG2P v6.17 H3F3B Achchuthan Shanmugasundram edited their review of gene: H3F3B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for H3-3B-related neurodevelopmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33268356). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03308.; Changed phenotypes to: OMIM:619721.0, H3-3B-related neurodevelopmental disorder, MONDO:0030607, H3F3B associated neurodevelopmental disorder
DDG2P v6.17 H3F3A Achchuthan Shanmugasundram edited their review of gene: H3F3A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for H3-3A-related Bryant-Li-Bhoj neurodevelopmental syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 31942419, 33057194, 33268356). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02443.; Changed publications to: 31942419, 33057194, 33268356; Changed phenotypes to: H3-3A-related Bryant-Li-Bhoj neurodevelopmental syndrome, MONDO:0030606, H3-3A-related Bryant-Li-Bhoj neurodevelopmental syndrome, OMIM:619720, OMIM:619720.0
DDG2P v6.17 GTF2IRD1 Achchuthan Shanmugasundram edited their review of gene: GTF2IRD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GTF2IRD1-related neurodevelopmental disorder are limited, biallelic_autosomal and undetermined (PMID:36308390). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03437.; Changed phenotypes to: MONDO:0700092, GTF2IRD1-related neurodevelopmental disorder
DDG2P v6.17 GTF2E2 Achchuthan Shanmugasundram edited their review of gene: GTF2E2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GTF2E2-related DNA repair-proficient trichothiodystrophy are strong, biallelic_autosomal and undetermined (PMID:26996949). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01727.; Changed phenotypes to: GTF2E2-related DNA repair-proficient trichothiodystrophy, OMIM:616943.0, MONDO:0014841, DNA Repair-Proficient Trichothiodystrophy
DDG2P v6.17 GSPT2 Achchuthan Shanmugasundram edited their review of gene: GSPT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GSPT2-related intellectual disability are limited, monoallelic_X_hemizygous and loss of function (PMIDs: 28414775, 31555424). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01434.; Changed publications to: 31555424, 28414775; Changed phenotypes to: GSPT2-related intellectual disability, MONDO:0001071
DDG2P v6.17 GRIN1 Achchuthan Shanmugasundram edited their review of gene: GRIN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GRIN1-related epileptic encephalopathy are definitive, monoallelic_autosomal and undetermined (PMIDs: 23934111, 25864721, 26933583, 27164704, 28228639, 28389307, 29194067, 29365063, 30355546, 31176596, 33062288, 33403508, 34227748, 34413877, 34884460, 35393335). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01109. The DDG2P confidence category, allelic requirement and molecular mechanism for GRIN1-related neurodevelopmental disorder with or without hyperkinetic movements and seizures are definitive, biallelic_autosomal and loss of function (PMIDs: 26350515, 27164704, 28051072, 34611970). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03206.; Changed publications to: 29365063, 35393335, 33062288, 34611970, 34884460, 30355546, 33403508, 28389307, 26933583, 26350515, 34413877, 28228639, 31176596, 23934111, 25864721, 29194067, 28051072, 34227748, 27164704; Changed phenotypes to: GRIN1-related neurodevelopmental disorder with or without hyperkinetic movements and seizures, MONDO:0060629, GRIN1-associated Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, OMIM:617820, OMIM:617820.0, EPILEPTIC ENCEPHALOPATHY, GRIN1-related epileptic encephalopathy, OMIM:614254.0, MONDO:0013655
DDG2P v6.17 GRIA4 Achchuthan Shanmugasundram edited their review of gene: GRIA4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GRIA4-related neurodevelopmental disorder with or without seizures and gait abnormalities are limited, monoallelic_autosomal and undetermined (PMID:29220673). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02815.; Changed phenotypes to: NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT SEIZURES AND GAIT ABNORMALITIES, OMIM:617864, MONDO:0060641, GRIA4-related neurodevelopmental disorder with or without seizures and gait abnormalities, OMIM:617864.0
DDG2P v6.17 GRHL2 Achchuthan Shanmugasundram edited their review of gene: GRHL2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GRHL2-related ectodermal dysplasia and short stature syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 25152456, 27612988). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00084.; Changed publications to: 25152456, 27612988; Changed phenotypes to: GRHL2-related ectodermal dysplasia and short stature syndrome, OMIM:616029.0, ECTODERMAL DYSPLASIA/SHORT STATURE SYNDROME, OMIM:616029
DDG2P v6.17 GOT2 Achchuthan Shanmugasundram edited their review of gene: GOT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GOT2-related malate-aspartate shuttle-related encephalopathy are strong, biallelic_autosomal and undetermined (PMID:31422819). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02788.; Changed phenotypes to: GOT2-related malate-aspartate shuttle-related encephalopathy, Malate-Aspartate Shuttle-Related Encephalopathy, OMIM:618721.0, MONDO:0032880
DDG2P v6.17 GNE Achchuthan Shanmugasundram edited their review of gene: GNE: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GNE-related congenital myopathy are limited, biallelic_autosomal and undetermined (PMID:35121750). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03240. The DDG2P confidence category, allelic requirement and molecular mechanism for GNE-related sialuria are limited, monoallelic_autosomal and undetermined (PMIDs: 10330343, 10356312, 11326336, 11486897, 27142465, 29923088, 32053088). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03241.; Changed publications to: 11326336, 11486897, 27142465, 10356312, 10330343, 35121750, 32053088, 29923088; Changed phenotypes to: MONDO:0010028, OMIM:269921.0, GNE-related sialuria, GNE-associated congenital myopathy, GNE-related congenital myopathy, MONDO:0019952, GNE-associated sialuria, OMIM:269921
DDG2P v6.17 GNB2 Achchuthan Shanmugasundram edited their review of gene: GNB2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GNB2-related developmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 28219978, 31698099, 33057194, 34183358). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02876.; Changed publications to: 28219978, 31698099, 34183358, 33057194; Changed phenotypes to: OMIM:619503.0, GNB2-related developmental disorder (monoallelic), MONDO:0859185, GNB2-related developmental disorder
DDG2P v6.17 GNAI3 Achchuthan Shanmugasundram edited their review of gene: GNAI3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GNAI3-related auriculocondylar syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 11102934, 22560091, 23315542, 25026904, 33723370, 34789173, 35170830, 39014351). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01127.; Changed publications to: 33723370, 39014351, 35170830, 34789173, 23315542, 25026904, 22560091, 11102934; Changed phenotypes to: GNAI3-related auriculocondylar syndrome, AURICULOCONDYLAR SYNDROME, OMIM:602483, OMIM:602483.0, MONDO:0011234
DDG2P v6.17 GNAI1 Achchuthan Shanmugasundram edited their review of gene: GNAI1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GNAI1-related neurodevelopmental disorder with hypotonia, impaired speech, and behavioural abnormalities are moderate, monoallelic_autosomal and undetermined (PMIDs: 33473207, 34819662). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01703.; Changed phenotypes to: MONDO:0859243, OMIM:619854.0, GNAI1-related neurodevelopmental disorder with hypotonia, impaired speech, and behavioural abnormalities, OMIM:619854, GNAI1-related neurodevelopmental disorder with hypotonia, impaired speech, and behavioural abnormalities
DDG2P v6.17 GMPPB Achchuthan Shanmugasundram edited their review of gene: GMPPB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GMPPB-related muscular dystrophy-dystroglycanopathy are definitive, biallelic_autosomal and undetermined (PMIDs: 23768512, 24780531, 25681410, 26133662, 27766311, 27874200, 28433477, 28456886, 30126629, 30684953, 31211170, 31378432, 34333724, 34633329). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00893.; Changed publications to: 24780531, 28433477, 28456886, 23768512, 30684953, 27874200, 34333724, 30126629, 26133662, 25681410, 31378432, 34633329, 27766311, 31211170; Changed phenotypes to: MONDO:0014140, OMIM:615350.0, GMPPB-related muscular dystrophy-dystroglycanopathy, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 14, OMIM:615350
DDG2P v6.17 GLUL Achchuthan Shanmugasundram edited their review of gene: GLUL: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GLUL-related congenital systemic glutamine deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 16267323, 21353613). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00560.; Changed phenotypes to: OMIM:610015.0, CONGENITAL SYSTEMIC GLUTAMINE DEFICIENCY, OMIM:610015, GLUL-related congenital systemic glutamine deficiency, MONDO:0012393
DDG2P v6.17 GLE1 Achchuthan Shanmugasundram edited their review of gene: GLE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GLE1-related arthrogryposis, lethal, with anterior horn cell disease are definitive, biallelic_autosomal and undetermined (PMID:18204449). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01494.; Changed phenotypes to: ARTHROGRYPOSIS, LETHAL, WITH ANTERIOR HORN CELL DISEASE, OMIM:611890, GLE1-related arthrogryposis, lethal, with anterior horn cell disease, OMIM:611890.0, MONDO:0012750
DDG2P v6.17 GJC2 Achchuthan Shanmugasundram edited their review of gene: GJC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GJC2-related lymphatic malformation are moderate, monoallelic_autosomal and undetermined (PMID:20537300). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00533. The DDG2P confidence category, allelic requirement and molecular mechanism for GJC2-related leukodystrophy, hypomyelinating are definitive, biallelic_autosomal and undetermined (PMIDs: 15192806, 16969684, 18094336, 19056803, 8733901). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00695.; Changed publications to: 16969684, 20537300, 19056803, 8733901, 18094336, 15192806; Changed phenotypes to: MONDO:0013278, LEUKODYSTROPHY, HYPOMYELINATING, 2, OMIM:608804, OMIM:608804.0, MONDO:0012125, LYMPHEDEMA, HEREDITARY, IC, OMIM:613480, OMIM:613480.0, GJC2-related leukodystrophy, hypomyelinating, GJC2-related lymphatic malformation
DDG2P v6.17 GJA8 Achchuthan Shanmugasundram edited their review of gene: GJA8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GJA8-related cataract are definitive, monoallelic_autosomal and undetermined (PMIDs: 10480374, 11846744, 14627691, 16604058, 18006672, 28455998, 29464339, 30262699, 30373400, 30498267, 9497259). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01251.; Changed publications to: 16604058, 28455998, 30373400, 29464339, 9497259, 11846744, 18006672, 30498267, 30262699, 14627691, 10480374; Changed phenotypes to: OMIM:116200.0, MONDO:0007285, CATARACT-MICROCORNEA SYNDROME, OMIM:116150, GJA8-related cataract
DDG2P v6.17 GJA3 Achchuthan Shanmugasundram edited their review of gene: GJA3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GJA3-related cataract are definitive, monoallelic_autosomal and undetermined (PMIDs: 10205266, 10746562, 15448617, 21681855, 22312188, 22550389, 22876138, 24772942, 26683566, 28877251, 29461512, 29934635). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01295.; Changed publications to: 10746562, 29934635, 29461512, 21681855, 22876138, 10205266, 26683566, 22550389, 28877251, 22312188, 15448617, 24772942; Changed phenotypes to: OMIM:601885.0, CATARACT ZONULAR PULVERULENT CATARACT TYPE 3, OMIM:601885, GJA3-related cataract, MONDO:0011162
DDG2P v6.17 GIGYF1 Achchuthan Shanmugasundram edited their review of gene: GIGYF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GIGYF1-related developmental disorder are limited, monoallelic_autosomal and loss of function (PMIDs: 31439631, 33057194, 35917186, 36924980). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02879.; Changed publications to: 36924980, 31439631, 33057194, 35917186; Changed phenotypes to: MONDO:0700092, GIGYF1-related developmental disorder
DDG2P v6.17 GEMIN4 Achchuthan Shanmugasundram edited their review of gene: GEMIN4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GEMIN4-related neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities are strong, biallelic_autosomal and undetermined (PMIDs: 25558065, 27878435, 30237576, 35861185). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02994.; Changed publications to: 25558065, 35861185, 27878435, 30237576; Changed phenotypes to: MONDO:0060664, OMIM:617913.0, NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, CATARACTS, AND RENAL ABNORMALITIES, OMIM:617913, GEMIN4-related neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities
DDG2P v6.17 GDF6 Achchuthan Shanmugasundram edited their review of gene: GDF6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GDF6-related oculo-skeletal syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 18425797, 19129173, 21070663, 25457163, 32737436). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00462.; Changed publications to: 21070663, 19129173, 25457163, 18425797, 32737436; Changed phenotypes to: OMIM:118100.0, GDF6 Oculo-Skeletal Syndrome, OMIM:118100, MONDO:0007306, GDF6-related oculo-skeletal syndrome
DDG2P v6.17 GDF5 Achchuthan Shanmugasundram edited their review of gene: GDF5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GDF5-related acromesomelic chondrodysplasia, Grebe type are definitive, biallelic_autosomal and loss of function (PMIDs: 12121354, 12124730, 12357473, 12900894, 16222676, 18629880, 23812741, 2703235, 9288098). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00087. The DDG2P confidence category, allelic requirement and molecular mechanism for GDF5-related symphalangism spectrum disorder are definitive, monoallelic_autosomal and loss of function (PMIDs: 10080184, 11846737, 11857750, 16127465, 16532400, 16892395, 18283415). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01320.; Changed publications to: 12357473, 2703235, 12124730, 16222676, 11857750, 9288098, 11846737, 12900894, 16127465, 18629880, 23812741, 18283415, 12121354, 16532400, 10080184, 16892395; Changed phenotypes to: MONDO:0008703, GDF5-related Symphalangism Spectrum Disorder, OMIM:185800, MONDO:0014125, OMIM:200700.0, GDF5-related symphalangism spectrum disorder, ACROMESOMELIC CHONDRODYSPLASIA GREBE TYPE, OMIM:200700, GDF5-related acromesomelic chondrodysplasia, Grebe type, OMIM:615298.0
DDG2P v6.17 GDF3 Achchuthan Shanmugasundram edited their review of gene: GDF3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GDF3-related multiple malformations are limited, monoallelic_autosomal and undetermined (PMIDs: 19864492, 29260090). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00932.; Changed publications to: 29260090, 19864492; Changed phenotypes to: GDF3-related multiple malformations, GDF3 multiple malformations, OMIM:613702, OMIM:613702.0, MONDO:0013375
DDG2P v6.17 GCH1 Achchuthan Shanmugasundram edited their review of gene: GCH1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GCH1-related GTP cyclohydrolase 1 deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 10987649, 12552057, 15389992, 20842687, 29471552, 7730309, 9667588). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01026. The DDG2P confidence category, allelic requirement and molecular mechanism for GCH1-related dystonia are definitive, monoallelic_autosomal and undetermined (PMIDs: 10078749, 10208576, 10732814, 11113234, 11359069, 11486899, 11956954, 12023430, 12874420, 14509676, 16289769, 17111153, 17410324, 17557242, 17804835, 17898029, 18044725, 18345435, 18511327, 18621497, 19533203, 19566901, 20082337, 20108370, 20437540, 20491893, 21834904, 21935284, 22373569, 24018121, 24509643, 24948553, 25119902, 25634433, 26400349, 28087438, 28415164, 28582483, 28958832, 29290055, 29577080, 29948246, 7874165, 9576537, 9585358, 9667588). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01085.; Changed publications to: 29471552, 20082337, 17111153, 29577080, 28958832, 17410324, 20108370, 11359069, 17898029, 26400349, 9576537, 22373569, 24948553, 24509643, 25119902, 17804835, 20437540, 24018121, 9667588, 21935284, 12552057, 19533203, 9585358, 29290055, 18621497, 18345435, 7730309, 21834904, 7874165, 11113234, 11486899, 28415164, 12023430, 10987649, 29948246, 10208576, 19566901, 28582483, 15389992, 10732814, 16289769, 18044725, 17557242, 20491893, 10078749, 14509676, 28087438, 18511327, 25634433, 20842687, 11956954, 12874420; Changed phenotypes to: OMIM:233910.0, DYSTONIA TYPE 5, OMIM:128230, OMIM:128230.0, GCH1-related dystonia, GCH1-related GTP cyclohydrolase 1 deficiency, GTP CYCLOHYDROLASE 1 DEFICIENCY, OMIM:233910, MONDO:0007495
DDG2P v6.17 GCDH Achchuthan Shanmugasundram edited their review of gene: GCDH: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GCDH-related glutaricacidemia are definitive, biallelic_autosomal and undetermined (PMIDs: 10699052, 11174631, 7795610, 8900227, 8900228). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00451.; Changed phenotypes to: GLUTARICACIDEMIA TYPE 1, OMIM:231670, GCDH-related glutaricacidemia, OMIM:231670.0
DDG2P v6.17 GAD1 Achchuthan Shanmugasundram edited their review of gene: GAD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GAD1-related cerebral palsy spastic quadriplegic are limited, biallelic_autosomal and undetermined (PMID:15571623). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00998.; Changed phenotypes to: OMIM:619124.0, GAD1-related cerebral palsy spastic quadriplegic, CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 1, OMIM:603513, MONDO:0030856
DDG2P v6.17 GABRG1 Achchuthan Shanmugasundram edited their review of gene: GABRG1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABRG1-related epileptic encephalopathy are limited, monoallelic_autosomal and undetermined (PMID:36121006). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03350.; Changed phenotypes to: GABRG1-associated epileptic encephalopathy, MONDO:0100062, GABRG1-related epileptic encephalopathy
DDG2P v6.17 GABRB3 Achchuthan Shanmugasundram edited their review of gene: GABRB3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABRB3-related childhood absence epilepsy are definitive, monoallelic_autosomal and undetermined (PMIDs: 18514161, 23934111, 27476654). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00479.; Changed publications to: 23934111, 27476654, 18514161; Changed phenotypes to: GABRB3-related childhood absence epilepsy, CHILDHOOD ABSENCE EPILEPSY TYPE 5, OMIM:612269, MONDO:0012843, OMIM:612269.0
DDG2P v6.17 GABRB2 Achchuthan Shanmugasundram edited their review of gene: GABRB2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABRB2-related epilepsy and intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:29100083). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02377.; Changed phenotypes to: Epilepsy and intellectual disability, GABRB2-related epilepsy and intellectual disability, OMIM:617829.0, MONDO:0020631
DDG2P v6.17 GABRA2 Achchuthan Shanmugasundram edited their review of gene: GABRA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABRA2-related epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMIDs: 29422393, 29961870, 31032849). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03475.; Changed publications to: 29961870, 31032849, 29422393; Changed phenotypes to: GABRA2-related epileptic encephalopathy, OMIM:618557.0, MONDO:0032812
DDG2P v6.17 GABBR2 Achchuthan Shanmugasundram edited their review of gene: GABBR2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABBR2-related epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMIDs: 25262651, 26740508, 28856709, 29100083, 29369404). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01145.; Changed publications to: 26740508, 29100083, 28856709, 25262651, 29369404; Changed phenotypes to: EPILEPTIC ENCEPHALOPATHY, GABBR2-related epileptic encephalopathy, MONDO:0033368, OMIM:617904.0
DDG2P v6.17 GABBR1 Achchuthan Shanmugasundram edited their review of gene: GABBR1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for GABBR1-related neurodevelopmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:36103875). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03347.; Changed phenotypes to: GABBR1-related neurodevelopmental disorder, OMIM:620502.0, GABBR1-associated neurodevelopmental disorder, MONDO:0957779
DDG2P v6.17 FZR1 Achchuthan Shanmugasundram edited their review of gene: FZR1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FZR1-related intellectual disability and epilepsy are strong, monoallelic_autosomal and undetermined (PMIDs: 31318984, 34788397). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03223.; Changed phenotypes to: OMIM:620145.0, FZR1-related intellectual disability and epilepsy, MONDO:0859325
DDG2P v6.17 FXN Achchuthan Shanmugasundram edited their review of gene: FXN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FXN-related Friedreich ataxia are definitive, biallelic_autosomal and loss of function (PMIDs: 10633128, 22409940, 22691228, 24705334, 25566998, 26704351, 28405347, 30681346). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03444.; Changed publications to: 22409940, 10633128, 24705334, 28405347, 30681346, 25566998, 22691228, 26704351; Changed phenotypes to: FXN-related Friedreich ataxia, MONDO:0100340, OMIM:229300.0
DDG2P v6.17 FTO Achchuthan Shanmugasundram edited their review of gene: FTO: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FTO-related growth retardation, developmental delay, coarse facies, and early death are limited, biallelic_autosomal and undetermined (PMID:19559399). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00102.; Changed phenotypes to: GROWTH RETARDATION DEVELOPMENTAL DELAY COARSE FACIES AND EARLY DEATH, OMIM:612938, OMIM:612938.0, FTO-related growth retardation, developmental delay, coarse facies, and early death
DDG2P v6.17 FRMD7 Achchuthan Shanmugasundram edited their review of gene: FRMD7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FRMD7-related nystagmus, congenital are definitive, monoallelic_X_hemizygous and loss of function (PMIDs: 16240070, 17013395, 17397053, 17962394, 18087240, 19072571, 21746984, 25678693). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00559.; Changed rating: GREEN; Changed publications to: 17962394, 17013395, 17397053, 18087240, 16240070, 19072571, 21746984, 25678693; Changed phenotypes to: NYSTAGMUS 1, CONGENITAL, X-LINKED, OMIM:310700, MONDO:0010693, FRMD7-related nystagmus, congenital, OMIM:310700.0
DDG2P v6.17 FRMD5 Achchuthan Shanmugasundram edited their review of gene: FRMD5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FRMD5-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:36206744). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03410.; Changed phenotypes to: FRMD5-related developmental disorder, OMIM:620094.0, MONDO:0859305
DDG2P v6.17 FOXP4 Achchuthan Shanmugasundram edited their review of gene: FOXP4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FOXP4-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMIDs: 33110267, 36301021). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03059.; Changed publications to: 36301021, 33110267; Changed phenotypes to: MONDO:0700092, FOXP4-related Developmental Disorder, FOXP4-related developmental disorder
DDG2P v6.17 FOXI3 Achchuthan Shanmugasundram edited their review of gene: FOXI3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FOXI3-related microtia and craniofacial microsomia are limited, monoallelic_autosomal and undetermined (PMID:36260083). The cross-cutting modifier is typified by incomplete penetrance. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03399.; Changed phenotypes to: OMIM:620444.0, MONDO:0958194, FOXI3-related microtia and craniofacial microsomia
DDG2P v6.17 FOXE1 Achchuthan Shanmugasundram edited their review of gene: FOXE1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FOXE1-related Bamforth-Lazarus syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 16882747, 35963604, 9697705). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00542.; Changed publications to: 35963604, 9697705, 16882747; Changed phenotypes to: MONDO:0009437, BAMFORTH-LAZARUS SYNDROME, OMIM:241850, OMIM:241850.0, FOXE1-related Bamforth-Lazarus syndrome
DDG2P v6.17 FOSL2 Achchuthan Shanmugasundram edited their review of gene: FOSL2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FOSL2-related neurodevelopmental disorder with scalp and enamel defects are moderate, monoallelic_autosomal and undetermined (PMID:36197437). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03482.; Changed phenotypes to: MONDO:0968978, OMIM:620789.0, FOSL2-related neurodevelopmental disorder with scalp and enamel defects
DDG2P v6.17 FN1 Achchuthan Shanmugasundram edited their review of gene: FN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FN1-related spondylometaphyseal dysplasia with corner fractures are strong, monoallelic_autosomal and undetermined (PMID:29100092). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02384.; Changed phenotypes to: Spondylometaphyseal Dysplasia with Corner Fractures, OMIM:184255, OMIM:184255.0, FN1-related spondylometaphyseal dysplasia with corner fractures, MONDO:0008479
DDG2P v6.17 FLVCR1 Achchuthan Shanmugasundram edited their review of gene: FLVCR1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FLVCR1-related ataxia, posterior column, with retinitis pigmentosa are definitive, biallelic_autosomal and undetermined (PMIDs: 21070897, 21267618, 30656474, 9409377). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00551.; Changed publications to: 21267618, 21070897, 30656474, 9409377; Changed phenotypes to: FLVCR1-related ataxia, posterior column, with retinitis pigmentosa, OMIM:609033.0, ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA, OMIM:609033, MONDO:0012177
DDG2P v6.17 FLT4 Achchuthan Shanmugasundram edited their review of gene: FLT4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FLT4-related Milroy disease are definitive, monoallelic_autosomal and undetermined (PMIDs: 10835628, 10856194, 12960217, 16924388, 16965327, 19289394). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01266. The DDG2P confidence category, allelic requirement and molecular mechanism for FLT4-related congenital heart disease are strong, monoallelic_autosomal and loss of function (PMID:33067626). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03441.; Changed publications to: 10856194, 33067626, 12960217, 10835628, 16924388, 19289394, 16965327; Changed phenotypes to: MILROY DISEASE, OMIM:153100, OMIM:153100.0, FLT4-related Milroy disease, MONDO:0032913, FLT4-related congenital heart disease, MONDO:0007919, OMIM:618780.0, CONGENITAL HEART DISEASE
DDG2P v6.17 FICD Achchuthan Shanmugasundram commented on gene: FICD: The DDG2P confidence category, allelic requirement and molecular mechanism for FICD-related infancy-onset diabetes and neurodevelopmental disorder are limited, biallelic_autosomal and loss of function (PMID:36704923). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03557.
DDG2P v6.17 FGFR3 Achchuthan Shanmugasundram edited their review of gene: FGFR3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related lacrimo-auriculo-dento-digital syndrome (LADD) are definitive, monoallelic_autosomal and undetermined (PMIDs: 16501574, 28483234). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00012. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related Muenke syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 10914960, 11197897, 9042914, 9279753, 9279764, 9525367, 9600744, 9950359). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00178. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related Crouzon syndrome with acanthosis nigricans are definitive, monoallelic_autosomal and gain of function (PMIDs: 11426459, 23437153, 31016899, 32860240, 34388723, 37397405, 7493034, 8880573). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00864. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related achondroplasia are definitive, monoallelic_autosomal and gain of function (PMIDs: 10611230, 11186940, 16411219, 16912704, 7758520, 7847369, 7913883, 8078586, 8599370, 8844216, 8949407, 9001669, 9401015). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00944. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related thanatophoric dysplasia, type 2 are definitive, monoallelic_autosomal and gain of function (PMID:7773297). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01101. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related camptodactyly tall stature and hearing loss syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 17033969, 27139183). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01202. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related hypochondroplasia are definitive, monoallelic_autosomal and gain of function (PMIDs: 10215410, 11015576, 11055896, 16912704, 7670477, 8589686, 9452043). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01257. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR3-related thanatophoric dysplasia, type 1 are definitive, monoallelic_autosomal and gain of function (PMIDs: 10360402, 10910625, 11309183, 19449430, 7647778, 7773297, 8589699, 8845844, 9215781, 9790257). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01321.; Changed publications to: 16912704, 8949407, 8078586, 10215410, 11309183, 11055896, 23437153, 11426459, 9279764, 9950359, 7913883, 11186940, 9215781, 28483234, 11197897, 37397405, 16501574, 9042914, 16411219, 7847369, 8845844, 8589699, 27139183, 8880573, 9279753, 7670477, 17033969, 10914960, 9001669, 7647778, 8599370, 9452043, 7493034, 19449430, 10360402, 7773297, 10611230, 31016899, 9525367, 9401015, 8844216, 11015576, 34388723, 32860240, 9600744, 8589686, 7758520, 10910625, 9790257; Changed phenotypes to: MONDO:0859577, MONDO:0012833, FGFR3-related thanatophoric dysplasia, type 1, FGFR3-related Crouzon syndrome with acanthosis nigricans, CAMPTODACTYLY TALL STATURE AND HEARING LOSS SYNDROME, OMIM:610474, HYPOCHONDROPLASIA, OMIM:146000, OMIM:620192.0, MONDO:0008546, OMIM:100800.0, THANATOPHORIC DYSPLASIA TYPE 2, OMIM:187601, FGFR3-related thanatophoric dysplasia, type 2, OMIM:146000.0, MONDO:0008547, CROUZON SYNDROME WITH ACANTHOSIS NIGRICANS, OMIM:612247, OMIM:610474.0, MUENKE SYNDROME, OMIM:602849, FGFR3-related achondroplasia, FGFR3-related Muenke syndrome, OMIM:187600.0, MONDO:0011274, MONDO:0012504, THANATOPHORIC DYSPLASIA TYPE 1, OMIM:187600, LACRIMO-AURICULO-DENTO-DIGITAL SYNDROME, OMIM:149730, ACHONDROPLASIA, OMIM:100800, OMIM:187601.0, FGFR3-related lacrimo-auriculo-dento-digital syndrome (LADD), MONDO:0007793, FGFR3-related hypochondroplasia, MONDO:0007037, OMIM:612247.0, OMIM:602849.0, FGFR3-related camptodactyly tall stature and hearing loss syndrome
DDG2P v6.17 FGFR2 Achchuthan Shanmugasundram edited their review of gene: FGFR2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Crouzon syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 10574673, 15523492, 17621648, 22038757, 7558045, 7581378, 7607643, 7655462, 7773284, 7874170, 7987400, 8528214, 8956050, 9152842, 9677057). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00144. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Apert Syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 7668257, 7719344, 8651276, 9002682, 9217234, 9452027, 9973282). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00331. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related lacrimo-auriculo-dento-digital syndrome (LADD) are definitive, monoallelic_autosomal and gain of function (PMIDs: 16501574, 32715658). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00621. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Jackson-Weiss syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 7874170, 9385368). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01005. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Antley-Bixler syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 10633130, 15793702, 9605588). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01090. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Beare-Stevenson cutis gyrata syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 12000365, 19610084, 8696350, 9545103). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01273. The DDG2P confidence category, allelic requirement and molecular mechanism for FGFR2-related Pfeiffer syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 10394936, 10731087, 10945669, 11380927, 11556600, 11807866, 7719333, 9150725, 9457499, 9475591). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01586.; Changed publications to: 9457499, 22038757, 8696350, 17621648, 8528214, 11807866, 7655462, 8956050, 9002682, 9475591, 7719344, 16501574, 15523492, 9217234, 7581378, 9973282, 11380927, 9385368, 15793702, 11556600, 7874170, 9150725, 9605588, 7719333, 7668257, 10633130, 10574673, 9545103, 12000365, 7773284, 7987400, 32715658, 9677057, 10731087, 9152842, 10394936, 10945669, 7558045, 9452027, 7607643, 8651276, 19610084; Changed phenotypes to: OMIM:149730.0, OMIM:123150.0, MONDO:0020667, MONDO:0007400, OMIM:123790.0, MONDO:0007412, MONDO:0007043, FGFR2-related lacrimo-auriculo-dento-digital syndrome (LADD), OMIM:101600.0, OMIM:101200.0, MONDO:0007405, FGFR2-related Pfeiffer syndrome, CROUZON SYNDROME, OMIM:123500, ACROCEPHALOSYNDACTYLY TYPE V, OMIM:101600, OMIM:207410.0, MONDO:0100302, OMIM:123500.0, FGFR2-related Apert Syndrome, APERT SYNDROME, OMIM:101200, LACRIMO-AURICULO-DENTO-DIGITAL SYNDROME, OMIM:149730, ANTLEY-BIXLER SYNDROME, OMIM:207410, FGFR2-related Jackson-Weiss syndrome, JACKSON-WEISS SYNDROME, OMIM:123150, FGFR2-related Antley-Bixler syndrome, BEARE-STEVENSON CUTIS GYRATA SYNDROME, OMIM:123790, MONDO:0007041, FGFR2-related Crouzon syndrome, FGFR2-related lacrimo-auriculo-dento-digital syndrome, OMIM:149730, FGFR2-related Beare-Stevenson cutis gyrata syndrome, FGFR2-related Pfeiffer syndrome, OMIM:101600
DDG2P v6.17 FGF13 Achchuthan Shanmugasundram edited their review of gene: FGF13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FGF13-related neurodevelopmental disorder are strong, monoallelic_X_hemizygous and gain of function (PMIDs: 27073347, 33245860, 34184986). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03095. The DDG2P confidence category, allelic requirement and molecular mechanism for FGF13-related neurodevelopmental disorder are limited, monoallelic_X_heterozygous and gain of function (PMIDs: 33245860, 34871784, 37536293). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03096.; Changed publications to: 27073347, 34871784, 37536293, 34184986, 33245860; Changed phenotypes to: FGF13-related neurodevelopmental disorder (X-linked dominant), OMIM:301058.0, MONDO:0025353, FGF13-related neurodevelopmental disorder, FGF13-related neurodevelopmental disorder (hemizygous); Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v6.17 FDXR Achchuthan Shanmugasundram edited their review of gene: FDXR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FDXR-related optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome are strong, biallelic_autosomal and loss of function (PMIDs: 28965846, 30250212, 32499495, 33938912). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03502.; Changed publications to: 32499495, 28965846, 33938912, 30250212; Changed phenotypes to: OMIM:617717.0, FDXR-related optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, MONDO:0034092
DDG2P v6.17 FUK Achchuthan Shanmugasundram edited their review of gene: FUK: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FCSK-related congenital disorder of glycosylation are strong, biallelic_autosomal and undetermined (PMID:30503518). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02632.; Changed phenotypes to: OMIM:618324.0, FCSK-related congenital disorder of glycosylation, MONDO:0020777, CONGENITAL DISORDER OF GLYCOSYLATION, MONDO:0015286
DDG2P v6.17 FBXW7 Achchuthan Shanmugasundram edited their review of gene: FBXW7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FBXW7-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMIDs: 33057194, 35395208). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02875.; Changed publications to: 35395208, 33057194; Changed phenotypes to: OMIM:620012.0, MONDO:0859280, FBXW7-related developmental disorder (monoallelic), FBXW7-related developmental disorder
DDG2P v6.17 FBXW4 Achchuthan Shanmugasundram edited their review of gene: FBXW4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FBXW4-related split-hand and foot malformation are limited, monoallelic_autosomal and undetermined (PMIDs: 12913067, 12974740, 16691619, 16761290, 29263051, 38250576). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00400.; Changed publications to: 12913067, 38250576, 29263051, 16691619, 16761290, 12974740; Changed phenotypes to: MONDO:0009525, FBXW4-related split-hand and foot malformation, SPLIT-HAND/FOOT MALFORMATION TYPE 3, OMIM:246560, OMIM:246560.0
DDG2P v6.17 FBXW11 Achchuthan Shanmugasundram edited their review of gene: FBXW11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FBXW11-related syndromic intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:31402090). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02790.; Changed phenotypes to: FBXW11-related syndromic intellectual disability, MONDO:0030057, OMIM:618914.0, SYNDROMIC INTELLECTUAL DISABILITY, OMIM:612100
DDG2P v6.17 FBXO28 Achchuthan Shanmugasundram edited their review of gene: FBXO28: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FBXO28-related developmental and epileptic encephalopathy with profound intellectual disability are definitive, monoallelic_autosomal and undetermined (PMIDs: 30160831, 33280099, 37543484). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03080.; Changed publications to: 33280099, 37543484, 30160831; Changed phenotypes to: FBXO28-related developmental and epileptic encephalopathy with profound intellectual disability, MONDO:0030695, FBX028-related developmental and epileptic encephalopathy with profound intellectual disability, OMIM:619777.0
DDG2P v6.17 FBLN1 Achchuthan Shanmugasundram edited their review of gene: FBLN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FBLN1-related synpolydactyly, 3/3-prime/4, associated with metacarpal and metatarsal synostoses are limited, biallelic_autosomal and undetermined (PMID:11836357). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00356.; Changed publications to: 11836357; Changed phenotypes to: SYNPOLYDACTYLY, 3/3-PRIME/4, ASSOCIATED WITH METACARPAL AND METATARSAL SYNOSTOSES, OMIM:608180, FBLN1-related synpolydactyly, 3/3-prime/4, associated with metacarpal and metatarsal synostoses, MONDO:0011984, OMIM:608180.0
DDG2P v6.17 FASN Achchuthan Shanmugasundram edited their review of gene: FASN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for FASN-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01238.; Changed phenotypes to: MONDO:0700092, FASN-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 EZH2 Achchuthan Shanmugasundram edited their review of gene: EZH2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EZH2-related Weaver syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 24214728, 26694085, 26762561, 30793471). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01503.; Changed publications to: 26694085, 24214728, 26762561, 30793471; Changed phenotypes to: MONDO:0010193, WEAVER SYNDROME 2, OMIM:614421, OMIM:277590.0, EZH2-related Weaver syndrome
DDG2P v6.17 EXTL3 Achchuthan Shanmugasundram edited their review of gene: EXTL3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EXTL3-related neuro immuno skeletal dysplasia syndrome are strong, biallelic_autosomal and undetermined (PMID:28132690). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02593.; Changed phenotypes to: OMIM:617425.0, EXTL3-related neuro immuno skeletal dysplasia syndrome, Neuro immuno skeletal Dysplasia Syndrome, MONDO:0044312
DDG2P v6.17 EXOSC3 Achchuthan Shanmugasundram edited their review of gene: EXOSC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EXOSC3-related pontocerebellar hypoplasia are definitive, biallelic_autosomal and undetermined (PMID:34085948). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00730.; Changed phenotypes to: PONTOCEREBELLAR HYPOPLASIA TYPE 1, OMIM:607596, MONDO:0013853, OMIM:614678.0, EXOSC3-related pontocerebellar hypoplasia
DDG2P v6.17 ERLIN2 Achchuthan Shanmugasundram edited their review of gene: ERLIN2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ERLIN2-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00030.; Changed phenotypes to: OMIM:611225.0, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, ERLIN2-related intellectual developmental disorder
DDG2P v6.17 ERI1 Achchuthan Shanmugasundram edited their review of gene: ERI1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ERI1-related severe growth restriction and skeletal dysplasia are moderate, biallelic_autosomal and loss of function (PMID:37352860). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03515. The DDG2P confidence category, allelic requirement and molecular mechanism for ERI1-related brachydactyly and mild neurodevelopmental delay are moderate, biallelic_autosomal and loss of function (PMIDs: 28488351, 36208065, 37352860). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03516.; Changed publications to: 37352860, 36208065, 28488351; Changed phenotypes to: ERI1-related brachydactyly and mild neurodevelopmental delay, OMIM:620662.0, MONDO:0958005, ERI1-related severe growth restriction and skeletal dysplasia, MONDO:0958006, OMIM:620663.0
DDG2P v6.17 ERBB3 Achchuthan Shanmugasundram edited their review of gene: ERBB3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ERBB3-related lethal congenital contracture syndrome are strong, biallelic_autosomal and undetermined (PMID:17701904). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01134. The DDG2P confidence category, allelic requirement and molecular mechanism for ERBB3-related Hirschprung disease with intestinal pseudo-obstruction are strong, biallelic_autosomal and undetermined (PMID:33497358). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02558.; Changed publications to: 17701904, 33497358; Changed phenotypes to: Hirschprung disease with intestinal pseudo-obstruction, ERBB3-related Hirschprung disease with intestinal pseudo-obstruction, MONDO:0011868, MONDO:8000011, OMIM:243180.0, ERBB3-related lethal congenital contracture syndrome, OMIM:607598.0, LETHAL CONGENITAL CONTRACTURE SYNDROME TYPE 2, OMIM:607598
DDG2P v6.17 EPB41L3 Achchuthan Shanmugasundram edited their review of gene: EPB41L3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EPB41L3-related developmental disorder with delayed myelination and seizures are moderate, biallelic_autosomal and loss of function (PMID:39292993). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03579.; Changed phenotypes to: MONDO:0100038, EPB41L3-related developmental disorder with delayed myelination and seizures
DDG2P v6.17 EPB41L1 Achchuthan Shanmugasundram edited their review of gene: EPB41L1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EPB41L1-related intellectual disability are limited, monoallelic_autosomal and undetermined (PMID:21376300). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01970.; Changed phenotypes to: OMIM:614257.0, EPB41L1-related intellectual disability, INTELLECTUAL DISABILITY, OMIM:616579, MONDO:0013658
DDG2P v6.17 ENTPD1 Achchuthan Shanmugasundram edited their review of gene: ENTPD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ENTPD1-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01520.; Changed phenotypes to: MONDO:0700092, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, ENTPD1-related intellectual developmental disorder
DDG2P v6.17 EMG1 Achchuthan Shanmugasundram edited their review of gene: EMG1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EMG1-related Bowen-Conradi syndrome are strong, biallelic_autosomal and undetermined (PMIDs: 19463982, 25708872, 26676230, 27798105). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01877.; Changed publications to: 25708872, 19463982, 26676230, 27798105; Changed phenotypes to: OMIM:211180.0, Bowen-Conradi syndrome, OMIM:211180, EMG1-related Bowen-Conradi syndrome, MONDO:0008879
DDG2P v6.17 ELP2 Achchuthan Shanmugasundram edited their review of gene: ELP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ELP2-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00778.; Changed phenotypes to: OMIM:617270.0, MONDO:0014996, ELP2-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 EIF4A3 Achchuthan Shanmugasundram edited their review of gene: EIF4A3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EIF4A3-related Richieri-Costa-Pereira syndrome are definitive, biallelic_autosomal and undetermined (PMID:24360810). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01453.; Changed phenotypes to: MONDO:0009998, RICHIERI-COSTA-PEREIRA SYNDROME, OMIM:268305, EIF4A3-related Richieri-Costa-Pereira syndrome, OMIM:268305.0
DDG2P v6.17 EIF4A2 Achchuthan Shanmugasundram edited their review of gene: EIF4A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EIF4A2-related neurodevelopmental disorder with hypotonia and epilepsy are moderate, monoallelic_autosomal and undetermined (PMID:36528028). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03471. The DDG2P confidence category, allelic requirement and molecular mechanism for EIF4A2-related neurodevelopmental disorder are limited, biallelic_autosomal and undetermined (PMID:36528028). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03472.; Changed phenotypes to: MONDO:0957541, EIF4A2-related neurodevelopmental disorder with hypotonia and epilepsy, EIF4A2-related neurodevelopmental disorder, Autosomal dominant EIF4A2-related neurodevelopmental disorder with hypotonia and epilepsy, OMIM:620455.0, Autosomal recessive EIF4A2-related neurodevelopmental disorder
DDG2P v6.17 EIF2AK2 Achchuthan Shanmugasundram edited their review of gene: EIF2AK2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EIF2AK2-related developmental delay, leukoencephalopathy, and neurologic decompensation are strong, monoallelic_autosomal and undetermined (PMID:32197074). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02948.; Changed phenotypes to: OMIM:618877.0, MONDO:0030035, EIF2AK2-associated Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation, EIF2AK2-related developmental delay, leukoencephalopathy, and neurologic decompensation
DDG2P v6.17 EIF2AK1 Achchuthan Shanmugasundram edited their review of gene: EIF2AK1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EIF2AK1-related neurodevelopmental syndrome are limited, monoallelic_autosomal and undetermined (PMID:32197074). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02947.; Changed phenotypes to: EIF2AK1-associated Neurodevelopmental Syndrome, MONDO:0030036, EIF2AK1-related neurodevelopmental syndrome, OMIM:618878.0
DDG2P v6.17 EED Achchuthan Shanmugasundram edited their review of gene: EED: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EED-related Weaver-like overgrowth syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 25787343, 27193220, 27868325, 28475857). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02232.; Changed publications to: 25787343, 27868325, 28475857, 27193220; Changed phenotypes to: EED-related Weaver-like overgrowth syndrome, Weaver-like overgrowth syndrome, OMIM:617561.0, MONDO:0060510
DDG2P v6.17 EDNRB Achchuthan Shanmugasundram edited their review of gene: EDNRB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for EDNRB-related Waardenburg syndrome with Hirschsprung are definitive, biallelic_autosomal and loss of function (PMIDs: 11773966, 11891690, 16237557, 21373256, 21715336, 23360229, 25852447, 28502583, 30394532, 40702859, 7778600, 8001158). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03082.; Changed publications to: 11773966, 40702859, 21715336, 30394532, 21373256, 8001158, 16237557, 11891690, 23360229, 7778600, 25852447, 28502583; Changed phenotypes to: ABCD SYNDROME, OMIM:600501, MONDO:0010192, OMIM:277580.0, EDNRB-related Waardenburg syndrome with Hirschsprung; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.17 WDR34 Achchuthan Shanmugasundram edited their review of gene: WDR34: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DYNC2I2-related severe asphyxiating thoracic dysplasia are definitive, biallelic_autosomal and undetermined (PMID:24183449). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01550.; Changed phenotypes to: MONDO:0014287, OMIM:615633.0, DYNC2I2-related severe asphyxiating thoracic dysplasia, SEVERE ASPHYXIATING THORACIC DYSPLASIA
DDG2P v6.17 DYNC1H1 Achchuthan Shanmugasundram edited their review of gene: DYNC1H1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DYNC1H1-related spinal muscular atrophy, lower extremity-predominant are definitive, monoallelic_autosomal and undetermined (PMIDs: 22459677, 22847149, 24307404, 25484024, 25609763, 26846447, 27066557, 28193117, 28554554, 29306600, 30122514, 30246859, 32947049, 34368388, 35606327, 35899263, 36720598, 36882741, 37395972). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00192. The DDG2P confidence category, allelic requirement and molecular mechanism for DYNC1H1-related severe intellectual disability with neuronal migration disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 22368300, 24307404, 25609763, 27331017, 27754416, 28193117, 28395088, 34092403, 34786417, 34803881, 35099838, 36175372, 36636459, 37181555, 37903666). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01629.; Changed publications to: 35099838, 32947049, 25609763, 30246859, 34786417, 37395972, 27754416, 37903666, 26846447, 35899263, 36636459, 37181555, 29306600, 36720598, 34368388, 22459677, 22368300, 28193117, 24307404, 27066557, 28395088, 34803881, 30122514, 36882741, 25484024, 35606327, 34092403, 36175372, 28554554, 22847149, 27331017; Changed phenotypes to: SEVERE ID WITH NEURONAL MIGRATION DISORDER, OMIM:600112, OMIM:158600.0, OMIM:614563.0, DYNC1H1-related spinal muscular atrophy, lower extremity-predominant, MONDO:0013805, DYNC1H1-related severe intellectual disability with neuronal migration disorder, SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, AD, OMIM:158600
DDG2P v6.17 DSP Achchuthan Shanmugasundram edited their review of gene: DSP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DSP-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03014.; Changed phenotypes to: DSP-related developmental disorder, MONDO:0700092
DDG2P v6.17 DSE Achchuthan Shanmugasundram edited their review of gene: DSE: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DSE-related Ehlers-Danlos syndrome, musculocontractural are limited, biallelic_autosomal and undetermined (PMID:23704329). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01694.; Changed phenotypes to: OMIM:615539.0, MONDO:0014236, EHLERS-DANLOS SYNDROME, MUSCULOCONTRACTURAL TYPE 2, OMIM:615539, DSE-related Ehlers-Danlos syndrome, musculocontractural
DDG2P v6.17 DPYSL5 Achchuthan Shanmugasundram edited their review of gene: DPYSL5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DPYSL5-related developmental disorder are strong, monoallelic_autosomal and undetermined (PMID:33894126). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02874.; Changed phenotypes to: DPYSL5-related developmental disorder, DPYSL5-related developmental disorder (monoallelic), MONDO:0030331, OMIM:619435.0
DDG2P v6.17 DOLK Achchuthan Shanmugasundram edited their review of gene: DOLK: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DOLK-related congenital disorder of glycosylation are definitive, biallelic_autosomal and undetermined (PMIDs: 17273964, 22242004). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00513.; Changed publications to: 17273964, 22242004; Changed phenotypes to: OMIM:610768.0, CONGENITAL DISORDERS OF GLYCOSYLATION, OMIM:612379, MONDO:0012556, DOLK-related congenital disorder of glycosylation
DDG2P v6.17 DNM1L Achchuthan Shanmugasundram edited their review of gene: DNM1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DNM1L-related developmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 26604000, 26992161, 27328748, 29877124, 30801875, 30850373, 30939602, 31475481, 31587467). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02853.; Changed publications to: 30850373, 30939602, 26992161, 30801875, 26604000, 31587467, 31475481, 27328748, 29877124; Changed phenotypes to: DNM1L-related developmental disorder, MONDO:0013726, DNM1L-related developmental disorder (monoallelic), OMIM:614388.0
DDG2P v6.17 DNM1 Achchuthan Shanmugasundram edited their review of gene: DNM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DNM1-related microcephaly, developmental and epileptic encephalopathy (monoallelic) are strong, monoallelic_autosomal and dominant negative (PMIDs: 25262651, 26611353, 28667181, 29397573, 29427836, 30455886, 32909139, 34172529, 34386584, 36413998, 37039969, 37132416, 37248033, 38009673). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00371. The DDG2P confidence category, allelic requirement and molecular mechanism for DNM1-related microcephaly, developmental and epileptic encephalopathy (biallelic) are moderate, biallelic_autosomal and loss of function (PMIDs: 34172529, 36413998, 36553519, 37900685). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03414.; Changed publications to: 29427836, 38009673, 34172529, 32909139, 36553519, 34386584, 26611353, 37900685, 36413998, 29397573, 25262651, 28667181, 37132416, 37248033, 30455886, 37039969; Changed phenotypes to: OMIM:620352.0, DNM1-related microcephaly, developmental and epileptic encephalopathy (biallelic), MONDO:0957248, DNM1-related microcephaly, developmental and epileptic encephalopathy (monoallelic), DNM1-associated microcephaly, developmental and epileptic encephalopathy
DDG2P v6.17 DNAAF5 Achchuthan Shanmugasundram edited their review of gene: DNAAF5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DNAAF5-related primary ciliary dyskinesia are strong, biallelic_autosomal and undetermined (PMID:23040496). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01197.; Changed phenotypes to: DNAAF5-related primary ciliary dyskinesia, MONDO:0013940, CILIARY DYSKINESIA, PRIMARY, 18, OMIM:614874, OMIM:614874.0
DDG2P v6.17 DNA2 Achchuthan Shanmugasundram edited their review of gene: DNA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DNA2-related microcephalic primordial dwarfism with or without poikiloderma and cataracts are limited, biallelic_autosomal and undetermined (PMIDs: 24389050, 31045292, 37055165). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00662.; Changed rating: RED; Changed publications to: 24389050, 31045292, 37055165; Changed phenotypes to: PRIMORDIAL DWARFISM SECKEL SYNDROME 8, OMIM:615807, MONDO:0014350, DNA2-related microcephalic primordial dwarfism with or without poikiloderma and cataracts, OMIM:615807, OMIM:615807.0, DNA2-related microcephalic primordial dwarfism with or without poikiloderma and cataracts
DDG2P v6.17 DLX5 Achchuthan Shanmugasundram edited their review of gene: DLX5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DLX5-related split-hand and foot malformation are limited, biallelic_autosomal and undetermined (PMID:22121204). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00118.; Changed phenotypes to: DLX5-related split-hand and foot malformation, MONDO:0009080, SPLIT HAND AND FOOT MALFORMATION, OMIM:220600, OMIM:220600.0
DDG2P v6.17 DLG2 Achchuthan Shanmugasundram commented on gene: DLG2: The DDG2P confidence category, allelic requirement and molecular mechanism for DLG2-related neurodevelopmental disorder are limited, monoallelic_autosomal and undetermined (PMID:37860969). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03568.
DDG2P v6.17 DIP2C Achchuthan Shanmugasundram commented on gene: DIP2C: The DDG2P confidence category, allelic requirement and molecular mechanism for DIP2C-related developmental disorder with speech delay are moderate, monoallelic_autosomal and loss of function (PMID:38421105). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03573.
DDG2P v6.17 DIP2B Achchuthan Shanmugasundram edited their review of gene: DIP2B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DIP2B-related intellectual developmental disorder, FRA12A type are limited, monoallelic_autosomal and undetermined (PMID:17236128). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01009.; Changed phenotypes to: OMIM:136630.0, DIP2B-related intellectual developmental disorder, FRA12A type, MONDO:0007634, INTELLECTUAL DEVELOPMENTAL DISORDER, FRA12A TYPE, OMIM:136630
DDG2P v6.17 DHX37 Achchuthan Shanmugasundram edited their review of gene: DHX37: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHX37-related intellectual disability and central nervous system anomalies are limited, biallelic_autosomal and undetermined (PMID:31256877). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02755.; Changed phenotypes to: DHX37-related intellectual disability and central nervous system anomalies, MONDO:0032888, OMIM:618731.0, Intellectual Disability and Central Nervous System anomalies
DDG2P v6.17 DHX34 Achchuthan Shanmugasundram edited their review of gene: DHX34: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHX34-related intellectual disability are limited, biallelic_autosomal and undetermined (PMID:31256877). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02758.; Changed phenotypes to: DHX34-related intellectual disability, INTELLECTUAL DISABILITY, OMIM:616579, MONDO:0001071
DDG2P v6.17 DHX30 Achchuthan Shanmugasundram edited their review of gene: DHX30: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHX30-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMID:29100085). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02380.; Changed phenotypes to: Neurodevelopmental Disorder, DHX30-related neurodevelopmental disorder, MONDO:0060622, OMIM:617804.0
DDG2P v6.17 DHX16 Achchuthan Shanmugasundram edited their review of gene: DHX16: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHX16-related intellectual disability, central nervous system anomalies and seizures are limited, monoallelic_autosomal and undetermined (PMID:31256877). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02756.; Changed phenotypes to: Intellectual Disability, Central Nervous System anomalies and Seizures, DHX16-related intellectual disability, central nervous system anomalies and seizures, OMIM:618733.0
DDG2P v6.17 DHRS3 Achchuthan Shanmugasundram edited their review of gene: DHRS3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHRS3 related craniosynostosis are limited, biallelic_autosomal and undetermined. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02351.; Changed phenotypes to: MONDO:0015469, DHRS3 related craniosynostosis
DDG2P v6.17 DHPS Achchuthan Shanmugasundram edited their review of gene: DHPS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHPS-related neurodevelopmental disorder of hypusination are strong, biallelic_autosomal and undetermined (PMID:30661771). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02644.; Changed phenotypes to: Neurodevelopmental Disorder of Hypusination, DHPS-related neurodevelopmental disorder of hypusination, OMIM:618480.0, MONDO:0032775
DDG2P v6.17 DHFR Achchuthan Shanmugasundram edited their review of gene: DHFR: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHFR-related megaloblastic anemia due to dihydrofolate reductase deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 21310276, 21310277). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00614.; Changed phenotypes to: OMIM:613839.0, MONDO:0013456, MEGALOBLASTIC ANEMIA DUE TO DIHYDROFOLATE REDUCTASE DEFICIENCY, OMIM:613839, DHFR-related megaloblastic anemia due to dihydrofolate reductase deficiency
DDG2P v6.17 DHDDS Achchuthan Shanmugasundram edited their review of gene: DHDDS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DHDDS-related epilepsy and intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:29100083). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02379.; Changed phenotypes to: OMIM:617836.0, Epilepsy and intellectual disability, MONDO:0044326, DHDDS-related epilepsy and intellectual disability
DDG2P v6.17 DENND5B Achchuthan Shanmugasundram commented on gene: DENND5B: The DDG2P confidence category, allelic requirement and molecular mechanism for DENND5B-related neurodevelopmental disorder with cortical migration and white matter abnormalities are limited, monoallelic_autosomal and loss of function (PMID:38387458). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03547.
DDG2P v6.17 DEAF1 Achchuthan Shanmugasundram edited their review of gene: DEAF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DEAF1-related intellectual developmental disorder are definitive, monoallelic_autosomal and dominant negative (PMIDs: 21076407, 24726472). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00255. The DDG2P confidence category, allelic requirement and molecular mechanism for DEAF1-related autism, intellectual disability, basal ganglia dysfunction and epilepsy are strong, biallelic_autosomal and loss of function (PMIDs: 26048982, 26834045). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02423.; Changed publications to: 24726472, 21076407, 26048982, 26834045; Changed phenotypes to: OMIM:615828.0, Autism, intellectual disability, basal ganglia dysfunction and epilepsy, OMIM:617171.0, DEAF1-related autism, intellectual disability, basal ganglia dysfunction and epilepsy, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 24, OMIM:615828, DEAF1-related intellectual developmental disorder
DDG2P v6.17 DDX6 Achchuthan Shanmugasundram edited their review of gene: DDX6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDX6-related intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:31422817). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02445.; Changed phenotypes to: MONDO:0032851, DDX6-related intellectual disability, INTELLECTUAL DISABILITY, OMIM:616579, OMIM:618653.0
DDG2P v6.17 DDX59 Achchuthan Shanmugasundram edited their review of gene: DDX59: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDX59-related orofaciodigital syndrome are strong, biallelic_autosomal and undetermined (PMID:23972372). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01525.; Changed phenotypes to: MONDO:0008267, DDX59-related orofaciodigital syndrome, OMIM:174300.0, OROFACIODIGITAL SYNDROME
DDG2P v6.17 DDX54 Achchuthan Shanmugasundram edited their review of gene: DDX54: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDX54-related intellectual disability and central nervous system anomalies are limited, biallelic_autosomal and undetermined (PMID:31256877). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02757.; Changed phenotypes to: DDX54-related intellectual disability and central nervous system anomalies, Intellectual Disability and Central Nervous System anomalies
DDG2P v6.17 DDX23 Achchuthan Shanmugasundram edited their review of gene: DDX23: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDX23-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02872.; Changed phenotypes to: DDX23-related developmental disorder (monoallelic), MONDO:0700092, DDX23-related developmental disorder
DDG2P v6.17 DDR2 Achchuthan Shanmugasundram edited their review of gene: DDR2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDR2-related spondyloepimetaphyseal dysplasia short limb-hand type are definitive, biallelic_autosomal and undetermined (PMIDs: 19110212, 8434618). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00916.; Changed publications to: 8434618, 19110212; Changed phenotypes to: OMIM:271665.0, SPONDYLOEPIMETAPHYSEAL DYSPLASIA SHORT LIMB-HAND TYPE, OMIM:271665, DDR2-related spondyloepimetaphyseal dysplasia short limb-hand type, MONDO:0010077
DDG2P v6.17 DDB1 Achchuthan Shanmugasundram edited their review of gene: DDB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DDB1-related neurodevelopmental syndrome are strong, monoallelic_autosomal and undetermined (PMID:33743206). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03117.; Changed phenotypes to: OMIM:619426.0, DDB1-associated neurodevelopmental syndrome, MONDO:0859169, DDB1-related neurodevelopmental syndrome
DDG2P v6.17 DARS Achchuthan Shanmugasundram edited their review of gene: DARS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DARS1-related hypomyelination with brain stem and spinal cord involvement and leg spasticity are definitive, biallelic_autosomal and undetermined (PMID:23643384). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01417.; Changed phenotypes to: DARS1-related hypomyelination with brain stem and spinal cord involvement and leg spasticity, MONDO:0014115, HYPOMYELINATION WITH BRAIN STEM AND SPINAL CORD INVOLVEMENT AND LEG SPASTICITY., OMIM:615281, OMIM:615281.0
DDG2P v6.17 DAG1 Achchuthan Shanmugasundram edited their review of gene: DAG1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DAG1-related muscular dystrophy-dystroglycanopathy limb-girdle are definitive, biallelic_autosomal and undetermined (PMID:21388311). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00925.; Changed phenotypes to: OMIM:613818.0, MONDO:0013440, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C7, OMIM:613818, DAG1-related muscular dystrophy-dystroglycanopathy limb-girdle
DDG2P v6.17 DACT1 Achchuthan Shanmugasundram edited their review of gene: DACT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for DACT1-related multiple malformations of neural tube, ear, genitourinary and gastrointestinal systems are limited, monoallelic_autosomal and loss of function (PMIDs: 22610794, 28054444, 36066768). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02805.; Changed publications to: 36066768, 22610794, 28054444; Changed phenotypes to: OMIM:617466.0, Multiple malformations of neural tube, ear, genitourinary and gastrointestinal systems, DACT1-related multiple malformations of neural tube, ear, genitourinary and gastrointestinal systems, MONDO:0054582
DDG2P v6.17 CYP1B1 Achchuthan Shanmugasundram edited their review of gene: CYP1B1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CYP1B1-related primary congenital glaucoma, type 3A are definitive, biallelic_autosomal and undetermined (PMIDs: 10227395, 12372064, 15342693, 19643970, 19807744, 27777502, 9097971, 9463332, 9497261). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01364.; Changed publications to: 9497261, 12372064, 19807744, 9097971, 15342693, 27777502, 10227395, 9463332, 19643970; Changed phenotypes to: CYP1B1-related primary congenital glaucoma, type 3A, MONDO:0009277, PRIMARY CONGENITAL GLAUCOMA TYPE 3A, OMIM:231300, OMIM:231300.0
DDG2P v6.17 CYFIP2 Achchuthan Shanmugasundram edited their review of gene: CYFIP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CYFIP2-related epileptic encephalopathy, early infantile are definitive, monoallelic_autosomal and undetermined (PMIDs: 29534297, 29667327, 30664714, 31689829). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02991.; Changed phenotypes to: CYFIP2-related epileptic encephalopathy, early infantile, EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, OMIM:618468, OMIM:618008.0, MONDO:0033374
DDG2P v6.17 CYC1 Achchuthan Shanmugasundram edited their review of gene: CYC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CYC1-related mitochondrial complex III deficiency, nuclear are definitive, biallelic_autosomal and undetermined (PMID:23910460). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00894.; Changed phenotypes to: OMIM:615453.0, CYC1-related mitochondrial complex III deficiency, nuclear, MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 6, OMIM:615453, MONDO:0014194
DDG2P v6.17 CUX2 Achchuthan Shanmugasundram edited their review of gene: CUX2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CUX2-related developmental epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMID:29630738). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02420.; Changed phenotypes to: MONDO:0029138, OMIM:618141.0, CUX2-related developmental epileptic encephalopathy, Developmental epileptic encephalopathy
DDG2P v6.17 CUX1 Achchuthan Shanmugasundram edited their review of gene: CUX1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CUX1-related neurodevelopmental disorder are moderate, monoallelic_autosomal and loss of function (PMIDs: 30014507, 37644171). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02990.; Changed rating: GREEN; Changed publications to: 37644171, 30014507; Changed phenotypes to: GLOBAL DEVELOPMENTAL DELAY WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT, CUX1-related neurodevelopmental disorder, MONDO:0032680, OMIM:618330.0
DDG2P v6.17 CSNK1G1 Achchuthan Shanmugasundram edited their review of gene: CSNK1G1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CSNK1G1-related early infantile epileptic encephalopathy and microcephaly are limited, monoallelic_autosomal and undetermined (PMID:24463883). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00754.; Changed phenotypes to: CSNK1G1-related early infantile epileptic encephalopathy and microcephaly, EARLY INFANTILE EPILEPTIC ENCEPHALOPATHY AND MICROCEPHALY
DDG2P v6.17 CRYBB3 Achchuthan Shanmugasundram edited their review of gene: CRYBB3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRYBB3-related cataract are definitive, biallelic_autosomal and undetermined (PMIDs: 15914629, 19182255, 23508780, 27326458). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00941.; Changed publications to: 23508780, 19182255, 27326458, 15914629; Changed phenotypes to: OMIM:609741.0, CATARACT, CONGENITAL NUCLEAR, AUTOSOMAL RECESSIVE 2, OMIM:609741, CRYBB3-related cataract, MONDO:0012336
DDG2P v6.17 CRYBA4 Achchuthan Shanmugasundram edited their review of gene: CRYBA4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRYBA4-related cataract with or wihout microcornea or microphthalmia are definitive, monoallelic_autosomal and undetermined non-loss-of-function (PMIDs: 15452067, 16960806, 20577656). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01130.; Changed rating: GREEN; Changed publications to: 15452067, 16960806, 20577656; Changed phenotypes to: MICROPHTHALMIA ISOLATED WITH CATARACT TYPE 4, OMIM:610426, MONDO:0012489, CRYBA4-related cataract with or wihout microcornea or microphthalmia, OMIM:610425.0
DDG2P v6.17 CRLS1 Achchuthan Shanmugasundram edited their review of gene: CRLS1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRLS1-related mitochondrial disorder are limited, biallelic_autosomal and undetermined (PMID:35147173). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03459.; Changed phenotypes to: OMIM:620167.0, MONDO:0859337, CRLS1-related mitochondrial disorder
DDG2P v6.17 CRKL Achchuthan Shanmugasundram edited their review of gene: CRKL: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRKL-related bladder exstrophy plus are limited, monoallelic_autosomal and undetermined (PMIDs: 24764164, 30628148, 34355505). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02557.; Changed publications to: 24764164, 30628148, 34355505; Changed phenotypes to: CRKL-related bladder exstrophy plus, Bladder exstrophy plus
DDG2P v6.17 CRELD1 Achchuthan Shanmugasundram edited their review of gene: CRELD1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRELD1-related atrioventricular septal defect susceptibility are limited, monoallelic_autosomal and undetermined (PMIDs: 12632326, 21080147, 22740159). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01141. The DDG2P confidence category, allelic requirement and molecular mechanism for CRELD1-related neurodevelopmental disorder with hypotonia and seizures are moderate, biallelic_autosomal and undetermined (PMID:37947183). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03532.; Changed publications to: 37947183, 22740159, 12632326, 21080147; Changed phenotypes to: OMIM:606217.0, MONDO:0958329, CRELD1-related atrioventricular septal defect susceptibility, CRELD1-related neurodevelopmental disorder with hypotonia and seizures, MONDO:0011650, OMIM:620771.0, CRELD1-related neurodevelopmental disorder with hypotonia and seizures, OMIM:620771, CRELD1-related atrioventricular septal defect susceptibility, OMIM:606217
DDG2P v6.17 CRADD Achchuthan Shanmugasundram edited their review of gene: CRADD: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CRADD-related intellectual developmental disorder with variant lissencephaly are limited, biallelic_autosomal and undetermined (PMIDs: 22279524, 27773430). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01409.; Changed publications to: 22279524, 27773430; Changed phenotypes to: OMIM:614499.0, MONDO:0013785, CRADD-related intellectual developmental disorder with variant lissencephaly, INTELLECTUAL DEVELOPMENTAL DISORDER, autosomal recessive 34, with variant lissencephaly, OMIM:614499
DDG2P v6.17 CPSF3 Achchuthan Shanmugasundram edited their review of gene: CPSF3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CPSF3-related neurodevelopmental disorder with seizures and microcephaly are moderate, biallelic_autosomal and undetermined (PMID:35121750). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03239.; Changed phenotypes to: CPSF3-associated neurodevelopmental disorder with seizures and microcephaly, CPSF3-related neurodevelopmental disorder with seizures and microcephaly, MONDO:0859250, OMIM:619876.0
DDG2P v6.17 COX18 Achchuthan Shanmugasundram edited their review of gene: COX18: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COX18-related peripheral neuropathy are limited, biallelic_autosomal and loss of function (PMIDs: 37468577, 38960055, 39006432). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03567.; Changed publications to: 39006432, 38960055, 37468577
DDG2P v6.17 COX10 Achchuthan Shanmugasundram edited their review of gene: COX10: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COX10-related Leigh syndrome are definitive, biallelic_autosomal and undetermined (PMIDs: 10767350, 12928484, 15455402). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01068.; Changed publications to: 12928484, 10767350, 15455402; Changed phenotypes to: OMIM:619046.0, LEIGH SYNDROME, OMIM:256000, COX10-related Leigh syndrome, MONDO:0033635
DDG2P v6.17 COQ5 Achchuthan Shanmugasundram edited their review of gene: COQ5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COQ5-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00825.; Changed phenotypes to: MONDO:0700092, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, COQ5-related intellectual developmental disorder
DDG2P v6.17 COPB1 Achchuthan Shanmugasundram edited their review of gene: COPB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly are limited, biallelic_autosomal and undetermined (PMID:33632302). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03110.; Changed phenotypes to: COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly, MONDO:0031002, OMIM:619255.0
DDG2P v6.17 COL9A3 Achchuthan Shanmugasundram edited their review of gene: COL9A3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COL9A3-related multiple epiphyseal dysplasia are definitive, monoallelic_autosomal and dominant negative (PMIDs: 10090888, 10655510, 15551337). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01100. The DDG2P confidence category, allelic requirement and molecular mechanism for COL9A3-related Stickler syndrome are limited, biallelic_autosomal and loss of function (PMIDs: 24273071, 30450842, 31090205). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02091.; Changed publications to: 10090888, 24273071, 30450842, 10655510, 31090205, 15551337; Changed phenotypes to: OMIM:600969.0, COL9A3-related Stickler syndrome, OMIM:620022.0, MONDO:0031047, MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 3, OMIM:600969, COL9A3-related multiple epiphyseal dysplasia, Stickler syndrome, MONDO:0010964; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v6.17 COL6A1 Achchuthan Shanmugasundram edited their review of gene: COL6A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COL6A1-related myopathy are definitive, monoallelic_autosomal and undetermined (PMIDs: 11932968, 15955946, 36779064, 8782832). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01750.; Changed publications to: 15955946, 36779064, 8782832, 11932968; Changed phenotypes to: MONDO:0024530, COL6A1-related myopathy, COL6A1 associated myopathy, OMIM:158810.0
DDG2P v6.17 COL1A1 Achchuthan Shanmugasundram edited their review of gene: COL1A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COL1A1-related osteogenesis imperfecta spectrum are definitive, monoallelic_autosomal and dominant negative (PMIDs: 11286507, 12538651, 15024692, 15728585, 1613761, 1634225, 1737847, 1770532, 18409203, 1864604, 1874719, 1988452, 2037280, 21834035, 2295701, 2298750, 2309707, 2339700, 2500431, 2511192, 2794057, 2913053, 3082886, 3108247, 3403550, 3667599, 7789952, 7816518, 7881420, 8097422, 8100209, 8364588, 8408653, 8456809, 8723681, 8757037, 8786074, 8910493, 8950680, 9067755, 9295084). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00021. The DDG2P confidence category, allelic requirement and molecular mechanism for COL1A1-related Caffey disease are definitive, monoallelic_autosomal and undetermined (PMIDs: 15864348, 34272483). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00575.; Changed publications to: 2511192, 3403550, 9067755, 2309707, 12538651, 1988452, 2500431, 8757037, 8786074, 8910493, 8723681, 8408653, 2339700, 1737847, 8100209, 3082886, 7881420, 34272483, 2913053, 15024692, 9295084, 1874719, 7816518, 1634225, 18409203, 15864348, 2298750, 21834035, 1613761, 15728585, 1864604, 11286507, 3108247, 8950680, 8097422, 2794057, 7789952, 2295701, 3667599, 8364588, 1770532, 8456809, 2037280; Changed phenotypes to: OMIM:166220.0, MONDO:0008148, CAFFEY DISEASE, OMIM:114000, MONDO:0007244, OMIM:114000.0, COL1A1-related Caffey disease, COL1A1-related osteogenesis imperfecta spectrum, COL1A1-RELATED OSTEOGENESIS IMPERFECTA, OMIM:166200
DDG2P v6.17 COL11A2 Achchuthan Shanmugasundram edited their review of gene: COL11A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for COL11A2-related otospondylomegaepiphyseal dysplasia are definitive, biallelic_autosomal and dominant negative (PMIDs: 10677296, 15558753, 16189708, 16637051, 21204229, 21208667, 32341816, 37347055, 7859284, 9188673). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00117. The DDG2P confidence category, allelic requirement and molecular mechanism for COL11A2-related deafness (monoallelic) are definitive, monoallelic_autosomal and undetermined (PMIDs: 10581026, 10733181, 11177008, 15562903). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00879. The DDG2P confidence category, allelic requirement and molecular mechanism for COL11A2-related deafness (biallelic) are definitive, biallelic_autosomal and undetermined (PMIDs: 16033917, 25633957). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00926. The DDG2P confidence category, allelic requirement and molecular mechanism for COL11A2-related Stickler syndrome are definitive, monoallelic_autosomal and dominant negative (PMIDs: 10718438, 14234962, 15372529, 15558753, 18381781, 22796475, 25780254, 7833911, 9506662, 9805126). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01074.; Changed publications to: 15562903, 10718438, 14234962, 7859284, 16189708, 9506662, 11177008, 9805126, 16033917, 25780254, 15372529, 16637051, 22796475, 18381781, 10581026, 10677296, 32341816, 37347055, 15558753, 9188673, 7833911, 21208667, 25633957, 21204229, 10733181; Changed phenotypes to: DEAFNESS AUTOSOMAL RECESSIVE TYPE 53, OMIM:609706, OMIM:215150.0, COL11A2-related deafness (monoallelic), OMIM:184840.0, STICKLER SYNDROME TYPE 3, OMIM:184840, MONDO:0012333, COL11A2-related deafness (biallelic), MONDO:0044206, MONDO:0008490, AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA, OMIM:215150, DEAFNESS AUTOSOMAL DOMINANT TYPE 13, OMIM:601868, COL11A2-related Stickler syndrome, COL11A2-related otospondylomegaepiphyseal dysplasia, OMIM:609706.0
DDG2P v6.17 CNOT9 Achchuthan Shanmugasundram edited their review of gene: CNOT9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CNOT9-related developmental disorder with seizures are moderate, monoallelic_autosomal and loss of function (PMIDs: 30309886, 37092538). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03501.; Changed publications to: 30309886, 37092538
DDG2P v6.17 CNOT2 Achchuthan Shanmugasundram edited their review of gene: CNOT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CNOT2-related neurodevelopmental disorder with hypotonia are strong, monoallelic_autosomal and loss of function (PMIDs: 21299754, 31145527, 31512373, 36224108). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03500.; Changed publications to: 36224108, 21299754, 31512373, 31145527; Changed phenotypes to: OMIM:618608.0, MONDO:0032832, CNOT2-related neurodevelopmental disorder with hypotonia
DDG2P v6.17 CNOT1 Achchuthan Shanmugasundram edited their review of gene: CNOT1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CNOT1-related holoprosencephaly with or without pancreatic agenesis are strong, monoallelic_autosomal and undetermined (PMIDs: 31006510, 31006513). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02776. The DDG2P confidence category, allelic requirement and molecular mechanism for CNOT1-related neurodevelopmental disorder are strong, monoallelic_autosomal and undetermined (PMID:32553196). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03009.; Changed phenotypes to: OMIM:619033.0, MONDO:0032787, CNOT1-related neurodevelopmental disorder, OMIM:618500.0, MONDO:0033618, CNOT1-related holoprosencephaly with or without pancreatic agenesis, HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS, OMIM:618500
DDG2P v6.17 CLPP Achchuthan Shanmugasundram edited their review of gene: CLPP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLPP-related Perrault syndrome are strong, biallelic_autosomal and undetermined (PMID:23541340). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00456.; Changed phenotypes to: OMIM:614129.0, CLPP-related Perrault syndrome, MONDO:0013588, PERRAULT SYNDROME
DDG2P v6.17 CLP1 Achchuthan Shanmugasundram edited their review of gene: CLP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLP1-related pontocerebellar hypoplasia are strong, biallelic_autosomal and undetermined (PMID:24766809). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00820.; Changed phenotypes to: PONTOCEREBELLAR HYPOPLASIA, TYPE 10, OMIM:615803, CLP1-related pontocerebellar hypoplasia, OMIM:615803.0, MONDO:0014349
DDG2P v6.17 CLIC2 Achchuthan Shanmugasundram edited their review of gene: CLIC2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLIC2-related intellectual developmental disorder are limited, monoallelic_X_hemizygous and undetermined (PMID:22814392). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01667.; Changed phenotypes to: INTELLECTUAL DEVELOPMENTAL DISORDER, X-linked, syndromic 32, OMIM:300886, CLIC2-related intellectual developmental disorder, OMIM:300886.0, MONDO:0010473
DDG2P v6.17 CLDN5 Achchuthan Shanmugasundram edited their review of gene: CLDN5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLDN5-related neurodevelopmental disorder are limited, monoallelic_autosomal and undetermined (PMIDs: 35714222, 36477332). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03328.; Changed publications to: 36477332, 35714222; Changed phenotypes to: MONDO:0700092, CLDN5-related neurodevelopmental disorder
DDG2P v6.17 CLDN19 Achchuthan Shanmugasundram edited their review of gene: CLDN19: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLDN19-related hypomagnesemia with ocular involvement are definitive, biallelic_autosomal and undetermined (PMID:17033971). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00685.; Changed phenotypes to: OMIM:248190.0, MONDO:0009548, CLDN19-related hypomagnesemia with ocular involvement, HYPOMAGNESEMIA 5, RENAL, WITH OCULAR INVOLVEMENT, OMIM:248190
DDG2P v6.17 CLCN6 Achchuthan Shanmugasundram edited their review of gene: CLCN6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLCN6-related developmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 28074849, 29667327, 33217309). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03073.; Changed publications to: 28074849, 29667327, 33217309; Changed phenotypes to: CLCN6-related Developmental Disorder, OMIM:619173.0, CLCN6-related developmental disorder
DDG2P v6.17 CLCN4 Achchuthan Shanmugasundram edited their review of gene: CLCN4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CLCN4-related infantile epileptic encephalopathy and/or intellectual disability are strong, monoallelic_X_hemizygous and undetermined (PMIDs: 23647072, 25644381, 27550844). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01457.; Changed publications to: 23647072, 27550844, 25644381; Changed phenotypes to: OMIM:300114.0, INFANTILE EPILEPTIC ENCEPHALOPATHY AND/OR INTELLECTUAL DISABILITY, CLCN4-related infantile epileptic encephalopathy and/or intellectual disability
DDG2P v6.17 CIT Achchuthan Shanmugasundram edited their review of gene: CIT: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CIT-related primary microcephaly are strong, biallelic_autosomal and undetermined (PMID:27453578). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01871.; Changed phenotypes to: CIT-related primary microcephaly, PRIMARY MICROCEPHALY, OMIM:615414, OMIM:617090.0, MONDO:0014908
DDG2P v6.17 CHRNA2 Achchuthan Shanmugasundram edited their review of gene: CHRNA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CHRNA2-related nocturnal frontal lobe epilepsy are strong, monoallelic_autosomal and undetermined (PMIDs: 16826524, 25770198, 25847220, 30809122). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00766.; Changed rating: GREEN; Changed publications to: 30809122, 16826524, 25770198, 25847220; Changed phenotypes to: CHRNA2-related nocturnal frontal lobe epilepsy, OMIM:610353.0, CHRNA2-RELATED NOCTURNAL FRONTAL LOBE EPILEPSY, AUTOSOMAL DOMINANT, OMIM:291607, MONDO:0012474
DDG2P v6.17 CHRM1 Achchuthan Shanmugasundram edited their review of gene: CHRM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CHRM1-related intellectual disability are limited, monoallelic_autosomal and undetermined (PMID:34212451). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03213.; Changed phenotypes to: CHRM1-related intellectual disability, MONDO:0001071, CHRM1-associated intellectual disability
DDG2P v6.17 CHD3 Achchuthan Shanmugasundram edited their review of gene: CHD3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CHD3-related macrocephaly and impaired speech and language are strong, monoallelic_autosomal and undetermined (PMIDs: 30397230, 32483341, 33358638, 33571694, 34535214, 35346573, 36565043). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02440.; Changed publications to: 35346573, 36565043, 30397230, 34535214, 32483341, 33358638, 33571694; Changed phenotypes to: MONDO:0032600, Macrocephaly and impaired speech and language, CHD3-related macrocephaly and impaired speech and language, OMIM:618205.0
DDG2P v6.17 CFL2 Achchuthan Shanmugasundram edited their review of gene: CFL2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CFL2-related nemaline myopathy are strong, biallelic_autosomal and undetermined (PMID:17160903). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00394.; Changed phenotypes to: CFL2-related nemaline myopathy, MONDO:0012538, OMIM:610687.0, NEMALINE MYOPATHY 7, OMIM:610687
DDG2P v6.17 CELSR1 Achchuthan Shanmugasundram edited their review of gene: CELSR1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CELSR1-related fetal hydrops are limited, monoallelic_autosomal and loss of function (PMID:38272662). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03683.; Changed phenotypes to: MONDO:0015193, CELSR1-related fetal hydrops
DDG2P v6.17 CDON Achchuthan Shanmugasundram edited their review of gene: CDON: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDON-related holoprosencephaly are definitive, monoallelic_autosomal and undetermined (PMID:21802063). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00943.; Changed phenotypes to: HOLOPROSENCEPHALY 11, OMIM:614226, MONDO:0013642, OMIM:614226.0, CDON-related holoprosencephaly
DDG2P v6.17 CDK8 Achchuthan Shanmugasundram edited their review of gene: CDK8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDK8-related syndromic intellectual disability are definitive, monoallelic_autosomal and undetermined (PMID:30905399). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02783.; Changed phenotypes to: MONDO:0032897, SYNDROMIC INTELLECTUAL DISABILITY, OMIM:612100, CDK8-related syndromic intellectual disability, OMIM:618748.0
DDG2P v6.17 CDK19 Achchuthan Shanmugasundram edited their review of gene: CDK19: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDK19-related intellectual disability and epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMID:32330417). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02961.; Changed phenotypes to: CDK19-associated Intellectual Disability and Epileptic Encephalopathy, CDK19-related intellectual disability and epileptic encephalopathy, OMIM:618916.0, MONDO:0030059
DDG2P v6.17 CDK13 Achchuthan Shanmugasundram edited their review of gene: CDK13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDK13-related syndromic intellectual disability with or without congenital heart disease are definitive, monoallelic_autosomal and undetermined (PMIDs: 27479907, 28807008, 29021403, 29222009, 29393965, 31883531, 35063350, 35651941, 36599938, 37351084). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01767.; Changed publications to: 35063350, 36599938, 28807008, 31883531, 29021403, 29222009, 27479907, 37351084, 29393965, 35651941; Changed phenotypes to: MONDO:0044302, CDK13-related syndromic intellectual disability with or without congenital heart disease, OMIM:617360.0, Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease
DDG2P v6.17 CDH2 Achchuthan Shanmugasundram edited their review of gene: CDH2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDH2-related syndromic neurodevelopmental disorder with corpus callosum, axon, cardiac, ocular, and genital defects are strong, monoallelic_autosomal and undetermined (PMIDs: 31585109, 31650526). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02812.; Changed phenotypes to: Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects, CDH2-related syndromic neurodevelopmental disorder with corpus callosum, axon, cardiac, ocular, and genital defects, OMIM:618929.0, MONDO:0030065
DDG2P v6.17 CDH1 Achchuthan Shanmugasundram edited their review of gene: CDH1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDH1-related blepharo-cheiro-dontic syndrome are definitive, monoallelic_autosomal and undetermined (PMID:29348693). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01974.; Changed phenotypes to: Blepharo-cheiro-dontic syndrome, OMIM:119580.0, CDH1-related blepharo-cheiro-dontic syndrome, MONDO:0054740
DDG2P v6.17 CDC42 Achchuthan Shanmugasundram edited their review of gene: CDC42: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDC42-related neurodevelopmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 26386261, 26708094, 29394990). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02933.; Changed publications to: 26708094, 26386261, 29394990; Changed phenotypes to: CDC42-related neurodevelopmental disorder, CDC42-related Neurodevelopmental Disorder, OMIM:616737.0
DDG2P v6.17 CDC40 Achchuthan Shanmugasundram edited their review of gene: CDC40: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CDC40-related neurodegenerative pontocerebellar hypoplasia with microcephaly are limited, biallelic_autosomal and undetermined (PMID:33220177). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03070.; Changed phenotypes to: CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly, CDC40-related neurodegenerative pontocerebellar hypoplasia with microcephaly, OMIM:619302.0, MONDO:0030259
DDG2P v6.17 CCDC22 Achchuthan Shanmugasundram edited their review of gene: CCDC22: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CCDC22-related syndromic intellectual disability are strong, monoallelic_X_hemizygous and undetermined (PMIDs: 24916641, 36073196). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01275.; Changed publications to: 36073196, 24916641; Changed phenotypes to: OMIM:300963.0, SYNDROMIC X-LINKED INTELLECTUAL DISABILITY, CCDC22-related syndromic intellectual disability, MONDO:0010499
DDG2P v6.17 CBFB Achchuthan Shanmugasundram edited their review of gene: CBFB: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CBFB-related cleidocranial dysplasia are moderate, monoallelic_autosomal and undetermined (PMID:36241386). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03513.; Changed phenotypes to: OMIM:620099.0, CBFB-related cleidocranial dysplasia, MONDO:0859307
DDG2P v6.17 CAPRIN1 Achchuthan Shanmugasundram edited their review of gene: CAPRIN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CAPRIN1-related neurodevelopmental disorder are moderate, monoallelic_autosomal and loss of function (PMIDs: 23849776, 35979925). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01316.; Changed publications to: 35979925, 23849776; Changed phenotypes to: CAPRIN1-related neurodevelopmental disorder, OMIM:620782.0, MONDO:0968945
DDG2P v6.17 CAMK2G Achchuthan Shanmugasundram edited their review of gene: CAMK2G: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CAMK2G-related intellectual developmental disorder are strong, monoallelic_autosomal and undetermined (PMIDs: 23033978, 30184290). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02985.; Changed phenotypes to: OMIM:618522.0, MONDO:0032795, INTELLECTUAL DEVELOPMENTAL DISORDER 59, OMIM:618522, CAMK2G-related intellectual developmental disorder
DDG2P v6.17 CACNA2D1 Achchuthan Shanmugasundram edited their review of gene: CACNA2D1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CACNA2D1-related neurodevelopmental disorder are limited, biallelic_autosomal and undetermined (PMID:35293990). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03462.; Changed phenotypes to: CACNA2D1-related neurodevelopmental disorder, MONDO:0859327, OMIM:620149.0
DDG2P v6.17 CACNA1H Achchuthan Shanmugasundram edited their review of gene: CACNA1H: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CACNA1H-related epilepsy, childhood absence, susceptibility to are limited, monoallelic_autosomal and undetermined (PMIDs: 12891677, 17696120). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01454.; Changed publications to: 12891677, 17696120; Changed phenotypes to: OMIM:611942.0, MONDO:0012763, EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 6, OMIM:611942, CACNA1H-related epilepsy, childhood absence, susceptibility to
DDG2P v6.17 CACNA1A Achchuthan Shanmugasundram edited their review of gene: CACNA1A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for CACNA1A-related epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMIDs: 11342703, 11812585, 23934111, 27476654, 28742085, 28927557, 29366381). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00626.; Changed publications to: 29366381, 11812585, 23934111, 27476654, 28927557, 11342703, 28742085; Changed phenotypes to: CACNA1A-related epileptic encephalopathy, MONDO:0014917, EPILEPTIC ENCEPHALOPATHY, OMIM:617106.0
DDG2P v6.17 C1QBP Achchuthan Shanmugasundram edited their review of gene: C1QBP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for C1QBP-related severe neonatal-, childhood-, or later-onset cardiomyopathy associated with combined respiratory-chain deficiencies are strong, biallelic_autosomal and undetermined (PMID:28942965). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02371.; Changed phenotypes to: Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies, MONDO:0054677, OMIM:617713.0, C1QBP-related severe neonatal-, childhood-, or later-onset cardiomyopathy associated with combined respiratory-chain deficiencies
DDG2P v6.17 C12orf57 Achchuthan Shanmugasundram edited their review of gene: C12orf57: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for C12orf57-related Temtamy syndrome; coloboma, hypoplastic corpus callosum, and intellectual disability are strong, biallelic_autosomal and undetermined (PMIDs: 23453666, 24798461). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00263.; Changed publications to: 23453666, 24798461; Changed phenotypes to: COLOBOMA, HYPOPLASTIC CORPUS CALLOSUM AND INTELLECTUAL DISABILITY, OMIM:218340, coloboma, hypoplastic corpus callosum, and intellectual disability, TEMTAMY SYNDROME, MONDO:0009033, C12orf57-related Temtamy syndrome, OMIM:218340.0
DDG2P v6.17 BSN Achchuthan Shanmugasundram edited their review of gene: BSN: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BSN-related epilepsy are limited, monoallelic_autosomal and undetermined (PMID:36600631). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03460. The DDG2P confidence category, allelic requirement and molecular mechanism for BSN-related epilepsy are limited, biallelic_autosomal and undetermined (PMID:36600631). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03461.; Changed phenotypes to: BSN-related epilepsy, MONDO:0005027
DDG2P v6.17 BORCS8 Achchuthan Shanmugasundram edited their review of gene: BORCS8: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BORCS8-related early-infantile neurological disorder with severe intellectual disability, hypotonia and congenital heart disease are moderate, biallelic_autosomal and loss of function (PMID:38128568). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03556.; Changed phenotypes to: OMIM:620987.0, BORCS8-related early-infantile neurological disorder with severe intellectual disability, hypotonia and congenital heart disease, MONDO:0975837
DDG2P v6.17 KIAA1109 Achchuthan Shanmugasundram edited their review of gene: KIAA1109: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BLTP1-related brain atrophy, dandy walker and contractures are strong, biallelic_autosomal and undetermined (PMIDs: 25558065, 29290337). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01979.; Changed publications to: 29290337, 25558065; Changed phenotypes to: OMIM:617822.0, BLTP1-related brain atrophy, dandy walker and contractures, MONDO:0060631, Brain atrophy, Dandy Walker and Contractures
DDG2P v6.17 BICD2 Achchuthan Shanmugasundram edited their review of gene: BICD2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BICD2-related proximal spinal muscular atrophy with brain anomalies are definitive, monoallelic_autosomal and undetermined (PMID:23664120). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00609.; Changed phenotypes to: OMIM:615290.0, BICD2-related proximal spinal muscular atrophy with brain anomalies, Proximal spinal muscular atrophy with brain anomalies
DDG2P v6.17 BHLHA9 Achchuthan Shanmugasundram edited their review of gene: BHLHA9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BHLHA9-related mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type are definitive, biallelic_autosomal and dominant negative (PMIDs: 25466284, 29263794, 30107244, 31152918, 31912643, 34272776, 36565049). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00920. The DDG2P confidence category, allelic requirement and molecular mechanism for BHLHA9-related split hand and foot malformation are definitive, monoallelic_autosomal and undetermined (PMIDs: 22147889, 23790188). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02025.; Changed publications to: 25466284, 29263794, 34272776, 31152918, 23790188, 31912643, 22147889, 30107244, 36565049; Changed phenotypes to: BHLHA9-related split hand and foot malformation, MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE, OMIM:69432, BHLHA9-related mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type, SPLIT HAND AND FOOT MALFORMATION, OMIM:220600, OMIM:609432.0, MONDO:0012271, MONDO:0016576
DDG2P v6.17 BFSP2 Achchuthan Shanmugasundram edited their review of gene: BFSP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BFSP2-related cataract are definitive, monoallelic_autosomal and undetermined (PMIDs: 10634598, 10729115, 21836522). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00555.; Changed publications to: 21836522, 10729115, 10634598; Changed phenotypes to: CATARACT AUTOSOMAL DOMINANT BFSP2-RELATED, OMIM:611597, OMIM:611597.0, MONDO:0012701, BFSP2-related cataract
DDG2P v6.17 BCORL1 Achchuthan Shanmugasundram edited their review of gene: BCORL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BCORL1-related Shukla-Vernon syndrome are limited, monoallelic_X_hemizygous and undetermined (PMIDs: 24123876, 30941876, 33810051, 34400773). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02922.; Changed publications to: 30941876, 33810051, 24123876, 34400773; Changed phenotypes to: MONDO:0026727, BCORL1-related Shukla-Vernon syndrome, OMIM:301029.0, Shukla-Vernon Syndrome
DDG2P v6.17 BAP1 Achchuthan Shanmugasundram edited their review of gene: BAP1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BAP1-related neurodevelopmental syndrome are moderate, monoallelic_autosomal and undetermined (PMID:35051358). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03243.; Changed phenotypes to: MONDO:0859230, BAP1-associated neurodevelopmental syndrome, BAP1-related neurodevelopmental syndrome, OMIM:619762.0
DDG2P v6.17 BANF1 Achchuthan Shanmugasundram edited their review of gene: BANF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for BANF1-related Nestor-Guillermo progeria syndrome are moderate, biallelic_autosomal and loss of function (PMIDs: 21549337, 21932319, 32783369, 36039758, 36842139). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00506.; Changed publications to: 32783369, 36039758, 21932319, 36842139, 21549337; Changed phenotypes to: BANF1-related Nestor-Guillermo progeria syndrome, OMIM:614008.0, NESTOR-GUILLERMO PROGERIA SYNDROME, OMIM:614008, MONDO:0013523
DDG2P v6.17 B3GAT3 Achchuthan Shanmugasundram edited their review of gene: B3GAT3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for B3GAT3-related multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects are limited, biallelic_autosomal and undetermined (PMID:31438591). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02786.; Changed phenotypes to: MONDO:0009511, OMIM:245600.0, B3GAT3-related multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects, MULTIPLE JOINT DISLOCATIONS, SHORT STATURE, AND CRANIOFACIAL DYSMORPHISM WITH OR WITHOUT CONGENITAL HEART DEFECTS, OMIM:245600
DDG2P v6.17 AXIN1 Achchuthan Shanmugasundram edited their review of gene: AXIN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AXIN1-related caudal duplication anomaly are limited, monoallelic_autosomal and undetermined (PMIDs: 12376942, 16773576). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00854.; Changed publications to: 16773576, 12376942; Changed phenotypes to: CAUDAL DUPLICATION ANOMALY, OMIM:607864, AXIN1-related caudal duplication anomaly, OMIM:607864.0, MONDO:0011928
DDG2P v6.17 ATP8A2 Achchuthan Shanmugasundram edited their review of gene: ATP8A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP8A2-related cerebellar ataxia, intellectual developmental disorder, and dysequilibrium syndrome are limited, biallelic_autosomal and undetermined (PMIDs: 16075202, 22892528). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01367.; Changed phenotypes to: ATP8A2-related cerebellar ataxia, intellectual developmental disorder, and dysequilibrium syndrome, OMIM:615268.0, CEREBELLAR ATAXIA, INTELLECTUAL DEVELOPMENTAL DISORDER, AND DYSEQUILIBRIUM SYNDROME 4, OMIM:615268, MONDO:0014104
DDG2P v6.17 ATP6V1E1 Achchuthan Shanmugasundram edited their review of gene: ATP6V1E1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP6V1E1-related cutis laxa are strong, biallelic_autosomal and undetermined (PMID:28065471). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02591.; Changed phenotypes to: OMIM:617402.0, ATP6V1E1-related cutis laxa, MONDO:0027462, Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal Recessive Cutis Laxa
DDG2P v6.17 ATP6V1A Achchuthan Shanmugasundram edited their review of gene: ATP6V1A: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP6V1A-related cutis laxa are strong, biallelic_autosomal and undetermined (PMIDs: 28065471, 33320377). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02592. The DDG2P confidence category, allelic requirement and molecular mechanism for ATP6V1A-related epileptic encephalopathy, infantile or early childhood are definitive, monoallelic_autosomal and undetermined (PMIDs: 29668857, 32045939). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02984.; Changed publications to: 28065471, 29668857, 32045939, 33320377; Changed phenotypes to: Autosomal Recessive Cutis Laxa, OMIM:617403.0, OMIM:618012.0, ATP6V1A-related epileptic encephalopathy, infantile or early childhood, MONDO:0020632, ATP6V1A-related cutis laxa, MONDO:0027451, EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3, OMIM:618012
DDG2P v6.17 ATP6V0A1 Achchuthan Shanmugasundram edited their review of gene: ATP6V0A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP6V0A1-related developmental disorder are definitive, monoallelic_autosomal and undetermined (PMIDs: 28135719, 30842224, 33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02891.; Changed publications to: 30842224, 33057194, 28135719; Changed phenotypes to: OMIM:619970.0, MONDO:0031021, ATP6V0A1-related developmental disorder (monoallelic), ATP6V0A1-related developmental disorder
DDG2P v6.17 ATP6AP2 Achchuthan Shanmugasundram edited their review of gene: ATP6AP2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP6AP2-related intellectual developmental disorder with epilepsy are limited, monoallelic_X_hemizygous and undetermined (PMIDs: 15746149, 26467484, 30985297, 35779466, 38274877). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01458.; Changed publications to: 35779466, 26467484, 38274877, 30985297, 15746149; Changed phenotypes to: INTELLECTUAL DEVELOPMENTAL DISORDER X-LINKED WITH EPILEPSY, OMIM:300423, ATP6AP2-related intellectual developmental disorder with epilepsy, MONDO:0010319, OMIM:300423.0
DDG2P v6.17 ATP5D Achchuthan Shanmugasundram edited their review of gene: ATP5D: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP5F1D-related metabolic disorder are strong, biallelic_autosomal and undetermined (PMID:29478781). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02597.; Changed phenotypes to: OMIM:618120.0, MONDO:0020858, ATP5F1D-related metabolic disorder, ATP5F1D metabolic disorder
DDG2P v6.17 ATP5A1 Achchuthan Shanmugasundram edited their review of gene: ATP5A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP5F1A-related failure to thrive, hyperlactatemia and hyperammonemia are strong, monoallelic_autosomal and undetermined (PMID:34483339). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03218. The DDG2P confidence category, allelic requirement and molecular mechanism for ATP5F1A-related mitochondrial encephalopathy are strong, biallelic_autosomal and undetermined (PMIDs: 23596069, 23599390). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03219.; Changed publications to: 34483339, 23596069, 23599390; Changed phenotypes to: ATP5F1A-related failure to thrive, hyperlactatemia and hyperammonemia, ATP5F1A-related mitochondrial encephalopathy, OMIM:615228.0, OMIM:620358.0, MONDO:0014091, ATP5F1A-related mitochondrial encephalopathy, OMIM:615228, MONDO:0957254
DDG2P v6.17 ATP1A3 Achchuthan Shanmugasundram edited their review of gene: ATP1A3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP1A3-related alternating hemiplegia of childhood are strong, monoallelic_autosomal and undetermined (PMIDs: 22842232, 33880529). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01055.; Changed phenotypes to: MONDO:0013900, OMIM:614820.0, ALTERNATING HEMIPLEGIA OF CHILDHOOD, OMIM:104290, ATP1A3-related alternating hemiplegia of childhood
DDG2P v6.17 ATP1A1 Achchuthan Shanmugasundram edited their review of gene: ATP1A1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATP1A1-related renal hypomagnesemia refractory seizures and intellectual disability are strong, monoallelic_autosomal and undetermined (PMID:30388404). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02626.; Changed phenotypes to: ATP1A1-related renal hypomagnesemia refractory seizures and intellectual disability, MONDO:0020788, Renal Hypomagnesemia Refractory Seizures and Intellectual Disability, OMIM:618314.0
DDG2P v6.17 ATOH7 Achchuthan Shanmugasundram edited their review of gene: ATOH7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATOH7-related persistent hyperplastic primary vitreous are strong, biallelic_autosomal and loss of function (PMIDs: 21441919, 22068589, 22645276, 26933893, 28192794). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00770.; Changed publications to: 21441919, 26933893, 28192794, 22068589, 22645276; Changed phenotypes to: ATOH7-related persistent hyperplastic primary vitreous, OMIM:221900, ATOH7-related persistent hyperplastic primary vitreous, OMIM:221900.0, MONDO:0009097
DDG2P v6.17 ATN1 Achchuthan Shanmugasundram edited their review of gene: ATN1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATN1-related congenital hypotonia, epilepsy, developmental delay, digit abnormalities are strong, monoallelic_autosomal and undetermined (PMID:30827498). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02647.; Changed phenotypes to: MONDO:0032781, ATN1-related congenital hypotonia, epilepsy, developmental delay, digit abnormalities, congenital hypotonia, epilepsy, developmental delay, digit abnormalities, OMIM:618494.0
DDG2P v6.17 ATG4D Achchuthan Shanmugasundram edited their review of gene: ATG4D: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ATG4D-related neurodevelopmental disorder are limited, biallelic_autosomal and undetermined (PMID:36765070). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03428.; Changed phenotypes to: ATG4D-related neurodevelopmental disorder, MONDO:0700092
DDG2P v6.17 ASH1L Achchuthan Shanmugasundram edited their review of gene: ASH1L: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ASH1L-related intellectual disability are strong, monoallelic_autosomal and undetermined (PMIDs: 25961944, 28394464, 29276005, 29753921, 31673123, 34373061, 35241855). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01097.; Changed publications to: 28394464, 29753921, 29276005, 35241855, 31673123, 25961944, 34373061; Changed phenotypes to: ASH1L-related intellectual disability, OMIM:617796.0, MONDO:0030918, INTELLECTUAL DISABILITY, OMIM:616579
DDG2P v6.17 ASCL1 Achchuthan Shanmugasundram edited their review of gene: ASCL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ASCL1-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00387.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, MONDO:0700092, ASCL1-related intellectual developmental disorder
DDG2P v6.17 ASCC3 Achchuthan Shanmugasundram edited their review of gene: ASCC3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ASCC3-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00133.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, ASCC3-related intellectual developmental disorder, OMIM:620700.0, MONDO:0958204
DDG2P v6.17 ARPC4 Achchuthan Shanmugasundram edited their review of gene: ARPC4: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ARPC4-related microcephaly and developmental delay are strong, monoallelic_autosomal and undetermined (PMIDs: 35047857, 36513617). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03238.; Changed publications to: 35047857, 36513617; Changed phenotypes to: OMIM:620141.0, MONDO:0859324, ARPC4-related microcephaly and developmental delay
DDG2P v6.17 ARL3 Achchuthan Shanmugasundram edited their review of gene: ARL3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ARL3-related Joubert syndrome are strong, biallelic_autosomal and undetermined (PMID:30269812). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02622.; Changed phenotypes to: ARL3-related Joubert syndrome, MONDO:0032570, JOUBERT SYNDROME, OMIM:614615, OMIM:618161.0
DDG2P v6.17 ARL14EP Achchuthan Shanmugasundram edited their review of gene: ARL14EP: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ARL14EP-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00194.; Changed phenotypes to: MONDO:0700092, ARL14EP-related intellectual developmental disorder, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ARF1-related periventricular nodular heterotopia are strong, monoallelic_autosomal and undetermined (PMIDs: 28868155, 33057194, 34353862). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02983.; Changed publications to: 28868155, 33057194, 34353862; Changed phenotypes to: OMIM:618185.0, PERIVENTRICULAR NODULAR HETEROTOPIA 8, OMIM:618615, MONDO:0032588, ARF1-related periventricular nodular heterotopia
DDG2P v6.17 AP2S1 Achchuthan Shanmugasundram edited their review of gene: AP2S1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AP2S1-related developmental disorder are moderate, monoallelic_autosomal and undetermined (PMID:33057194). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02867.; Changed phenotypes to: AP2S1-related developmental disorder, MONDO:0700092, AP2S1-related developmental disorder (monoallelic)
DDG2P v6.17 AP2M1 Achchuthan Shanmugasundram edited their review of gene: AP2M1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AP2M1-related developmental and epileptic encephalopathy are strong, monoallelic_autosomal and undetermined (PMID:31104773). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02769.; Changed phenotypes to: MONDO:0032823, Developmental and Epileptic Encephalopathy, AP2M1-related developmental and epileptic encephalopathy, OMIM:618587.0
DDG2P v6.17 AP1B1 Achchuthan Shanmugasundram edited their review of gene: AP1B1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AP1B1-related keratitis-ichthyosis-deafness syndrome (KIDAR) are moderate, biallelic_autosomal and undetermined (PMIDs: 31630788, 31630791, 33349978, 33452671, 35144013). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02834.; Changed rating: GREEN; Changed publications to: 31630788, 33349978, 33452671, 35144013, 31630791; Changed phenotypes to: MEDNIK-like Syndrome, AP1B1-related keratitis-ichthyosis-deafness syndrome (KIDAR), MONDO:0009440, OMIM:242150.0
DDG2P v6.17 ANO3 Achchuthan Shanmugasundram edited their review of gene: ANO3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ANO3-related dystonia are limited, monoallelic_autosomal and undetermined (PMIDs: 33502045, 38079528). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03570.; Changed publications to: 33502045, 38079528; Changed phenotypes to: OMIM:615034.0, ANO3-related dystonia, ANO3-related dystonia, OMIM:615034, MONDO:0014019
DDG2P v6.17 ANKRD26 Achchuthan Shanmugasundram edited their review of gene: ANKRD26: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ANKRD26-related thrombocytopenia are strong, monoallelic_autosomal and undetermined (PMIDs: 10521306, 21211618). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00781.; Changed phenotypes to: OMIM:188000.0, THROMBOCYTOPENIA 2, OMIM:188000, ANKRD26-related thrombocytopenia, MONDO:0008555
DDG2P v6.17 ANKRD11 Achchuthan Shanmugasundram edited their review of gene: ANKRD11: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ANKRD11-related KBG syndrome are definitive, monoallelic_autosomal and undetermined (PMIDs: 21782149, 23184435, 23494856, 25424714, 25464108, 25543316, 25652421, 25838844, 26269249, 27667800, 27900361, 28250421, 28449295, 28566769, 28815928, 29224748, 30088855, 30877071, 31566922, 32820523, 33262785, 33354850, 33476899, 33653342, 33955014, 34247373, 34547584, 35394473, 35598261, 35682590, 35833929, 36584991, 36628575, 37665295). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00381.; Changed publications to: 25543316, 31566922, 28250421, 37665295, 29224748, 23184435, 36628575, 34547584, 25652421, 28449295, 25464108, 30088855, 33354850, 33955014, 28815928, 21782149, 25424714, 35682590, 35833929, 25838844, 36584991, 23494856, 33262785, 32820523, 35394473, 34247373, 27667800, 33653342, 30877071, 26269249, 28566769, 33476899, 27900361, 35598261; Changed phenotypes to: OMIM:148050.0, KBG SYNDROME, OMIM:148050, ANKRD11-related KBG syndrome, MONDO:0007846
DDG2P v6.17 ANGPT2 Achchuthan Shanmugasundram commented on gene: ANGPT2: The DDG2P confidence category, allelic requirement and molecular mechanism for ANGPT2-related non-immune hydrops fetalis are limited, biallelic_autosomal and loss of function (PMID:34876502). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03493.
DDG2P v6.17 AMOTL1 Achchuthan Shanmugasundram edited their review of gene: AMOTL1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature are moderate, monoallelic_autosomal and undetermined (PMID:36751037). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03429.; Changed phenotypes to: AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature, MONDO:0971064
DDG2P v6.17 ALPL Achchuthan Shanmugasundram edited their review of gene: ALPL: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ALPL-related hypophosphatasia are definitive, biallelic_autosomal and loss of function (PMIDs: 14982838, 3174660, 33093890, 33101980, 33160095). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00284.; Changed publications to: 33101980, 33160095, 14982838, 3174660, 33093890; Changed phenotypes to: MONDO:0018570, HYPOPHOSPHATASIA, OMIM:241500, ALPL-related hypophosphatasia
DDG2P v6.17 ALG13 Achchuthan Shanmugasundram edited their review of gene: ALG13: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ALG13-related congenital disorder of glycosylation are strong, monoallelic_X_heterozygous and undetermined (PMIDs: 22492991, 23934111, 28887793). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01271.; Changed publications to: 28887793, 23934111, 22492991; Changed phenotypes to: OMIM:300884.0, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IS, OMIM:300884, MONDO:0010472, ALG13-related congenital disorder of glycosylation
DDG2P v6.17 ALDOA Achchuthan Shanmugasundram edited their review of gene: ALDOA: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ALDOA-related glycogen storage disease are definitive, biallelic_autosomal and undetermined (PMIDs: 2825199, 8598869). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00859.; Changed publications to: 8598869, 2825199; Changed phenotypes to: ALDOA-related glycogen storage disease, MONDO:0012747, OMIM:611881.0, GLYCOGEN STORAGE DISEASE XII, OMIM:611881
DDG2P v6.17 ALDH1A2 Achchuthan Shanmugasundram edited their review of gene: ALDH1A2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ALDH1A2-related diaphragmatic hernia and pulmonary hypoplasia are strong, biallelic_autosomal and undetermined (PMID:33565183). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03158.; Changed phenotypes to: MONDO:0859571, OMIM:620025.0, ALDH1A2-related diaphragmatic hernia and pulmonary hypoplasia
DDG2P v6.17 ALAD Achchuthan Shanmugasundram edited their review of gene: ALAD: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ALAD-related acute hepatic porphyria are limited, biallelic_autosomal and undetermined (PMID:2063868). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00549.; Changed phenotypes to: ALAD-related acute hepatic porphyria, ACUTE HEPATIC PORPHYRIA, OMIM:612740, MONDO:0013000, OMIM:612740.0
DDG2P v6.17 AKT3 Achchuthan Shanmugasundram edited their review of gene: AKT3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AKT3-related hemimegalencephaly are strong, monoallelic_autosomal and undetermined (PMIDs: 22500628, 22729224). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01092.; Changed phenotypes to: AKT3-related hemimegalencephaly, OMIM:603387.0, HEMIMEGALENCEPHALY AKT3, OMIM:603387, MONDO:0011313
DDG2P v6.17 AKT2 Achchuthan Shanmugasundram edited their review of gene: AKT2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AKT2-related hypoinsulinemic hypoglycemia and hemihypertrophy are definitive, monoallelic_autosomal and undetermined (PMIDs: 21979934, 24285683, 26003998, 28541532). The cross-cutting modifier is restricted mutation set. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03220.; Changed publications to: 21979934, 26003998, 24285683, 28541532; Changed phenotypes to: MONDO:0009416, AKT2-related hypoinsulinemic hypoglycemia and hemihypertrophy, OMIM:240900.0, AKT2-related hypoinsulinemic hypoglycemia and hemihypertrophy, OMIM:240900
DDG2P v6.17 AIFM1 Achchuthan Shanmugasundram edited their review of gene: AIFM1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AIFM1-related combined oxidative phosphorylation deficiency are strong, monoallelic_X_hemizygous and undetermined (PMIDs: 20362274, 23217327). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01641.; Changed phenotypes to: COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6, OMIM:300816, OMIM:300816.0, AIFM1-related combined oxidative phosphorylation deficiency
DDG2P v6.17 AGPS Achchuthan Shanmugasundram edited their review of gene: AGPS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AGPS-related rhizomelic chondrodysplasia punctata are definitive, biallelic_autosomal and loss of function (PMIDs: 11152660, 21990100, 24849933, 35986576, 7807941). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00018.; Changed publications to: 7807941, 21990100, 35986576, 11152660, 24849933; Changed phenotypes to: MONDO:0010823, OMIM:600121.0, RHIZOMELIC CHONDRODYSPLASIA PUNCTATA TYPE 3, OMIM:600121, AGPS-related rhizomelic chondrodysplasia punctata
DDG2P v6.17 AGO1 Achchuthan Shanmugasundram edited their review of gene: AGO1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AGO1-related developmental disorder are strong, monoallelic_autosomal and undetermined (PMID:35060114). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02852.; Changed phenotypes to: AGO1-related developmental disorder (monoallelic), AGO1-related developmental disorder, OMIM:620292.0, MONDO:0859531
DDG2P v6.17 AFG3L2 Achchuthan Shanmugasundram edited their review of gene: AFG3L2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AFG3L2-related ataxia and seizures are definitive, biallelic_autosomal and loss of function (PMIDs: 22022284, 28449981, 31111429, 32237276, 32248051). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03166.; Changed rating: GREEN; Changed publications to: 22022284, 32237276, 31111429, 32248051, 28449981; Changed phenotypes to: MONDO:0013776, AFG3L2-related ataxia and seizures, OMIM:614487.0, AFG3L2-related ataxia and seizures, OMIM:614487
DDG2P v6.17 AFF3 Achchuthan Shanmugasundram edited their review of gene: AFF3: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for AFF3-related KINSSHIP syndrome are strong, monoallelic_autosomal and undetermined (PMIDs: 33961779, 36576140, 38811945). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01978. The DDG2P confidence category, allelic requirement and molecular mechanism for AFF3-related intellectual disability are moderate, monoallelic_autosomal and undetermined (PMID:38811945). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03581.; Changed publications to: 33961779, 38811945, 36576140; Changed phenotypes to: AFF3-related intellectual disability, MONDO:0001071, AFF3-related KINSSHIP syndrome, OMIM:619297, AFF3-related KINSSHIP syndrome, OMIM:619297.0, MONDO:0851095
DDG2P v6.17 ADSL Achchuthan Shanmugasundram edited their review of gene: ADSL: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADSL-related adenylosuccinase deficiency are definitive, biallelic_autosomal and undetermined (PMIDs: 10090474, 12016589, 18830228, 6150139, 9545543). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00673.; Changed publications to: 9545543, 6150139, 18830228, 12016589, 10090474; Changed phenotypes to: ADSL-related adenylosuccinase deficiency, ADENYLOSUCCINASE DEFICIENCY, OMIM:103050, OMIM:103050.0
DDG2P v6.17 ADRA2B Achchuthan Shanmugasundram edited their review of gene: ADRA2B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADRA2B-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00688.; Changed phenotypes to: ADRA2B-related intellectual developmental disorder, MONDO:0700092, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER
DDG2P v6.17 ADK Achchuthan Shanmugasundram edited their review of gene: ADK: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADK-related intellectual developmental disorder are limited, biallelic_autosomal and undetermined (PMID:21937992). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00813.; Changed phenotypes to: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, OMIM:614300.0, MONDO:0100255, ADK-related intellectual developmental disorder
DDG2P v6.17 ADCY5 Achchuthan Shanmugasundram edited their review of gene: ADCY5: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADCY5-related developmental disorder are strong, monoallelic_autosomal and undetermined. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02885.; Changed phenotypes to: ADCY5-related developmental disorder, MONDO:0700092, ADCY5-related developmental disorder (monoallelic)
DDG2P v6.17 ADARB1 Achchuthan Shanmugasundram edited their review of gene: ADARB1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADARB1-related microcephaly, intellectual disability, and seizures are limited, biallelic_autosomal and undetermined (PMID:32220291). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02943.; Changed phenotypes to: ADARB1-related microcephaly, intellectual disability, and seizures, OMIM:618862.0, MONDO:0030025, ADARB1-associated Microcephaly, Intellectual Disability, and Seizures
DDG2P v6.17 ADAMTS9 Achchuthan Shanmugasundram edited their review of gene: ADAMTS9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADAMTS9-related nephronophthisis related ciliopathy are strong, biallelic_autosomal and undetermined (PMID:30609407). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02635.; Changed phenotypes to: MONDO:0009728, ADAMTS9-related nephronophthisis related ciliopathy, Nephronophthisis Related Ciliopathy
DDG2P v6.17 ADAMTS18 Achchuthan Shanmugasundram edited their review of gene: ADAMTS18: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ADAMTS18-related microcornea, myopic chorioretinal atrophy, and telecanthus are definitive, biallelic_autosomal and loss of function (PMIDs: 22686506, 23818446, 24874986). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P02048.; Changed phenotypes to: Microcornea, myopic chorioretinal atrophy, and telecanthus, OMIM:615458, OMIM:615458.0, MONDO:0014195, ADAMTS18-related microcornea, myopic chorioretinal atrophy, and telecanthus
DDG2P v6.17 ACVR2B Achchuthan Shanmugasundram edited their review of gene: ACVR2B: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACVR2B-related heterotaxy syndrome are limited, monoallelic_autosomal and undetermined (PMIDs: 21864452, 30622330, 9916847). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00465.; Changed publications to: 30622330, 21864452, 9916847; Changed phenotypes to: OMIM:613751.0, MONDO:0013403, HETEROTAXY SYNDROME, OMIM:207574, ACVR2B-related heterotaxy syndrome
DDG2P v6.17 ACTC1 Achchuthan Shanmugasundram edited their review of gene: ACTC1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACTC1-related distal arthrogryposis with congenital heart disease are moderate, monoallelic_autosomal and loss of function (PMIDs: 37457373, 38278647). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03543.; Changed publications to: 37457373, 38278647
DDG2P v6.17 ACTA2 Achchuthan Shanmugasundram edited their review of gene: ACTA2: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACTA2-related Moyamoya disease are strong, monoallelic_autosomal and undetermined (PMID:35567597). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00398.; Changed phenotypes to: MONDO:0013542, OMIM:614042.0, MOYAMOYA DISEASE 5, OMIM:614042, ACTA2-related Moyamoya disease
DDG2P v6.17 ACTA1 Achchuthan Shanmugasundram edited their review of gene: ACTA1: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACTA1-related nemaline myopathy are strong, biallelic_autosomal and undetermined (PMID:10508519). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P01161.; Changed phenotypes to: OMIM:161800.0, ACTA1-related nemaline myopathy, MONDO:0008070, NEMALINE MYOPATHY 3, OMIM:161800
DDG2P v6.17 ACBD6 Achchuthan Shanmugasundram edited their review of gene: ACBD6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACBD6-related intellectual developmental disorder are strong, biallelic_autosomal and loss of function (PMIDs: 21937992, 26748517, 36457943, 37951597). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00748.; Changed rating: GREEN; Changed publications to: 26748517, 21937992, 36457943, 37951597; Changed phenotypes to: ACBD6-related intellectual developmental disorder, MONDO:0968976, AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER, OMIM:620785.0
DDG2P v6.17 ACADS Achchuthan Shanmugasundram edited their review of gene: ACADS: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ACADS-related short chain acyl-CoA dehydrogenase deficiency are definitive, biallelic_autosomal and undetermined (PMID:2808706). The cross-cutting modifier is potential secondary finding. More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00672.; Changed phenotypes to: OMIM:201470.0, MONDO:0008722, SHORT CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY, OMIM:201470, ACADS-related short chain acyl-CoA dehydrogenase deficiency
DDG2P v6.17 ABCC9 Achchuthan Shanmugasundram edited their review of gene: ABCC9: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ABCC9-related Cantu Syndrome are definitive, monoallelic_autosomal and gain of function (PMIDs: 22608503, 22610116, 30089727, 31175705, 31828977, 33529173, 34453476). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03442. The DDG2P confidence category, allelic requirement and molecular mechanism for ABCC9-related intellectual disability, myopathy and white matter abnormalities are moderate, biallelic_autosomal and loss of function (PMIDs: 31575858, 38217872). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03920.; Changed publications to: 31175705, 34453476, 31575858, 30089727, 31828977, 22608503, 33529173, 22610116, 38217872; Changed phenotypes to: OMIM:619719.0, MONDO:0009406, MONDO:0859224, CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA, OMIM:239850, ABCC9-related intellectual disability, myopathy and white matter abnormalities, OMIM:239850.0, ABCC9-related Cantu Syndrome; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.17 ABCB7 Achchuthan Shanmugasundram edited their review of gene: ABCB7: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ABCB7-related anemia, sideroblastic, with ataxia are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 10196363, 11843825, 22398176, 26242992, 34354969). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00928.; Changed publications to: 10196363, 26242992, 22398176, 11843825, 34354969; Changed phenotypes to: ABCB7-related anemia, sideroblastic, with ataxia, OMIM:301310.0, ANEMIA, SIDEROBLASTIC, WITH ATAXIA, OMIM:301310
DDG2P v6.17 ABCB6 Achchuthan Shanmugasundram edited their review of gene: ABCB6: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for ABCB6-related microphthalmia, isolated, with coloboma are limited, monoallelic_autosomal and undetermined (PMID:22226084). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00318.; Changed phenotypes to: OMIM:614497.0, MICROPHTHALMIA, ISOLATED, WITH COLOBOMA 7, OMIM:614497, ABCB6-related microphthalmia, isolated, with coloboma, MONDO:0013783
DDG2P v6.16 ZNF599 Achchuthan Shanmugasundram Source Expert Review Removed was added to ZNF599.
Rating Changed from Red List (low evidence) to No List (delete)
DDG2P v6.16 SLC24A1 Achchuthan Shanmugasundram Source Expert Review Removed was added to SLC24A1.
Rating Changed from Red List (low evidence) to No List (delete)
DDG2P v6.16 MYOC Achchuthan Shanmugasundram Source Expert Review Removed was added to MYOC.
Rating Changed from Red List (low evidence) to No List (delete)
DDG2P v6.16 ZNRF3 Achchuthan Shanmugasundram gene: ZNRF3 was added
gene: ZNRF3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to ZNRF3-related neurodevelopmental disorder with macrocephaly; MONDO:0100038
Mode of pathogenicity for gene: ZNRF3 was set to Other
DDG2P v6.16 ZNF335 Achchuthan Shanmugasundram gene: ZNF335 was added
gene: ZNF335 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 38549403; 27540107; 29652087; 23178126; 40583037; 33216650; 34982360; 31187448
Phenotypes for gene: ZNF335 were set to MONDO:0014043; ZNF335-related microcephaly, epilepsy, cerebral and/or cerebellar atrophy and short stature; OMIM:615095.0
DDG2P v6.16 XPO1 Achchuthan Shanmugasundram gene: XPO1 was added
gene: XPO1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: XPO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: XPO1 were set to 36807877; 40819229
Phenotypes for gene: XPO1 were set to XPO1-related neurodevelopmental disorder with microcephaly
DDG2P v6.16 WIPI2 Achchuthan Shanmugasundram gene: WIPI2 was added
gene: WIPI2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPI2 were set to 30968111; 34557665
Phenotypes for gene: WIPI2 were set to WIPI2-related neurodevelopmental disorder with white matter loss and hypoplasia of vermis and corpus callosum; OMIM:618453.0; MONDO:0032759
DDG2P v6.16 WDR83OS Achchuthan Shanmugasundram gene: WDR83OS was added
gene: WDR83OS was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 39471804; 30250217
Phenotypes for gene: WDR83OS were set to MONDO:0975877; WDR83OS-related neurodevelopmental disorder with hypercholanemia
DDG2P v6.16 WDR44 Achchuthan Shanmugasundram gene: WDR44 was added
gene: WDR44 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
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 38191484
Phenotypes for gene: WDR44 were set to MONDO:0005308; WDR44-related ciliopathy
Mode of pathogenicity for gene: WDR44 was set to Other
DDG2P v6.16 WBP4 Achchuthan Shanmugasundram gene: WBP4 was added
gene: WBP4 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WBP4 were set to 37963460
Phenotypes for gene: WBP4 were set to MONDO:0971043; WBP4-related neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities
DDG2P v6.16 UNC79 Achchuthan Shanmugasundram gene: UNC79 was added
gene: UNC79 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UNC79 were set to 37183800
Phenotypes for gene: UNC79 were set to UNC79-related intellectual disability with focal motor seizures
DDG2P v6.16 UNC13A Achchuthan Shanmugasundram gene: UNC13A was added
gene: UNC13A was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: UNC13A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UNC13A were set to 41125872; 27648472; 28192369; 36447687
Phenotypes for gene: UNC13A were set to UNC13A-related congenital epileptic encephalopathy and severe neuromuscular disorder; MONDO:0100038; UNC13A-related neurodevelopmental disorder with ataxia and tremor or dyskinetic movements
DDG2P v6.16 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment; MONDO:0015286
DDG2P v6.16 UBR5 Achchuthan Shanmugasundram gene: UBR5 was added
gene: UBR5 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to UBR5-related neurodevelopmental disorder; MONDO:0700092
DDG2P v6.16 TRIM71 Achchuthan Shanmugasundram gene: TRIM71 was added
gene: TRIM71 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TRIM71 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRIM71 were set to 38833623
Phenotypes for gene: TRIM71 were set to TRIM71-related neurodevelopmental disorder with ventriculomegaly and hydrocephalus; MONDO:0032862; OMIM:618667.0
DDG2P v6.16 TRAPPC6B Achchuthan Shanmugasundram gene: TRAPPC6B was added
gene: TRAPPC6B was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 31687267; 40350395; 37713627; 28626029
Phenotypes for gene: TRAPPC6B were set to TRAPPC6B-related neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy; MONDO:0060640; OMIM:617862.0
DDG2P v6.16 TONSL Achchuthan Shanmugasundram gene: TONSL was added
gene: TONSL was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TONSL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TONSL were set to 30773277; 30773278
Phenotypes for gene: TONSL were set to TONSL-related sponastrime dysplasia; MONDO:0010068; OMIM:271510.0
DDG2P v6.16 TMEM184B Achchuthan Shanmugasundram gene: TMEM184B was added
gene: TMEM184B was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 40885185
Phenotypes for gene: TMEM184B were set to TMEM184B-related neurodevelopmental disorder
DDG2P v6.16 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to MONDO:0700092; TM2D3-related neurodevelopmental disorder with microcephaly and congenital malformations
DDG2P v6.16 TIMM22 Achchuthan Shanmugasundram gene: TIMM22 was added
gene: TIMM22 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: TIMM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMM22 were set to 30452684
Phenotypes for gene: TIMM22 were set to TIMM22-related combined oxidative phosphorylation deficiency; OMIM:618851.0
DDG2P v6.16 C14orf80 Achchuthan Shanmugasundram gene: C14orf80 was added
gene: C14orf80 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: C14orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf80 were set to 30842647; 39979680
Phenotypes for gene: C14orf80 were set to TEDC1-related neurodevelopmental disorder with growth impairment, microcephaly, and endocrine abnormalities.
DDG2P v6.16 TAF1C Achchuthan Shanmugasundram gene: TAF1C was added
gene: TAF1C was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 40371665; 32779182
Phenotypes for gene: TAF1C were set to TAF1C-related neurodevelopmental disorder
DDG2P v6.16 SREBF2 Achchuthan Shanmugasundram gene: SREBF2 was added
gene: SREBF2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SREBF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SREBF2 were set to 26350204; 38847193
Phenotypes for gene: SREBF2 were set to SREBF2-related complex dermatological, neurological, and skeletal abnormalities
Mode of pathogenicity for gene: SREBF2 was set to Other
DDG2P v6.16 SPTSSA Achchuthan Shanmugasundram gene: SPTSSA was added
gene: SPTSSA was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SPTSSA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to OMIM:620416.0; MONDO:0957308; SPTSSA-related complex hereditary spastic paraplegia
DDG2P v6.16 SP9 Achchuthan Shanmugasundram gene: SP9 was added
gene: SP9 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP9 were set to 38288683
Phenotypes for gene: SP9 were set to MONDO:0100038; SP9-related neurodevelopmental disorder with or without epileptic encephalopathy
DDG2P v6.16 SNUPN Achchuthan Shanmugasundram gene: SNUPN was added
gene: SNUPN was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SNUPN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNUPN were set to 38366623; 38413582
Phenotypes for gene: SNUPN were set to SNUPN-related muscular dystrophy with or without multi-system involvement; MONDO:0971171
DDG2P v6.16 SLIT3 Achchuthan Shanmugasundram gene: SLIT3 was added
gene: SLIT3 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLIT3 were set to 33933663; 29100090
Phenotypes for gene: SLIT3 were set to SLIT3-related congenital anomalies
DDG2P v6.16 SLC39A14 Achchuthan Shanmugasundram gene: SLC39A14 was added
gene: SLC39A14 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SLC39A14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A14 were set to 36247901; 27231142; 36138644
Phenotypes for gene: SLC39A14 were set to MONDO:0014864; OMIM:617013.0; SLC39A14-related early onset dystonia parkinsonism
DDG2P v6.16 SLC25A13 Achchuthan Shanmugasundram gene: SLC25A13 was added
gene: SLC25A13 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SLC25A13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A13 were set to 29152073; 37063661; 40992288; 36599957
Phenotypes for gene: SLC25A13 were set to SLC25A13-related citrullinemia; OMIM:605814.0; MONDO:0011601
DDG2P v6.16 SF1 Achchuthan Shanmugasundram gene: SF1 was added
gene: SF1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SF1 were set to 40987292
Phenotypes for gene: SF1 were set to MONDO:0700092; SF1-related neurodevelopmental disorder
DDG2P v6.16 SEPHS1 Achchuthan Shanmugasundram gene: SEPHS1 was added
gene: SEPHS1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEPHS1 were set to 38531365
Phenotypes for gene: SEPHS1 were set to MONDO:0700092; SEPHS1-related neurodevelopmental disorder
Mode of pathogenicity for gene: SEPHS1 was set to Other
DDG2P v6.16 RYBP Achchuthan Shanmugasundram gene: RYBP was added
gene: RYBP was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RYBP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RYBP were set to 39891528
Phenotypes for gene: RYBP were set to RYBP-related neurodevelopmental disorder with congenital anomalies; MONDO:0100038
DDG2P v6.16 RREB1 Achchuthan Shanmugasundram gene: RREB1 was added
gene: RREB1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RREB1 were set to 38332451; 40418122
Phenotypes for gene: RREB1 were set to RREB1-related RASopathy syndrome with congenital heart disease, genitourinary malformations, and developmental delay
DDG2P v6.16 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to RPS6KC1-related complex neurodevelopmental disorder with spasticity and hypoplasia of corpus callosum; MONDO:0100038
DDG2P v6.16 ROBO1 Achchuthan Shanmugasundram gene: ROBO1 was added
gene: ROBO1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 29194579; 35227688; 30692597; 28286008
Phenotypes for gene: ROBO1 were set to MONDO:0957210; ROBO1-related neurooculorenal syndrome; OMIM:620305.0
DDG2P v6.16 RNU5B-1 Achchuthan Shanmugasundram gene: RNU5B-1 was added
gene: RNU5B-1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5B-1 were set to 40442284; 40379786
Phenotypes for gene: RNU5B-1 were set to RNU5B-1-related neurodevelopmental disorder with abnormal brain imaging and congenital anomalies
DDG2P v6.16 RNU2-2P Achchuthan Shanmugasundram gene: RNU2-2P was added
gene: RNU2-2P was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU2-2P were set to 40442284; 40210679
Phenotypes for gene: RNU2-2P were set to RNU2-2-related neurodevelopmental disorder with seizures and hyperventilation; MONDO:0100038
DDG2P v6.16 RICTOR Achchuthan Shanmugasundram gene: RICTOR was added
gene: RICTOR was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: RICTOR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RICTOR were set to 39738822
Phenotypes for gene: RICTOR were set to RICTOR-related neurodevelopmental disorder
Mode of pathogenicity for gene: RICTOR was set to Other
DDG2P v6.16 RFX7 Achchuthan Shanmugasundram gene: RFX7 was added
gene: RFX7 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RFX7 were set to 39007708; 25961944; 25363760; 33584783; 33658631; 36334883
Phenotypes for gene: RFX7 were set to RFX7-related neurodevelopmental disorder with autism and other behavioural abnormalities; MONDO:0957228; OMIM:620330.0
DDG2P v6.16 RFX4 Achchuthan Shanmugasundram gene: RFX4 was added
gene: RFX4 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RFX4 were set to 33658631; 25961944
Phenotypes for gene: RFX4 were set to MONDO:0100038; RFX4-related neurodevelopmental disorder with autism and other behavioural abnormalities
DDG2P v6.16 RFX3 Achchuthan Shanmugasundram gene: RFX3 was added
gene: RFX3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RFX3 were set to 27525107; 37717291; 33658631; 21792059; 35982159; 25844147; 31981491
Phenotypes for gene: RFX3 were set to RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities; MONDO:0100038
DDG2P v6.16 RCC1 Achchuthan Shanmugasundram gene: RCC1 was added
gene: RCC1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RCC1 were set to 40683276
Phenotypes for gene: RCC1 were set to RCC1-related infection-induced acute-onset axonal neuropathy with cerebral and cerebellar atrophy
DDG2P v6.16 RBCK1 Achchuthan Shanmugasundram gene: RBCK1 was added
gene: RBCK1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RBCK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBCK1 were set to 35017290; 38077957; 38329383; 38588043; 38922716; 32187699; 23798481
Phenotypes for gene: RBCK1 were set to RBCK1-related polyglucosan body cardiac and skeletal myopathy with or without immunodeficiency; MONDO:0014389; OMIM:615895.0
DDG2P v6.16 RAB5C Achchuthan Shanmugasundram gene: RAB5C was added
gene: RAB5C was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAB5C were set to 37552066
Phenotypes for gene: RAB5C were set to RAB5C-related neurodevelopmental disorder
Mode of pathogenicity for gene: RAB5C was set to Other
DDG2P v6.16 PSMD11 Achchuthan Shanmugasundram gene: PSMD11 was added
gene: PSMD11 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: PSMD11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSMD11 were set to 38866022
Phenotypes for gene: PSMD11 were set to PSMD11-related neurodevelopmental disorder with or without obesity
DDG2P v6.16 PPP2R5C Achchuthan Shanmugasundram gene: PPP2R5C was added
gene: PPP2R5C was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R5C were set to 39978342
Phenotypes for gene: PPP2R5C were set to PPP2R5C-related neurodevelopmental disorder with macrocephaly and hypotonia, with or without seizures; MONDO:0100038
Mode of pathogenicity for gene: PPP2R5C was set to Other
DDG2P v6.16 PPP2R2B Achchuthan Shanmugasundram gene: PPP2R2B was added
gene: PPP2R2B was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: PPP2R2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R2B were set to 25356899; 39565297
Phenotypes for gene: PPP2R2B were set to PPP2R2B-related neurodevelopmental disorder
DDG2P v6.16 PPP1R3F Achchuthan Shanmugasundram gene: PPP1R3F was added
gene: PPP1R3F was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to PPP1R3F-related neurodevelopmental disorder
DDG2P v6.16 POP1 Achchuthan Shanmugasundram gene: POP1 was added
gene: POP1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: POP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POP1 were set to 32134183; 28067412; 21455487; 38351533; 27380734
Phenotypes for gene: POP1 were set to OMIM:617396.0; MONDO:0054561; POP1-related anauxetic dysplasia
DDG2P v6.16 PLXNB2 Achchuthan Shanmugasundram gene: PLXNB2 was added
gene: PLXNB2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to 38458752
Phenotypes for gene: PLXNB2 were set to PLXNB2-related hearing loss, amelogenesis imperfecta and intellectual disability
DDG2P v6.16 PLD1 Achchuthan Shanmugasundram gene: PLD1 was added
gene: PLD1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD1 were set to 39553471; 27799408; 33645542; 39681445; 37770978
Phenotypes for gene: PLD1 were set to MONDO:0008913; OMIM:212093.0; PLD1-related cardiac valvular dysplasia
DDG2P v6.16 PKDCC Achchuthan Shanmugasundram gene: PKDCC was added
gene: PKDCC was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to 38860479; 37592254; 30478137; 36896672
Phenotypes for gene: PKDCC were set to MONDO:0032935; PKDCC-related rhizomelic limb shortening with dysmorphic features and short stature; OMIM:618821.0
DDG2P v6.16 PISD Achchuthan Shanmugasundram gene: PISD was added
gene: PISD was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 38801004; 31263216; 30858161; 30488656
Phenotypes for gene: PISD were set to OMIM:618889.0; MONDO:0030045; PISD-related spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function
DDG2P v6.16 PHF12 Achchuthan Shanmugasundram gene: PHF12 was added
gene: PHF12 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PHF12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PHF12 were set to MONDO:0700092; PHF12-related developmental disorder
DDG2P v6.16 PHEX Achchuthan Shanmugasundram gene: PHEX was added
gene: PHEX was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PHEX 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: PHEX were set to 2894375; 18252791; 15029877; 39877728; 39710377; 16055933; 34633109; 32329911; 38722819; 35896147; 37059315
Phenotypes for gene: PHEX were set to MONDO:0010619; PHEX-related hypophosphatemic rickets; OMIM:307800.0
DDG2P v6.16 PARS2 Achchuthan Shanmugasundram gene: PARS2 was added
gene: PARS2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PARS2 were set to 29410512; 32514400; 28077841; 39253392; 37956963; 38469956; 25629079; 29915213; 38087948
Phenotypes for gene: PARS2 were set to MONDO:0032752; PARS2-related developmental and epileptic encephalopathy with or without cardiomyopathy; OMIM:618437.0
DDG2P v6.16 PACSIN3 Achchuthan Shanmugasundram gene: PACSIN3 was added
gene: PACSIN3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: PACSIN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PACSIN3 were set to 29202928; 38637313
Phenotypes for gene: PACSIN3 were set to PACSIN3-related childhood-onset myopathy with hyperCKaemia
DDG2P v6.16 NUP188 Achchuthan Shanmugasundram gene: NUP188 was added
gene: NUP188 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 32275884
Phenotypes for gene: NUP188 were set to OMIM:618804.0; NUP188-related neurodegeneration, cataracts and facial dysmorphisms; MONDO:0032926
DDG2P v6.16 NUDCD2 Achchuthan Shanmugasundram gene: NUDCD2 was added
gene: NUDCD2 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD2 were set to 37272762
Phenotypes for gene: NUDCD2 were set to NUDCD2-related brain and cardiac malformations with cholestasis and renal failure
DDG2P v6.16 NSUN6 Achchuthan Shanmugasundram gene: NSUN6 was added
gene: NSUN6 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
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 NSUN6-related neurodevelopmental disorder
DDG2P v6.16 MMS19 Achchuthan Shanmugasundram gene: MMS19 was added
gene: MMS19 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMS19 were set to 38411040
Phenotypes for gene: MMS19 were set to MMS19-related dihydropyrimidine dehydrogenase deficiency
DDG2P v6.16 MIR140 Achchuthan Shanmugasundram gene: MIR140 was added
gene: MIR140 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: MIR140 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR140 were set to 30804514
Phenotypes for gene: MIR140 were set to MONDO:0032835; MIR140-related spondyloepiphyseal dysplasia, Nishimura type
Mode of pathogenicity for gene: MIR140 was set to Other
DDG2P v6.16 MARK4 Achchuthan Shanmugasundram gene: MARK4 was added
gene: MARK4 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: MARK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MARK4 were set to 38041405
Phenotypes for gene: MARK4 were set to MONDO:0700092; MARK4-related neurodevelopmental disorder
Mode of pathogenicity for gene: MARK4 was set to Other
DDG2P v6.16 MAP3K20 Achchuthan Shanmugasundram gene: MAP3K20 was added
gene: MAP3K20 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: MAP3K20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAP3K20 were set to 26755636; 32021595; 38451290; 27816943
Phenotypes for gene: MAP3K20 were set to MONDO:0054695; MAP3K20-related ectodermal dysplasia with craniosynostosis, sensorineural hearing loss, and limb anomalies; OMIM:617760.0; MAP3K20-related centronuclear myopathy; OMIM:616890.0; MAP3K20-related split-foot malformation with mesoaxial polydactyly; MONDO:0014816
DDG2P v6.16 KNL1 Achchuthan Shanmugasundram gene: KNL1 was added
gene: KNL1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: KNL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KNL1 were set to 26621532; 37937525; 27149178; 26626498; 27784895; 22983954
Phenotypes for gene: KNL1 were set to MONDO:0011437; KNL1-related primary microcephaly; OMIM:604321.0
DDG2P v6.16 KCNB2 Achchuthan Shanmugasundram gene: KCNB2 was added
gene: KCNB2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to KCNB2-related neurodevelopmental disorder
DDG2P v6.16 HMGA2 Achchuthan Shanmugasundram gene: HMGA2 was added
gene: HMGA2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: HMGA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HMGA2 were set to 21803798; 38516887; 38840187; 32421827; 29655892; 25809938
Phenotypes for gene: HMGA2 were set to MONDO:0020795; HMGA2-related Silver-Russell-like syndrome
DDG2P v6.16 HEATR5B Achchuthan Shanmugasundram gene: HEATR5B was added
gene: HEATR5B was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 38622473; 33824466
Phenotypes for gene: HEATR5B were set to HEATR5B-related pontocerebellar hypoplasia
DDG2P v6.16 GTF3C5 Achchuthan Shanmugasundram gene: GTF3C5 was added
gene: GTF3C5 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C5 were set to 38520561
Phenotypes for gene: GTF3C5 were set to GTF3C5-related neurodevelopmental disorder with growth restriction, skeletal anomalies, cerebellar hypoplasia and hearing loss; MONDO:0100038
DDG2P v6.16 GTF3C3 Achchuthan Shanmugasundram gene: GTF3C3 was added
gene: GTF3C3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: GTF3C3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C3 were set to 39636576
Phenotypes for gene: GTF3C3 were set to GTF3C3-related neurodevelopmental disorder with hypoplasia of corpus callosum and/or cerebellar atrophy; MONDO:0100038
DDG2P v6.16 GSC Achchuthan Shanmugasundram gene: GSC was added
gene: GSC was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: GSC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSC were set to 24290375
Phenotypes for gene: GSC were set to MONDO:0011227; OMIM:602471.0; GSC-related short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS)
DDG2P v6.16 GABRA4 Achchuthan Shanmugasundram gene: GABRA4 was added
gene: GABRA4 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: GABRA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA4 were set to 38565639
Phenotypes for gene: GABRA4 were set to GABRA4-related neurodevelopmental disorder with seizures; MONDO:0100038
Mode of pathogenicity for gene: GABRA4 was set to Other
DDG2P v6.16 FRYL Achchuthan Shanmugasundram gene: FRYL was added
gene: FRYL was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities
DDG2P v6.16 FEZF2 Achchuthan Shanmugasundram gene: FEZF2 was added
gene: FEZF2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: FEZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEZF2 were set to 38425142
Phenotypes for gene: FEZF2 were set to FEZF2-related neurodevelopmental disorder
DDG2P v6.16 FASTKD5 Achchuthan Shanmugasundram gene: FASTKD5 was added
gene: FASTKD5 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: FASTKD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FASTKD5 were set to 40499538
Phenotypes for gene: FASTKD5 were set to MONDO:0009723; FASTKD5-related Leigh syndrome
DDG2P v6.16 FAM177A1 Achchuthan Shanmugasundram gene: FAM177A1 was added
gene: FAM177A1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM177A1 were set to 38767059; 25558065
Phenotypes for gene: FAM177A1 were set to FAM177A1-related neurodevelopmental disorder with macrocephaly; MONDO:0100038
DDG2P v6.16 EIF3B Achchuthan Shanmugasundram gene: EIF3B was added
gene: EIF3B was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: EIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EIF3B were set to 41033306
Phenotypes for gene: EIF3B were set to EIF3B-related neurodevelopmental disorder with cardiac anomalies and craniofacial dysmorphism
DDG2P v6.16 EIF3A Achchuthan Shanmugasundram gene: EIF3A was added
gene: EIF3A was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: EIF3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EIF3A were set to 41033306
Phenotypes for gene: EIF3A were set to EIF3A-related neurodevelopmental disorder with cardiac anomalies and craniofacial dysmorphism; MONDO:0100038
DDG2P v6.16 EFL1 Achchuthan Shanmugasundram gene: EFL1 was added
gene: EFL1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFL1 were set to 31151987; 29970384; 28331068
Phenotypes for gene: EFL1 were set to MONDO:0044205; OMIM:617941.0; EFL1-related Shwachman-Diamond syndrome
DDG2P v6.16 DRG1 Achchuthan Shanmugasundram gene: DRG1 was added
gene: DRG1 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: DRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DRG1 were set to 37179472
Phenotypes for gene: DRG1 were set to MONDO:0957990; OMIM:620641.0; DRG1-related neurodevelopmental disorder with microcephaly and dysmorphic facial features (Tan-Almurshedi syndrome)
DDG2P v6.16 DOCK4 Achchuthan Shanmugasundram gene: DOCK4 was added
gene: DOCK4 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DOCK4 were set to 38526744
Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder
DDG2P v6.16 DOCK3 Achchuthan Shanmugasundram gene: DOCK3 was added
gene: DOCK3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: DOCK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK3 were set to 29130632; 30976111; 28195318; 40151040
Phenotypes for gene: DOCK3 were set to DOCK3-related neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia; MONDO:0032661; OMIM:618292.0
DDG2P v6.16 DOCK2 Achchuthan Shanmugasundram gene: DOCK2 was added
gene: DOCK2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: DOCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK2 were set to 34872585; 26083206; 36541113; 30838481; 33928462
Phenotypes for gene: DOCK2 were set to OMIM:616433.0; MONDO:0014637; DOCK2-related severe combined immunodeficiency
DDG2P v6.16 DDX17 Achchuthan Shanmugasundram gene: DDX17 was added
gene: DDX17 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDX17 were set to 39405200
Phenotypes for gene: DDX17 were set to MONDO:0700092; DDX17-related neurodevelopmental disorder
DDG2P v6.16 CLDND1 Achchuthan Shanmugasundram gene: CLDND1 was added
gene: CLDND1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: CLDND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLDND1 were set to 38493358
Phenotypes for gene: CLDND1 were set to CLDND1-related leukodystrophy
DDG2P v6.16 CIAO1 Achchuthan Shanmugasundram gene: CIAO1 was added
gene: CIAO1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIAO1 were set to 38950322; 38411040
Phenotypes for gene: CIAO1 were set to CIAO1-related neuromuscular disorder with intellectual disability; MONDO:0975806
DDG2P v6.16 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 38429302
Phenotypes for gene: CELSR3 were set to CELSR3-related neurodevelopmental disorder with or without urinary tract abnormalities; MONDO:0100038
DDG2P v6.16 CELF4 Achchuthan Shanmugasundram gene: CELF4 was added
gene: CELF4 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to CELF4-related neurodevelopmental disorder with overgrowth
DDG2P v6.16 CDO1 Achchuthan Shanmugasundram gene: CDO1 was added
gene: CDO1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: CDO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDO1 were set to 39949058
Phenotypes for gene: CDO1 were set to CDO1-related neurodevelopmental disorder
DDG2P v6.16 CAPN15 Achchuthan Shanmugasundram gene: CAPN15 was added
gene: CAPN15 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 32885237; 33410501; 40485323; 36786328; 37596828
Phenotypes for gene: CAPN15 were set to OMIM:619318.0; MONDO:0036189; CAPN15-related oculogastrointestinal neurodevelopmental syndrome
DDG2P v6.16 ATXN7L3 Achchuthan Shanmugasundram gene: ATXN7L3 was added
gene: ATXN7L3 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATXN7L3 were set to 38753057
Phenotypes for gene: ATXN7L3 were set to ATXN7L3-related developmental delay, hypotonia and facial dysmorphism
DDG2P v6.16 ADAMTS19 Achchuthan Shanmugasundram gene: ADAMTS19 was added
gene: ADAMTS19 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 32323311; 31844321
Phenotypes for gene: ADAMTS19 were set to OMIM:620067.0; MONDO:0859572; ADAMTS19-related cardiac valvular dysplasia
DDG2P v6.16 ADAMTS15 Achchuthan Shanmugasundram gene: ADAMTS15 was added
gene: ADAMTS15 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to 35962790
Phenotypes for gene: ADAMTS15 were set to MONDO:0957819; ADAMTS15-related distal arthrogryposis; OMIM:620545.0
DDG2P v6.16 ABCA2 Achchuthan Shanmugasundram gene: ABCA2 was added
gene: ABCA2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31231135; 38228874; 31047799
Phenotypes for gene: ABCA2 were set to OMIM:618808.0; MONDO:0032930; ABCA2-related intellectual developmental disorder with poor growth and with or without seizures or ataxia
DDG2P v6.16 UROC1 Achchuthan Shanmugasundram Source Expert Review Red was added to UROC1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 TTC12 Achchuthan Shanmugasundram Source Expert Review Green was added to TTC12.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 TRIT1 Achchuthan Shanmugasundram Source Expert Review Red was added to TRIT1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 TERT Achchuthan Shanmugasundram Mode of inheritance for gene TERT was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.16 SLC13A1 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC13A1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 SHOX Achchuthan Shanmugasundram Mode of inheritance for gene SHOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v6.16 SCN1B Achchuthan Shanmugasundram Mode of inheritance for gene SCN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.16 RTEL1 Achchuthan Shanmugasundram Mode of inheritance for gene RTEL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.16 PIK3R1 Achchuthan Shanmugasundram Mode of inheritance for gene PIK3R1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v6.16 NRXN2 Achchuthan Shanmugasundram Source Expert Review Red was added to NRXN2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 MYH10 Achchuthan Shanmugasundram Mode of pathogenicity for gene MYH10 was changed from to Other
DDG2P v6.16 MIR184 Achchuthan Shanmugasundram Source Expert Review Green was added to MIR184.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 LRPAP1 Achchuthan Shanmugasundram Source Expert Review Green was added to LRPAP1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 KCTD1 Achchuthan Shanmugasundram Source Expert Review Red was added to KCTD1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 ITGA6 Achchuthan Shanmugasundram Mode of inheritance for gene ITGA6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.16 INPP4A Achchuthan Shanmugasundram Source Expert Review Green was added to INPP4A.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 HK1 Achchuthan Shanmugasundram Mode of pathogenicity for gene HK1 was changed from to Other
DDG2P v6.16 GSPT2 Achchuthan Shanmugasundram Source Expert Review Red was added to GSPT2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 GIGYF1 Achchuthan Shanmugasundram Source Expert Review Red was added to GIGYF1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 FRMD7 Achchuthan Shanmugasundram Source Expert Review Green was added to FRMD7.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 FGF13 Achchuthan Shanmugasundram Mode of inheritance for gene FGF13 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v6.16 EDNRB Achchuthan Shanmugasundram Mode of inheritance for gene EDNRB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.16 DNA2 Achchuthan Shanmugasundram Source Expert Review Red was added to DNA2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
DDG2P v6.16 CUX1 Achchuthan Shanmugasundram Source Expert Review Green was added to CUX1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 CRYBA4 Achchuthan Shanmugasundram Source Expert Review Green was added to CRYBA4.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 COL9A3 Achchuthan Shanmugasundram Mode of inheritance for gene COL9A3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v6.16 CHRNA2 Achchuthan Shanmugasundram Source Expert Review Green was added to CHRNA2.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 AP1B1 Achchuthan Shanmugasundram Source Expert Review Green was added to AP1B1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 AFG3L2 Achchuthan Shanmugasundram Source Expert Review Green was added to AFG3L2.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 ACBD6 Achchuthan Shanmugasundram Source Expert Review Green was added to ACBD6.
Rating Changed from Red List (low evidence) to Green List (high evidence)
DDG2P v6.16 ABCC9 Achchuthan Shanmugasundram Mode of inheritance for gene ABCC9 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Polycystic liver disease v1.32 PKHD1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PKHD1.
Polycystic liver disease v1.32 PKHD1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: PKHD1.
Tag Q1_26_NHS_review tag was added to gene: PKHD1.
Polycystic liver disease v1.32 PKHD1 Ida Ertmanska reviewed gene: PKHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 4, with or without hepatic disease, OMIM:263200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.51 POLD1 Ida Ertmanska reviewed gene: POLD1: Rating: RED; Mode of pathogenicity: None; Publications: 31944473; Phenotypes: hearing loss disorder, MONDO:0005365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.23 MSX1 Ida Ertmanska Phenotypes for gene: MSX1 were changed from Ectodermal dysplasia 3, Witkop type, OMIM:189500 to Ectodermal dysplasia 3, Witkop type, OMIM:189500; Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600
Ectodermal dysplasia v4.22 MSX1 Ida Ertmanska Publications for gene: MSX1 were set to 24031111; 11369996
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: MSX1.
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska commented on gene: MSX1: Comment on mode of inheritance: There are 3 unrelated pedigrees reported in literature where affected individuals presented with tooth agenesis and/or nail dysplasia, harbouring biallelic variants in MSX1. However, the c*6C>T variant (present in 2/3 cases) is too common to cause a Mendelian disorder. In addition, all 3 studies used direct MSX1 sequencing. As such, the influence of other genes cannot be excluded. Due to scarce and conflicting evidence for recessive Ectodermal dysplasia, the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS:
PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).

ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).; to: BIALLELIC CASE REPORTS:
PMID: 25565750 Ceyhan et al., 2014
Report of Turkish cases with non-syndromic tooth agenesis and other dental anomalies: 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).

ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).
ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).; to: BIALLELIC CASE REPORTS:
PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).

ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).; to: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).
ClinGen Expert Panels have classified the link between MSX1 and AD tooth agenesis, selective, 1 as Definitive (Feb 2024), but AD tooth and nail syndrome has been classified as Disputed (Oct 2023).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).; to: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).
Only MSX1 was sequenced in all patients.

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected. Analysed two coding exons, exon-intron boundaries, and part of 3’-UTR of MSX1 only.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies. Method: linkage analysis in the pedigree followed by direct MSX1 sequencing.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia. Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).; to: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia (Witkop syndrome). Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska edited their review of gene: MSX1: Changed publications to: 16932841, 24031111, 25565750; Changed phenotypes to: Ectodermal dysplasia 3, Witkop type, OMIM:189500, Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska changed review comment from: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia. Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies.; to: PMID: 25565750 Ceyhan et al., 2014
Report of 5 heterozygotes and 1 homozygote; MSX1 variants reported: c.119C>G, p.Ala40Gly; c.347C>T, p.(Gly116Gly); c.463C>A, p.(Pro155Glu); c.95C>T, p.(Ala32Val); c*6C>T (3' UTR region, homozygous).
c*6C>T is common in population (MAF = 0.3962 in gnomAD, with total of 41187 homozygotes reported).

PMID: 24031111 Ghaderi et al., 2013
Case report - 2.5-year-old boy with early exfoliation of the primary canine, absence of the primary incisors, and nail dysplasia. Homozygous mutation was identified in 3'-UTR of MSX1 of proband (*6C>T), het parents unaffected.

PMID: 16932841 Chishti et al., 2006
2 distantly related Pakistani pedigrees with recessive mutation p.Ala219Thr (?), segregating with oligodontia and other dental anomalies.

MSX1 is associated with 3 autosomal dominant disease entities in OMIM: Ectodermal dysplasia 3, Witkop type, 189500; Orofacial cleft 5, 608874; Tooth agenesis, selective, 1, with or without orofacial cleft, 106600 (OMIM accessed 12th Feb 2026).
Ectodermal dysplasia v4.21 MSX1 Ida Ertmanska reviewed gene: MSX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Neonatal diabetes v5.17 PAX4 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Amy Cann, there are 2 unrelated individuals reported in literature with biallelic PAX4 LoF variants and transient neonatal diabetes. Other reports link variants in PAX4 to Maturity-onset diabetes of the young type 9 (onset in adulthood). The association between PAX4 and monogenic diabetes has been classified as REFUTED by ClinGen. Based on available evidence, this gene can only be rated Amber for Neonatal diabetes, until more evidence emerges.; to: Comment on list classification: As reviewed by Amy Cann, there are 2 unrelated individuals reported in literature with biallelic PAX4 LoF variants and transient neonatal diabetes. Other reports link heterozygous variants in PAX4 to Maturity-onset diabetes of the young type 9 (onset in adulthood). The association between PAX4 and monogenic diabetes has been classified as REFUTED by ClinGen. Based on available evidence, this gene can only be rated Amber for Neonatal diabetes, until more evidence emerges.
Neonatal diabetes v5.17 PAX4 Ida Ertmanska Phenotypes for gene: PAX4 were changed from neonatal diabetes; learning disorder; small for gestational age to Diabetes mellitus, type 2, OMIM:125853; type 2 diabetes mellitus,MONDO:0005148
Neonatal diabetes v5.16 PAX4 Ida Ertmanska Publications for gene: PAX4 were set to PMID: 40614820
Neonatal diabetes v5.15 PAX4 Ida Ertmanska edited their review of gene: PAX4: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v5.15 PAX4 Ida Ertmanska Classified gene: PAX4 as Amber List (moderate evidence)
Neonatal diabetes v5.15 PAX4 Ida Ertmanska Gene: pax4 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.14 PAX4 Ida Ertmanska commented on gene: PAX4: Comment on list classification: As reviewed by Amy Cann, there are 2 unrelated individuals reported in literature with biallelic PAX4 LoF variants and transient neonatal diabetes. Other reports link variants in PAX4 to Maturity-onset diabetes of the young type 9 (onset in adulthood). The association between PAX4 and monogenic diabetes has been classified as REFUTED by ClinGen. Based on available evidence, this gene can only be rated Amber for Neonatal diabetes, until more evidence emerges.
Neonatal diabetes v5.14 PAX4 Ida Ertmanska reviewed gene: PAX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 11723072, 25951767, 36595822, 40614820, 41475885; Phenotypes: Diabetes mellitus, type 2, OMIM:125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.7 ISCA-37401-Loss Achchuthan Shanmugasundram commented on Region: ISCA-37401-Loss: This region has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Optic neuropathy v5.44 SPG7 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: SPG7.
Optic neuropathy v5.44 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748; recurring variants are too common in the population to be associated with dominant disease). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; to: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748; recurring variants are too common in the population to be associated with dominant disease). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update. Expert review will be requested regarding the monoallelic cases.
Intellectual disability v9.259 SLITRK2 Ida Ertmanska Phenotypes for gene: SLITRK2 were changed from to Intellectual developmental disorder, X-linked 111, OMIM:301107; intellectual developmental disorder, X-linked 111, MONDO:0957203
Intellectual disability v9.258 SLITRK2 Ida Ertmanska Publications for gene: SLITRK2 were set to PMID: 35840571
Intellectual disability v9.257 SLITRK2 Ida Ertmanska Classified gene: SLITRK2 as Amber List (moderate evidence)
Intellectual disability v9.257 SLITRK2 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated individuals reported in literature with monoallelic variants in SLITRK2 and intellectual developmental disorder (7/8 are males). Several male patients inherited variants from unaffected heterozygous mothers. However, there is one heterozygous female reported with a de novo variants and a severe phenotype (severe ID, absent speech, seizures - PMID: 35840571). Thus, the MOI should be set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Intellectual disability v9.257 SLITRK2 Ida Ertmanska Gene: slitrk2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.256 SLITRK2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: SLITRK2.
Tag Q1_26_NHS_review tag was added to gene: SLITRK2.
Intellectual disability v9.256 SLITRK2 Ida Ertmanska edited their review of gene: SLITRK2: Changed publications to: 35840571, 38283150
Intellectual disability v9.256 SLITRK2 Ida Ertmanska reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35840571; Phenotypes: Intellectual developmental disorder, X-linked 111, OMIM:301107, intellectual developmental disorder, X-linked 111, MONDO:0957203; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v9.256 PHF12 Ida Ertmanska Phenotypes for gene: PHF12 were changed from to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.255 PHF12 Ida Ertmanska Publications for gene: PHF12 were set to
Intellectual disability v9.254 PHF12 Ida Ertmanska Classified gene: PHF12 as Amber List (moderate evidence)
Intellectual disability v9.254 PHF12 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature in large cohort studies of intellectual disability, ASD, and developmental disorders patients, harbouring heterozygous de novo variants in PHF12. The association between PHF12 and a complex neurodevelopmental disorder was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Based on available evidence this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.254 PHF12 Ida Ertmanska Gene: phf12 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.253 PHF12 Ida Ertmanska Tag Q1_26_NHS_review tag was added to gene: PHF12.
Intellectual disability v9.253 PHF12 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: PHF12.
Intellectual disability v9.253 PHF12 Ida Ertmanska changed review comment from: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.; to: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

Functional evidence:
PMID: 27956701 Graveline et al., 2017 - Phf12 (Pf1) -/- mouse embryos had global growth retardation and impaired development of skeleton, associated skeletal muscle, and brain. They died mid- to late-gestation due to developmental defects including edema and internal hemorrhage. Heterozygous Pf1+/- mice developed normally.

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.
Intellectual disability v9.253 PHF12 Ida Ertmanska changed review comment from: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.; to: The below publication information is taken from ClinGen evidence summary: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_329aa190-d20e-4f6b-9c85-58242a8a2d33-2025-02-19T110000.000Z?page=1&size=25&search=

Lelieveld SH, et al., 2016, PMID: 27479843
Cohort (Radboud University Medical Center) with unexplained intellectual disability, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.425C>A (p.Ser142Ter).

Deciphering Developmental Disorders Study, 2017, PMID: 28135719
DDD Study cohort with severe undiagnosed developmental disorders, no detailed clinical information available. Exome seq revealed de novo heterozygous NM_001033561.2(PHF12):c.2645del (p.Pro882GlnfsTer30).

C Yuen RK, et al., 2017, PMID: 28263302
ASD cohort (MSSNG), no detailed clinical information available. Method: Whole genome shotgun sequencing. Het for de novo NM_001033561.2(PHF12):c.1091dup (p.Asn365Ter).

Kaplanis J, et al., 2020, PMID: 33057194
31,058 parent-offspring trios of individuals with developmental disorders.
Cohort (GeneDx) with developmental disorders, no detailed clinical information available: GDX 15850 het for de novo NM_001033561.2(PHF12):c.2360-1G>A
DDD Study cohort: DDD13k.08251 - het for de novo NM_001033561.2(PHF12):c.1970C>G (p.Ser657Ter)
DDD Study cohort: DDD13k.05315 - het for de novo NM_001033561.2(PHF12):c.862C>T (p.Gln288Ter)
Cohort (Radboud University Medical Center) with unexplained intellectual disability: de novo heterozygous NM_001033561.2(PHF12):c.2542-2A>C

PHF12 is not yet linked to a disease entity in OMIM (accessed 10th Feb 2026). The gene-disease association between PHF12 and AD complex neurodevelopmental disorder (MONDO:0100038) was classified as Definitive by the Intellectual Disability and Autism ClinGen Expert Panel (Feb 2025). Gene2Phenotype rated its association with PHF12-related developmental disorder as Strong.
Intellectual disability v9.253 PHF12 Ida Ertmanska reviewed gene: PHF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479843, 28135719, 28263302, 33057194; Phenotypes: complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.253 RSF1 Ida Ertmanska Phenotypes for gene: RSF1 were changed from Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.252 RSF1 Ida Ertmanska changed review comment from: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is linked to AD Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM:620489 in OMIM (accessed 10th Feb 2026). It is not yet listed in ClinGen or Gene2Phenotype.
Sources: Literature; to: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is not yet linked to disease in OMIM, ClinGen or Gene2Phenotype (resources accessed 10th Feb 2026).
Sources: Literature
Intellectual disability v9.252 RSF1 Ida Ertmanska edited their review of gene: RSF1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.252 RSF1 Ida Ertmanska Classified gene: RSF1 as Amber List (moderate evidence)
Intellectual disability v9.252 RSF1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 individuals reported in literature with heterozygous RSF1 variants and syndromic intellectual disability / developmental delay. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.252 RSF1 Ida Ertmanska Gene: rsf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.251 RSF1 Ida Ertmanska gene: RSF1 was added
gene: RSF1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: RSF1.
Mode of inheritance for gene: RSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RSF1 were set to 41606215
Phenotypes for gene: RSF1 were set to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489
Review for gene: RSF1 was set to GREEN
Added comment: PMID: 41606215 Jost et al., 2026
Report of 11 unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1 (only 7 with detailed information). All individuals had an NDD: intellectual disability, autism spectrum disorder or developmental delay. Seq method: Exome seq / Genome Seq. 6 variants de novo, one inherited from mosaic mother. Phenotypic spectrum: ID 4/7 (3 mild and 1 moderate-severe), educational difficulties 7/7, seizures 2/7, ASD 3/7, extremities anomalies 4/7, variable skin defects 5/7, variable ophthalmological anomalies 3/7, and other.

RSF1 is linked to AD Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM:620489 in OMIM (accessed 10th Feb 2026). It is not yet listed in ClinGen or Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.58 JKAMP Ida Ertmanska Deleted their review
Malformations of cortical development v7.21 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
Malformations of cortical development v7.21 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.20 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
Malformations of cortical development v7.20 JKAMP Ida Ertmanska commented on gene: JKAMP: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. MRI findings were abnormal in 12/14 subjects, including cortical and or cerebral atrophy (11/14) and delayed myelination (6/14). Based on available evidence, JKAMP should be promoted to Green for Ataxia and cerebellar anomalies - narrow panel.
Malformations of cortical development v7.20 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.58 JKAMP Ida Ertmanska Classified gene: JKAMP as No list
Ataxia and cerebellar anomalies - narrow panel v8.58 JKAMP Ida Ertmanska Gene: jkamp has been removed from the panel.
Ataxia and cerebellar anomalies - narrow panel v8.57 JKAMP Ida Ertmanska Tag Q1_26_promote_green was removed from gene: JKAMP.
Tag curated_removed tag was added to gene: JKAMP.
Early onset or syndromic epilepsy v8.111 ASTN1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG. Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.; to: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG (PMIDs: 29706646; 41544630). Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.111 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from Intellectual disability; epilepsy; cortical malformations to neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.110 ASTN1 Ida Ertmanska Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Classified gene: ASTN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG. Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Gene: astn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ASTN1.
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska edited their review of gene: ASTN1: Changed rating: GREEN; Changed publications to: 41544630; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska commented on gene: ASTN1
Intellectual disability v9.250 ASTN1 Ida Ertmanska commented on gene: ASTN1: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. All reported individuals presented with developmental delay and/or intellectual disability, with variable severity. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.250 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.249 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from Intellectual disability to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.249 ASTN1 Ida Ertmanska Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Intellectual disability v9.248 ASTN1 Ida Ertmanska Tag watchlist was removed from gene: ASTN1.
Tag Q1_26_promote_green tag was added to gene: ASTN1.
Intellectual disability v9.248 ASTN1 Ida Ertmanska reviewed gene: ASTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41544630; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Distal myopathies v6.16 SPTAN1 Ida Ertmanska Classified gene: SPTAN1 as Amber List (moderate evidence)
Distal myopathies v6.16 SPTAN1 Ida Ertmanska Added comment: Comment on list classification: 14 unrelated families with SPTAN1-related distal myopathy have been reported in literature, harbouring heterozygous LoF variants in SPTAN1. Myopathy of lower limbs was accompanied by gait disturbance and feet abnormalities. Based on available evidence, this gene should be promoted to Green at the next update.
Distal myopathies v6.16 SPTAN1 Ida Ertmanska Gene: sptan1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v6.15 SPTAN1 Ida Ertmanska gene: SPTAN1 was added
gene: SPTAN1 was added to Distal myopathies. Sources: Literature
Q1_26_promote_green tags were added to gene: SPTAN1.
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 40023774; 40999194
Phenotypes for gene: SPTAN1 were set to distal myopathy, MONDO:0018949
Review for gene: SPTAN1 was set to GREEN
Added comment: PMID: 40023774 De Winter et al., 2025
Report of 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). Exome seq detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in 7 patients.

PMID: 40999194 Van de Vondel et al., 2026
Report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene (method: Exome seq). The deletion segregated with disease in 4 individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.
The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 10th Feb 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.57 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.57 JKAMP Ida Ertmanska Added comment: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. MRI findings were abnormal in 12/14 subjects, including cortical and or cerebral atrophy (11/14) and delayed myelination (6/14). Based on available evidence, JKAMP should be promoted to Green for Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.57 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.56 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
Ataxia and cerebellar anomalies - narrow panel v8.56 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Added comment: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. All individuals presented with early-onset, syndromic epilepsy. Based on available evidence, JKAMP should be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.107 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
Intellectual disability v9.248 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
Intellectual disability v9.248 JKAMP Ida Ertmanska Added comment: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. All individuals presented with syndromic developmental delay / regression and intellectual disability. The human phenotype was partially recapitulated by knockout studies in zebrafish. Based on available evidence, JKAMP should be promoted to Green for Intellectual disability at the next update.
Intellectual disability v9.248 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.247 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
Early onset or syndromic epilepsy v8.107 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Intellectual disability v9.247 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Differences in sex development v4.14 TACR3 Rabina Akhtar gene: TACR3 was added
gene: TACR3 was added to Differences in sex development. Sources: Research,Literature
Mode of inheritance for gene: TACR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACR3 were set to PMID: 22031817; 20332248; 40101754
Phenotypes for gene: TACR3 were set to HYPOGONADOTROPIC HYPOGONADISM 11 WITH OR WITHOUT ANOSMIA; HH11 (OMIM: 614840)
Penetrance for gene: TACR3 were set to Complete
Review for gene: TACR3 was set to GREEN
gene: TACR3 was marked as current diagnostic
Added comment: PMID:22031817 reports a 19 year old patient with small testes, micropenis and bilateral cryptorchidism, compound heterozygous TACR3 variant (c.824G>A and c.1003C>T)

PMID: 20332248 reports proband 3 of the study with micropenis and was found to be homozygous for TACR3 c.824G>A p.Trp275* variant

PMID: 40101754 performed a systematic review of the literature (245 publications) to extract clinical data and the association with gene variants from 775 males with delayed or arrested puberty due to CHH. The characteristics of the genitalia in patients with causal variants in the TACR3 was summarized in this paper. A total of 17 disease causing TACR3 variants were identified. Of those, 3 patients had cryptorchidism, 10 patients had micropenis, 2 patients had microorchidism, 3 patients had cryptorchidism and micropenis, and 2 patients had micropenis and microorchidism.

Additional male patient identified at WMGL with cryptorchidism and micropenis with a homozygous likely pathogenic TACR3 c.1057C>T p.(Pro353Ser)
Sources: Research, Literature
Differences in sex development v4.14 FGFR1 Rabina Akhtar gene: FGFR1 was added
gene: FGFR1 was added to Differences in sex development. Sources: Literature,Research
Mode of inheritance for gene: FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGFR1 were set to (PMID: 41108094; 34589657; 32853167)
Phenotypes for gene: FGFR1 were set to Hypogonadotropic hypogonadism 2 with out without anosmia
Penetrance for gene: FGFR1 were set to Complete
Review for gene: FGFR1 was set to GREEN
gene: FGFR1 was marked as current diagnostic
Added comment: PMID:41108094 reports a 14 year old male patient with micropenis, hypoplasia of the testes and angulation of the penis and was found to have a likely pathogenic FGFR1 c.263_264del p.Val88Alafs*22.

PMID:34589657 reports a 7 year old male patient with history of bilateral cryptorchidism and was found to have a pathogenic FGFR1 c.1955A>C p.His652pro.

PMID: 32853167 reports a 16 year old male with micropenis and bilateral cryptorchidism and was found to have a FGFR1 c.1864C>T p.Arg622*

Additional male patient identified at WMGL with bilateral cryptorchidism and micropenis was found to have FGFR1 c.2008G>A p.Glu670Lys
Sources: Literature, Research
Early onset or syndromic epilepsy v8.106 KCNT2 Nicholas Head reviewed gene: KCNT2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.246 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Intellectual disability v9.246 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Monogenic hearing loss v5.51 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Monogenic hearing loss v5.51 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Sensorineural hearing loss; Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Severe microcephaly v8.31 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Severe microcephaly v8.31 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Hereditary neuropathy or pain disorder v7.35 MORC2 Arina Puzriakova Publications for gene: MORC2 were set to
Hereditary neuropathy or pain disorder v7.34 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Hereditary neuropathy or pain disorder v7.34 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Hereditary neuropathy v1.506 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z 616688; Charcot-Marie-Tooth disease, axonal, type 2Z, 616688; axonal Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Hereditary ataxia with onset in adulthood v8.22 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Axonal type CMT disease type 2Z, 616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Ataxia and cerebellar anomalies - narrow panel v8.55 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090
Ataxia and cerebellar anomalies - narrow panel v8.54 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Ataxia and cerebellar anomalies - narrow panel v8.54 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Axonal type CMT disease type 2Z, 616688 to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v9.245 ATP2B1 Arina Puzriakova Publications for gene: ATP2B1 were set to 35358416; 35358416
Intellectual disability v9.244 ATP2B1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ATP2B1.
Paediatric or syndromic cardiomyopathy v7.93 NAA15 Matthew Edwards reviewed gene: NAA15: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.244 ATP2B1 Arina Puzriakova Phenotypes for gene: ATP2B1 were changed from Intellectual developmental disorder, autosomal dominant 66, 619910 to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910
Early onset or syndromic epilepsy v8.106 ATP2B1 Arina Puzriakova Phenotypes for gene: ATP2B1 were changed from Intellectual developmental disorder, autosomal dominant 66, 619910 to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910
Neonatal diabetes v5.14 PAX4 Amy Cann gene: PAX4 was added
gene: PAX4 was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: PAX4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX4 were set to PMID: 40614820
Phenotypes for gene: PAX4 were set to neonatal diabetes; learning disorder; small for gestational age
Penetrance for gene: PAX4 were set to Complete
Mode of pathogenicity for gene: PAX4 was set to Other
Review for gene: PAX4 was set to GREEN
Added comment: Russ-Silsby et al. 2025 (PMID: 40614820) report two homozygous PAX4 loss-of-function variants in two unrelated individuals with neonatal diabetes (NDM) diagnosed aged 6.5 and 9 weeks. In both cases diabetes was transient, remitting in early infancy and relapsing at the ages of 2.4 and 6.7 years. The authors performed genome sequencing on a cohort of 43 consanguineous individuals with NDM, where all the known genetic causes had been previously excluded. The two homozygous PAX4 loss-of-function variants identified were nonsense variant c.376C>T p.(Arg126Ter), and a c.-352_104del deletion affecting the first 4 PAX4 exons. Both variants were predicted to result in complete loss of PAX4 mRNA and the p.(Arg126Ter) variant was confirmed to cause nonsense-mediated decay in CRISPR-edited human induced pluripotent stem cell-derived pancreatic endoderm cells. The parents of the two probands were confirmed to be heterozygous for the respective familial PAX4 variants and did not have diabetes at the time of recruitment. No further recessive PAX4 loss-of-function variants were identified in a replication cohort of 6,087 individuals with suspected monogenic diabetes, including 476 individuals with NDM diagnosed before 6 months, suggesting the loss of PAX4 is a rare cause of monogenic diabetes. The diabetes remission observed in the two patients with complete PAX4 loss, suggests that pancreatic beta cells can develop in the absence of PAX4. However, functional profiling of PAX4 in human beta cell models support its role in the regulation of islet development and glucose-sensitive insulin secretion.
Sources: Literature
Early onset or syndromic epilepsy v8.105 BRSK1 Arina Puzriakova edited their review of gene: BRSK1: Changed rating: GREEN
Congenital hyperinsulinism v3.7 HK1 Ida Ertmanska Publications for gene: HK1 were set to https://doi.org/10.1101/2021.12.03.21267240
Retinal disorders v8.86 MORC2 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.; to: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with syndromic retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.
Retinal disorders v8.86 MORC2 Ida Ertmanska commented on gene: MORC2: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.
Retinal disorders v8.86 MORC2 Ida Ertmanska Phenotypes for gene: MORC2 were changed from Retinal dystrophy to Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Retinal dystrophy, HP:0000556
Retinal disorders v8.85 MORC2 Ida Ertmanska Publications for gene: MORC2 were set to PMID: 36791574, 32693025
Retinal disorders v8.84 MORC2 Ida Ertmanska Classified gene: MORC2 as Amber List (moderate evidence)
Retinal disorders v8.84 MORC2 Ida Ertmanska Gene: morc2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.83 MORC2 Ida Ertmanska Mode of inheritance for gene: MORC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.82 MORC2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: MORC2.
Tag Q1_26_NHS_review tag was added to gene: MORC2.
Retinal disorders v8.82 MORC2 Ida Ertmanska reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26659848, 32693025, 36791574, 39143067, 40302207; Phenotypes: Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, OMIM:619090, Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.105 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.243 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 26th Jan 2026.
Intellectual disability v9.243 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.242 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Intellectual disability v9.241 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Severe microcephaly v8.30 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Severe microcephaly v8.29 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 30th Jan 2026.
Severe microcephaly v8.29 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Ataxia and cerebellar anomalies - narrow panel v8.53 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Ataxia and cerebellar anomalies - narrow panel v8.52 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 30th Jan 2026.
Ataxia and cerebellar anomalies - narrow panel v8.52 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Early onset or syndromic epilepsy v8.104 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Early onset or syndromic epilepsy v8.103 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 30th Jan 2026.
Early onset or syndromic epilepsy v8.103 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436
Early onset or syndromic epilepsy v8.102 BRSK1 Ida Ertmanska Mode of inheritance for gene: BRSK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag Q1_26_NHS_review tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag watchlist was removed from gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Publications for gene: ATP2B1 were set to 35358416; 33057194
Early onset or syndromic epilepsy v8.100 ATP2B1 Ida Ertmanska Mode of inheritance for gene: ATP2B1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.; to: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). Heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy. Hence, this gene should be promoted to Green on this panel.
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.; to: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).; to: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska commented on gene: ATP2B1: Comment on list classification: There are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.
Intellectual disability v9.240 ATP2B1 Ida Ertmanska reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37926713; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, OMIM:619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: PMID: 40834682 Zhu et al., 2025
5 patients - 1 with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 individuals with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn).
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Since epilepsy may be the presenting and only features, ATP2B1 should be promoted to Green for Early onset or syndromic epilepsy.

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).; to: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33057194, 35358416, 40834682; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, OMIM:619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cystic kidney disease v8.2 CYP24A1 Eleanor Williams Tag Q1_26_MOI tag was added to gene: CYP24A1.
Cystic kidney disease v8.2 CYP24A1 Eleanor Williams edited their review of gene: CYP24A1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cystic kidney disease v8.2 CYP24A1 Eleanor Williams changed review comment from: The OMIM entry for this gene disease association Hypercalcemia, infantile, 1, OMIM:143880 records an autosomal recessive mode of inheritance but no publications since 2011 have been assessed. There is now evidence that individuals may present with disease in adult hood, and some evidence that those with monoallelic variants present with milder disease.

Update on monallelic cases:

PMID: 21675912 - Schlingmann et al 2011 - report 7 families with homozgyous or compound heterozgyous variants in CYP24A1 and infantile hypercalcaemia and 1 case with a heterozygous deletion affecting a splice site but the authors note that there may be another undetected variant outside of the coding region. Analysis was of a few candidate genes only. Renal cysts were not assessed.

PMID: 22337913 - Tebben et al 2012 - proband (aged 44 years) with hypercalcemia and hypercalciuria and elevated serum 1,25(OH)2D. Only CYP24A1 and CYP27B were sequenced. 2 splice mutations in CYP24A1 were identified. Seven family members from three generations showed chemical and clinical phenotypes with one or two CYP24A1 mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. Renal cysts were noted in the proband and one heterozygous child of the proband.

PMID: 24235083 - Colussi et al 2014 - report 2 unrelated probands with homozgyous variants in CYP24A1 and recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; heterozygous carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four).  The authors conclude that heterozygous carriers may also have subtle abnormalities of vitamin D metabolism that predispose them to events such as renal stones.                                                                                                                                      

PMID: 26214117 - Molin et al 2015 - report 25 patients out of a pool of 72 with hypercalcemia that had CYP24A1 variants. Only this gene was screened. 20 had biallelic variants, mostly with nephrocalincosis or renal stones. 5 neonates were heterozygous without renal disease. Further investigation of relatives found a further 21 heterozygotes who were found to have normal serum calcium and PTH levels. They note that while most heterozygous individuals remain asymptomatic, hypercalcemia may occur due to excessive vitamin D intake.

PMID: 27129455 - O'Keeffe et al 2016 - ABSTRACT ONLY ACCESSED - report a family with affected individuals with both biallelic and monallelic variants in CYP24A1. A gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations. However, they note that 2 subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia.

PMID: 34307984 - Hanna et al 2021 - report a high prevalance in of kidney cysts in patients with CYP24A1 deficiency. Looked at 16 patients from 12 pedigrees with confirmed pathogenic variants. Medullary and/or corticomedullary junction cysts were present in all cases. Heterozygous variants were reported in 2 families - patient 11, pedigree 7, and patients 1,2 and 3 in pedigree 1. Patient 10 was compound heterozygous. Family 1 is same family reported in Tebben et al 2012.

PMID: 38504242 - Wang et al 2024 - studied 6 patients with Idiopathic infantile hypercalcemia. 2 patients were found to have compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant (patient 1). Patient presented with hypercalcemia and had significant renal calcification.

PMID: 33249478 - Brancatella et al 2021 - ABSTRACT ONLY ACCESSED - a large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites. The 40 yo male proband proband, was homozygous for p.Arg223* pathogenic variant. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations, without any difference in the other biochemical parameters and in the rate of nephrolithiasis. The authors note that heterozygotes might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

In conclusion, while the bulk of patients with Hypercalcemia have biallelic variants, those with monoallelic variants generally present with a milder phenotype, which may be amplified by exposure to high levels of vitamin D.; to: The OMIM entry for this gene disease association Hypercalcemia, infantile, 1, OMIM:143880 records an autosomal recessive mode of inheritance but no publications since 2011 have been assessed. There is now evidence that individuals may present with disease in adult hood, and some evidence that those with monoallelic variants present with milder disease.

Update on monoallelic cases where a phenotype is assessed:

PMID: 21675912 - Schlingmann et al 2011 - report 7 families with homozgyous or compound heterozgyous variants in CYP24A1 and infantile hypercalcaemia and 1 case with a heterozygous deletion affecting a splice site but the authors note that there may be another undetected variant outside of the coding region. Analysis was of a few candidate genes only. Renal cysts were not assessed.

PMID: 22337913 - Tebben et al 2012 - proband (aged 44 years) with hypercalcemia and hypercalciuria and elevated serum 1,25(OH)2D. Only CYP24A1 and CYP27B were sequenced. 2 splice mutations in CYP24A1 were identified. Seven family members from three generations showed chemical and clinical phenotypes with one or two CYP24A1 mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. Renal cysts were noted in the proband and one heterozygous child of the proband.

PMID: 24235083 - Colussi et al 2014 - report 2 unrelated probands with homozgyous variants in CYP24A1 and recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; heterozygous carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four).  The authors conclude that heterozygous carriers may also have subtle abnormalities of vitamin D metabolism that predispose them to events such as renal stones.                                                                                                                                      

PMID: 26214117 - Molin et al 2015 - report 25 patients out of a pool of 72 with hypercalcemia that had CYP24A1 variants. Only this gene was screened. 20 had biallelic variants, mostly with nephrocalincosis or renal stones. 5 neonates were heterozygous without renal disease. Further investigation of relatives found a further 21 heterozygotes who were found to have normal serum calcium and PTH levels. They note that while most heterozygous individuals remain asymptomatic, hypercalcemia may occur due to excessive vitamin D intake.

PMID: 27129455 - O'Keeffe et al 2016 - ABSTRACT ONLY ACCESSED - report a family with affected individuals with both biallelic and monallelic variants in CYP24A1. A gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations. However, they note that 2 subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia.

PMID: 34307984 - Hanna et al 2021 - report a high prevalance in of kidney cysts in patients with CYP24A1 deficiency. Looked at 16 patients from 12 pedigrees with confirmed pathogenic variants. Medullary and/or corticomedullary junction cysts were present in all cases. Heterozygous variants were reported in 2 families - patient 11, pedigree 7, and patients 1,2 and 3 in pedigree 1. Patient 10 was compound heterozygous. Family 1 is same family reported in Tebben et al 2012.

PMID: 38504242 - Wang et al 2024 - studied 6 patients with Idiopathic infantile hypercalcemia. 2 patients were found to have compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant (patient 1). Patient presented with hypercalcemia and had significant renal calcification.

PMID: 33249478 - Brancatella et al 2021 - ABSTRACT ONLY ACCESSED - a large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites. The 40 yo male proband proband, was homozygous for p.Arg223* pathogenic variant. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations, without any difference in the other biochemical parameters and in the rate of nephrolithiasis. The authors note that heterozygotes might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

In conclusion, while the bulk of patients with Hypercalcemia have biallelic variants, those with monoallelic variants generally present with a milder phenotype or are asymptomatic, and therefore the mode of inheritance should be kept as biallelic until the association with disease is more clear.
Early onset or syndromic epilepsy v8.99 PAK2 Arina Puzriakova Publications for gene: PAK2 were set to 33693784; 38894571; 39876536; 39994693; 40262506; 40247748
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag watchlist tag was added to gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.; to: Comment on list classification: Rating Amber as only 2 cases have been reported with epilepsy to date. PAK2 has mostly been linked to Knobloch syndrome which is primarily characterised by ocular manifestations and prenatal/neonatal pulmonary features. Neurodevelopmental abnormalities are variable but not a defining feature in most cases. However, given there is a case without cardinal features of Knobloch syndrome, where epilepsy was the primary phenotype, this gene has been included on the panel as Amber in case additional evidence emerges that supports promotion to Green in the future.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; to: Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.


Other PAK2 cases not reporting epilepsy:

Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag Q1_26_promote_green was removed from gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Entity copied from Retinal disorders v8.82
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q1_26_promote_green tags were added to gene: PAK2.
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 33693784; 38894571; 39876536; 39994693; 40262506; 40247748
Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome, OMIM:618458
Retinal disorders v8.82 PAK2 Arina Puzriakova changed review comment from: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; to: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.
Retinal disorders v8.82 PAK2 Arina Puzriakova Classified gene: PAK2 as Amber List (moderate evidence)
Retinal disorders v8.82 PAK2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.
Retinal disorders v8.82 PAK2 Arina Puzriakova Gene: pak2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.81 PAK2 Arina Puzriakova Publications for gene: PAK2 were set to 33693784
Retinal disorders v8.80 PAK2 Arina Puzriakova Tag Q1_26_promote_green tag was added to gene: PAK2.
Retinal disorders v8.80 PAK2 Arina Puzriakova edited their review of gene: PAK2: Added comment: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; Changed rating: GREEN; Changed publications to: 33693784, 38894571, 39876536, 39994693, 40262506, 40247748; Changed phenotypes to: Knobloch 2 syndrome, OMIM:618458
Retinal disorders v8.80 PAK2 Arina Puzriakova Phenotypes for gene: PAK2 were changed from Knobloch 2 syndrome to Knobloch 2 syndrome, OMIM:618458
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Classified gene: PAICS as Amber List (moderate evidence)
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green - three unrelated cases with phosphoribosylaminoimidazole carboxylase deficiency, an inborn error of de novo purine synthesis caused by biallelic variants in the PAICS gene (PMID: 31600779; 39604553; 39726239)

Inclusion on this panel would also ensure inclusion on the Paediatric disorders super panel which is relevant to the polymalformative syndrome or neurodevelopmental disorder displayed by affected individuals.
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Gene: paics has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.90 PAICS Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (?Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859) accessed on 27-01-2026
Likely inborn error of metabolism v8.90 PAICS Arina Puzriakova Phenotypes for gene: PAICS were changed from Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859 to ?Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859
Likely inborn error of metabolism v8.89 PAICS Arina Puzriakova gene: PAICS was added
gene: PAICS was added to Likely inborn error of metabolism. Sources: Literature
Q1_26_promote_green tags were added to gene: PAICS.
Mode of inheritance for gene: PAICS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAICS were set to 31600779; 39604553; 39726239
Phenotypes for gene: PAICS were set to Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859
Review for gene: PAICS was set to GREEN
Added comment: Pelet et al. 2019 (PMID: 31600779) report an AR inborn error of de novo purine synthesis due to homozygous missense variant in PAICS (c.158A>G; p.Lys53Arg) in 2 siblings from the Faroe islands. Catalytic activity of the mutant protein in patient skin fibroblasts was approx 10% of wild type levels. The siblings had multiple malformations resulting in early neonatal death.

Weng et al. 2024 (PMID: 39604553) identified two Taiwanese siblings with compound heterozygous variants, c.535T>C (p.Ser179Pro) and c.1207C>T (p.Arg403Ter). They presented a markedly different clinical course, with both being born at term following uncomplicated pregnancies. However, clinical manifestations did start to emerge from infancy and manifested as progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Phenotypic variability could be attributed to residual enzyme activities where the Ser179Pro and Arg403Ter proteins had residual activities decreased to 76 and 21%, respectively, compared to 10% of the Lys35Arg protein of Faroe Island patients.

Boussion et al. 2025 (PMID: 39726239) reported a 7-year-old boy homozygous for the same p.Lys53Arg mutation as the Faroe cases. This individual presented with a multiple malformations including complex congenital heart disease, skeletal and esophageal defects but normal neurodevelopment. There was a similarly affected sibling with suspected PAICS deficiency, but this was not molecularly confirmed.
Sources: Literature
Fetal anomalies v6.137 PAICS Arina Puzriakova Publications for gene: PAICS were set to 31178128; 31600779; 3965093; 38179855; 30758658
Adult-onset neurological disorders v8.0 Achchuthan Shanmugasundram Added Panel Adult-onset neurological disorders
Set list of related panels to R54; R56; R60; R458; R459; R460; R461; Hereditary ataxia with onset in adulthood; Adult onset dystonia; chorea or related movement disorder; Adult onset hereditary spastic paraplegia; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy
Set child panels to: Hereditary ataxia with onset in adulthood; Adult onset neurodegenerative disorder; Adult onset hereditary spastic paraplegia; Adult onset dystonia, chorea or related movement disorder
Set panel types to: GMS Rare Disease Virtual; Super Panel
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Classified gene: RAB5B as Amber List (moderate evidence)
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Added comment: Comment on list classification: The rating of this gene will remain amber on this panel as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Gene: rab5b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v0.5 MARS Achchuthan Shanmugasundram changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1; to: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1.
Childhood interstitial lung disease v0.5 TMEM173 Achchuthan Shanmugasundram commented on gene: TMEM173: TMEM173 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TINF2 Achchuthan Shanmugasundram commented on gene: TINF2: TINF2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TERT Achchuthan Shanmugasundram commented on gene: TERT: TERT has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TERC Achchuthan Shanmugasundram commented on gene: TERC: TERC has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TBX4 Achchuthan Shanmugasundram commented on gene: TBX4: TBX4 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 STAT5B Achchuthan Shanmugasundram commented on gene: STAT5B: STAT5B has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 STAT1 Achchuthan Shanmugasundram commented on gene: STAT1: STAT1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SLC7A7 Achchuthan Shanmugasundram commented on gene: SLC7A7: SLC7A7 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SLC34A2 Achchuthan Shanmugasundram commented on gene: SLC34A2: SLC34A2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPC Achchuthan Shanmugasundram commented on gene: SFTPC: SFTPC has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPB Achchuthan Shanmugasundram commented on gene: SFTPB: SFTPB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPA2 Achchuthan Shanmugasundram commented on gene: SFTPA2: SFTPA2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPA1 Achchuthan Shanmugasundram commented on gene: SFTPA1: SFTPA1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 RTEL1 Achchuthan Shanmugasundram commented on gene: RTEL1: RTEL1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB9 Achchuthan Shanmugasundram commented on gene: PSMB9: PSMB9 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB8 Achchuthan Shanmugasundram commented on gene: PSMB8: PSMB8 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB4 Achchuthan Shanmugasundram commented on gene: PSMB4: PSMB4 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PARN Achchuthan Shanmugasundram commented on gene: PARN: PARN has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 OAS1 Achchuthan Shanmugasundram commented on gene: OAS1: OAS1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 NKX2-1 Achchuthan Shanmugasundram commented on gene: NKX2-1: NKX2-1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 NAF1 Achchuthan Shanmugasundram commented on gene: NAF1: NAF1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 MARS Achchuthan Shanmugasundram commented on gene: MARS: MARS has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 LRBA Achchuthan Shanmugasundram commented on gene: LRBA: LRBA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 ITGA3 Achchuthan Shanmugasundram commented on gene: ITGA3: ITGA3 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 GATA2 Achchuthan Shanmugasundram commented on gene: GATA2: GATA2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FOXF1 Achchuthan Shanmugasundram commented on gene: FOXF1: FOXF1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FLNA Achchuthan Shanmugasundram commented on gene: FLNA: FLNA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FARSB Achchuthan Shanmugasundram commented on gene: FARSB: FARSB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FARSA Achchuthan Shanmugasundram commented on gene: FARSA: FARSA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 CSF2RB Achchuthan Shanmugasundram commented on gene: CSF2RB: CSF2RB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 CSF2RA Achchuthan Shanmugasundram commented on gene: CSF2RA: CSF2RA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 COPA Achchuthan Shanmugasundram commented on gene: COPA: COPA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 BMPR2 Achchuthan Shanmugasundram commented on gene: BMPR2: BMPR2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 ABCA3 Achchuthan Shanmugasundram commented on gene: ABCA3: ABCA3 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 WRN Achchuthan Shanmugasundram commented on gene: WRN: WRN has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 TP53 Achchuthan Shanmugasundram commented on gene: TP53: TP53 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 T Achchuthan Shanmugasundram commented on gene: T: T has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 RECQL4 Achchuthan Shanmugasundram commented on gene: RECQL4: RECQL4 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 RB1 Achchuthan Shanmugasundram commented on gene: RB1: RB1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 PTPN11 Achchuthan Shanmugasundram commented on gene: PTPN11: PTPN11 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 NF1 Achchuthan Shanmugasundram commented on gene: NF1: NF1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 NBN Achchuthan Shanmugasundram commented on gene: NBN: NBN has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 KRAS Achchuthan Shanmugasundram commented on gene: KRAS: KRAS has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 HRAS Achchuthan Shanmugasundram commented on gene: HRAS: HRAS has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 DICER1 Achchuthan Shanmugasundram commented on gene: DICER1: DICER1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 CBL Achchuthan Shanmugasundram commented on gene: CBL: CBL has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 BUB1B Achchuthan Shanmugasundram commented on gene: BUB1B: BUB1B has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 WT1 Achchuthan Shanmugasundram commented on gene: WT1: WT1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIP13 Achchuthan Shanmugasundram commented on gene: TRIP13: TRIP13 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIM37 Achchuthan Shanmugasundram commented on gene: TRIM37: TRIM37 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIM28 Achchuthan Shanmugasundram commented on gene: TRIM28: TRIM28 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TP53 Achchuthan Shanmugasundram commented on gene: TP53: TP53 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SUFU Achchuthan Shanmugasundram commented on gene: SUFU: SUFU has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SOS1 Achchuthan Shanmugasundram commented on gene: SOS1: SOS1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SMARCB1 Achchuthan Shanmugasundram commented on gene: SMARCB1: SMARCB1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SMARCA4 Achchuthan Shanmugasundram commented on gene: SMARCA4: SMARCA4 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 REST Achchuthan Shanmugasundram commented on gene: REST: REST has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PTPN11 Achchuthan Shanmugasundram commented on gene: PTPN11: PTPN11 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PTCH1 Achchuthan Shanmugasundram commented on gene: PTCH1: PTCH1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PHOX2B Achchuthan Shanmugasundram commented on gene: PHOX2B: PHOX2B has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 KRAS Achchuthan Shanmugasundram commented on gene: KRAS: KRAS has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 HRAS Achchuthan Shanmugasundram commented on gene: HRAS: HRAS has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 GPR161 Achchuthan Shanmugasundram commented on gene: GPR161: GPR161 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 GPC3 Achchuthan Shanmugasundram commented on gene: GPC3: GPC3 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 EZH2 Achchuthan Shanmugasundram commented on gene: EZH2: EZH2 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 ELP1 Achchuthan Shanmugasundram commented on gene: ELP1: ELP1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 DIS3L2 Achchuthan Shanmugasundram commented on gene: DIS3L2: DIS3L2 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 DICER1 Achchuthan Shanmugasundram commented on gene: DICER1: DICER1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CTR9 Achchuthan Shanmugasundram commented on gene: CTR9: CTR9 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CDKN1C Achchuthan Shanmugasundram commented on gene: CDKN1C: CDKN1C has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CBL Achchuthan Shanmugasundram commented on gene: CBL: CBL has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 BUB1B Achchuthan Shanmugasundram commented on gene: BUB1B: BUB1B has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 ALK Achchuthan Shanmugasundram commented on gene: ALK: ALK has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Adult onset hereditary spastic paraplegia v6.6 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Adult onset neurodegenerative disorder v8.10 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Childhood onset dystonia, chorea or related movement disorder v7.13 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Hereditary neuropathy or pain disorder v7.33 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Hereditary ataxia with onset in adulthood v8.21 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Adult onset dystonia, chorea or related movement disorder v5.3 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Cystic kidney disease v8.2 CYP24A1 Eleanor Williams reviewed gene: CYP24A1: Rating: ; Mode of pathogenicity: None; Publications: 21675912, 22337913, 24235083, 26214117, 2712945, 34307984, 38504242, 33249478; Phenotypes: ; Mode of inheritance: None
Pulmonary fibrosis familial v1.8 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Pyruvate dehydrogenase (PDH) deficiency v1.38 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Rhabdomyolysis and metabolic muscle disorders v5.14 Eleanor Williams Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Segmental overgrowth disorders - Deep sequencing v4.5 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Structural eye disease v4.37 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Thoracic aortic aneurysm or dissection (GMS) v4.5 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Tubulointerstitial kidney disease v3.15 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
White matter disorders and cerebral calcification - narrow panel v7.9 Eleanor Williams Panel types changed to Component Of Super Panel; GMS signed-off
Progressive cardiac conduction disease v2.13 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Primary lymphoedema v4.21 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Primary immunodeficiency or monogenic inflammatory bowel disease v8.76 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Pituitary hormone deficiency v4.4 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex V deficiency v3.3 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex IV deficiency v4.14 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex III deficiency v2.7 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial liver disease, including transient infantile liver failure v1.14 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial DNA maintenance disorder v3.9 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex I deficiency v3.19 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Paediatric pseudo-obstruction syndrome v2.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Paediatric motor neuronopathies v3.12 Ida Ertmanska Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Paediatric disorders - additional genes v7.29 Ida Ertmanska Panel types changed to Component Of Super Panel; GMS signed-off
Osteopetrosis v1.38 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Multi locus imprinting disorders v1.18 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Mosaic skin disorders - deep sequencing v3.27 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Intellectual disability v9.240 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17,OMIM:618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v9.239 AIMP2 Eleanor Williams Publications for gene: AIMP2 were set to 29215095
Intellectual disability v9.238 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Early onset or syndromic epilepsy v8.97 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, OMIM:618006 to Leukodystrophy, hypomyelinating, 17, OMIM:618006; eukodystrophy, hypomyelinating, 17, MONDO:0054817
Cholestasis v3.18 SCYL1 Eleanor Williams Classified gene: SCYL1 as Amber List (moderate evidence)
Cholestasis v3.18 SCYL1 Eleanor Williams Gene: scyl1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.17 SCYL1 Eleanor Williams Tag Q1_26_NHS_review tag was added to gene: SCYL1.
Neurological segmental overgrowth v3.3 Ida Ertmanska Panel types changed to Component Of Super Panel; GMS signed-off
Multiple monogenic benign skin tumours v2.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited renal cancer v1.28 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Multi locus imprinting disorders v1.17 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Paediatric or syndromic cardiomyopathy v7.92 BRAF Eleanor Williams Tag Q1_26_NHS_review tag was added to gene: BRAF.
Inherited prostate cancer v1.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited predisposition to GIST v1.15 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited predisposition to acute myeloid leukaemia (AML) v3.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited polyposis and early onset colorectal cancer - germline testing v3.11 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Fetal anomalies v6.136 CYP11A1 Eleanor Williams Tag Q1_26_MOI tag was added to gene: CYP11A1.
Mosaic skin disorders - deep sequencing v3.26 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.10 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Monogenic diabetes v3.8 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited pancreatic cancer v3.2 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited ovarian cancer (without breast cancer) v4.9 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited MMR deficiency (Lynch syndrome) v1.13 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial liver disease, including transient infantile liver failure v1.13 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited breast cancer and ovarian cancer v2.18 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial DNA maintenance disorder v3.8 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hypophosphataemia or rickets v4.2 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hypogonadotropic hypogonadism (GMS) v4.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hyperthyroidism v3.5 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hereditary Erythrocytosis v2.17 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Glycogen storage disease v2.6 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex V deficiency v3.2 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex IV deficiency v4.13 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex III deficiency v2.6 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex I deficiency v3.18 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Familial tumours of the nervous system v2.14 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.7 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Malformations of cortical development v7.19 Ida Ertmanska Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Lysosomal storage disorder v3.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Long QT syndrome v3.12 Ida Ertmanska Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Severe insulin resistance and lipodystrophy syndromes v4.67 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.29 Ida Ertmanska Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Endocrine neoplasia v3.4 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital adrenal hypoplasia v4.11 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Differences in sex development v4.14 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
DDG2P v6.15 Achchuthan Shanmugasundram Panel types changed to Component Of Super Panel; GMS signed-off
Cystic kidney disease v8.2 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Congenital myopathy v6.45 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital myaesthenic syndrome v5.7 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital muscular dystrophy v6.8 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital hypothyroidism v3.3 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital hyperinsulinism v3.6 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital disorders of glycosylation v7.12 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Common craniosynostosis syndromes v1.16 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Skeletal dysplasia v8.32 FGFR3 Eleanor Williams Phenotypes for gene: FGFR3 were changed from Thanatophoric dysplasia, type I 187600; Muenke syndrome 602849; CATSHL syndrome 610474; SADDAN 616482; Thanatophoric dysplasia, type II 187601; Achondroplasia 100800; LADD syndrome 149730; Hypochondroplasia 146000; Crouzon syndrome with acanthosis nigricans 612247 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Skeletal dysplasia v8.31 FGFR3 Eleanor Williams Publications for gene: FGFR3 were set to
Ataxia and cerebellar anomalies - narrow panel v8.51 GRID2 Eleanor Williams Publications for gene: GRID2 were set to 9285588; 21460832; 25841024; 35882834; 37944084
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams edited their review of gene: GRID2: Changed publications to: 23611888, 24078737
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams commented on gene: GRID2
Cerebral vascular malformations v4.10 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hereditary ataxia with onset in adulthood v8.20 GRID2 Eleanor Williams Phenotypes for gene: GRID2 were changed from Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204 to Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204; autosomal recessive spinocerebellar ataxia 18, MONDO:0014530
Hereditary ataxia with onset in adulthood v8.19 GRID2 Eleanor Williams Mode of pathogenicity for gene: GRID2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Catecholaminergic polymorphic VT v5.3 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams Phenotypes for gene: GRID2 were changed from Spinocerebellar ataxia, autosomal recessive 18, 616204 to Spinocerebellar ataxia, autosomal recessive 18, 616204; Progressive cerebellar ataxia, HP:0002073; autosomal recessive spinocerebellar ataxia 18, MONDO:0014530
Ataxia and cerebellar anomalies - narrow panel v8.49 GRID2 Eleanor Williams Mode of pathogenicity for gene: GRID2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Ataxia and cerebellar anomalies - narrow panel v8.48 GRID2 Eleanor Williams Publications for gene: GRID2 were set to 25841024
Bardet Biedl syndrome v2.9 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Autoinflammatory disorders v2.35 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Ataxia and cerebellar anomalies - narrow panel v8.47 Achchuthan Shanmugasundram Panel types changed to Component Of Super Panel; GMS signed-off
Adult onset leukodystrophy v6.8 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Rare anaemia v3.17 PPOX Sharon Whatley Deleted their review
Rare anaemia v3.17 PPOX Sharon Whatley Deleted their comment
Congenital hyperinsulinism v3.5 HK1 Sarah Flanagan reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 40033430, PMID: 36333503; Phenotypes: Congenital Hyperinsulinism, hyperinsulinaemic hypoglycaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Polycystic liver disease v1.31 PKHD1 Florentina Sava reviewed gene: PKHD1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 28375157, PMID: 21945273, PMID: 30600684, PMID: 33554127, Internal Sheffield data, KDIGO guidelines, ClinGen PKHD1 gene; Phenotypes: Ductal plate malformation, Polycystic liver disease, Congenital hepatic fibrosis, Caroli's disease, Biliary dysplasia; Mode of inheritance: Other; Current diagnostic: yes
Cholestasis v3.16 SCYL1 Ida Ertmanska commented on gene: SCYL1: Comment on list classification: As reviewed by Karen Stals, biallelic mutations in SCYL1 were reported in at least 7 pedigrees where affected individuals presented with acute liver failure with onset in infancy / early childhood. Based on available evidence, this gene should be promoted to Green for Cholestasis.
Cholestasis v3.16 SCYL1 Ida Ertmanska Phenotypes for gene: SCYL1 were changed from Liver failure; cholestasis; ataxia; peripheral neuropathy; cerebellar atrophy to cholestasis, MONDO:0001751; acute liver failure, MONDO:0019542; Spinocerebellar ataxia, autosomal recessive 21, OMIM:616719
Cholestasis v3.15 SCYL1 Ida Ertmanska Publications for gene: SCYL1 were set to PMID: 30842961; PMID: 33442927; PMID: 30842961; PMID: 29419818
Cholestasis v3.14 SCYL1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: SCYL1.
Cholestasis v3.14 SCYL1 Ida Ertmanska reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29419818, 30842961, 33442927; Phenotypes: cholestasis, MONDO:0001751, acute liver failure, MONDO:0019542, Spinocerebellar ataxia, autosomal recessive 21, OMIM:616719; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.92 BRAF Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BRAF.
Paediatric or syndromic cardiomyopathy v7.92 BRAF Ida Ertmanska reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 19206169; Phenotypes: Cardiofaciocutaneous syndrome, OMIM:115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.135 CYP11A1 Ida Ertmanska reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11502818, 29995203, 30620006, 35418949, 39457196; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v4.10 CYP11A1 Ida Ertmanska Publications for gene: CYP11A1 were set to 11502818; 29995203; 31671693; 12161514; 15507506; 16705068; 18182448; 19116240
Congenital adrenal hypoplasia v4.9 CYP11A1 Ida Ertmanska Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743 to drenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743; Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400
Differences in sex development v4.13 CYP11A1 Ida Ertmanska Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743; Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400
Differences in sex development v4.12 CYP11A1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: CYP11A1.
Differences in sex development v4.12 CYP11A1 Ida Ertmanska edited their review of gene: CYP11A1: Added comment: Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency / differences in sex development (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Differences in sex development.; Changed rating: GREEN; Changed publications to: 11502818, 29995203, 30620006, 35418949, 39457196; Changed phenotypes to: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences in sex development v4.12 CYP11A1 Ida Ertmanska commented on gene: CYP11A1
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: CYP11A1.
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska edited their review of gene: CYP11A1: Changed publications to: 11502818, 29995203, 30620006, 35418949, 39457196
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 biallelic cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska commented on gene: CYP11A1: Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Congenital adrenal hypoplasia.
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11502818, 29995203, 35418949, 39457196; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 SLITRK2 Mike Spiller gene: SLITRK2 was added
gene: SLITRK2 was added to Intellectual disability. Sources: NHS GMS,Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to PMID: 35840571
Review for gene: SLITRK2 was set to GREEN
Added comment: Gene is associated with Intellectual developmental disorder, X-linked 111 (OMIM 301107).
Association based on PMID: 35840571 - 7 probands, 6 male one female. Female de novo, males mix of de novo and maternally inherited. ID levels range from borderline-severe, 5 patients moderate-severe.
One LOF, others missenses distributed through the gene. Missenses well supported by mouse data including inability to rescue KO phenotypes, as well as HEK293 transcfection studies..

Also 2 hemizygous LOF on CVA with consistent phenotypes (NHS GMS).
Sources: NHS GMS, Literature
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR3.
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska edited their review of gene: FGFR3: Added comment: Comment on mode of inheritance: FGFR3 variants are associated with several dominant conditions that include skeletal dysplasia. However, evidence of recessive inheritance is lacking. To date, one family has been reported with autosomal recessive Camptodactyly-Tall Stature-Scoliosis-Hearing Loss (CATSHL) syndrome. 3 other families were reported with a dominantly inherited CATSHL syndrome. All dominant cases involve a missense change at the same residue (621), while recessive disease was cause by a missense variant p.Thr546Lys. The mode of inheritance for FGFR3 should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted for Skeletal dysplasia, until more cases emerge in support of recessive inheritance.; Changed publications to: 17033969, 24864036, 27139183, 37990933; Changed phenotypes to: CATSHL syndrome, OMIM:610474, camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v9.18 FGFR3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 20th Jan 2026.
Arthrogryposis v9.18 FGFR3 Ida Ertmanska Phenotypes for gene: FGFR3 were changed from CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Arthrogryposis v9.17 FGFR3 Ida Ertmanska Phenotypes for gene: FGFR3 were changed from CATSHL syndrome 610474 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Arthrogryposis v9.16 FGFR3 Ida Ertmanska Publications for gene: FGFR3 were set to 17033969
Arthrogryposis v9.15 FGFR3 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR3.
Arthrogryposis v9.15 FGFR3 Ida Ertmanska commented on gene: FGFR3: Comment on mode of inheritance: Mutations in FGFR3 may rarely cause Camptodactyly-Tall Stature-Scoliosis-Hearing Loss (CATSHL) syndrome. To date, 3 families with dominant and 1 with recessive CATSHL syndrome have been reported. All dominant cases involve a missense change at the same residue (621), while recessive disease was cause by a missense variant p.Thr546Lys. The mode of inheritance for FGFR3 should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted for Arthrogryposis, until more cases emerge in support of recessive inheritance.
Arthrogryposis v9.15 FGFR3 Ida Ertmanska reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033969, 24864036, 27139183, 37990933; Phenotypes: CATSHL syndrome, OMIM:610474; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Tag to_be_confirmed_NHSE was removed from gene: HMBS.
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Added comment: Comment on mode of inheritance: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Green. GMS reviewers note that this panel is used for biochemically undiagnosed porphyria - acute and non-acute. The MOI was updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as suggested by the NHS Genomic Medicine Service.
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Tag technical-limitations tag was added to gene: SHOX.
Possible mitochondrial disorder - nuclear genes v4.19 BTD Ida Ertmanska changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green. ClinGen mitochondrial gene curation expert panel classified the association between BTD and Leigh syndrome as Moderate. Biotinidase deficiency leads to deficiency of a number of carboxylases including pyruvate carboxylase (PC) and PC is also a green gene on this panel.
Cytopenia - NOT Fanconi anaemia v4.31 RPL17 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotype in OMIM (MIM #621262) and this OMIM record was last accessed on 20 January 2026.
Cytopenia - NOT Fanconi anaemia v4.31 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anemia 22, OMIM:621262; Diamond-Blackfan anemia 22, MONDO:0979244
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed phenotypes to: Diamond-Blackfan anemia 22, OMIM:621262, Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram commented on gene: RPL17: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

The GMS reviewers noted that it would be appropriate to add this gene with green rating to R92 Rare anaemia in addition to R91 Cytopenia - NOT Fanconi anaemia.
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #621262) and this OMIM record was last accessed on 20 January 2026.
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anemia 22, OMIM:621262; Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed phenotypes to: Diamond-Blackfan anemia 22, OMIM:621262, Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram Deleted their comment
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram Entity copied from Cytopenia - NOT Fanconi anaemia v4.30
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram gene: RPL17 was added
gene: RPL17 was added to Rare anaemia. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL17 were set to 39088281
Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia, MONDO:0015253
Penetrance for gene: RPL17 were set to Incomplete
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Classified gene: SHOX as Amber List (moderate evidence)
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Gene: shox has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.29 SHOX Achchuthan Shanmugasundram reviewed gene: SHOX: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hypogonadotropic hypogonadism (GMS) v4.4 PROKR2 Ida Ertmanska Phenotypes for gene: PROKR2 were changed from Hypogonadotropic hypogonadism type 3 (OMIM 244200) to Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Tag watchlist was removed from gene: AIMP2.
Tag Q1_26_promote_green tag was added to gene: AIMP2.
Intellectual disability v9.236 AIMP2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: AIMP2.
Intellectual disability v9.236 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic AIMP2 variants and a complex neurodevelopmental phenotype. 5/6 presentations included syndromic ID/DD. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; Changed rating: GREEN; Changed publications to: 26795593, 35140751, 35568357, 38374194; Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 AIMP2 Ida Ertmanska changed review comment from: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).; to: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

PMID: 26795593 Helbig et al., 2016
Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM).

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).
Intellectual disability v9.236 AIMP2 Ida Ertmanska commented on gene: AIMP2
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Phenotypes for gene: AIMP2 were changed from Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.94 AIMP2 Ida Ertmanska Publications for gene: AIMP2 were set to 29215095; 26795593
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are at least 6 unrelated individuals reported with biallelic variants in AIMP2, of which 5 presented with seizures / epilepsy. Based on available evidence, this gene should be promoted to Green at the next GMS update.; Changed publications to: 35140751, 35568357, 38374194; Changed phenotypes to: eukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska reviewed gene: AIMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.78 AIPL1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: AIPL1.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. The overwhelming majority of reported patients has biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant AIPL1 (p.Ala352_Pro355del) has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease. In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.; to: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. An overwhelming majority of reported patients harbour biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant p.Ala352_Pro355del in AIPL1 has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease (MAF = 0.01129). In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska edited their review of gene: AIPL1: Added comment: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. The overwhelming majority of reported patients has biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant AIPL1 (p.Ala352_Pro355del) has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease. In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.; Changed publications to: 10873396, 15249368, 21474771, 21900377, 24426771, 25274777, 31576779, 33067476, 38880373; Changed phenotypes to: Leber congenital amaurosis 4, OMIM:604393, Leber congenital amaurosis, MONDO:0018998
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 21900377 Pennesi et al., 2011
The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn). Sequenced 14 LCA-causing genes.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 21900377 Pennesi et al., 2011
The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn). Sequenced 14 LCA-causing genes.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska changed review comment from: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.; to: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Functional evidence in mouse models supports this mechanism of disease. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska commented on gene: GRID2: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska Phenotypes for gene: GRID2 were changed from Spinocerebellar ataxia, autosomal recessive 18, 616204 to Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204
Hereditary ataxia with onset in adulthood v8.17 GRID2 Ida Ertmanska Publications for gene: GRID2 were set to 25841024
Hereditary ataxia with onset in adulthood v8.16 GRID2 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: GRID2.
Hereditary ataxia with onset in adulthood v8.16 GRID2 Ida Ertmanska reviewed gene: GRID2: 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: 9285588, 21460832, 25841024, 35882834, 37944084; Phenotypes: Progressive cerebellar ataxia, HP:0002073, Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 GRID2 Ida Ertmanska edited their review of gene: GRID2: Added comment: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is not in the scope of this panel. Hence, GRID2 should remain Green with a BIALLELIC mode of inheritance, until more evidence emerges.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 GRID2 Ida Ertmanska reviewed gene: GRID2: 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: 9285588, 21460832, 25841024, 35882834, 37944084; Phenotypes: Progressive cerebellar ataxia, HP:0002073; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 DHDDS Ida Ertmanska reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 38451541; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v8.46 SCN8A Ida Ertmanska reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v8.78 MORC2 Siying Lin gene: MORC2 was added
gene: MORC2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to PMID: 36791574, 32693025
Phenotypes for gene: MORC2 were set to Retinal dystrophy
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 was set to Other
Review for gene: MORC2 was set to GREEN
Added comment: PMID 32693025 - 5 out of 6 affected individuals who had dilated eye exams had retinal pigmentary abnormalities
PMID 36791574 - retinopathy seen in at least 3 out of 7 affected individuals
Sources: Literature
Early onset or syndromic epilepsy v8.93 CRNKL1 John Taylor reviewed gene: CRNKL1: 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: 40857589; Phenotypes: microcephaly, pontocerebellar hypoplasia, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.93 C12orf66 John Taylor reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: 39824192; Phenotypes: Seizure, Intellectual disability, delayed speech.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 BRSK1 John Taylor reviewed gene: BRSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41035394; Phenotypes: Epilepsy, global developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported; to: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska reviewed gene: AIPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33067476; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: Evidence for this gene disease association includes a Caucasian family with four affected siblings, eight individuals from a first nations Canadian cohort, and a functional animal model. Individuals reported in literature with biallelic variants in WASHC5 were diagnosed with Ritscher-Schinzel syndrome, which includes intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5 (KIAA0196). 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Paediatric or syndromic cardiomyopathy v7.92 GATA6 Ida Ertmanska commented on gene: GATA6
Dilated and arrhythmogenic cardiomyopathy v3.10 GATA6 Ida Ertmanska commented on gene: GATA6
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska Tag disputed was removed from gene: SGCD.
Paediatric or syndromic cardiomyopathy v7.92 SGCD Ida Ertmanska commented on gene: SGCD
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska commented on gene: SGCD
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska Tag disputed tag was added to gene: SGCD.
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in CELSR3 gene with epilepsy/ seizures (five families with each MOI). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 34951123; 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:34951123 (2022) reported trio-based whole-exome sequencing in a cohort of 462 cases with febrile seizures (FS)/ epilepsy with antecedent FS (EFS+), where five heterozygous missense variants in CELSR3 gene were identified in eight individuals from five unrelated families. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders.

PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Seizures were reported in six patients from five unrelated families.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram changed review comment from: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature; to: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight patients with ID/DD) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature
Intellectual disability v9.234 PHF12 Sophie Ellis gene: PHF12 was added
gene: PHF12 was added to Intellectual disability. Sources: ClinGen
Mode of inheritance for gene: PHF12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Penetrance for gene: PHF12 were set to unknown
Mode of pathogenicity for gene: PHF12 was set to Other
Review for gene: PHF12 was set to GREEN
gene: PHF12 was marked as current diagnostic
Added comment: ClinGen Definitive Classification - 02/19/2025
Sources: ClinGen
Adult onset hereditary spastic paraplegia v6.5 GJC2 Ida Ertmanska commented on gene: GJC2: Comment on list classification: There are at least 3 families reported in literature with individuals affected by late-onset spastic paraplegia harbouring biallelic missense variants in GJC2. In one family, 3 siblings with the same homozygous GJC2 variant presented with a variable phenotype (1 sibling diagnosed with spastic paraplegia, and 2 sibs with hypomyelinating leukodystrophy), which may indicate the two disease entities are part of a spectrum. All individuals presented with lower limb spasticity and pyramidal disturbances. Based on available evidence, this gene should be promoted to Green for Adult onset hereditary spastic paraplegia.
Childhood onset hereditary spastic paraplegia v8.26 GJC2 Ida Ertmanska Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating,2, 608804, AR; Spastic paraplegia 44, autosomal recessive, 613206, AR; Lymphatic malformation 3, 613480, AD to ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Leukodystrophy, hypomyelinating, 2, OMIM:608804
Adult onset hereditary spastic paraplegia v6.5 GJC2 Ida Ertmanska Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive; Spastic paraplegia 44, autosomal recessive 613206, AR; Leukodystrophy, hypomyelinating, 2, 608804, AR to ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Leukodystrophy, hypomyelinating, 2, OMIM:608804
Adult onset hereditary spastic paraplegia v6.4 GJC2 Ida Ertmanska Publications for gene: GJC2 were set to Orthmann-Murphy et al. (2009); 19056803
Adult onset hereditary spastic paraplegia v6.3 GJC2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: GJC2.
Adult onset hereditary spastic paraplegia v6.3 GJC2 Ida Ertmanska reviewed gene: GJC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19056803, 22833003, 31431325, 37915394; Phenotypes: ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.25 GJC2 Ida Ertmanska Publications for gene: GJC2 were set to Orthmann-Murphy et al. (2009); 19056803
Childhood onset hereditary spastic paraplegia v8.24 GJC2 Ida Ertmanska reviewed gene: GJC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19056803, 22833003, 31431325, 37915394; Phenotypes: ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.25 ALPL Claire Smith gene: ALPL was added
gene: ALPL was added to Amelogenesis imperfecta. Sources: Literature,Expert Review
Mode of inheritance for gene: ALPL was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Penetrance for gene: ALPL were set to Complete
Review for gene: ALPL was set to GREEN
Added comment: According to the review of ALPL literature, PMID: 39872235
"78.8% of adults with pediatric-onset HPP have dental involvement vs 42.6% of those with adult-onset HPP."
"clinical observations can include enamel hypoplasia and discoloration (possibly contributing to increased caries prevalence), delayed tooth eruption, tooth mobility, and malocclusion (misalignment of upper and lower teeth due to incorrect positions along the dental arches)"

(Note that enamel hypoplasia, although it can mean just specific teeth being affected, is also a term often used to reflect amelogenesis imperfecta in the presence of diseases affecting other organ systems, this is because the original definition of amelogenesis imperfecta excluded it being part of syndromic diseases, this is now changing)

According to Chavez et al.'s ALPL review PMID: 32758526
"Ameloblasts, odontoblasts, cementoblasts, osteoblasts, and periodontal ligament (PDL) cells express TNAP (encoded by ALPL) ( (Bowden and Foster, 2019, Zweifler et al., 2015), indicating the enzyme may function in all aspects of dental and periodontal mineralization."

ALPL is also included on the panel used by Fulgent genetics to screen patients with amelogenesis imperfecta
https://fulgentgenetics.com/Amelogenesis-Imperfecta
Sources: Literature, Expert Review
Optic neuropathy v5.43 SDHA Ida Ertmanska Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000; mitochondrial respiratory chain complex II deficiency 252011 to Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Cardiomyopathy, dilated, 1GG, OMIM:613642; Pheochromocytoma/paraganglioma syndrome 5, OMIM:614165
Optic neuropathy v5.42 SDHA Ida Ertmanska Publications for gene: SDHA were set to 27683074
Optic neuropathy v5.41 SDHA Ida Ertmanska Mode of inheritance for gene: SDHA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v5.40 SDHA Ida Ertmanska Classified gene: SDHA as Amber List (moderate evidence)
Optic neuropathy v5.40 SDHA Ida Ertmanska Gene: sdha has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.39 SDHA Ida Ertmanska reviewed gene: SDHA: Rating: AMBER; Mode of pathogenicity: None; Publications: 27683074, 33471299; Phenotypes: Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cholestasis v3.14 SCYL1 Karen Stals changed review comment from: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy(episodes may resolve), with later development of a neurological phenotype.
Sources: Literature; to: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy (episodes may resolve), with later development of a neurological phenotype.
Sources: Literature
Cholestasis v3.14 SCYL1 Karen Stals gene: SCYL1 was added
gene: SCYL1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL1 were set to PMID: 30842961; PMID: 33442927; PMID: 30842961; PMID: 29419818
Phenotypes for gene: SCYL1 were set to Liver failure; cholestasis; ataxia; peripheral neuropathy; cerebellar atrophy
Penetrance for gene: SCYL1 were set to Complete
Review for gene: SCYL1 was set to GREEN
gene: SCYL1 was marked as current diagnostic
Added comment: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy(episodes may resolve), with later development of a neurological phenotype.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.9 RAD51C Achchuthan Shanmugasundram Mode of inheritance for gene: RAD51C was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.234 WASHC4 Ida Ertmanska Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, 615817 to Intellectual developmental disorder, autosomal recessive 43, OMIM:615817
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska commented on gene: WASHC5: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.233 WASHC5 Ida Ertmanska edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690, 39988189
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.; to: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563; Ritscher-Schinzel syndrome, 220210 to Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.232 WASHC4 Ida Ertmanska changed review comment from: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.; to: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel - regardless of severity. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.
Intellectual disability v9.232 WASHC4 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC4.
Intellectual disability v9.232 WASHC5 Ida Ertmanska Publications for gene: WASHC5 were set to 24065355; 24916641
Intellectual disability v9.231 WASHC5 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC5.
Intellectual disability v9.231 WASHC5 Ida Ertmanska edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690; Changed phenotypes to: Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.231 WASHC5 Ida Ertmanska reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36130690; Phenotypes: Ritscher-Schinzel syndrome, OMIM:220210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.231 WASHC4 Ida Ertmanska reviewed gene: WASHC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 43, OMIM:615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska changed review comment from: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges.; to: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges. The MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska edited their review of gene: RAD51C: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Achchuthan Shanmugasundram Phenotypes for gene: RAD51C were changed from Fanconi anemia, complementation group O, 613390; 613390 Fanconi anemia, complementation group O to Fanconi anemia, complementation group O, OMIM:613390; Fanconi anemia complementation group O, MONDO:0013248
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.231
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q1_26_promote_green tags were added to gene: KDM2A.
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Classified gene: KDM2A as Amber List (moderate evidence)
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Gene: kdm2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: KDM2A.
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: KDM2A was set to GREEN
Added comment: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska commented on gene: RAD51C: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges.
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated families) for the association of biallelic PRMT9 variants with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram gene: PRMT9 was added
gene: PRMT9 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRMT9 were set to 41260215
Phenotypes for gene: PRMT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PRMT9 was set to GREEN
Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Clinical examinations revealed that 14 individuals developed epilepsy, which was suspected in one other individual.

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025).; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska Publications for gene: RAD51C were set to 20400963; 22232082
Confirmed Fanconi anaemia or Bloom syndrome v2.6 RAD51C Ida Ertmanska reviewed gene: RAD51C: Rating: AMBER; Mode of pathogenicity: None; Publications: 20400963, 26681308, 29278735, 37031326; Phenotypes: Fanconi anemia, complementation group O, OMIM:613390, Fanconi anemia complementation group O, MONDO:0013248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: GREEN
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: RED
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family (child without seizures is aged 9 years old, while the onset of seizure on the other child was at 10 years of age). One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: WSB2.
Tag Q1_26_promote_green tag was added to gene: WSB2.
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of PRMT9 with syndromic intellectual disability (>20 unrelated families). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.228 PRMT9 Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992; 38561334
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Changed rating: GREEN
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Global developmental delay was present un 33 individuals and mild - severe intellectual disability was present in 29 individuals (moderate and above in 11 patients, where ID was mild-moderate or severity not reported in others).

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.; Changed publications to: 21937992, 38561334, 41260215
Optic neuropathy v5.39 SPG7 Achchuthan Shanmugasundram Phenotypes for gene: SPG7 were changed from SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, OMIM:607259; autosomal dominant optic atroph, MONDO:0020250 to Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska changed review comment from: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska Deleted their comment
Optic neuropathy v5.38 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 23065789, 24466038, 24727571, 32548275, 33841295, 37983191
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.2275G>A, p.Ala759Thr has MAF = 0.0009866 in gnomAD v4 (European), no homozygotes reported.
SPG7 c.1339C>T, p.Gln447Ter has 1 allele recorded in gnomAD v4.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; to: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748; recurring variants are too common in the population to be associated with dominant disease). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; to: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.
Optic neuropathy v5.38 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Optic neuropathy v5.38 SPG7 Ida Ertmanska edited their review of gene: SPG7: Added comment: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; Changed rating: GREEN; Changed publications to: 23065789, 24466038, 24727571, 32548275, 33841295; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.


SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.38 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: None
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: An overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.87 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 27604308; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska changed review comment from: PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.; to: PMID: 39978794 Jimoh et al., 2025
Reported 7 patients with mitochondrial dysfunction associated with ragged blue fibers in their muscle biopsies: P4 and P11C with homozygous SPG7 variant p.Leu78Ter, P32 and P46 with heterozygous p.Ala510Val, P38 with heterozygous p.Ser645Thr, P48 with heterozygous p.Val540Met, and P49 with heterozygous c.1552 + 1G>T. Authors pose that dominant / semi-dominant inheritance is likely for SPG7, as they have not found additional pathogenic AFG3L2 variants in the monoallelic cases - though the phenotype is notably milder.

PMID: 30252181 Magri et al., 2018
Proband: 25-year-old woman, presented at 5yo with severe vision impairment and signs of primary optic atrophy. At 6yo, manifested a slowly progressive motor impairment characterized by bradykinesia, internal rotation of right foot, and gait and balance instability. Mild ID, WISC-R IQ = 62 (assessed at 10yo). Compound het (digenic): de novo variant in AFG3L2 NM_006796.2:c.1402C>T, p.R468C & SPG7 variant NM_003119.3:c.(376+1_377-1)_(861+1_862-1)del, p.Glu127SerfsTer2. Mother and twin brothers carried heterozygous SPG7 deletion alone and were unaffected.
In PMID: 26539208 Charif et al., 2015, authors described the same AFG3L2 c.1402C>T mutation segregating in a family with optic atrophy and mild ID in an autosomal dominant manner - no ataxia, spasticity, or extrapyramidal involvement (AFG3L2 contribution to phenotype?).
Functional study: Yeast cells lacking the endogenous m-AAA protease exhibit a respiratory defect (OXPHOS phenotype), which is complemented by wild-type AFG3L2 (AFG3L2-WT) but not by mutant AFG3L2-R468C.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

Functional evidence: SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes (PMID: 24767997 Almontashiri et al., 2014). In 6-month-old mice, EM analysis showed the presence of swollen mitochondria in Spg7−/− spinal cord axons; Spg7−/− mice display motor impairment at 6 and 10 months of age; Spg7+/- mice were used as controls (PMID: 33045469 Sambri et al., 2020).

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Intellectual disability v9.227 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy, including global developmental delay and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.227 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.226 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from CONGENITAL SYSTEMIC GLUTAMINE DEFICIENCY (CSGD) to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Intellectual disability v9.225 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram changed review comment from: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).; to: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.87 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital, 610015; seizures to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Early onset or syndromic epilepsy v8.86 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323; 30158707
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram commented on gene: GLUL: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioural abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fit into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed does not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fit into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3A Achchuthan Shanmugasundram changed review comment from: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature; to: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

Functional evidence was available from zebrafish model with mutations in the orthologous eif3s10 gene, which resulted in developmental abnormalities, including thin heart tubes, lack of craniofacial cartilage, and embryonic lethality.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Classified gene: EIF3B as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Gene: eif3b has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.27 EIF3B Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIF3B.
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 GTF2I Achchuthan Shanmugasundram changed review comment from: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay/ intellectual disability and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Hereditary ataxia with onset in adulthood v8.16 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Hereditary ataxia with onset in adulthood v8.16 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 25681447; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Hereditary ataxia with onset in adulthood v8.15 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska edited their review of gene: SPG7: Added comment: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; Changed rating: GREEN; Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska commented on gene: SPG7
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). Method: SPG7 sequencing only / NGS targeted panel.

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.27 EIF3B Achchuthan Shanmugasundram gene: EIF3B was added
gene: EIF3B was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: EIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3B were set to 41033306
Phenotypes for gene: EIF3B were set to syndromic disease, MONDO:0002254
Review for gene: EIF3B was set to GREEN
Added comment: PMID:41033306 (2025) reported 14 unrelated individuals with heterozygous de novo or loss-of-function variants in EIF3B gene. The clinical phenotype varied but predominantly included cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities.

11 of 14 individuals had congenital heart defect including four with tetralogy of Fallot, neurodevelopmental phenotype including developmental delay, speech and language delay, and mild or specific learning disabilities were reported in eight individuals. Behavioral abnormalities, including attention-deficit hyperactivity disorder and autism spectrum disorder, were also noted.

Facial differences were observed in eleven individuals. While features varied, several individuals exhibited differences in the eye region that overlapped with those previously reported in individuals with 7q22.3 micro-deletions, including ptosis, arched eyebrows, downslanting palpebral fissures, hypertelorism, and epicanthal folds. Cleft lip and palate and hearing loss and/or inner and middle ear malformations were reported in four individuals each.

Functional evidence was available from zebrafish model with mutations in the orthologous eif3ba gene, which resulted in developmental abnormalities, including thin heart tubes, lack of craniofacial cartilage, and embryonic lethality.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). Method: SPG7 sequencing only / NGS targeted panel.

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 25681447; 32893728; 33774748; 32161564; 31068484; 23065789; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748).; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748).
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 34405107 Campins-Romeu et al., 2021
Report of a 28‐year‐old Caucasian male with gait and speech problems, neurological problems started at age 17 years. Brain MRI demonstrated mild cerebellar atrophy and T2‐weighted hyperintensities of the cerebral peduncles. Carried compound heterozygous variants in SPG7: c.1529C > T (p.Ala510Val) and c.1715C > T (p.Ala572Val).

PMID: 26506339 Thal et al., 2015
Caucasian man with a homozygous Ala510Val SPG7 case with spastic ataxia. Developed a slowly-progressive spastic-ataxic gait disorder starting at age 59 years accompanied by mild dysdiadochokinesis, mild dysmetria in finger-nose test as well as mild dysmetria in the heel-shin slide, corresponding to a mild cerebellar atrophy, followed by chronic progressive external ophthalmoplegia (cPEO) in later years.
SPG7 variant c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported.

PMID: 22964162 van Gassen et al., 2012
Large Dutch cohort - identified 60 patients with mutations in the SPG7 gene, with clinical details provided for 49 patients from 37 families - all with confirmed homozygous or compound heterozygous variants in SPG7.

MONOALLELIC CASES:
PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. p.Ala510Val was the most commonly detected SPG7 mutation (65%).
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs:
In Family 13, the mother had a heterozygous Arg485_Glu487del mutation: at age 72 years, she had a very slight cerebellar phenotype without spasticity or pyramidal signs.
The mother of Patient 5, who also had a heterozygous Arg485_Glu487del mutation, had a cerebellar gait and cerebellar atrophy on MRI.
The brother of the index case in Family 3 with a heterozygous Ala510Val mutation developed a late-onset peripheral neuropathy. The patient had abolished reflexes at the age of 59 years, with pyramidal signs.

Patient 24 - from PMID: 16534102 Elleuch et al., 2006 - heterozygous for SPG7: c.246_248del, p.Gln82del - transmitted from an asymptomatic mother (?)
Patient 25 - isolated index case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

CONTRADICTORY EVIDENCE:
PMID: 31854126 Verdura et al., 2019
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts. 'This case challenges the notion of an autosomal dominant inheritance for SPG7'; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Classified gene: EIF3A as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed does not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Gene: eif3a has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.25 EIF3A Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIF3A.
Paediatric disorders - additional genes v7.25 EIF3A Achchuthan Shanmugasundram gene: EIF3A was added
gene: EIF3A was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: EIF3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3A were set to 41033306
Phenotypes for gene: EIF3A were set to syndromic disease, MONDO:0002254
Review for gene: EIF3A was set to GREEN
Added comment: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Classified gene: LSM1 as Amber List (moderate evidence)
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families reported with biallelic LSM 1 variants (c.231+4A>C in five families and p.Asn40Tyr in one family) and with FICUS syndrome (which includes global developmental delay/ intellectual disability). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Gene: lsm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: LSM1.
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram gene: LSM1 was added
gene: LSM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LSM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM1 were set to 31010896; 36100156; 40204357
Phenotypes for gene: LSM1 were set to FICUS syndrome, OMIM:621193; FICUS syndrome, MONDO:0978296
Review for gene: LSM1 was set to GREEN
Added comment: PMID:31010896 (2019) reported two siblings with global developmental delay, and multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. They were identified with a homozygous non-canonical splice variant in LSM1 gene (c.231+4A>C) through whole-genome sequencing. There is also functional evidence available from expression studies and mouse model. Lsm1 knockout mice had a partially overlapping phenotype that affected the brain, heart, and eye.

PMID:36100156 (2022) reported the identification of a homozygous missense variant (p.Asn40Tyr) in LSM1 gene via whole-exome in two similarly affected siblings with global neurodevelopmental delay and intellectual disability.

PMID:40204357 (2025) reported six paediatric patients from four unrelated families with homozygous c.231+4A>C variant. They presented with dysmorphic facial features, global developmental delay/ intellectual disability and multisystemic involvement, including urological, cardiac and skeletal manifestations. This variant was identified in Muslim Arab and Ashkenazi Jewish populations and determined as representing a hotspot variant through haplotype analysis. RT-qPCR functional validation demonstrated exon 3 skipping and elevated mutant isoform. The variant was classified as 'Pathogenic' according to the ACMG classification.

This gene has been associated with relevant phenotypes in OMIM (MIM #621193, OMIM record last accessed 06 January 2026), but not yet in Gene2Phenotype.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.92 ATAD3A Matthew Edwards reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33575671, 39472908; Phenotypes: perinatal mitochondrial cardiac failure; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ATP2A2.
Tag Q1_26_NHS_review tag was added to gene: ATP2A2.
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska Mode of inheritance for gene: ATP2A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Epidermolysis bullosa and congenital skin fragility v2.11 ATP2A2 Ida Ertmanska Classified gene: ATP2A2 as Amber List (moderate evidence)
Epidermolysis bullosa and congenital skin fragility v2.11 ATP2A2 Ida Ertmanska Gene: atp2a2 has been classified as Amber List (Moderate Evidence).
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel and should be rated Red.; to: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in adolescence. Based on the available evidence, this gene should be updated to Green on Epidermolysis bullosa and congenital skin fragility. As per internal communication with Veronica Kinsler, this is the closest Dermatology panel fit at this time.
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Changed rating: GREEN
Intellectual disability v9.222 GTF2I Achchuthan Shanmugasundram Mode of inheritance for gene: GTF2I was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram edited their review of gene: GTF2I: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Classified gene: GTF2I as Amber List (moderate evidence)
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Added comment: Comment on list classification: Although five of seven patients presented with mild global developmental delay/ intellectual disability (moderate and severe in one each), they all displayed syndromic phenotype including dysmorphic features. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Gene: gtf2i has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: GTF2I.
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram gene: GTF2I was added
gene: GTF2I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GTF2I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GTF2I were set to 40962490
Phenotypes for gene: GTF2I were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: GTF2I was set to GREEN
Added comment: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Classified gene: EIPR1 as Amber List (moderate evidence)
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Gene: eipr1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.26 EIPR1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIPR1.
Severe microcephaly v8.26 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Classified gene: EIPR1 as Amber List (moderate evidence)
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated families) for the association of this gene with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Gene: eipr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIPR1.
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.23 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Childhood onset hereditary spastic paraplegia v8.23 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with seizures, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.215 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with GDD/ ID, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.215 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.214 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram changed review comment from: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (beyond -3 SD), while it is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature; to: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (OFC beyond -3 SD), while OFC is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Classified gene: TM2D3 as Amber List (moderate evidence)
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with severe microcephaly (OFC beyond -3 SD). Hence, this gene can be promoted to green rating in the next GMS update.
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Gene: tm2d3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.24 TM2D3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: TM2D3.
Severe microcephaly v8.24 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurocardiorenal malformation syndrome, OMIM:621379
Review for gene: TM2D3 was set to GREEN
Added comment: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (beyond -3 SD), while it is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Classified gene: TM2D3 as Amber List (moderate evidence)
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with severe global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Gene: tm2d3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: TM2D3.
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram changed review comment from: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature; to: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurocardiorenal malformation syndrome, OMIM:621379
Review for gene: TM2D3 was set to GREEN
Added comment: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there are three patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (severe - -8SD). Hence, this gene can only be rated amber with current evidence.; to: Comment on list classification: Although there are three unrelated patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (being severe - -8SD). Hence, this gene can only be rated amber with current evidence.
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (severe - -8SD). Hence, this gene can only be rated amber with current evidence.
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.22 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to AMBER
Added comment: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia. The severity of microcephaly is not available in the publication.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). The eight-year-old patient had severe microcephaly (−8 SD), while severity of microcephaly was not recorded for one-year-old patient.

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram changed review comment from: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: Cerebellar hypoplasia/atrophy was reported in three unrelated foetuses and three other unrelated patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.44 SNAPIN Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: SNAPIN.
Ataxia and cerebellar anomalies - narrow panel v8.44 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to GREEN
Added comment: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four foetuses from three unrelated families reported with biallelic SNAPIN variants and with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.134 SNAPIN Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: SNAPIN.
Fetal anomalies v6.134 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Fetal anomalies v6.134 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.133 BHLHE22 Arina Puzriakova Tag watchlist tag was added to gene: BHLHE22.
Fetal anomalies v6.133 BHLHE22 Arina Puzriakova changed review comment from: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.; to: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication. Discussed with R21 expert group and agreed to demote to Amber awaiting publication.
Fetal anomalies v6.133 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to GREEN
Added comment: PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination.

Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Iron metabolism disorders - NOT common HFE mutations v3.3 FECH Ida Ertmanska commented on gene: FECH: Comment on list classification: As the iron deficiency resulting from FECH mutations is mild (low to low-normal serum iron), this gene does not fit into the scope of this panel, and it should remain Amber.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: MNS1.
Amelogenesis imperfecta v4.25 SMARCD2 Ida Ertmanska commented on gene: SMARCD2: Comment on list classification: While there are several cases reported with biallelic SMARCD2 variants and a 'dental' phenotype, the symptoms are very mild and they do not fit into the scope of this panel. Hence, this gene should remain Amber for Amelogenesis imperfecta until more evidence emerges.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green if agreed under additional Expert Review.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene will be recommended for promotion to Green if agreed under additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green with additional Expert Review.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green if agreed under additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska Tag watchlist was removed from gene: MNS1.
Tag Q1_26_promote_green tag was added to gene: MNS1.
Tag Q1_26_NHS_review tag was added to gene: MNS1.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska edited their review of gene: MNS1: Changed rating: GREEN
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects would mean laterality of organs is determined at random (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance, this gene is recommended for promotion to Green with Expert Review. ; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green with additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. However, there is a number of confounding factors to highlight here. 7/9 families were reported to be consanguineous. 3 families were genotyped using a PCD gene panel only. The most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. The laterality defect presented with incomplete penetrance, although a mouse model supports this finding. Additionally, association of this gene with primary ciliary dyskinesia (PCD) - a primary finding for most cases described here - is Disputed in ClinGen.
Due to some conflicting evidence present in literature, this gene can only be rated Amber for Laterality disorders and isomerism.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects would mean laterality of organs is determined at random (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance, this gene is recommended for promotion to Green with Expert Review.
Ehlers Danlos syndrome with a likely monogenic cause v4.5 FLNA Ida Ertmanska Mode of inheritance for gene: FLNA was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: FLNA.
Tag Q1_26_NHS_review tag was added to gene: FLNA.
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with cerebellar hypoplasia. There is also functional evidence available from mouse model, which does not provide any details on cerebellar abnormalities. Hence, this gene should be rated amber with current evidence. The 'watchlist' tag is added.
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.42 WSB2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: WSB2.
Ataxia and cerebellar anomalies - narrow panel v8.42 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to AMBER
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Although brain abnormalities were reported in four of five patients, cerebellar hypoplasia and/ or atrophy was only reported in two patients.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with either IUGR or Oligohydramnios. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.131 WSB2 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: WSB2.
Fetal anomalies v6.131 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Intrauterine growth restriction (IUGR) was reported in two unrelated patients and Oligohydramnios was reported in a different unrelated patient.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: WSB2.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.80 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to AMBER
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although intellectual disability has only been noted in one of four families (family with two patients where ID is moderate in one and severity not given in other), the phenotype is syndromic and GDD is present in all four families. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: WSB2.
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 GNAS Ida Ertmanska reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 41307550; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova changed review comment from: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025; to: Comment on phenotypes: OMIM phenotype (?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Fetal anomalies v6.130 MIA3 Arina Puzriakova changed review comment from: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025; to: Comment on phenotypes: OMIM phenotype (?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to ?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.130 MIA3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Fetal anomalies v6.130 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to ?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Severe insulin resistance and lipodystrophy syndromes v4.66 WRN Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: WRN.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB8 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PSMB8.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB4 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PSMB4.
Severe insulin resistance and lipodystrophy syndromes v4.66 POC1A Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: POC1A.
Severe insulin resistance and lipodystrophy syndromes v4.66 PIK3R1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PIK3R1.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCYT1A Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PCYT1A.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCNT Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PCNT.
Severe insulin resistance and lipodystrophy syndromes v4.66 MFN2 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: MFN2.
Severe insulin resistance and lipodystrophy syndromes v4.66 EPHX1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: EPHX1.
Severe insulin resistance and lipodystrophy syndromes v4.66 BLM Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: BLM.
Severe insulin resistance and lipodystrophy syndromes v4.66 ALMS1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: ALMS1.
Severe insulin resistance and lipodystrophy syndromes v4.66 WRN Achchuthan Shanmugasundram commented on gene: WRN: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB8 Achchuthan Shanmugasundram commented on gene: PSMB8: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB4 Achchuthan Shanmugasundram commented on gene: PSMB4: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 POC1A Achchuthan Shanmugasundram commented on gene: POC1A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PIK3R1 Achchuthan Shanmugasundram commented on gene: PIK3R1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCYT1A Achchuthan Shanmugasundram commented on gene: PCYT1A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCNT Achchuthan Shanmugasundram commented on gene: PCNT: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 MFN2 Achchuthan Shanmugasundram commented on gene: MFN2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 EPHX1 Achchuthan Shanmugasundram commented on gene: EPHX1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 BLM Achchuthan Shanmugasundram commented on gene: BLM: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 ALMS1 Achchuthan Shanmugasundram commented on gene: ALMS1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.65 WRN Achchuthan Shanmugasundram Source Expert Review Green was added to WRN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PSMB8 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMB8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PSMB4 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 POC1A Achchuthan Shanmugasundram Source Expert Review Green was added to POC1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PIK3R1 Achchuthan Shanmugasundram Source Expert Review Green was added to PIK3R1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PCYT1A Achchuthan Shanmugasundram Source Expert Review Green was added to PCYT1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PCNT Achchuthan Shanmugasundram Source Expert Review Green was added to PCNT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 MFN2 Achchuthan Shanmugasundram Source Expert Review Green was added to MFN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 EPHX1 Achchuthan Shanmugasundram Source Expert Review Green was added to EPHX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 BLM Achchuthan Shanmugasundram Source Expert Review Green was added to BLM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 ALMS1 Achchuthan Shanmugasundram Source Expert Review Green was added to ALMS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Classified gene: RAB5B as Amber List (moderate evidence)
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is only one human case and functional evidence from C. elegans and proband's lung biopsy reported so far, this gene should be rated amber with current evidence.
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Gene: rab5b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v0.3 RAB5B Achchuthan Shanmugasundram changed review comment from: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia; to: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia.
Childhood interstitial lung disease v0.3 RAB5B Achchuthan Shanmugasundram edited their review of gene: RAB5B: Added comment: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia; Changed rating: AMBER
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: MVK.
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska edited their review of gene: MVK: Added comment: Comment on list classification: There are at least 9 unrelated families reported in literature with porokeratosis / disseminated superficial actinic porokeratosis (DSAP), with heterozygous germline mutations in MVK, with confirmed postnatal second-hit mosaic MVK mutation in 2 cases. Other genes in the pathway have been implicated in porokeratosis. Based on available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.; Changed rating: GREEN
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska Phenotypes for gene: MVK were changed from Porokeratosis 3, multiple types, OMIM:175900 to Porokeratosis 3, multiple types, OMIM:175900; porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Mosaic skin disorders - deep sequencing v3.24 MVK Ida Ertmanska Publications for gene: MVK were set to 24781643
Mosaic skin disorders - deep sequencing v3.23 MVK Ida Ertmanska Classified gene: MVK as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.23 MVK Ida Ertmanska Gene: mvk has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.22 MVK Ida Ertmanska Tag curated_removed was removed from gene: MVK.
Mosaic skin disorders - deep sequencing v3.22 MVK Ida Ertmanska reviewed gene: MVK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22983302, 26794421, 31207227, 31753123, 39386107; Phenotypes: Porokeratosis 3, multiple types, OMIM:175900, porokeratosis 3, disseminated superficial actinic type, MONDO:0008293; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v4.13 MVK Ida Ertmanska Phenotypes for gene: MVK were changed from Porokeratosis 3, multiple types, OMIM:175900 to Porokeratosis 3, multiple types, OMIM:175900; porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Rare genetic inflammatory skin disorders v4.12 MVK Ida Ertmanska Publications for gene: MVK were set to 26794421; 39386107
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska changed review comment from: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature; to: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska edited their review of gene: MVK: Added comment: Comment on list classification: There are at least 9 unrelated families reported in literature with porokeratosis / disseminated superficial actinic porokeratosis (DSAP), with heterozygous germline mutations in MVK, with confirmed postnatal second-hit mosaic MVK mutation in 2 cases. Other genes in the pathway have been implicated in porokeratosis. Based on available evidence, this gene should be promoted to Green for Rare genetic inflammatory skin disorders.; Changed phenotypes to: Porokeratosis 3, multiple types, OMIM:175900, porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska edited their review of gene: MVK: Changed publications to: 22983302, 26794421, 31207227, 31753123, 39386107
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska Classified gene: MVK as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska Gene: mvk has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: MVK.
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska changed review comment from: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature; to: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska gene: MVK was added
gene: MVK was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: MVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVK were set to 26794421; 39386107
Phenotypes for gene: MVK were set to Porokeratosis 3, multiple types, OMIM:175900
Review for gene: MVK was set to GREEN
Added comment: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Tag Q4_25_promote_green was removed from gene: PMVK.
Tag curated_removed tag was added to gene: PMVK.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Classified gene: PMVK as No list
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Added comment: Comment on list classification: Gene added to Rare genetic inflammatory skin disorders instead.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Gene: pmvk has been removed from the panel.
Pigmentary skin disorders v4.11 PMVK Ida Ertmanska Classified gene: PMVK as No list
Pigmentary skin disorders v4.11 PMVK Ida Ertmanska Gene: pmvk has been removed from the panel.
Pigmentary skin disorders v4.10 PMVK Ida Ertmanska Deleted their review
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Classified gene: PMVK as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Added comment: Comment on list classification: There are at least 13 unrelated individuals reported in literature with germline heterozygous variants in PMVK, diagnosed with a type of porokeratosis. Based on the available evidence, PMVK should be promoted to Green for Rare genetic inflammatory skin disorders.
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Gene: pmvk has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.8 PMVK Ida Ertmanska gene: PMVK was added
gene: PMVK was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976; 27052676; 37315547; 41296516
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, OMIM:175800; porokeratosis, MONDO:0006602
Review for gene: PMVK was set to GREEN
Added comment: Porokeratosis is characterised by keratotic lesions with an atrophic center rimmed by an elevated border. Disease onset is mostly in childhood or adolescence.

PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES. Age of onset: mostly between 5-10 yo.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man, presented with persistent non-pruritic skin lesions since childhood: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Sources: Literature
Cerebellar hypoplasia v1.86 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar Hypoplasia type 2C; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia type 2C,612390 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Cerebellar hypoplasia v1.85 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to PMID: 18711368
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Classified gene: TSEN34 as Amber List (moderate evidence)
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Added comment: Comment on list classification: There is only one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2 (PMID: 20952379 Namavar et al., 2011). While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature (see literature review on Intellectual disability panel). Hence, TSEN34 should be demoted from Green, until more evidence emerges.
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Gene: tsen34 has been classified as Amber List (Moderate Evidence).
DDG2P v6.14 TSEN34 Ida Ertmanska commented on gene: TSEN34
Fetal anomalies v6.129 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Fetal anomalies v6.129 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Fetal anomalies v6.129 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: AMBER; Mode of pathogenicity: None; Publications: 20952379, 27370523, 32476018, 37544645; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.129 BHLHE22 Arina Puzriakova commented on gene: BHLHE22: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag watchlist tag was added to gene: BHLHE22.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Intellectual disability v9.209 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag watchlist tag was added to gene: BHLHE22.
Intellectual disability v9.209 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (6/7 individuals available for examination exhibited significant GDD and ID). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram commented on gene: TMEM173: The 'new-gene-name' tag has been added as the official HGNC gene symbol for TMEM173 is STING1.
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: TMEM173.
Childhood interstitial lung disease v0.2 TERC Achchuthan Shanmugasundram Tag locus-type-rna-long-non-coding tag was added to gene: TERC.
Childhood interstitial lung disease v0.2 NAF1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NAF1.
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram commented on gene: MARS: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: MARS.
Childhood interstitial lung disease v0.2 CSF2RA Achchuthan Shanmugasundram Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Childhood interstitial lung disease v0.2 FARSB Achchuthan Shanmugasundram reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Rajab interstitial lung disease with brain calcifications 1, OMIM:613658, Rajab interstitial lung disease with brain calcifications 1, MONDO:0100215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 FARSA Achchuthan Shanmugasundram reviewed gene: FARSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013, Rajab interstitial lung disease with brain calcifications 2, MONDO:0100220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 LRBA Achchuthan Shanmugasundram reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: combined immunodeficiency due to LRBA deficiency, MONDO:0013863, Immunodeficiency, common variable, 8, with autoimmunity, OMIM:614700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SLC7A7 Achchuthan Shanmugasundram reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: lysinuric protein intolerance, MONDO:0009109, Lysinuric protein intolerance, OMIM:222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 GATA2 Achchuthan Shanmugasundram reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Immunodeficiency 21, OMIM:614172, monocytopenia with susceptibility to infections, MONDO:0013607; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 RAB5B Achchuthan Shanmugasundram reviewed gene: RAB5B: Rating: GREEN; Mode of pathogenicity: ; Publications: 35121658; Phenotypes: interstitial lung disease, MONDO:0015925; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TBX4 Achchuthan Shanmugasundram reviewed gene: TBX4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891, Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, OMIM:601360, congenital alveolar dysplasia due to TBX4, MONDO:0100097, autosomal recessive amelia, MONDO:0011054; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 PSMB9 Achchuthan Shanmugasundram reviewed gene: PSMB9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 6, MONDO:0968983, Proteasome-associated autoinflammatory syndrome 6, OMIM:620796; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 OAS1 Achchuthan Shanmugasundram reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary alveolar proteinosis with hypogammaglobulinemia, MONDO:0020840, Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 NKX2-1 Achchuthan Shanmugasundram reviewed gene: NKX2-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 CSF2RB Achchuthan Shanmugasundram reviewed gene: CSF2RB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 5, MONDO:0013712, Surfactant metabolism dysfunction, pulmonary, 5, OMIM:614370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 BMPR2 Achchuthan Shanmugasundram reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated, OMIM:178600, Pulmonary venoocclusive disease 1, OMIM:265450, pulmonary hypertension, primary, 1, MONDO:0024533, pulmonary venoocclusive disease 1, MONDO:0020713, Pulmonary hypertension, familial primary, 1, with or without HHT, OMIM:178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 PSMB8 Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 RTEL1 Achchuthan Shanmugasundram reviewed gene: RTEL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, MONDO:0014613, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3, OMIM:616373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 ABCA3 Achchuthan Shanmugasundram reviewed gene: ABCA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921, interstitial lung disease due to ABCA3 deficiency, MONDO:0012582; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 CSF2RA Achchuthan Shanmugasundram reviewed gene: CSF2RA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 4, OMIM:300770, surfactant metabolism dysfunction, pulmonary, 4, MONDO:0010424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SLC34A2 Achchuthan Shanmugasundram reviewed gene: SLC34A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary alveolar microlithiasis, MONDO:0009928, Pulmonary alveolar microlithiasis, OMIM:265100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 PSMB4 Achchuthan Shanmugasundram reviewed gene: PSMB4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 3, MONDO:0054699, ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram reviewed gene: MARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung and liver disease, OMIM:615486, severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, MONDO:0014206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SFTPC Achchuthan Shanmugasundram reviewed gene: SFTPC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 2, MONDO:0024465, SFTPC-related interstitial lung disease, MONDO:0018603, Surfactant metabolism dysfunction, pulmonary, 2, OMIM:610913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 ITGA3 Achchuthan Shanmugasundram reviewed gene: ITGA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, OMIM:614748, epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, MONDO:0013881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: STING-associated vasculopathy, infantile-onset, OMIM:615934, STING-associated vasculopathy with onset in infancy, MONDO:0014405; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 COPA Achchuthan Shanmugasundram reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Autoinflammation and autoimmunity, systemic, with immune dysregulation 1}, OMIM:616414, autoimmune interstitial lung disease-arthritis syndrome, MONDO:0014629; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 NAF1 Achchuthan Shanmugasundram reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MONDO:0957261, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 SFTPB Achchuthan Shanmugasundram reviewed gene: SFTPB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 1, MONDO:0009929, Surfactant metabolism dysfunction, pulmonary, 1, OMIM:265120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 FOXF1 Achchuthan Shanmugasundram reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380, alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 STAT5B Achchuthan Shanmugasundram reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MONDO:0100211, Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 TINF2 Achchuthan Shanmugasundram reviewed gene: TINF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal dominant 3, OMIM:613990; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TERC Achchuthan Shanmugasundram reviewed gene: TERC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, MONDO:0013879, Dyskeratosis congenita, autosomal dominant 1, OMIM:127550, dyskeratosis congenita, autosomal dominant 1, MONDO:0007485, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, OMIM:614743; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 SFTPA2 Achchuthan Shanmugasundram reviewed gene: SFTPA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung disease 2, OMIM:178500, interstitial lung disease 2, MONDO:0800497; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 FLNA Achchuthan Shanmugasundram reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: heterotopia, periventricular, X-linked dominant, MONDO:0010233, Heterotopia, periventricular, 1, OMIM:300049; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Childhood interstitial lung disease v0.2 STAT1 Achchuthan Shanmugasundram reviewed gene: STAT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant, OMIM:614162, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, MONDO:0013599; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 PARN Achchuthan Shanmugasundram reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4, OMIM:616371, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, MONDO:0014612; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TERT Achchuthan Shanmugasundram reviewed gene: TERT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989, dyskeratosis congenita, autosomal dominant 2, MONDO:0013521, Dyskeratosis congenita, autosomal dominant 2, OMIM:613989, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1, OMIM:614742, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, MONDO:0013878; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SFTPA1 Achchuthan Shanmugasundram reviewed gene: SFTPA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung disease 1, OMIM:619611, interstitial lung disease 1, MONDO:0030608; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood interstitial lung disease v0.1 FARSB Achchuthan Shanmugasundram gene: FARSB was added
gene: FARSB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FARSB were set to Rajab interstitial lung disease with brain calcifications 1, OMIM:613658; Rajab interstitial lung disease with brain calcifications 1, MONDO:0100215
Childhood interstitial lung disease v0.1 FARSA Achchuthan Shanmugasundram gene: FARSA was added
gene: FARSA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013; Rajab interstitial lung disease with brain calcifications 2, MONDO:0100220
Childhood interstitial lung disease v0.1 LRBA Achchuthan Shanmugasundram gene: LRBA was added
gene: LRBA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity, OMIM:614700; combined immunodeficiency due to LRBA deficiency, MONDO:0013863
Childhood interstitial lung disease v0.1 SLC7A7 Achchuthan Shanmugasundram gene: SLC7A7 was added
gene: SLC7A7 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SLC7A7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC7A7 were set to Lysinuric protein intolerance, OMIM:222700; lysinuric protein intolerance, MONDO:0009109
Childhood interstitial lung disease v0.1 GATA2 Achchuthan Shanmugasundram gene: GATA2 was added
gene: GATA2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GATA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GATA2 were set to Immunodeficiency 21, OMIM:614172; monocytopenia with susceptibility to infections, MONDO:0013607
Childhood interstitial lung disease v0.1 RAB5B Achchuthan Shanmugasundram gene: RAB5B was added
gene: RAB5B was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RAB5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5B were set to 35121658
Phenotypes for gene: RAB5B were set to interstitial lung disease, MONDO:0015925
Childhood interstitial lung disease v0.1 TBX4 Achchuthan Shanmugasundram gene: TBX4 was added
gene: TBX4 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TBX4 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: TBX4 were set to autosomal recessive amelia, MONDO:0011054; Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891; Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, OMIM:601360; congenital alveolar dysplasia due to TBX4, MONDO:0100097
Childhood interstitial lung disease v0.1 PSMB9 Achchuthan Shanmugasundram gene: PSMB9 was added
gene: PSMB9 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PSMB9 were set to proteasome-associated autoinflammatory syndrome 6, MONDO:0968983; Proteasome-associated autoinflammatory syndrome 6, OMIM:620796
Childhood interstitial lung disease v0.1 OAS1 Achchuthan Shanmugasundram gene: OAS1 was added
gene: OAS1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042; pulmonary alveolar proteinosis with hypogammaglobulinemia, MONDO:0020840
Childhood interstitial lung disease v0.1 NKX2-1 Achchuthan Shanmugasundram gene: NKX2-1 was added
gene: NKX2-1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NKX2-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978; NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520
Childhood interstitial lung disease v0.1 CSF2RB Achchuthan Shanmugasundram gene: CSF2RB was added
gene: CSF2RB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CSF2RB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CSF2RB were set to Surfactant metabolism dysfunction, pulmonary, 5, OMIM:614370; surfactant metabolism dysfunction, pulmonary, 5, MONDO:0013712
Childhood interstitial lung disease v0.1 BMPR2 Achchuthan Shanmugasundram gene: BMPR2 was added
gene: BMPR2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BMPR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BMPR2 were set to Pulmonary hypertension, familial primary, 1, with or without HHT, OMIM:178600; pulmonary hypertension, primary, 1, MONDO:0024533; Pulmonary venoocclusive disease 1, OMIM:265450; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated, OMIM:178600; pulmonary venoocclusive disease 1, MONDO:0020713
Childhood interstitial lung disease v0.1 PSMB8 Achchuthan Shanmugasundram gene: PSMB8 was added
gene: PSMB8 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB8 were set to proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040
Childhood interstitial lung disease v0.1 RTEL1 Achchuthan Shanmugasundram gene: RTEL1 was added
gene: RTEL1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RTEL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RTEL1 were set to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3, OMIM:616373; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, MONDO:0014613
Childhood interstitial lung disease v0.1 ABCA3 Achchuthan Shanmugasundram gene: ABCA3 was added
gene: ABCA3 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ABCA3 were set to interstitial lung disease due to ABCA3 deficiency, MONDO:0012582; Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921
Childhood interstitial lung disease v0.1 CSF2RA Achchuthan Shanmugasundram gene: CSF2RA was added
gene: CSF2RA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CSF2RA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CSF2RA were set to Surfactant metabolism dysfunction, pulmonary, 4, OMIM:300770; surfactant metabolism dysfunction, pulmonary, 4, MONDO:0010424
Childhood interstitial lung disease v0.1 SLC34A2 Achchuthan Shanmugasundram gene: SLC34A2 was added
gene: SLC34A2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SLC34A2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC34A2 were set to Pulmonary alveolar microlithiasis, OMIM:265100; pulmonary alveolar microlithiasis, MONDO:0009928
Childhood interstitial lung disease v0.1 PSMB4 Achchuthan Shanmugasundram gene: PSMB4 was added
gene: PSMB4 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB4 were set to proteasome-associated autoinflammatory syndrome 3, MONDO:0054699; ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591
Childhood interstitial lung disease v0.1 MARS Achchuthan Shanmugasundram gene: MARS was added
gene: MARS was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: MARS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MARS were set to severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, MONDO:0014206; Interstitial lung and liver disease, OMIM:615486
Childhood interstitial lung disease v0.1 SFTPC Achchuthan Shanmugasundram gene: SFTPC was added
gene: SFTPC was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SFTPC were set to Surfactant metabolism dysfunction, pulmonary, 2, OMIM:610913; SFTPC-related interstitial lung disease, MONDO:0018603; surfactant metabolism dysfunction, pulmonary, 2, MONDO:0024465
Childhood interstitial lung disease v0.1 ITGA3 Achchuthan Shanmugasundram gene: ITGA3 was added
gene: ITGA3 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ITGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGA3 were set to epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, MONDO:0013881; Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, OMIM:614748
Childhood interstitial lung disease v0.1 TMEM173 Achchuthan Shanmugasundram gene: TMEM173 was added
gene: TMEM173 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TMEM173 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TMEM173 were set to STING-associated vasculopathy with onset in infancy, MONDO:0014405; STING-associated vasculopathy, infantile-onset, OMIM:615934
Childhood interstitial lung disease v0.1 COPA Achchuthan Shanmugasundram gene: COPA was added
gene: COPA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: COPA were set to autoimmune interstitial lung disease-arthritis syndrome, MONDO:0014629; {Autoinflammation and autoimmunity, systemic, with immune dysregulation 1}, OMIM:616414
Childhood interstitial lung disease v0.1 NAF1 Achchuthan Shanmugasundram gene: NAF1 was added
gene: NAF1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NAF1 were set to pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MONDO:0957261; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365
Childhood interstitial lung disease v0.1 SFTPB Achchuthan Shanmugasundram gene: SFTPB was added
gene: SFTPB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SFTPB were set to Surfactant metabolism dysfunction, pulmonary, 1, OMIM:265120; surfactant metabolism dysfunction, pulmonary, 1, MONDO:0009929
Childhood interstitial lung disease v0.1 FOXF1 Achchuthan Shanmugasundram gene: FOXF1 was added
gene: FOXF1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FOXF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FOXF1 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934
Childhood interstitial lung disease v0.1 STAT5B Achchuthan Shanmugasundram gene: STAT5B was added
gene: STAT5B was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: STAT5B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STAT5B were set to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MONDO:0100211
Childhood interstitial lung disease v0.1 TINF2 Achchuthan Shanmugasundram gene: TINF2 was added
gene: TINF2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TINF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TINF2 were set to Dyskeratosis congenita, autosomal dominant 3, OMIM:613990
Childhood interstitial lung disease v0.1 TERC Achchuthan Shanmugasundram gene: TERC was added
gene: TERC was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TERC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TERC were set to dyskeratosis congenita, autosomal dominant 1, MONDO:0007485; Dyskeratosis congenita, autosomal dominant 1, OMIM:127550; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, MONDO:0013879; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, OMIM:614743
Childhood interstitial lung disease v0.1 SFTPA2 Achchuthan Shanmugasundram gene: SFTPA2 was added
gene: SFTPA2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SFTPA2 were set to interstitial lung disease 2, MONDO:0800497; Interstitial lung disease 2, OMIM:178500
Childhood interstitial lung disease v0.1 FLNA Achchuthan Shanmugasundram gene: FLNA was added
gene: FLNA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: FLNA were set to heterotopia, periventricular, X-linked dominant, MONDO:0010233; Heterotopia, periventricular, 1, OMIM:300049
Childhood interstitial lung disease v0.1 STAT1 Achchuthan Shanmugasundram gene: STAT1 was added
gene: STAT1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: STAT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STAT1 were set to Immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant, OMIM:614162; autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, MONDO:0013599
Childhood interstitial lung disease v0.1 PARN Achchuthan Shanmugasundram gene: PARN was added
gene: PARN was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PARN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PARN were set to pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, MONDO:0014612; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4, OMIM:616371
Childhood interstitial lung disease v0.1 TERT Achchuthan Shanmugasundram gene: TERT was added
gene: TERT was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TERT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: TERT were set to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1, OMIM:614742; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; dyskeratosis congenita, autosomal dominant 2, MONDO:0013521; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, MONDO:0013878
Childhood interstitial lung disease v0.1 SFTPA1 Achchuthan Shanmugasundram gene: SFTPA1 was added
gene: SFTPA1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: SFTPA1 were set to Interstitial lung disease 1, OMIM:619611; interstitial lung disease 1, MONDO:0030608
Childhood interstitial lung disease v0.0 Achchuthan Shanmugasundram Added Panel Childhood interstitial lung disease
Set list of related panels to R462
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram changed review comment from: It is only duplications in this gene are relevant for this panel.; to: Duplications in this gene are only relevant for this panel. Hence, 'gene-duplication' tag has been added.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram Tag gene-duplication tag was added to gene: T.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram commented on gene: T: It is only duplications in this gene are relevant for this panel.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram commented on gene: T: Added new-gene-name tag, new approved HGNC gene symbol is TBXT.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram reviewed gene: T: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: T.
Sarcoma of possible germline origin v0.2 TP53 Achchuthan Shanmugasundram reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Colorectal cancer}, OMIM:114500, basal cell carcinoma, susceptibility to, 7, MONDO:0013876, adrenocortical carcinoma, hereditary, MONDO:0008734, {Glioma susceptibility 1}, OMIM:137800, nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775, Li-Fraumeni syndrome, OMIM:151623, Li-Fraumeni syndrome, MONDO:0018875, {Basal cell carcinoma 7}, OMIM:614740, choroid plexus papilloma, MONDO:0009837, {Adrenocortical carcinoma, pediatric}, OMIM:202300, {Choroid plexus papilloma}, OMIM:260500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 RECQL4 Achchuthan Shanmugasundram reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Rothmund-Thomson syndrome, type 2, OMIM:268400, Rothmund-Thomson syndrome type 2, MONDO:0016369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 WRN Achchuthan Shanmugasundram reviewed gene: WRN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Werner syndrome, MONDO:0010196, Werner syndrome, OMIM:277700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 RB1 Achchuthan Shanmugasundram reviewed gene: RB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Retinoblastoma, OMIM:180200, Retinoblastoma, trilateral, OMIM:180200, hereditary retinoblastoma, MONDO:0018160; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 PTPN11 Achchuthan Shanmugasundram reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 1, OMIM:163950, Noonan syndrome 1, MONDO:0008104; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neurofibromatosis type 1, MONDO:0018975, Neurofibromatosis, type 1, OMIM:162200, neurofibromatosis-Noonan syndrome, MONDO:0011035, Neurofibromatosis, familial spinal, OMIM:162210, Leukemia, juvenile myelomonocytic, OMIM:607785, Neurofibromatosis-Noonan syndrome, OMIM:601321; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 NBN Achchuthan Shanmugasundram reviewed gene: NBN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nijmegen breakage syndrome, OMIM:251260, Nijmegen breakage syndrome, MONDO:0009623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 KRAS Achchuthan Shanmugasundram reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 3, OMIM:609942, cardiofaciocutaneous syndrome 2, MONDO:0014112, Noonan syndrome 3, MONDO:0012371, Cardiofaciocutaneous syndrome 2, OMIM:615278, RAS-associated autoimmune leukoproliferative disorder, OMIM:614470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 HRAS Achchuthan Shanmugasundram reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Costello syndrome, MONDO:0009026, Costello syndrome, OMIM:218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 DICER1 Achchuthan Shanmugasundram reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pleuropulmonary blastoma, OMIM:601200, Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800, Rhabdomyosarcoma, embryonal, 2, OMIM:180295, rhabdomyosarcoma, embryonal, 2, MONDO:0859046, DICER1-related tumor predisposition, MONDO:0100216; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sarcoma of possible germline origin v0.2 CBL Achchuthan Shanmugasundram reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563, CBL-related disorder, MONDO:0013308, ?Juvenile myelomonocytic leukemia, OMIM:607785; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 BUB1B Achchuthan Shanmugasundram reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 1, MONDO:0009759, Mosaic variegated aneuploidy syndrome 1, OMIM:257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.1 TP53 Achchuthan Shanmugasundram gene: TP53 was added
gene: TP53 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TP53 were set to {Colorectal cancer}, OMIM:114500; basal cell carcinoma, susceptibility to, 7, MONDO:0013876; adrenocortical carcinoma, hereditary, MONDO:0008734; {Glioma susceptibility 1}, OMIM:137800; nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775; Li-Fraumeni syndrome, OMIM:151623; Li-Fraumeni syndrome, MONDO:0018875; {Basal cell carcinoma 7}, OMIM:614740; choroid plexus papilloma, MONDO:0009837; {Adrenocortical carcinoma, pediatric}, OMIM:202300; {Choroid plexus papilloma}, OMIM:260500
Sarcoma of possible germline origin v0.1 T Achchuthan Shanmugasundram gene: T was added
gene: T was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: T was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.1 RECQL4 Achchuthan Shanmugasundram gene: RECQL4 was added
gene: RECQL4 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RECQL4 were set to Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369
Sarcoma of possible germline origin v0.1 WRN Achchuthan Shanmugasundram gene: WRN was added
gene: WRN was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WRN were set to Werner syndrome, MONDO:0010196; Werner syndrome, OMIM:277700
Sarcoma of possible germline origin v0.1 RB1 Achchuthan Shanmugasundram gene: RB1 was added
gene: RB1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RB1 were set to Retinoblastoma, OMIM:180200; Retinoblastoma, trilateral, OMIM:180200; hereditary retinoblastoma, MONDO:0018160
Sarcoma of possible germline origin v0.1 PTPN11 Achchuthan Shanmugasundram gene: PTPN11 was added
gene: PTPN11 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTPN11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTPN11 were set to Noonan syndrome 1, OMIM:163950; Noonan syndrome 1, MONDO:0008104
Sarcoma of possible germline origin v0.1 NF1 Achchuthan Shanmugasundram gene: NF1 was added
gene: NF1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: NF1 were set to neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, OMIM:162200; neurofibromatosis-Noonan syndrome, MONDO:0011035; Neurofibromatosis, familial spinal, OMIM:162210; Leukemia, juvenile myelomonocytic, OMIM:607785; Neurofibromatosis-Noonan syndrome, OMIM:601321
Sarcoma of possible germline origin v0.1 NBN Achchuthan Shanmugasundram gene: NBN was added
gene: NBN was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NBN were set to Nijmegen breakage syndrome, OMIM:251260; Nijmegen breakage syndrome, MONDO:0009623
Sarcoma of possible germline origin v0.1 KRAS Achchuthan Shanmugasundram gene: KRAS was added
gene: KRAS was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KRAS were set to Noonan syndrome 3, OMIM:609942; cardiofaciocutaneous syndrome 2, MONDO:0014112; Noonan syndrome 3, MONDO:0012371; Cardiofaciocutaneous syndrome 2, OMIM:615278; RAS-associated autoimmune leukoproliferative disorder, OMIM:614470
Sarcoma of possible germline origin v0.1 HRAS Achchuthan Shanmugasundram gene: HRAS was added
gene: HRAS was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HRAS were set to Costello syndrome, MONDO:0009026; Costello syndrome, OMIM:218040
Sarcoma of possible germline origin v0.1 DICER1 Achchuthan Shanmugasundram gene: DICER1 was added
gene: DICER1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Pleuropulmonary blastoma, OMIM:601200; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; rhabdomyosarcoma, embryonal, 2, MONDO:0859046; DICER1-related tumor predisposition, MONDO:0100216
Sarcoma of possible germline origin v0.1 CBL Achchuthan Shanmugasundram gene: CBL was added
gene: CBL was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CBL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CBL were set to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563; CBL-related disorder, MONDO:0013308; ?Juvenile myelomonocytic leukemia, OMIM:607785
Sarcoma of possible germline origin v0.1 BUB1B Achchuthan Shanmugasundram gene: BUB1B was added
gene: BUB1B was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BUB1B were set to mosaic variegated aneuploidy syndrome 1, MONDO:0009759; Mosaic variegated aneuploidy syndrome 1, OMIM:257300
Sarcoma of possible germline origin v0.0 Achchuthan Shanmugasundram Added Panel Sarcoma of possible germline origin
Set list of related panels to R457
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Embryonal tumour of possible germline origin v0.5 ISCA-37401-Loss Achchuthan Shanmugasundram Phenotypes for Region: ISCA-37401-Loss were changed from Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072 to Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072; WAGR syndrome, MONDO:0008681
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram edited their review of Region: ISCA-37401-Loss: Changed rating: GREEN; Changed phenotypes to: Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072, WAGR syndrome, MONDO:0008681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram Added comment: Comment on phenotypes: The OMIM record (MIM #194072) was last accessed on 30 December 2025.
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram Phenotypes for Region: ISCA-37401-Loss were changed from Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072 to Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: ZNF865.
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Classified gene: ZNF865 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.209 ZNF865 Ida Ertmanska Classified gene: ZNF865 as Amber List (moderate evidence)
Intellectual disability v9.209 ZNF865 Ida Ertmanska Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.208 ZNF865 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: ZNF865.
Ataxia and cerebellar anomalies - narrow panel v8.40 ZNF865 Ida Ertmanska gene: ZNF865 was added
gene: ZNF865 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ZNF865 was set to GREEN
Added comment: PMID: 40936200 Bradbrook et al., 2025
Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies.
On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears.
14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals.

This gene is not yet linked to any phenotype in OMIM (accessed 30th Dec 2025).
Sources: Literature
Intellectual disability v9.208 ZNF865 Ida Ertmanska gene: ZNF865 was added
gene: ZNF865 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ZNF865 was set to GREEN
Added comment: PMID: 40936200 Bradbrook et al., 2025
Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies.
On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears.
14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals.

This gene is not yet linked to any phenotype in OMIM (accessed 30th Dec 2025).
Sources: Literature
Embryonal tumour of possible germline origin v0.3 ISCA-37401-Loss Achchuthan Shanmugasundram Entity copied from Childhood solid tumours v5.8
Embryonal tumour of possible germline origin v0.3 ISCA-37401-Loss Achchuthan Shanmugasundram Region: ISCA-37401-Loss was added
Region: ISCA-37401-Loss was added to Embryonal tumour of possible germline origin. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-37401-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37401-Loss were set to Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072
Embryonal tumour of possible germline origin v0.2 WT1 Achchuthan Shanmugasundram reviewed gene: WT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Frasier syndrome, OMIM:136680, Denys-Drash syndrome, OMIM:194080, Wilms tumor 1, MONDO:0008679, Frasier syndrome, MONDO:0007635, Denys-Drash syndrome, MONDO:0008682, Wilms tumor, type 1, OMIM:194070; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 TRIP13 Achchuthan Shanmugasundram reviewed gene: TRIP13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 3, MONDO:0054736, Mosaic variegated aneuploidy syndrome 3, OMIM:617598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 TRIM37 Achchuthan Shanmugasundram reviewed gene: TRIM37: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mulibrey nanism, MONDO:0009664, Mulibrey nanism, OMIM:253250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 TRIM28 Achchuthan Shanmugasundram reviewed gene: TRIM28: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor 7, MONDO:0979876, Wilms tumor 7, OMIM:621332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 TP53 Achchuthan Shanmugasundram reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Basal cell carcinoma 7}, OMIM:614740, Li-Fraumeni syndrome, MONDO:0018875, adrenocortical carcinoma, hereditary, MONDO:0008734, nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775, {Glioma susceptibility 1}, OMIM:137800, {Colorectal cancer}, OMIM:114500, {Adrenocortical carcinoma, pediatric}, OMIM:202300, choroid plexus papilloma, MONDO:0009837, Li-Fraumeni syndrome, OMIM:151623, {Choroid plexus papilloma}, OMIM:260500, basal cell carcinoma, susceptibility to, 7, MONDO:0013876; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SUFU Achchuthan Shanmugasundram reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: basal cell nevus syndrome 2, MONDO:0958189, {Medulloblastoma}, OMIM:155255, {Meningioma, familial, susceptibility to}, OMIM:607174, Basal cell nevus syndrome 2, OMIM:620343; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SOS1 Achchuthan Shanmugasundram reviewed gene: SOS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 4, MONDO:0012547, Noonan syndrome 4, OMIM:610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: SMARCB1-related schwannomatosis, MONDO:0024517, {Schwannomatosis-1, susceptibility to}, OMIM:162091, rhabdoid tumor predisposition syndrome 1, MONDO:0012252, {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SMARCA4 Achchuthan Shanmugasundram reviewed gene: SMARCA4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325, Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 REST Achchuthan Shanmugasundram reviewed gene: REST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor 6, MONDO:0014779, {Wilms tumor 6, susceptibility to}, OMIM:616806; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 PTPN11 Achchuthan Shanmugasundram reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 1, MONDO:0008104, Noonan syndrome 1, OMIM:163950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 PTCH1 Achchuthan Shanmugasundram reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Basal cell nevus syndrome 1, OMIM:109400, basal cell nevus syndrome 1, MONDO:0958174; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 PHOX2B Achchuthan Shanmugasundram reviewed gene: PHOX2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neuroblastoma, susceptibility to, 2, MONDO:0700041, Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026, {Neuroblastoma, susceptibility to, 2}, OMIM:613013; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 KRAS Achchuthan Shanmugasundram reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: RAS-associated autoimmune leukoproliferative disorder, OMIM:614470, cardiofaciocutaneous syndrome 2, MONDO:0014112, Cardiofaciocutaneous syndrome 2, OMIM:615278, Noonan syndrome 3, OMIM:609942, Noonan syndrome 3, MONDO:0012371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 HRAS Achchuthan Shanmugasundram reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Costello syndrome, MONDO:0009026, Costello syndrome, OMIM:218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 GPR161 Achchuthan Shanmugasundram reviewed gene: GPR161: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Medulloblastoma predisposition syndrome}, OMIM:155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 GPC3 Achchuthan Shanmugasundram reviewed gene: GPC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Simpson-Golabi-Behmel syndrome type 1, MONDO:0020602, Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Embryonal tumour of possible germline origin v0.2 EZH2 Achchuthan Shanmugasundram reviewed gene: EZH2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Weaver syndrome, OMIM:277590, Weaver syndrome, MONDO:0010193; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 ELP1 Achchuthan Shanmugasundram reviewed gene: ELP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Medulloblastoma}, OMIM:155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 DIS3L2 Achchuthan Shanmugasundram reviewed gene: DIS3L2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Perlman syndrome, MONDO:0009965, Perlman syndrome, OMIM:267000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 DICER1 Achchuthan Shanmugasundram reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800, rhabdomyosarcoma, embryonal, 2, MONDO:0859046, DICER1-related tumor predisposition, MONDO:0100216, Rhabdomyosarcoma, embryonal, 2, OMIM:180295, Pleuropulmonary blastoma, OMIM:601200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 CTR9 Achchuthan Shanmugasundram reviewed gene: CTR9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor, MONDO:0006058; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 CDKN1C Achchuthan Shanmugasundram reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Beckwith-Wiedemann syndrome, MONDO:0007534, Beckwith-Wiedemann syndrome, OMIM:130650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Embryonal tumour of possible germline origin v0.2 CBL Achchuthan Shanmugasundram reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563, ?Juvenile myelomonocytic leukemia, OMIM:607785, CBL-related disorder, MONDO:0013308; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 BUB1B Achchuthan Shanmugasundram reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 1, MONDO:0009759, Mosaic variegated aneuploidy syndrome 1, OMIM:257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 ALK Achchuthan Shanmugasundram reviewed gene: ALK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neuroblastoma, susceptibility to, 3, MONDO:0013083, {Neuroblastoma, susceptibility to, 3}, OMIM:613014; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.1 WT1 Achchuthan Shanmugasundram gene: WT1 was added
gene: WT1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: WT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: WT1 were set to Frasier syndrome, OMIM:136680; Wilms tumor, type 1, OMIM:194070; Wilms tumor 1, MONDO:0008679; Frasier syndrome, MONDO:0007635; Denys-Drash syndrome, OMIM:194080; Denys-Drash syndrome, MONDO:0008682
Embryonal tumour of possible germline origin v0.1 TRIP13 Achchuthan Shanmugasundram gene: TRIP13 was added
gene: TRIP13 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, OMIM:617598; mosaic variegated aneuploidy syndrome 3, MONDO:0054736
Embryonal tumour of possible germline origin v0.1 TRIM37 Achchuthan Shanmugasundram gene: TRIM37 was added
gene: TRIM37 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIM37 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRIM37 were set to mulibrey nanism, MONDO:0009664; Mulibrey nanism, OMIM:253250
Embryonal tumour of possible germline origin v0.1 TRIM28 Achchuthan Shanmugasundram gene: TRIM28 was added
gene: TRIM28 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIM28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TRIM28 were set to Wilms tumor 7, MONDO:0979876; Wilms tumor 7, OMIM:621332
Embryonal tumour of possible germline origin v0.1 TP53 Achchuthan Shanmugasundram gene: TP53 was added
gene: TP53 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TP53 were set to {Colorectal cancer}, OMIM:114500; {Adrenocortical carcinoma, pediatric}, OMIM:202300; choroid plexus papilloma, MONDO:0009837; {Choroid plexus papilloma}, OMIM:260500; Li-Fraumeni syndrome, MONDO:0018875; nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775; {Basal cell carcinoma 7}, OMIM:614740; Li-Fraumeni syndrome, OMIM:151623; basal cell carcinoma, susceptibility to, 7, MONDO:0013876; {Glioma susceptibility 1}, OMIM:137800; adrenocortical carcinoma, hereditary, MONDO:0008734
Embryonal tumour of possible germline origin v0.1 SUFU Achchuthan Shanmugasundram gene: SUFU was added
gene: SUFU was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SUFU were set to {Medulloblastoma}, OMIM:155255; Basal cell nevus syndrome 2, OMIM:620343; {Meningioma, familial, susceptibility to}, OMIM:607174; basal cell nevus syndrome 2, MONDO:0958189
Embryonal tumour of possible germline origin v0.1 SOS1 Achchuthan Shanmugasundram gene: SOS1 was added
gene: SOS1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SOS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOS1 were set to Noonan syndrome 4, OMIM:610733; Noonan syndrome 4, MONDO:0012547
Embryonal tumour of possible germline origin v0.1 SMARCB1 Achchuthan Shanmugasundram gene: SMARCB1 was added
gene: SMARCB1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SMARCB1 were set to SMARCB1-related schwannomatosis, MONDO:0024517; rhabdoid tumor predisposition syndrome 1, MONDO:0012252; {Schwannomatosis-1, susceptibility to}, OMIM:162091; {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322
Embryonal tumour of possible germline origin v0.1 SMARCA4 Achchuthan Shanmugasundram gene: SMARCA4 was added
gene: SMARCA4 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SMARCA4 were set to Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325
Embryonal tumour of possible germline origin v0.1 REST Achchuthan Shanmugasundram gene: REST was added
gene: REST was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: REST was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: REST were set to Wilms tumor 6, MONDO:0014779; {Wilms tumor 6, susceptibility to}, OMIM:616806
Embryonal tumour of possible germline origin v0.1 PTPN11 Achchuthan Shanmugasundram gene: PTPN11 was added
gene: PTPN11 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTPN11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTPN11 were set to Noonan syndrome 1, MONDO:0008104; Noonan syndrome 1, OMIM:163950
Embryonal tumour of possible germline origin v0.1 PTCH1 Achchuthan Shanmugasundram gene: PTCH1 was added
gene: PTCH1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTCH1 were set to Basal cell nevus syndrome 1, OMIM:109400; basal cell nevus syndrome 1, MONDO:0958174
Embryonal tumour of possible germline origin v0.1 PHOX2B Achchuthan Shanmugasundram gene: PHOX2B was added
gene: PHOX2B was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PHOX2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PHOX2B were set to central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026; neuroblastoma, susceptibility to, 2, MONDO:0700041; {Neuroblastoma, susceptibility to, 2}, OMIM:613013; Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880
Embryonal tumour of possible germline origin v0.1 KRAS Achchuthan Shanmugasundram gene: KRAS was added
gene: KRAS was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KRAS were set to Noonan syndrome 3, MONDO:0012371; cardiofaciocutaneous syndrome 2, MONDO:0014112; Cardiofaciocutaneous syndrome 2, OMIM:615278; RAS-associated autoimmune leukoproliferative disorder, OMIM:614470; Noonan syndrome 3, OMIM:609942
Embryonal tumour of possible germline origin v0.1 HRAS Achchuthan Shanmugasundram gene: HRAS was added
gene: HRAS was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HRAS were set to Costello syndrome, MONDO:0009026; Costello syndrome, OMIM:218040
Embryonal tumour of possible germline origin v0.1 GPR161 Achchuthan Shanmugasundram gene: GPR161 was added
gene: GPR161 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: GPR161 were set to {Medulloblastoma predisposition syndrome}, OMIM:155255
Embryonal tumour of possible germline origin v0.1 GPC3 Achchuthan Shanmugasundram gene: GPC3 was added
gene: GPC3 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GPC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: GPC3 were set to Simpson-Golabi-Behmel syndrome type 1, MONDO:0020602; Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870
Embryonal tumour of possible germline origin v0.1 EZH2 Achchuthan Shanmugasundram gene: EZH2 was added
gene: EZH2 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: EZH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: EZH2 were set to Weaver syndrome, OMIM:277590; Weaver syndrome, MONDO:0010193
Embryonal tumour of possible germline origin v0.1 ELP1 Achchuthan Shanmugasundram gene: ELP1 was added
gene: ELP1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ELP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ELP1 were set to {Medulloblastoma}, OMIM:155255
Embryonal tumour of possible germline origin v0.1 DIS3L2 Achchuthan Shanmugasundram gene: DIS3L2 was added
gene: DIS3L2 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DIS3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DIS3L2 were set to Perlman syndrome, MONDO:0009965; Perlman syndrome, OMIM:267000
Embryonal tumour of possible germline origin v0.1 DICER1 Achchuthan Shanmugasundram gene: DICER1 was added
gene: DICER1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Rhabdomyosarcoma, embryonal, 2, OMIM:180295; DICER1-related tumor predisposition, MONDO:0100216; rhabdomyosarcoma, embryonal, 2, MONDO:0859046; Pleuropulmonary blastoma, OMIM:601200; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800
Embryonal tumour of possible germline origin v0.1 CTR9 Achchuthan Shanmugasundram gene: CTR9 was added
gene: CTR9 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CTR9 were set to Wilms tumor, MONDO:0006058
Embryonal tumour of possible germline origin v0.1 CDKN1C Achchuthan Shanmugasundram gene: CDKN1C was added
gene: CDKN1C was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CDKN1C was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Phenotypes for gene: CDKN1C were set to Beckwith-Wiedemann syndrome, MONDO:0007534; Beckwith-Wiedemann syndrome, OMIM:130650
Embryonal tumour of possible germline origin v0.1 CBL Achchuthan Shanmugasundram gene: CBL was added
gene: CBL was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CBL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CBL were set to CBL-related disorder, MONDO:0013308; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563; ?Juvenile myelomonocytic leukemia, OMIM:607785
Embryonal tumour of possible germline origin v0.1 BUB1B Achchuthan Shanmugasundram gene: BUB1B was added
gene: BUB1B was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1, OMIM:257300; mosaic variegated aneuploidy syndrome 1, MONDO:0009759
Embryonal tumour of possible germline origin v0.1 ALK Achchuthan Shanmugasundram gene: ALK was added
gene: ALK was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALK were set to {Neuroblastoma, susceptibility to, 3}, OMIM:613014; neuroblastoma, susceptibility to, 3, MONDO:0013083
Mitochondrial disorders v9.40 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Likely inborn error of metabolism v8.86 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial DNA maintenance and integrity; Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Thymidine kinase 2 deficiency (Disorders of pyrimidine metabolism) to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Possible mitochondrial disorder - nuclear genes v4.19 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, 617069 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Undiagnosed metabolic disorders v1.642 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Thymidine kinase 2 deficiency (Disorders of pyrimidine metabolism); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Mitochondrial DNA maintenance disorder v3.7 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, 617069 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Intellectual disability v9.207 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Rhabdomyolysis and metabolic muscle disorders v5.13 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Neonatal diabetes v5.13 RNU6ATAC Ida Ertmanska Phenotypes for gene: RNU6ATAC were changed from neonatal diabetes; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia to neonatal diabetes mellitus, MONDO:0016391; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia
Neonatal diabetes v5.12 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Neonatal diabetes v5.12 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6ATAC.
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska changed review comment from: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU4ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).; to: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska commented on gene: RNU6ATAC: Comment on list classification: There are 7 individuals from 4 unrelated families with biallelic RNU6ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska edited their review of gene: RNU6ATAC: Changed rating: GREEN
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska reviewed gene: RNU6ATAC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neonatal diabetes mellitus, MONDO:0016391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.85 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Undiagnosed metabolic disorders v1.641 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Skeletal muscle channelopathy v3.7 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from Can resemble skeletal muscle channelopathy to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Neonatal diabetes v5.11 RNU4ATAC Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4ATAC.
Neonatal diabetes v5.11 RNU4ATAC Ida Ertmanska Phenotypes for gene: RNU4ATAC were changed from neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis to RNU4ATAC spectrum disorder, MONDO:0100558; neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis
Neonatal diabetes v5.10 RNU4ATAC Ida Ertmanska Classified gene: RNU4ATAC as Amber List (moderate evidence)
Neonatal diabetes v5.10 RNU4ATAC Ida Ertmanska Gene: rnu4atac has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.9 RNU4ATAC Ida Ertmanska commented on gene: RNU4ATAC: Comment on list classification: There are 12 unrelated individuals with biallelic RNU4ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.
Neonatal diabetes v5.9 RNU4ATAC Ida Ertmanska reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: RNU4ATAC spectrum disorder, MONDO:0100558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v4.5 RAP1B Ida Ertmanska Phenotypes for gene: RAP1B were changed from Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (OMIM #620654) to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MONDO:0958000
Bleeding and platelet disorders v4.4 RAP1B Ida Ertmanska Publications for gene: RAP1B were set to PMID: 32627184; 35451551; 37850357
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RAP1B.
Tag Q4_25_NHS_review tag was added to gene: RAP1B.
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Classified gene: RAP1B as Amber List (moderate evidence)
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Gene: rap1b has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.2 RAP1B Ida Ertmanska reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32627184, 35451551; Phenotypes: Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.92 BRAF Matthew Edwards reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Skeletal dysplasia v8.29 H2AFY Ida Ertmanska Tag currently-ngs-unreportable tag was added to gene: H2AFY.
Tag cnv tag was added to gene: H2AFY.
Skeletal dysplasia v8.29 H2AFY Ida Ertmanska Phenotypes for gene: H2AFY were changed from Liebenberg syndrome to Liebenberg syndrome; brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520
Skeletal dysplasia v8.28 H2AFY Ida Ertmanska Publications for gene: H2AFY were set to PMID: 30711920, PMID: 23587911
Skeletal dysplasia v8.27 H2AFY Ida Ertmanska Classified gene: H2AFY as Amber List (moderate evidence)
Skeletal dysplasia v8.27 H2AFY Ida Ertmanska Gene: h2afy has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska changed review comment from: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber for Skeletal dysplasia.; to: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and H2AFY should remain Amber for Skeletal dysplasia.
Ataxia and cerebellar anomalies - narrow panel v8.39 ATP6V0C Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current analysis pipeline and the the gene should remain Amber.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska commented on gene: H2AFY: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber for Skeletal dysplasia.
Ataxia and cerebellar anomalies - narrow panel v8.39 ATP6V0C Ida Ertmanska commented on gene: ATP6V0C: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current analysis pipeline and the the gene should remain Amber.
Ataxia and cerebellar anomalies - narrow panel v8.39 ATP6V0C Ida Ertmanska Phenotypes for gene: ATP6V0C were changed from to progressive ataxia and cognitive decline
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska edited their review of gene: ATP6V0C: Changed phenotypes to: progressive ataxia and cognitive decline
Embryonal tumour of possible germline origin v0.0 Achchuthan Shanmugasundram Added Panel Embryonal tumour of possible germline origin
Set list of related panels to R456
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska reviewed gene: H2AFY: Rating: AMBER; Mode of pathogenicity: None; Publications: 23022097, 23587911, 30711920; Phenotypes: brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska Classified gene: ATP6V0C as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska Tag currently-ngs-unreportable tag was added to gene: ATP6V0C.
Pulmonary alveolar microlithiasis v1.2 SLC34A2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #265100) and the OMIM record was last accessed on 29 December 2025.
Pulmonary alveolar microlithiasis v1.2 SLC34A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC34A2 were changed from to Pulmonary alveolar microlithiasis, OMIM:265100; pulmonary alveolar microlithiasis, MONDO:0009928
Familial tumours of the nervous system v2.13 SUFU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #155255 & #607174) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.13 SUFU Achchuthan Shanmugasundram Phenotypes for gene: SUFU were changed from to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial tumours of the nervous system v2.12 SMARCE1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607174) and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.12 SMARCE1 Achchuthan Shanmugasundram Phenotypes for gene: SMARCE1 were changed from to {Meningioma, familial, susceptibility to}, OMIM:607174
Familial tumours of the nervous system v2.11 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162091 & #609322) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.11 SMARCB1 Achchuthan Shanmugasundram Phenotypes for gene: SMARCB1 were changed from to {Schwannomatosis-1, susceptibility to}, OMIM:162091; {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322; rhabdoid tumor predisposition syndrome 1, MONDO:0012252; SMARCB1-related schwannomatosis, MONDO:0024517
Familial tumours of the nervous system v2.10 NF2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #101000 in OMIM and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.10 NF2 Achchuthan Shanmugasundram Phenotypes for gene: NF2 were changed from to Schwannomatosis, vestibular, OMIM:101000; NF2-related schwannomatosis, MONDO:0007039
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615670) and the OMIM record was last accessed on 29 December 2025.; to: Comment on phenotypes: This gene has been associated with MIM #615670 in OMIM and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615670) and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram Phenotypes for gene: LZTR1 were changed from to {Schwannomatosis-2, susceptibility to}, OMIM:615670; LZTR1-related schwannomatosis, MONDO:0014299
Familial tumours of the nervous system v2.8 CDKN2A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #155601, #155755 & #606719) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.8 CDKN2A Achchuthan Shanmugasundram Phenotypes for gene: CDKN2A were changed from {Melanoma and neural system tumor syndrome}, OMIM:155755; Astrocytoma; Glioblastoma; Schwannoma; Neurofibroma; Meningioma; Malignant peripheral nerve sheath tumours to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719; melanoma, cutaneous malignant, susceptibility to, 2, MONDO:0007964; melanoma and neural system tumor syndrome, MONDO:0007967; melanoma-pancreatic cancer syndrome, MONDO:0011713
Wiskott-Aldrich syndrome v1.3 WAS Achchuthan Shanmugasundram Phenotypes for gene: WAS were changed from Wiskott-Aldrich syndrome, OMIM:301000; Wilson disease, MONDO:0010200 to Wiskott-Aldrich syndrome, OMIM:301000; Wiskott-Aldrich syndrome, MONDO:0010518
Wiskott-Aldrich syndrome v1.2 WAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #301000) and the OMIM record was last accessed on 29 December 2025.
Wiskott-Aldrich syndrome v1.2 WAS Achchuthan Shanmugasundram Phenotypes for gene: WAS were changed from to Wiskott-Aldrich syndrome, OMIM:301000; Wilson disease, MONDO:0010200
Wilson disease v1.2 ATP7B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #277900) and the OMIM record was last accessed on 29 December 2025.
Wilson disease v1.2 ATP7B Achchuthan Shanmugasundram Phenotypes for gene: ATP7B were changed from to Wilson disease, OMIM:277900; Wilson disease, MONDO:0010200
von Willebrand disease v1.3 VWF Achchuthan Shanmugasundram Phenotypes for gene: VWF were changed from von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:001330; von Willebrand disease 3, MONDO:0010191 to von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:0013304; von Willebrand disease 3, MONDO:0010191
von Willebrand disease v1.2 VWF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #193400, #277480 & #613554) and the OMIM records were last accessed on 29 December 2025.
von Willebrand disease v1.2 VWF Achchuthan Shanmugasundram Phenotypes for gene: VWF were changed from to von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:001330; von Willebrand disease 3, MONDO:0010191
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska changed review comment from: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature; to: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

The minimal region of overlap for all patients included a single gene (ATP6V0C); RNA-seq using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase. Hence, ATP6V0C is the mostly likely candidate gene.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska gene: ATP6V0C was added
gene: ATP6V0C was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
cnv tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP6V0C were set to 41349538
Review for gene: ATP6V0C was set to AMBER
Added comment: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature
Von Hippel Lindau syndrome v1.2 VHL Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #193300 in OMIM and the OMIM record was last accessed on 29 December 2025.
Von Hippel Lindau syndrome v1.2 VHL Achchuthan Shanmugasundram Phenotypes for gene: VHL were changed from to von Hippel-Lindau syndrome, OMIM:193300; von Hippel-Lindau disease, MONDO:0008667
Tuberous sclerosis v1.3 TSC2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613254) and the OMIM record was last accessed on 29 December 2025.
Tuberous sclerosis v1.3 TSC2 Achchuthan Shanmugasundram Phenotypes for gene: TSC2 were changed from to Tuberous sclerosis-2, OMIM:613254; tuberous sclerosis 2, MONDO:0013199
Tuberous sclerosis v1.2 TSC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #191100) and the OMIM record was last accessed on 29 December 2025.
Tuberous sclerosis v1.2 TSC1 Achchuthan Shanmugasundram Phenotypes for gene: TSC1 were changed from to Tuberous sclerosis-1, OMIM:191100; tuberous sclerosis 1, MONDO:0008612
Thiamine metabolism dysfunction syndrome 2 v1.2 SLC19A3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607483) and the OMIM record was last accessed on 29 December 2025.
Thiamine metabolism dysfunction syndrome 2 v1.2 SLC19A3 Achchuthan Shanmugasundram Phenotypes for gene: SLC19A3 were changed from to Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type), OMIM:607483; biotin-responsive basal ganglia disease, MONDO:0011841
Thanatophoric dysplasia v1.2 FGFR3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #187600 & #187601) and the OMIM records were last accessed on 29 December 2025.
Thanatophoric dysplasia v1.2 FGFR3 Achchuthan Shanmugasundram Phenotypes for gene: FGFR3 were changed from to Thanatophoric dysplasia, type I, OMIM:187600; Thanatophoric dysplasia, type II, OMIM:187601; thanatophoric dysplasia, MONDO:0017042
Tay-Sachs disease v1.2 HEXA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #272800) and the OMIM record was last accessed on 29 December 2025.
Tay-Sachs disease v1.2 HEXA Achchuthan Shanmugasundram Phenotypes for gene: HEXA were changed from to Tay-Sachs disease, OMIM:272800; Tay-Sachs disease, MONDO:0010100
Syndromic and non syndromic craniosynostosis involving midline sutures v1.2 SMAD6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #617439) and the OMIM record was last accessed on 29 December 2025.
Syndromic and non syndromic craniosynostosis involving midline sutures v1.2 SMAD6 Achchuthan Shanmugasundram Phenotypes for gene: SMAD6 were changed from to {Craniosynostosis 7, susceptibility to}, OMIM:617439; craniosynostosis 7, MONDO:0044315
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.2 HAVCR2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618398) and the OMIM record was last accessed on 29 December 2025.
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.2 HAVCR2 Achchuthan Shanmugasundram Phenotypes for gene: HAVCR2 were changed from to T-cell lymphoma, subcutaneous panniculitis-like, OMIM:618398; subcutaneous panniculitis-like T-cell lymphoma, MONDO:0019475
Spinal muscular atrophy type 1 rare mutation testing v1.2 SMN1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #253300 in OMIM and the OMIM record was last accessed on 29 December 2025.
Spinal muscular atrophy type 1 rare mutation testing v1.2 SMN1 Achchuthan Shanmugasundram Phenotypes for gene: SMN1 were changed from to Spinal muscular atrophy-1, OMIM:253300; spinal muscular atrophy, type 1, MONDO:0009669
Smith-Lemli-Opitz syndrome v1.2 DHCR7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #270400) and the OMIM record was last accessed on 29 December 2025.
Smith-Lemli-Opitz syndrome v1.2 DHCR7 Achchuthan Shanmugasundram Phenotypes for gene: DHCR7 were changed from to Smith-Lemli-Opitz syndrome, OMIM:270400; Smith-Lemli-Opitz syndrome, MONDO:0010035
Sitosterolaemia v1.3 ABCG8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #210250) and the OMIM record was last accessed on 29 December 2025.
Sitosterolaemia v1.3 ABCG8 Achchuthan Shanmugasundram Phenotypes for gene: ABCG8 were changed from to Sitosterolemia 1, OMIM:210250; sitosterolemia 1, MONDO:0020747
Sitosterolaemia v1.2 ABCG5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618666) and the OMIM record was last accessed on 29 December 2025.
Sitosterolaemia v1.2 ABCG5 Achchuthan Shanmugasundram Phenotypes for gene: ABCG5 were changed from to Sitosterolemia 2, OMIM:618666; sitosterolemia 2, MONDO:0020748
Short stature - SHOX deficiency v1.2 SHOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #12730, #249700 & #300582) and the OMIM records were last accessed on 29 December 2025.
Short stature - SHOX deficiency v1.2 SHOX Achchuthan Shanmugasundram Phenotypes for gene: SHOX were changed from to Leri-Weill dyschondrosteosis, OMIM:127300; Langer mesomelic dysplasia, OMIM:249700; Short stature, idiopathic familial, OMIM:300582; SHOX-related short stature, MONDO:0010367
Severe combined immunodeficiency with PNP deficiency v1.2 PNP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613179) and the OMIM record was last accessed on 29 December 2025.
Severe combined immunodeficiency with PNP deficiency v1.2 PNP Achchuthan Shanmugasundram Phenotypes for gene: PNP were changed from to Immunodeficiency due to purine nucleoside phosphorylase deficiency, OMIM:613179; purine nucleoside phosphorylase deficiency, MONDO:0013171
Severe combined immunodeficiency with adenosine deaminase deficiency v1.4 ADA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #102700) and the OMIM record was last accessed on 29 December 2025.
Severe combined immunodeficiency with adenosine deaminase deficiency v1.4 ADA Achchuthan Shanmugasundram Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, OMIM:102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, MONDO:0007064
Segmental or atypical neurofibromatosis type 1 testing v1.2 NF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162200, #162210 & #60132) and the OMIM records were last accessed on 29 December 2025.
Segmental or atypical neurofibromatosis type 1 testing v1.2 NF1 Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; neurofibromatosis type 1, MONDO:0018975; neurofibromatosis-Noonan syndrome, MONDO:0011035
SCID with features of gamma chain deficiency v1.2 IL2RG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300400 & #312863) and the OMIM records were last accessed on 29 December 2025.
SCID with features of gamma chain deficiency v1.2 IL2RG Achchuthan Shanmugasundram Phenotypes for gene: IL2RG were changed from to Severe combined immunodeficiency, X-linked, OMIM:300400; Combined immunodeficiency, X-linked, moderate, OMIM:312863; T-B+ severe combined immunodeficiency due to gamma chain deficiency, MONDO:0010315; combined immunodeficiency, X-linked, MONDO:0010730
Sandhoff disease v1.2 HEXB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #268800) and the OMIM record was last accessed on 29 December 2025.
Sandhoff disease v1.2 HEXB Achchuthan Shanmugasundram Phenotypes for gene: HEXB were changed from to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800; Sandhoff disease, MONDO:0010006
Retinoblastoma v1.2 RB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #180200) and the OMIM record was last accessed on 29 December 2025.
Retinoblastoma v1.2 RB1 Achchuthan Shanmugasundram Phenotypes for gene: RB1 were changed from to Retinoblastoma, OMIM:180200; Retinoblastoma, trilateral, OMIM:180200; hereditary retinoblastoma, MONDO:0018160
PTEN Hamartoma Tumour Syndrome v1.4 PTEN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #158350) and the OMIM record was last accessed on 29 December 2025.
PTEN Hamartoma Tumour Syndrome v1.4 PTEN Achchuthan Shanmugasundram Phenotypes for gene: PTEN were changed from to Cowden syndrome 1, OMIM:158350; Lhermitte-Duclos disease, OMIM:158350; PTEN harmartoma tumor syndrome with immune disorder, MONDO:0700330
Pseudoxanthoma elasticum v1.3 ENPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208000) and the OMIM record was last accessed on 29 December 2025.
Pseudoxanthoma elasticum v1.3 ENPP1 Achchuthan Shanmugasundram Phenotypes for gene: ENPP1 were changed from to Arterial calcification, generalized, of infancy, 1, OMIM:208000; arterial calcification, generalized, of infancy, 1, MONDO:0008817
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska Tag Q4_25_MOI tag was added to gene: MUC5B.
Pseudoxanthoma elasticum v1.2 ABCC6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #264800) and the OMIM record was last accessed on 29 December 2025.
Pseudoxanthoma elasticum v1.2 ABCC6 Achchuthan Shanmugasundram Phenotypes for gene: ABCC6 were changed from to Pseudoxanthoma elasticum, OMIM:264800; autosomal recessive inherited pseudoxanthoma elasticum, MONDO:0009925
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.; to: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b -/- knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska commented on gene: MUC5B: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska edited their review of gene: MUC5B: Changed rating: GREEN; Changed publications to: 24317696, 33526882, 35023825; Changed phenotypes to: {Pulmonary fibrosis, idiopathic, susceptibility to}, OMIM:178500, Pulmonary fibrosis, HP:0002206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary hyperaldosteronism - KCNJ5 v1.2 KCNJ5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613677) and the OMIM record was last accessed on 29 December 2025.
Primary hyperaldosteronism - KCNJ5 v1.2 KCNJ5 Achchuthan Shanmugasundram Phenotypes for gene: KCNJ5 were changed from to Hyperaldosteronism, familial, type III, OMIM:613677; familial hyperaldosteronism type III, MONDO:0013359
POLG-related disorder v1.2 POLG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #157640, #203700, #258450, #607459 & #613662) and the OMIM records were last accessed on 29 December 2025.
POLG-related disorder v1.2 POLG Achchuthan Shanmugasundram Phenotypes for gene: POLG were changed from to Progressive external ophthalmoplegia, autosomal dominant 1, OMIM:157640; Progressive external ophthalmoplegia, autosomal recessive 1, OMIM:258450; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1, MONDO:0024528; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, MONDO:0009783; sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, MONDO:0011835; mitochondrial DNA depletion syndrome 4a, MONDO:0008758; mitochondrial DNA depletion syndrome 4b, MONDO:0013350
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska commented on gene: MUC5B
Phenylketonuria v1.2 PAH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #261600) and the OMIM record was last accessed on 29 December 2025.
Phenylketonuria v1.2 PAH Achchuthan Shanmugasundram Phenotypes for gene: PAH were changed from to Phenylketonuria, OMIM:261600; phenylketonuria, MONDO:0009861
Peutz Jeghers Syndrome v1.2 STK11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #175200) and the OMIM record was last accessed on 29 December 2025.
Peutz Jeghers Syndrome v1.2 STK11 Achchuthan Shanmugasundram Phenotypes for gene: STK11 were changed from to Peutz-Jeghers syndrome, OMIM:175200; Peutz-Jeghers syndrome, MONDO:0008280
Nijmegen breakage syndrome v1.2 NBN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #251260) and the OMIM record was last accessed on 29 December 2025.
Nijmegen breakage syndrome v1.2 NBN Achchuthan Shanmugasundram Phenotypes for gene: NBN were changed from to Nijmegen breakage syndrome, OMIM:251260; Nijmegen breakage syndrome, MONDO:0009623
Niemann-Pick disease type A or B v1.2 SMPD1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #257200 & #607616) and the OMIM records were last accessed on 29 December 2025.
Niemann-Pick disease type A or B v1.2 SMPD1 Achchuthan Shanmugasundram Phenotypes for gene: SMPD1 were changed from to Niemann-Pick disease, type A, OMIM:257200; Niemann-Pick disease, type B, OMIM:607616; Niemann-Pick disease type A, MONDO:0009756; Niemann-Pick disease type B, MONDO:0011871
Niemann Pick disease type C v1.3 NPC2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607625) and the OMIM record was last accessed on 29 December 2025.
Niemann Pick disease type C v1.3 NPC2 Achchuthan Shanmugasundram Phenotypes for gene: NPC2 were changed from to Niemann-pick disease, type C2, OMIM:607625; Niemann-Pick disease, type C2, MONDO:0011873
Niemann Pick disease type C v1.2 NPC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #257220) and the OMIM record was last accessed on 29 December 2025.
Niemann Pick disease type C v1.2 NPC1 Achchuthan Shanmugasundram Phenotypes for gene: NPC1 were changed from to Niemann-Pick disease, type C1, OMIM:257220; Niemann-Pick disease, type D, OMIM:257220; Niemann-Pick disease, type C1, MONDO:0009757
Neurofibromatosis type 1 (GMS) v1.3 SPRED1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #611431) and the OMIM record was last accessed on 29 December 2025.
Neurofibromatosis type 1 (GMS) v1.3 SPRED1 Achchuthan Shanmugasundram Phenotypes for gene: SPRED1 were changed from to Legius syndrome, OMIM:611431; Legius syndrome, MONDO:0012669
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.3 SUFU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620343) and the OMIM record was last accessed on 29 December 2025.
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.3 SUFU Achchuthan Shanmugasundram Phenotypes for gene: SUFU were changed from to Basal cell nevus syndrome 2, OMIM:620343; basal cell nevus syndrome 2, MONDO:0958189
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.2 PTCH1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #109400) and the OMIM record was last accessed on 29 December 2025.
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.2 PTCH1 Achchuthan Shanmugasundram Phenotypes for gene: PTCH1 were changed from to Basal cell nevus syndrome 1, OMIM:109400; basal cell nevus syndrome 1, MONDO:0958174
Neutropaenia consistent with ELANE mutations v1.2 ELANE Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162800 & #202700) and the OMIM records were last accessed on 29 December 2025.
Neutropaenia consistent with ELANE mutations v1.2 ELANE Achchuthan Shanmugasundram Phenotypes for gene: ELANE were changed from to Neutropenia, cyclic, OMIM:162800; Neutropenia, severe congenital 1, autosomal dominant, OMIM:202700; ELANE-related neutropenia, MONDO:1060165
Neuronal ceroid lipofuscinosis type 2 v1.2 TPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #204500) and the OMIM record was last accessed on 29 December 2025.
Neuronal ceroid lipofuscinosis type 2 v1.2 TPP1 Achchuthan Shanmugasundram Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, OMIM:204500; neuronal ceroid lipofuscinosis 2, MONDO:0008769
Neurofibromatosis type 1 (GMS) v1.2 NF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162200, #162210 & #60132) and the OMIM records were last accessed on 29 December 2025.
Neurofibromatosis type 1 (GMS) v1.2 NF1 Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; neurofibromatosis type 1, MONDO:0018975; neurofibromatosis-Noonan syndrome, MONDO:0011035
Neonatal diabetes - small panel v1.5 KCNJ11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #610582 & #618856) and the OMIM records were last accessed on 29 December 2025.
Neonatal diabetes - small panel v1.5 KCNJ11 Achchuthan Shanmugasundram Phenotypes for gene: KCNJ11 were changed from to Diabetes mellitus, transient neonatal 3, OMIM:610582; Diabetes, permanent neonatal 2, with or without neurologic features, OMIM:618856; diabetes mellitus, transient neonatal, 3, MONDO:0012522; diabetes mellitus, permanent neonatal 2, MONDO:0030087
Neonatal diabetes - small panel v1.4 ABCC8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #618857 & #610374) and the OMIM records were last accessed on 29 December 2025.
Neonatal diabetes - small panel v1.4 ABCC8 Achchuthan Shanmugasundram Phenotypes for gene: ABCC8 were changed from to Diabetes mellitus, permanent neonatal 3, OMIM:618857; Diabetes mellitus, transient neonatal 2, OMIM:610374; diabetes mellitus, permanent neonatal 3, MONDO:0030088; diabetes mellitus, transient neonatal, 2, MONDO:0012480
Multiple exostoses v1.3 EXT2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #133701) and the OMIM record was last accessed on 29 December 2025.
Multiple exostoses v1.3 EXT2 Achchuthan Shanmugasundram Phenotypes for gene: EXT2 were changed from to Exostoses, multiple, type 2, OMIM:133701; exostoses, multiple, type 2, MONDO:0007586
Multiple exostoses v1.2 EXT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #133700) and the OMIM record was last accessed on 29 December 2025.
Multiple exostoses v1.2 EXT1 Achchuthan Shanmugasundram Phenotypes for gene: EXT1 were changed from to Exostoses, multiple, type 1, OMIM:133700; exostoses, multiple, type 1, MONDO:0007585
Multiple endocrine neoplasia type 2 v1.2 RET Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162300 & #171400) and the OMIM records were last accessed on 29 December 2025.
Multiple endocrine neoplasia type 2 v1.2 RET Achchuthan Shanmugasundram Phenotypes for gene: RET were changed from to Multiple endocrine neoplasia IIA, OMIM:171400; Multiple endocrine neoplasia IIB, OMIM:162300; multiple endocrine neoplasia type 2A, MONDO:0008234; multiple endocrine neoplasia type 2B, MONDO:0008082
Hereditary neuropathy or pain disorder v7.32 KIF21A Eleanor Williams Phenotypes for gene: KIF21A were changed from CFEOM; agenesis of the corpus callosum; peripheral neuropathy to CFEOM; agenesis of the corpus callosum; peripheral neuropathy, MONDO:0005244
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype correct as of 22nd Dec 2025
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Phenotypes for gene: LTBP3 were changed from Dental anomalies and short stature, OMIM:601216; Amelogenesis Imperfecta; syndromic AI with brachyolmia to Dental anomalies and short stature, OMIM:601216
Mucopolysaccharidosis type VI v1.2 ARSB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #253200) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type VI v1.2 ARSB Achchuthan Shanmugasundram Phenotypes for gene: ARSB were changed from to Mucopolysaccharidosis type VI (Maroteaux-Lamy), OMIM:253200; mucopolysaccharidosis type 6, MONDO:0009661
Mucopolysaccharidosis type IVA v1.2 GALNS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #253000) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IVA v1.2 GALNS Achchuthan Shanmugasundram Phenotypes for gene: GALNS were changed from to Mucopolysaccharidosis IVA, OMIM:253000; mucopolysaccharidosis type 4A, MONDO:0009659
Mucopolysaccharidosis type IIIB v1.2 NAGLU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #252920) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IIIB v1.2 NAGLU Achchuthan Shanmugasundram Phenotypes for gene: NAGLU were changed from to Mucopolysaccharidosis type IIIB (Sanfilippo B), OMIM:252920; mucopolysaccharidosis type 3B, MONDO:0009656
Mucopolysaccharidosis type IIIA v1.2 SGSH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #252900) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IIIA v1.2 SGSH Achchuthan Shanmugasundram Phenotypes for gene: SGSH were changed from to Mucopolysaccharidosis type IIIA (Sanfilippo A), OMIM:252900; mucopolysaccharidosis type 3A, MONDO:0009655
Mucopolysaccharidosis type II v1.2 IDS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #309900) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type II v1.2 IDS Achchuthan Shanmugasundram Phenotypes for gene: IDS were changed from to Mucopolysaccharidosis II, OMIM:309900; mucopolysaccharidosis type 2, MONDO:0010674
Mucopolysaccharidosis type IH or S v1.2 IDUA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #607014, #607015 & #607016) and the OMIM records were last accessed on 20 December 2025.
Mucopolysaccharidosis type IH or S v1.2 IDUA Achchuthan Shanmugasundram Phenotypes for gene: IDUA were changed from to Mucopolysaccharidosis Ih, OMIM:607014; Mucopolysaccharidosis Ih/s, OMIM:607015; Mucopolysaccharidosis Is, OMIM:607016; Hurler syndrome, MONDO:0011758; Hurler-Scheie syndrome, MONDO:0011759; Scheie syndrome, MONDO:0011760
Mucolipidosis II and III Alpha or Beta v1.2 GNPTAB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #252500 & #252600) and the OMIM records were last accessed on 20 December 2025.
Mucolipidosis II and III Alpha or Beta v1.2 GNPTAB Achchuthan Shanmugasundram Phenotypes for gene: GNPTAB were changed from to Mucolipidosis II alpha/beta, OMIM:252500; Mucolipidosis III alpha/beta, OMIM:252600; GNPTAB-mucolipidosis, MONDO:0100122
Monitoring for G(M)CSF escape mutations v1.2 CSF3R Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #617014) and the OMIM record was last accessed on 20 December 2025.
Monitoring for G(M)CSF escape mutations v1.2 CSF3R Achchuthan Shanmugasundram Phenotypes for gene: CSF3R were changed from to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014; autosomal recessive severe congenital neutropenia due to CSF3R deficiency, MONDO:0014865
Mitochondrial neurogastrointestinal encephalopathy v1.2 TYMP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #603041) and the OMIM record was last accessed on 20 December 2025.
Mitochondrial neurogastrointestinal encephalopathy v1.2 TYMP Achchuthan Shanmugasundram Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), OMIM:603041; mitochondrial DNA depletion syndrome 1, MONDO:0011283
Mitochondrial Complex V deficiency, TMEM70 type v1.2 TMEM70 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614052) and the OMIM record was last accessed on 20 December 2025.
Mitochondrial Complex V deficiency, TMEM70 type v1.2 TMEM70 Achchuthan Shanmugasundram Phenotypes for gene: TMEM70 were changed from to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, OMIM:614052; mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, MONDO:0013546
Lysosomal acid lipase deficiency v1.2 LIPA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #278000 & #620151) and the OMIM records were last accessed on 20 December 2025.
Lysosomal acid lipase deficiency v1.2 LIPA Achchuthan Shanmugasundram Phenotypes for gene: LIPA were changed from to Cholesteryl ester storage disease, OMIM:278000; Wolman disease, OMIM:620151; Wolman disease, MONDO:0019148; cholesteryl ester storage disease, MONDO:0019149
Lymphoproliferative syndrome with absent SAP expression v1.2 SH2D1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #308240) and the OMIM record was last accessed on 20 December 2025.
Lymphoproliferative syndrome with absent SAP expression v1.2 SH2D1A Achchuthan Shanmugasundram Phenotypes for gene: SH2D1A were changed from to Lymphoproliferative syndrome, X-linked, 1, OMIM:308240; X-linked lymphoproliferative disease due to SH2D1A deficiency, MONDO:0024551
Li Fraumeni Syndrome v1.5 TP53 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #151623) and the OMIM record was last accessed on 20 December 2025.
Li Fraumeni Syndrome v1.5 TP53 Achchuthan Shanmugasundram Phenotypes for gene: TP53 were changed from to Li-Fraumeni syndrome, OMIM:151623; Li-Fraumeni syndrome, MONDO:0018875
Li Fraumeni Syndrome v1.4 POT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #61584 & #620367) and the OMIM records were last accessed on 20 December 2025.
Li Fraumeni Syndrome v1.4 POT1 Achchuthan Shanmugasundram Phenotypes for gene: POT1 were changed from to Tumor predisposition syndrome 3, OMIM:615848; ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8, OMIM:620367; tumor predisposition syndrome 3, MONDO:0014368
Krabbe disease - Saposin A deficiency v1.2 PSAP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #611721 & #611722) and the OMIM records were last accessed on 20 December 2025.
Krabbe disease - Saposin A deficiency v1.2 PSAP Achchuthan Shanmugasundram Phenotypes for gene: PSAP were changed from to Combined SAP deficiency, OMIM:611721; Krabbe disease, atypical, OMIM:611722; PSAP-related sphingolipidosis, MONDO:0100517
Krabbe disease - GALC deficiency v1.2 GALC Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #245200) and the OMIM record was last accessed on 20 December 2025.
Krabbe disease - GALC deficiency v1.2 GALC Achchuthan Shanmugasundram Phenotypes for gene: GALC were changed from to Krabbe disease, OMIM:245200; Krabbe disease, MONDO:0009499
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.2 FOXP3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #304790) and the OMIM record was last accessed on 20 December 2025.
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.2 FOXP3 Achchuthan Shanmugasundram Phenotypes for gene: FOXP3 were changed from to Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked, OMIM:304790; immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, MONDO:0010580
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.3 PAX5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615545) and the OMIM record was last accessed on 20 December 2025.
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.3 PAX5 Achchuthan Shanmugasundram Phenotypes for gene: PAX5 were changed from to {Leukemia, acute lymphoblastic, susceptibility to, 3}, OMIM:615545; leukemia, acute lymphoblastic, susceptibility to, 3, MONDO:0014241
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.2 ETV6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #616216) and the OMIM record was last accessed on 20 December 2025.
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.2 ETV6 Achchuthan Shanmugasundram Phenotypes for gene: ETV6 were changed from to Thrombocytopenia 5, OMIM:616216; thrombocytopenia 5, MONDO:0014536
Inherited parathyroid cancer v1.2 CDC73 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #145001 & #608266) and the OMIM records were last accessed on 20 December 2025.
Inherited parathyroid cancer v1.2 CDC73 Achchuthan Shanmugasundram Phenotypes for gene: CDC73 were changed from to Hyperparathyroidism-jaw tumor syndrome, OMIM:145001; Parathyroid adenoma with cystic changes, OMIM:145001; Parathyroid carcinoma, OMIM:608266; parathyroid gland carcinoma, MONDO:0012004
Incontinentia pigmenti v1.3 IKBKG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #308300) and the OMIM record was last accessed on 20 December 2025.
Incontinentia pigmenti v1.3 IKBKG Achchuthan Shanmugasundram Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, OMIM:308300 to Incontinentia pigmenti, OMIM:308300; incontinentia pigmenti, MONDO:0010631
Hereditary angioedema types I and II v1.2 SERPING1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #106100) and the OMIM record was last accessed on 20 December 2025.
Hereditary angioedema types I and II v1.2 SERPING1 Achchuthan Shanmugasundram Phenotypes for gene: SERPING1 were changed from to Angioedema, hereditary, 1 and 2, OMIM:106100; hereditary angioedema with C1Inh deficiency, MONDO:0033946
Haemophagocytic syndrome with absent XIAP expression v1.3 XIAP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #300635 in OMIM and the OMIM record was last accessed on 20 December 2025.
Haemophagocytic syndrome with absent XIAP expression v1.3 XIAP Achchuthan Shanmugasundram Phenotypes for gene: XIAP were changed from Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385 to Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385
Haemophagocytic syndrome with absent XIAP expression v1.2 XIAP Achchuthan Shanmugasundram Phenotypes for gene: XIAP were changed from to Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385
Haemophagocytic syndrome with absent perforin expression v1.3 PRF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #603553 in OMIM and the OMIM record was last accessed on 20 December 2025.
Haemophagocytic syndrome with absent perforin expression v1.3 PRF1 Achchuthan Shanmugasundram Phenotypes for gene: PRF1 were changed from Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553 to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553; familial hemophagocytic lymphohistiocytosis 2, MONDO:0011337
Sickle cell, thalassaemia and other haemoglobinopathies v2.8 HBG2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #141749 & #613977), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.8 HBG2 Achchuthan Shanmugasundram Phenotypes for gene: HBG2 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; cyanosis, transient neonatal, MONDO:0013511
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.8 HBG2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #141749 & #613977), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.8 HBG2 Achchuthan Shanmugasundram Phenotypes for gene: HBG2 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; cyanosis, transient neonatal, MONDO:0013511
Sickle cell, thalassaemia and other haemoglobinopathies v2.7 HBG1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #141749 in OMIM and the OMIM record was last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.7 HBG1 Achchuthan Shanmugasundram Phenotypes for gene: HBG1 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.7 HBG1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #141749 in OMIM and the OMIM record was last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.7 HBG1 Achchuthan Shanmugasundram Phenotypes for gene: HBG1 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749
Sickle cell, thalassaemia and other haemoglobinopathies v2.6 HBB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #141749, #603902, #603903, #613985, #617971 & #617980), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.6 HBB Achchuthan Shanmugasundram Phenotypes for gene: HBB were changed from to Heinz body anemia, OMIM:140700; Delta-beta thalassemia, OMIM:141749; Hereditary persistence of fetal hemoglobin, OMIM:141749; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell disease, OMIM:603903; Thalassemia, beta, OMIM:613985; Methemoglobinemia, beta type, OMIM:617971; Erythrocytosis, familial, 6, OMIM:617980; dominant beta-thalassemia, MONDO:0011381; sickle cell disease, MONDO:0011382; beta-thalassemia HBB/LCRB, MONDO:0013517; hemoglobin M disease, MONDO:0018023; erythrocytosis, familial, 6, MONDO:0054801
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.6 HBB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #141749, #603902, #603903, #613985, #617971 & #617980), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.6 HBB Achchuthan Shanmugasundram Phenotypes for gene: HBB were changed from to Heinz body anemia, OMIM:140700; Delta-beta thalassemia, OMIM:141749; Hereditary persistence of fetal hemoglobin, OMIM:141749; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell disease, OMIM:603903; Thalassemia, beta, OMIM:613985; Methemoglobinemia, beta type, OMIM:617971; Erythrocytosis, familial, 6, OMIM:617980; dominant beta-thalassemia, MONDO:0011381; sickle cell disease, MONDO:0011382; beta-thalassemia HBB/LCRB, MONDO:0013517; hemoglobin M disease, MONDO:0018023; erythrocytosis, familial, 6, MONDO:0054801
Sickle cell, thalassaemia and other haemoglobinopathies v2.5 HBA2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.5 HBA2 Achchuthan Shanmugasundram Phenotypes for gene: HBA2 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Erythrocytosis, familial, 7, OMIM:617981; HBA2-related alpha thalassemia spectrum, MONDO:0100562
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.5 HBA2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.5 HBA2 Achchuthan Shanmugasundram Phenotypes for gene: HBA2 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Erythrocytosis, familial, 7, OMIM:617981; HBA2-related alpha thalassemia spectrum, MONDO:0100562
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.4 HBA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978, #617973 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.4 HBA1 Achchuthan Shanmugasundram Phenotypes for gene: HBA1 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Erythrocytosis, familial, 7, OMIM:617981; HBA1-related alpha thalassemia spectrum, MONDO:0100561; methemoglobinemia, alpha type, MONDO:0020835
Sickle cell, thalassaemia and other haemoglobinopathies v2.4 HBA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978, #617973 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.4 HBA1 Achchuthan Shanmugasundram Phenotypes for gene: HBA1 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Erythrocytosis, familial, 7, OMIM:617981; HBA1-related alpha thalassemia spectrum, MONDO:0100561; methemoglobinemia, alpha type, MONDO:0020835
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.2 GLB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #230500, #230600, #230650 & #253010), and these OMIM records were last accessed on 19 December 2025.
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.2 GLB1 Achchuthan Shanmugasundram Phenotypes for gene: GLB1 were changed from to GM1-gangliosidosis, type I, OMIM:230500; GM1-gangliosidosis, type II, OMIM:230600; GM1-gangliosidosis, type III, OMIM:230650; Mucopolysaccharidosis type IVB (Morquio), OMIM:253010; GM1 gangliosidosis, MONDO:0018149; mucopolysaccharidosis type 4B, MONDO:0009660
Glycogen storage disease V v1.3 PYGM Achchuthan Shanmugasundram Phenotypes for gene: PYGM were changed from Glycogen storage disease V, OMIM:232600; glycogen storage disease V, MONDO:0009293 to McArdle disease, OMIM:232600; glycogen storage disease V, MONDO:0009293
Glycogen storage disease V v1.2 PYGM Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #232600) and the OMIM record was last accessed on 18 December 2025.
Glycogen storage disease V v1.2 PYGM Achchuthan Shanmugasundram Phenotypes for gene: PYGM were changed from to Glycogen storage disease V, OMIM:232600; glycogen storage disease V, MONDO:0009293
Glucokinase-related fasting hyperglycaemia v1.2 GCK Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #125851, #125853, #602485 & #606176) and these OMIM records were last accessed on 19 December 2025.
Glucokinase-related fasting hyperglycaemia v1.2 GCK Achchuthan Shanmugasundram Phenotypes for gene: GCK were changed from to MODY, type II, OMIM:125851; Diabetes mellitus, noninsulin-dependent, late onset, OMIM:125853; Hyperinsulinemic hypoglycemia, familial, 3, OMIM:602485; Diabetes mellitus, permanent neonatal 1, OMIM:606176; maturity-onset diabetes of the young type 2, MONDO:0007453; permanent neonatal diabetes mellitus 1, MONDO:0100165; hyperinsulinism due to glucokinase deficiency, MONDO:0011236
Fetal anomalies v6.129 DHRSX Achchuthan Shanmugasundram Tag Pseudoautosomal region 1 tag was added to gene: DHRSX.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from Isolated complex IV deficiency; No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype; Mitochondrial complex IV deficiency to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from Isolated complex IV deficiency; No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Monogenic short stature v1.29 SLC13A1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC13A1.
Skeletal dysplasia v8.26 SLC13A1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC13A1.
Intellectual disability v9.206 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Fetal anomalies v6.129 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Intellectual disability v9.206 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Early onset or syndromic epilepsy v8.79 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Fetal anomalies v6.129 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Severe microcephaly v8.21 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Intellectual disability v9.206 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Fetal anomalies v6.129 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Hydrocephalus v5.7 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Fetal anomalies v6.129 BORCS5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BORCS5.
Fetal anomalies v6.129 SENP7 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SENP7.
Fetal anomalies v6.129 SLC12A9 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC12A9.
Intellectual disability v9.206 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Osteogenesis imperfecta v5.3 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.28 TNNI1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TNNI1.
Congenital myopathy v6.44 TNNI1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TNNI1.
Intellectual disability v9.206 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Early onset or syndromic epilepsy v8.79 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Monogenic hearing loss v5.49 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
DDG2P v6.14 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Childhood onset hereditary spastic paraplegia v8.22 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Ataxia and cerebellar anomalies - narrow panel v8.36 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska commented on gene: RNU12: Comment on list classification: There is one large consanguineous pedigree reported in literature, with a biallelic RNU12 mutation segregating with early-onset ataxia. RNU12 should be rated Red for Early onset or syndromic epilepsy, until more evidence emerges.
Ataxia and cerebellar anomalies - narrow panel v8.36 RNU12 Ida Ertmanska commented on gene: RNU12: Comment on list classification: There is one large consanguineous pedigree reported in literature, with a biallelic RNU12 mutation segregating with early-onset ataxia. RNU12 should be rated Red for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska gene: RNU12 was added
gene: RNU12 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 27863452; 33577674
Phenotypes for gene: RNU12 were set to ?Spinocerebellar ataxia, autosomal recessive 33, OMIM:620208
Review for gene: RNU12 was set to RED
Added comment: PMID: 27863452 Elsaid et al., 2017
Report of a large consanguineous pedigree with 6 individuals presenting with early-onset ataxia (onset <2 yrs old). Affected individuals were homozygous for RNU12 84C>U mutation. Method: WGS confirmed by Sanger. 2 other mutations segregates with disease in a recessive manner, affecting non-coding regions of genes POLDIP3 and PACSIN2 (uncertain significance).
Affected individuals showed a significant increase in RNU12 snRNA levels; expression of POLDIP3 and PACSIN2 did not differ between affected and unaffected members.
Phenotype spectrum: truncal ataxia 6/6, abnormal cerebellum 5/5 (5 assessed), hypotonia in infancy 5/6, mild learning difficulties 4/6, seizures (febrile / complex partial) 4/6, dysarthric speech 5/6, abnormal gait & falls 5/6.

Functional evidence: PMID: 33577674 Norppa and Frilander, 2021: Show that the 84C>U mutation leads to accelerated decay of the RNU12 snRNA, resulting in significantly reduced steady-state U12 snRNA levels (cell line model).

This gene is putatively linked to Spinocerebellar ataxia, autosomal recessive 33, MIM:620208 and linked to CDAGS syndrome, MIM:603116 (OMIM accessed 19th Dec 2025).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.36 RNU12 Ida Ertmanska gene: RNU12 was added
gene: RNU12 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 27863452; 33577674
Phenotypes for gene: RNU12 were set to ?Spinocerebellar ataxia, autosomal recessive 33, OMIM:620208
Review for gene: RNU12 was set to RED
Added comment: PMID: 27863452 Elsaid et al., 2017
Report of a large consanguineous pedigree with 6 individuals presenting with early-onset ataxia (onset <2 yrs old). Affected individuals were homozygous for RNU12 84C>U mutation. Method: WGS confirmed by Sanger. 2 other mutations segregates with disease in a recessive manner, affecting non-coding regions of genes POLDIP3 and PACSIN2 (uncertain significance).
Affected individuals showed a significant increase in RNU12 snRNA levels; expression of POLDIP3 and PACSIN2 did not differ between affected and unaffected members.
Phenotype spectrum: truncal ataxia 6/6, abnormal cerebellum 5/5 (5 assessed), hypotonia in infancy 5/6, mild learning difficulties 4/6, seizures (febrile / complex partial) 4/6, dysarthric speech 5/6, abnormal gait & falls 5/6.

Functional evidence: PMID: 33577674 Norppa and Frilander, 2021: Show that the 84C>U mutation leads to accelerated decay of the RNU12 snRNA, resulting in significantly reduced steady-state U12 snRNA levels (cell line model).

This gene is putatively linked to Spinocerebellar ataxia, autosomal recessive 33, MIM:620208 and linked to CDAGS syndrome, MIM:603116 (OMIM accessed 19th Dec 2025).
Sources: Literature
Hypertrophic cardiomyopathy v5.26 TBX1 Ida Ertmanska Publications for gene: TBX1 were set to PMID: 41130538
Hypertrophic cardiomyopathy v5.25 TBX1 Ida Ertmanska Phenotypes for gene: TBX1 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, HP:0001639
Hypertrophic cardiomyopathy v5.24 TBX1 Ida Ertmanska Classified gene: TBX1 as Red List (low evidence)
Hypertrophic cardiomyopathy v5.24 TBX1 Ida Ertmanska Gene: tbx1 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy v5.23 TBX1 Ida Ertmanska reviewed gene: TBX1: Rating: RED; Mode of pathogenicity: None; Publications: 41130538; Phenotypes: Hypertrophic cardiomyopathy, HP:0001639; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.206 SOX3 Ida Ertmanska changed review comment from: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 in OMIM (accessed 19th Dec 2025).; to: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 and Panhypopituitarism, X-linked, MIM:312000 in OMIM (accessed 19th Dec 2025).
Intellectual disability v9.206 SOX3 Ida Ertmanska Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 to Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032
Intellectual disability v9.205 SOX3 Ida Ertmanska Publications for gene: SOX3 were set to
Intellectual disability v9.204 SOX3 Ida Ertmanska Mode of inheritance for gene: SOX3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v9.203 SOX3 Ida Ertmanska edited their review of gene: SOX3: Added comment: Comment on list classification: While variants in SOX3 have been reported to cause a cognitive impairment, its severity does not meet the panel eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on available evidence, this gene should be rated Amber for Intellectual disability, until more evidence emerges.; Changed rating: AMBER; Changed phenotypes to: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123, X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v9.203 SOX3 Ida Ertmanska reviewed gene: SOX3: Rating: ; Mode of pathogenicity: None; Publications: 29175558, 35114986, 35295983; Phenotypes: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; Mode of inheritance: None
Mitochondrial disorders v9.38 MT-ATP8 Ida Ertmanska changed review comment from: As reviewed by Zornitza Stark, there are 3 individuals reported with primary mitochondrial disease and variants in MT-ATP8. Hence, this gene should remain Green for Mitochondrial disorders.; to: As reviewed by Zornitza Stark, there are 3 individuals reported with primary mitochondrial disease and variants in MT-ATP8. Hence, this gene should remain Green for Mitochondrial disorders.

This gene is not yet associated with a phenotype in OMIM (accessed 19th Dec 2025).
Mitochondrial disorders v9.38 MT-ATP8 Ida Ertmanska Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Mitochondrial disorders v9.37 MT-ATP8 Ida Ertmanska Publications for gene: MT-ATP8 were set to
Mitochondrial disorders v9.36 MT-ATP8 Ida Ertmanska reviewed gene: MT-ATP8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.31 KIF21A Ida Ertmanska Publications for gene: KIF21A were set to 39643435; 41282472
Hereditary neuropathy or pain disorder v7.30 KIF21A Ida Ertmanska Classified gene: KIF21A as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.30 KIF21A Ida Ertmanska Gene: kif21a has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: KIF21A.
Tag Q4_25_NHS_review tag was added to gene: KIF21A.
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska commented on gene: KIF21A: Comment on list classification: There are 3 unrelated individuals with progressive peripheral neuropathy reported with de novo heterozygous missense variants localised in the second coiled‑coil domain of KIF21A. Variants in other KIF21A domains are not known to cause neuropathy. Based on available evidence, KIF21A should be promoted to Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22699964, 32141982, 37921537, 39643435, 41282472; Phenotypes: CFEOM, agenesis of the corpus callosum, peripheral neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.78 EGFLAM Ida Ertmanska Phenotypes for gene: EGFLAM were changed from Congenital Stationary Night Blindness to Congenital stationary night blindness, HP:0007642
Retinal disorders v8.77 EGFLAM Ida Ertmanska Publications for gene: EGFLAM were set to PMID: 41343198
Retinal disorders v8.76 EGFLAM Ida Ertmanska Classified gene: EGFLAM as Amber List (moderate evidence)
Retinal disorders v8.76 EGFLAM Ida Ertmanska Gene: egflam has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.75 EGFLAM Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: EGFLAM.
Tag Q4_25_NHS_review tag was added to gene: EGFLAM.
Retinal disorders v8.75 EGFLAM Ida Ertmanska commented on gene: EGFLAM: Comment on list classification: As reviewed by Siying Lin, there are 3 individuals from 2 unrelated families reported with biallelic EGFLAM variants and Congenital stationary night blindness. In addition, a knockout mouse model supports the gene's association with a retinal phenotype. Based on available evidence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.75 EGFLAM Ida Ertmanska reviewed gene: EGFLAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 18641643, 41343198; Phenotypes: Congenital stationary night blindness, HP:0007642; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v3.14 APOA4 Ida Ertmanska Publications for gene: APOA4 were set to 21900878; 27262366; 33751222; 38096951; 39699959
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_NHS_review was removed from gene: APOA4.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: APOA4.
Tag Q4_25_NHS_review tag was added to gene: APOA4.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 28449784 Bois et al., 2017
13 patients with AApoAIV cardiac amyloidosis, mean age 75 years. Patients had cardiac dysfunction. Of 9 patients evaluated in detail, 8/9 had chronic kidney disease (various stages). Autopsy of 4 cases showed small vessel involvement and prominent medullary renal deposits Genetic analysis was performed, but 'did not identify definitive pathological mutations.'

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; to: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska edited their review of gene: APOA4: Added comment: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; Changed rating: GREEN; Changed publications to: 21900878, 27262366, 28449784, 33751222, 38096951, 39699959
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: APOA4.
Tag Q4_25_NHS_review tag was added to gene: APOA4.
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 28449784 Bois et al., 2017
13 patients with AApoAIV cardiac amyloidosis, mean age 75 years. Patients had cardiac dysfunction. Of 9 patients evaluated in detail, 8/9 had chronic kidney disease (various stages). Autopsy of 4 cases showed small vessel involvement and prominent medullary renal deposits Genetic analysis was performed, but 'did not identify definitive pathological mutations.'

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska edited their review of gene: APOA4: Added comment: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. Similarly, ApoA4 deposits have been reported in cases of cardiac amyloidosis. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; Changed rating: GREEN; Changed publications to: 21900878, 27262366, 28449784, 33751222, 38096951, 39699959
Respiratory ciliopathies including non-CF bronchiectasis v4.54 CFAP221 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #279000) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.54 CFAP221 Achchuthan Shanmugasundram Phenotypes for gene: CFAP221 were changed from Ciliary dyskinesia, primary, 55, OMIM:279000 to Ciliary dyskinesia, primary, 55, OMIM:279000
Respiratory ciliopathies including non-CF bronchiectasis v4.53 CFAP221 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP221.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 CFAP54 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 NEK10 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618781) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 NEK10 Achchuthan Shanmugasundram Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914 to Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914
Respiratory ciliopathies including non-CF bronchiectasis v4.52 NEK10 Achchuthan Shanmugasundram Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, OMIM:618781, MONDO:0032914 to Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914
Respiratory ciliopathies including non-CF bronchiectasis v4.51 NEK10 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v4.51 CFAP74 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620197) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.51 CFAP74 Achchuthan Shanmugasundram Phenotypes for gene: CFAP74 were changed from Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197 to Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197; ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP74.
Fetal anomalies v6.129 PHF5A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PHF5A.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: EFCAB1.
Fetal anomalies v6.129 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Intellectual disability v9.202 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Early onset or syndromic epilepsy v8.77 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Fetal anomalies v6.129 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Fetal anomalies v6.129 C1orf127 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621080) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.129 C1orf127 Achchuthan Shanmugasundram Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080; heterotaxy, visceral, 14, autosomal, MONDO:0976135
Fetal anomalies v6.128 C1orf127 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C1orf127.
Laterality disorders and isomerism v4.9 C1orf127 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621080) and the OMIM record was last accessed on 18 December 2025.
Laterality disorders and isomerism v4.9 C1orf127 Achchuthan Shanmugasundram Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080; heterotaxy, visceral, 14, autosomal, MONDO:0976135
Laterality disorders and isomerism v4.8 C1orf127 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C1orf127.
Retinal disorders v8.75 RNU4-2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU4-2.
Congenital myopathy v6.44 MYMX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619941) and the OMIM record was last accessed on 18 December 2025.
Congenital myopathy v6.44 MYMX Achchuthan Shanmugasundram Phenotypes for gene: MYMX were changed from ?Carey-Fineman-Ziter syndrome 2, OMIM:619941 to Carey-Fineman-Ziter syndrome 2, OMIM:619941; Carey-Fineman-Ziter syndrome 2, MONDO:0100292
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MYMX.
Multi locus imprinting disorders v1.16 NLRP5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620333) and the OMIM record was last accessed on 18 December 2025.
Multi locus imprinting disorders v1.16 NLRP5 Achchuthan Shanmugasundram Phenotypes for gene: NLRP5 were changed from Phenotype resulting from under expression: Biparental complete hydatidiform mole, Beckwith-Wiedemann Syndrome, Multi-locus imprinting disorder; Affected tissue: all to Oocyte/zygote/embryo maturation arrest 19, OMIM:620333; oocyte/zygote/embryo maturation arrest 19, MONDO:0957231
Monogenic short stature v1.29 NLRP5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620333) and the OMIM record was last accessed on 18 December 2025.
Monogenic short stature v1.29 NLRP5 Achchuthan Shanmugasundram Phenotypes for gene: NLRP5 were changed from IUGR; Short stature; Failure to thrive; body asymmetry; multilocus imprinting disturbances to Oocyte/zygote/embryo maturation arrest 19, OMIM:620333; oocyte/zygote/embryo maturation arrest 19, MONDO:0957231
Multi locus imprinting disorders v1.15 NLRP5 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: NLRP5.
Monogenic short stature v1.28 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Monogenic short stature v1.28 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Maternal effect gene- causing phenotypes that include IUGR to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230
Multi locus imprinting disorders v1.15 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Multi locus imprinting disorders v1.15 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475 to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230; Beckwith-Wiedemann syndrome due to imprinting defect of 11p15, MONDO:0016475
Multi locus imprinting disorders v1.14 NLRP2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NLRP2.
Multi locus imprinting disorders v1.14 NLRP2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: NLRP2.
Tag gene-checked was removed from gene: NLRP2.
Segmental overgrowth disorders - Deep sequencing v4.4 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Segmental overgrowth disorders - Deep sequencing v4.4 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475 to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230; Beckwith-Wiedemann syndrome due to imprinting defect of 11p15, MONDO:0016475
DDG2P v6.14 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621224) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.14 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from LEF1-related ectodermal dysplasia and limb malformation to LEF1-related ectodermal dysplasia and limb malformation; Ectodermal dysplasia 17 with or without limb malformations, OMIM:621224; ectodermal dysplasia 17 with or without limb malformations, MONDO:0979228
DDG2P v6.13 LEF1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: LEF1.
Ectodermal dysplasia v4.20 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621224) and the OMIM record was last accessed on 18 December 2025.
Ectodermal dysplasia v4.20 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to Ectodermal dysplasia 17 with or without limb malformations, OMIM:621224; ectodermal dysplasia 17 with or without limb malformations, MONDO:0979228
Ectodermal dysplasia v4.19 LEF1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: LEF1.
Intellectual disability v9.202 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Intellectual disability v9.201 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.201 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138
Intellectual disability v9.200 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
DDG2P v6.13 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.13 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from PAN2-related neurodevelopmental disorder with multiple congenital anomalies to PAN2-related neurodevelopmental disorder with multiple congenital anomalies; Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
DDG2P v6.12 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
Fetal anomalies v6.128 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.128 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from syndromic disease MONDO:0002254 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Fetal anomalies v6.127 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
Clefting v6.19 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
Clefting v6.19 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from cleft lip/palate MONDO:0016044; imperforate anus; dysmorphism to Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
Clefting v6.18 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
DDG2P v6.12 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.12 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from tall stature; cardiac anomalies; orofacial clefting; AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature to AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature; Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
DDG2P v6.11 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
Fetal anomalies v6.127 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.127 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related to Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
Fetal anomalies v6.126 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from prenatal-onset growth impairment and developmental delay to Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
DDG2P v6.11 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.11 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
Fetal anomalies v6.126 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.126 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from complex neurodevelopmental disorder, MONDO:0100038 to Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
Fetal anomalies v6.125 GON4L Achchuthan Shanmugasundram Tag gene-checked was removed from gene: GON4L.
Skeletal ciliopathies v6.4 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Skeletal ciliopathies v6.4 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Skeletal ciliopathies v6.3 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Neurological ciliopathies v6.12 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Neurological ciliopathies v6.12 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Neurological ciliopathies v6.11 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Ophthalmological ciliopathies v5.10 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Ophthalmological ciliopathies v5.10 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Ophthalmological ciliopathies v5.9 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Structural eye disease v4.36 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
DDG2P v6.10 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
DDG2P v6.10 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Fetal anomalies v6.125 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.179 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.179 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Rare multisystem ciliopathy disorders v1.178 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.178 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Rare multisystem ciliopathy disorders v1.177 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome 9, 258865 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Structural eye disease v4.34 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Retinal disorders v8.75 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621280) and the OMIM record was last accessed on 18 December 2025.
Retinal disorders v8.75 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa 100, OMIM:621280; retinitis pigmentosa, MONDO:0019200
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from TBC1D32-related ciliopathy to TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from OFD IX to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Fetal anomalies v6.123 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Malformations of cortical development v7.18 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Malformations of cortical development v7.18 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Malformations of cortical development v7.17 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Pituitary hormone deficiency v4.3 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Pituitary hormone deficiency v4.3 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Syndromic Hypopituitarism; orofaciodigital syndrome to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Syndromic Hypopituitarism
Pituitary hormone deficiency v4.2 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Thoracic dystrophies v1.24 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Hydrocephalus v5.7 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Thoracic dystrophies v1.23 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Thoracic dystrophies v1.23 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from OFD to Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375
Thoracic dystrophies v1.22 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TRIM63.
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621270) and the OMIM record was last accessed on 18 December 2025.
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy, MONDO:0005045; restrictive cardiomyopathy, MONDO:0005201 to Cardiomyopathy, familial hypertrophic, 31, OMIM:621270; cardiomyopathy, familial hypertrophic, 31, MONDO:0979573
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska Phenotypes for gene: APOA4 were changed from tubulointerstitial kidney disease; Chronic kidney disease to Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106; tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234
Tubulointerstitial kidney disease v3.12 APOA4 Ida Ertmanska Publications for gene: APOA4 were set to PMID 38096951
Tubulointerstitial kidney disease v3.11 APOA4 Ida Ertmanska Classified gene: APOA4 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v3.11 APOA4 Ida Ertmanska Gene: apoa4 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.29 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia with onset in adulthood v8.15 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v9.36 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed rating: AMBER
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_promote_green was removed from gene: APOA4.
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton Deleted their review
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their review
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their comment
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton changed review comment from: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.; to: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton Deleted their review
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton Deleted their review
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Classified gene: APOA4 as Amber List (moderate evidence)
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Gene: apoa4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.26 APOA4 Ida Ertmanska gene: APOA4 was added
gene: APOA4 was added to Hereditary systemic amyloidosis. Sources: Literature
Q4_25_promote_green tags were added to gene: APOA4.
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: APOA4 were set to 21900878; 27262366; 33751222; 38096951; 39699959
Phenotypes for gene: APOA4 were set to Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106; tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234; AApoAIV amyloidosis, MONDO:0018589
Review for gene: APOA4 was set to GREEN
Added comment: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their comment
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton Deleted their review
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton changed review comment from: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.; to: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v8.22 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed publications to: 21900878, 27262366, 33751222, 38096951, 39699959
Generalised arterial calcification in infancy v1.3 ENPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208000) and the OMIM record was last accessed on 18 December 2025.
Generalised arterial calcification in infancy v1.3 ENPP1 Achchuthan Shanmugasundram Phenotypes for gene: ENPP1 were changed from to Arterial calcification, generalized, of infancy, 1, OMIM:208000; arterial calcification, generalized, of infancy, 1, MONDO:0008817
Generalised arterial calcification in infancy v1.2 ABCC6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #61447) and the OMIM record was last accessed on 18 December 2025.
Generalised arterial calcification in infancy v1.2 ABCC6 Achchuthan Shanmugasundram Phenotypes for gene: ABCC6 were changed from to Arterial calcification, generalized, of infancy, 2, OMIM:614473; arterial calcification, generalized, of infancy, 2, MONDO:0013768
Gaucher disease v1.2 GBA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #230800, #230900, #231000, #231005 & #608013) and the OMIM records were last accessed on 18 December 2025.
Gaucher disease v1.2 GBA Achchuthan Shanmugasundram Phenotypes for gene: GBA were changed from to Gaucher disease, type I, OMIM:230800; Gaucher disease, type II, OMIM:230900; Gaucher disease, type III, OMIM:231000; Gaucher disease, type IIIC, OMIM:231005; Gaucher disease, perinatal lethal, OMIM:608013
Fumarate hydratase-related tumour syndromes v1.2 FH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #150800) and the OMIM record was last accessed on 18 December 2025.
Fumarate hydratase-related tumour syndromes v1.2 FH Achchuthan Shanmugasundram Phenotypes for gene: FH were changed from to Leiomyomatosis and renal cell cancer, OMIM:150800; hereditary leiomyomatosis and renal cell cancer, MONDO:0007888
Familial dysalbuminaemic hyperthyroxinaemia v1.2 ALB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615999) and the OMIM record was last accessed on 18 December 2025.
Familial dysalbuminaemic hyperthyroxinaemia v1.2 ALB Achchuthan Shanmugasundram Phenotypes for gene: ALB were changed from to [Dysalbuminemic hyperthyroxinemia], OMIM:615999; hyperthyroxinemia, familial dysalbuminemic, MONDO:0014448
Factor XIII deficiency v1.3 F13B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613235) and the OMIM record was last accessed on 18 December 2025.
Factor XIII deficiency v1.3 F13B Achchuthan Shanmugasundram Phenotypes for gene: F13B were changed from to Factor XIIIB deficiency, OMIM:613235; factor XIII, b subunit, deficiency of, MONDO:0013190
Factor XIII deficiency v1.2 F13A1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613225) and the OMIM record was last accessed on 18 December 2025.
Factor XIII deficiency v1.2 F13A1 Achchuthan Shanmugasundram Phenotypes for gene: F13A1 were changed from to Factor XIIIA deficiency, OMIM:613225; factor XIII, A subunit, deficiency of, MONDO:0013187
Factor XI deficiency v1.2 F11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #612416) and the OMIM record was last accessed on 18 December 2025.
Factor XI deficiency v1.2 F11 Achchuthan Shanmugasundram Phenotypes for gene: F11 were changed from to Factor XI deficiency, autosomal dominant, OMIM:612416; Factor XI deficiency, autosomal recessive, OMIM:612416; congenital factor XI deficiency, MONDO:0012897
Factor X deficiency v1.2 F10 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227600) and the OMIM record was last accessed on 18 December 2025.
Factor X deficiency v1.2 F10 Achchuthan Shanmugasundram Phenotypes for gene: F10 were changed from to Factor X deficiency, OMIM:227600; congenital factor X deficiency, MONDO:0009212
Factor VIII deficiency v1.2 F8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #306700) and the OMIM record was last accessed on 18 December 2025.
Factor VIII deficiency v1.2 F8 Achchuthan Shanmugasundram Phenotypes for gene: F8 were changed from to Hemophilia A, OMIM:306700; hemophilia A, MONDO:0010602
Factor VII deficiency v1.2 F7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227500) and the OMIM record was last accessed on 18 December 2025.
Factor VII deficiency v1.2 F7 Achchuthan Shanmugasundram Phenotypes for gene: F7 were changed from to Factor VII deficiency, OMIM:227500; congenital factor VII deficiency, MONDO:0009211
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 October 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 December 2025.
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 October 2025.
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram Phenotypes for gene: F5 were changed from to Factor V deficiency, OMIM:227400; congenital factor V deficiency, MONDO:0009210
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed publications to: 21900878 27262366, 33751222, 38096951, 39699959
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska reviewed gene: APOA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 38096951; Phenotypes: Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106, tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Factor IX deficiency v1.2 F9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300807 & #306900) and the OMIM records were last accessed on 17 December 2025.
Factor IX deficiency v1.2 F9 Achchuthan Shanmugasundram Phenotypes for gene: F9 were changed from to Thrombophilia, X-linked, due to factor IX defect, OMIM:300807; Hemophilia B, OMIM:306900; hemophilia B, MONDO:0010604; thrombophilia, X-linked, due to factor 9 defect, MONDO:0010432
Factor II deficiency v1.2 F2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613679) and the OMIM record was last accessed on 17 December 2025.
Factor II deficiency v1.2 F2 Achchuthan Shanmugasundram Phenotypes for gene: F2 were changed from to Dysprothrombinemia, OMIM:613679; Hypoprothrombinemia, OMIM:613679; congenital prothrombin deficiency, MONDO:0013361
Facioscapulohumeral muscular dystrophy - extended testing v1.2 SMCHD1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #158901) and the OMIM record was last accessed on 17 December 2025.
Facioscapulohumeral muscular dystrophy - extended testing v1.2 SMCHD1 Achchuthan Shanmugasundram Phenotypes for gene: SMCHD1 were changed from to Facioscapulohumeral muscular dystrophy 2, digenic, OMIM:158901; facioscapulohumeral muscular dystrophy 2, MONDO:0008031
Fabry disease v1.2 GLA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #301500) and the OMIM record was last accessed on 17 December 2025.
Fabry disease v1.2 GLA Achchuthan Shanmugasundram Phenotypes for gene: GLA were changed from to Fabry disease, OMIM:301500; Fabry disease, cardiac variant, OMIM:301500; Fabry disease, MONDO:0010526
Elastin-related phenotypes v1.2 ELN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #123700 & #185500) and the OMIM records were last accessed on 17 December 2025.
Elastin-related phenotypes v1.2 ELN Achchuthan Shanmugasundram Phenotypes for gene: ELN were changed from to Cutis laxa, autosomal dominant, OMIM:123700; Supravalvar aortic stenosis, OMIM:185500; cutis laxa, autosomal dominant 1, MONDO:0007411; supravalvular aortic stenosis, MONDO:0008504
Duchenne or Becker muscular dystrophy v1.2 DMD Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #310200 & #300376) and the OMIM records were last accessed on 17 December 2025.
Duchenne or Becker muscular dystrophy v1.2 DMD Achchuthan Shanmugasundram Phenotypes for gene: DMD were changed from to Duchenne muscular dystrophy, OMIM:310200; Becker muscular dystrophy, OMIM:300376; Duchenne muscular dystrophy, MONDO:0010679; Becker muscular dystrophy, MONDO:0010311
DICER1-related cancer predisposition v1.2 DICER1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #138800 & #601200) and the OMIM records were last accessed on 17 December 2025.
DICER1-related cancer predisposition v1.2 DICER1 Achchuthan Shanmugasundram Phenotypes for gene: DICER1 were changed from to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; DICER1-related tumor predisposition, MONDO:0100216
Cystinosis v1.2 CTNS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #219800) and the OMIM record was last accessed on 17 December 2025.
Cystinosis v1.2 CTNS Achchuthan Shanmugasundram Phenotypes for gene: CTNS were changed from to Cystinosis, atypical nephropathic, OMIM:219800; Cystinosis, nephropathic, OMIM:219800; nephropathic cystinosis, MONDO:0100151
Cystic fibrosis diagnostic test v1.2 CFTR Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #219700) and the OMIM record was last accessed on 17 December 2025.
Cystic fibrosis diagnostic test v1.2 CFTR Achchuthan Shanmugasundram Phenotypes for gene: CFTR were changed from to Cystic fibrosis, OMIM:219700; cystic fibrosis, MONDO:0009061
Congenital adrenal hyperplasia diagnostic test v1.2 CYP21A2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #201910) and the OMIM record was last accessed on 17 December 2025.
Congenital adrenal hyperplasia diagnostic test v1.2 CYP21A2 Achchuthan Shanmugasundram Phenotypes for gene: CYP21A2 were changed from to Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, OMIM:201910; Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency, OMIM:201910; classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, MONDO:0008728
Combined vitamin K-dependent clotting factor deficiency v1.3 VKORC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607473) and the OMIM record was last accessed on 17 December 2025.
Combined vitamin K-dependent clotting factor deficiency v1.3 VKORC1 Achchuthan Shanmugasundram Phenotypes for gene: VKORC1 were changed from to Vitamin K-dependent clotting factors, combined deficiency of, type 2, OMIM:607473; vitamin K-dependent clotting factors, combined deficiency of, type 2, MONDO:0011837
Combined vitamin K-dependent clotting factor deficiency v1.2 GGCX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #277450) and the OMIM record was last accessed on 17 December 2025.
Combined vitamin K-dependent clotting factor deficiency v1.2 GGCX Achchuthan Shanmugasundram Phenotypes for gene: GGCX were changed from to Vitamin K-dependent clotting factors, combined deficiency of, 1, OMIM:277450; vitamin K-dependent clotting factors, combined deficiency of, type 1, MONDO:0010187
Central congenital hypoventilation v1.6 PHOX2B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #209880) and the OMIM record was last accessed on 17 December 2025.
Central congenital hypoventilation v1.6 PHOX2B Achchuthan Shanmugasundram Phenotypes for gene: PHOX2B were changed from to Congenital central hypoventilation syndrome, OMIM:209880; central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026
Hereditary diffuse gastric cancer v2.4 CTNNA1 Achchuthan Shanmugasundram Phenotypes for gene: CTNNA1 were changed from to CTNNA1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100256
Hereditary diffuse gastric cancer v2.3 CDH1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #137215) and the OMIM record was last accessed on 17 December 2025.
Hereditary diffuse gastric cancer v2.3 CDH1 Achchuthan Shanmugasundram Phenotypes for gene: CDH1 were changed from Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215 to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215; CDH1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100488
Carney complex v1.2 PRKAR1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #160980) and the OMIM record was last accessed on 17 December 2025.
Carney complex v1.2 PRKAR1A Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1A were changed from to Carney complex, OMIM:160980; Carney complex, type 1, MONDO:0008057
Calcium-sensing receptor phenotypes v1.2 CASR Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #145980, #239200 & #601198) and these OMIM records were last accessed on 17 December 2025.
Calcium-sensing receptor phenotypes v1.2 CASR Achchuthan Shanmugasundram Phenotypes for gene: CASR were changed from to Hypocalciuric hypercalcemia, type I, OMIM:145980; Hyperparathyroidism, neonatal, OMIM:239200; Hypocalcemia, autosomal dominant, OMIM:601198; Hypocalcemia, autosomal dominant, with Bartter syndrome, OMIM:601198; familial hypocalciuric hypercalcemia 1, MONDO:0007791; neonatal severe primary hyperparathyroidism, MONDO:0009397; autosomal dominant hypocalcemia 1, MONDO:0011013
CADASIL v1.5 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #125310) and the OMIM record was last accessed on 17 December 2025.
CADASIL v1.5 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914
Blepharophimosis ptosis and epicanthus inversus v1.2 FOXL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #110100) and the OMIM record was last accessed on 17 December 2025.
Blepharophimosis ptosis and epicanthus inversus v1.2 FOXL2 Achchuthan Shanmugasundram Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, ptosis, and epicanthus inversus, OMIM:110100; blepharophimosis, ptosis, and epicanthus inversus syndrome, MONDO:0007201
Beckwith-Wiedemann syndrome v1.2 CDKN1C Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #130650) and the OMIM record was last accessed on 17 December 2025.
Beckwith-Wiedemann syndrome v1.2 CDKN1C Achchuthan Shanmugasundram Phenotypes for gene: CDKN1C were changed from to Beckwith-Wiedemann syndrome, OMIM:130650; Beckwith-Wiedemann syndrome, MONDO:0007534
Barth syndrome v1.3 TAZ Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #302060) and the OMIM record was last accessed on 17 December 2025.
Barth syndrome v1.3 TAZ Achchuthan Shanmugasundram Phenotypes for gene: TAZ were changed from to Barth syndrome, OMIM:302060; Barth syndrome, MONDO:0010543
BAP1 associated tumour predisposition syndrome v1.2 BAP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614327) and the OMIM record was last accessed on 17 December 2025.
BAP1 associated tumour predisposition syndrome v1.2 BAP1 Achchuthan Shanmugasundram Phenotypes for gene: BAP1 were changed from to Tumor predisposition syndrome, OMIM:614327; BAP1-related tumor predisposition syndrome, MONDO:0013692
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.2 FAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #601859) and the OMIM record was last accessed on 17 December 2025.
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.2 FAS Achchuthan Shanmugasundram Phenotypes for gene: FAS were changed from to Autoimmune lymphoproliferative syndrome, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158
Ataxia telangiectasia - mutation testing v1.2 ATM Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208900) and the OMIM record was last accessed on 17 December 2025.
Ataxia telangiectasia - mutation testing v1.2 ATM Achchuthan Shanmugasundram Phenotypes for gene: ATM were changed from to Ataxia telangiectasia, OMIM:208900; ataxia telangiectasia, MONDO:0008840
APC associated Polyposis v1.2 APC Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #135290, #175100 & #619182) and these OMIM records were last accessed on 17 December 2025.
APC associated Polyposis v1.2 APC Achchuthan Shanmugasundram Phenotypes for gene: APC were changed from to Desmoid disease, hereditary, OMIM:135290; Adenomatous polyposis coli, OMIM:175100; Brain tumor-polyposis syndrome 2, OMIM:175100; Gardner syndrome, OMIM:175100; Gastric adenocarcinoma and proximal polyposis of the stomach, OMIM:619182; desmoid tumor, MONDO:0007608; gastric adenocarcinoma and proximal polyposis of the stomach, MONDO:0017790; familial adenomatous polyposis 1, MONDO:0021056
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.7 FOXF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #265380) and the OMIM record was last accessed on 17 December 2025.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.7 FOXF1 Achchuthan Shanmugasundram Phenotypes for gene: FOXF1 were changed from to Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934
Alstrom syndrome v1.2 ALMS1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #203800) and the OMIM record was last accessed on 17 December 2025.
Alstrom syndrome v1.2 ALMS1 Achchuthan Shanmugasundram Phenotypes for gene: ALMS1 were changed from to Alstrom syndrome, OMIM:203800; Alstrom syndrome, MONDO:0008763
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.9 PRKAR1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #101800) and the OMIM record was last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.9 PRKAR1A Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis type 1, OMIM:101800; Acrodysostosis 1 with or without hormone resistance, MONDO:0007044
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.8 PDE4D Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614613) and the OMIM record was last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.8 PDE4D Achchuthan Shanmugasundram Phenotypes for gene: PDE4D were changed from to Acrodysostosis 2, with or without hormone resistance, OMIM:614613; acrodysostosis 2 with or without hormone resistance, MONDO:0013822
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.7 GNAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #103580, #603233, #612462 & #612463). These OMIM records were last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.7 GNAS Achchuthan Shanmugasundram Phenotypes for gene: GNAS were changed from to Pseudohypoparathyroidism Ia, OMIM:103580; Pseudohypoparathyroidism Ib, OMIM:603233; Pseudohypoparathyroidism Ic, OMIM:612462; Pseudopseudohypoparathyroidism, OMIM:612463; pseudohypoparathyroidism type 1A, MONDO:0007078; pseudohypoparathyroidism type 1B, MONDO:0011301; pseudohypoparathyroidism type 1C, MONDO:0012911; pseudopseudohypoparathyroidism, MONDO:0012912
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: OMIM records accessed on 17 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300755 & #307200) and OMIM records were last accessed on 17 December 2025.
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM records accessed on 17 December 2025.
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram Phenotypes for gene: BTK were changed from to Agammaglobulinemia, X-linked 1, OMIM:300755; Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200; Bruton-type agammaglobulinemia, MONDO:0010421; isolated growth hormone deficiency type III, MONDO:0010615
Fetal anomalies v6.123 PAICS Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859) accessed on 17-12-2025
Fetal anomalies v6.123 PAICS Arina Puzriakova Phenotypes for gene: PAICS were changed from Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Polyhydramnios; multiple congenital abnormalities; early neonatal death to Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859; Polyhydramnios; multiple congenital abnormalities; early neonatal death
Early onset or syndromic epilepsy v8.77 ATP2B1 Simon Thomas reviewed gene: ATP2B1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 40834682; Phenotypes: generalized epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.77 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
Intellectual disability v9.199 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
Fetal anomalies v6.122 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163; 40119123; 33778321
Fetal anomalies v6.121 MIA3 Arina Puzriakova commented on gene: MIA3: Another fetal case - PMID: 40130161 (2025) - Homozygous c.2768T>G, p.(Leu923*) was detected in a fetus from a Slovenian family who presented with short bones of extremities (7 percentile), fibular aplasia, bilateral radial aplasia, tibial aplasia, hypoplastic nasal bone, delayed ossification, and congenital contractures.
Skeletal dysplasia v8.26 MIA3 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 5 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.; to: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 6 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.
Skeletal dysplasia v8.26 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163; 33778321; 40948380; 40119123; 21606205; 34680893
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova edited their review of gene: MIA3: Changed publications to: 32101163, 33778321, 40948380, 40119123, 40130161, 21606205, 34680893
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova changed review comment from: At least four additional cases with biallelic variants in this gene and a severe skeletal dysplasia.

PMID: 33778321 (2021) - Indian family with third degree consanguinity, with a history of three pregnancy terminations due to clinical suspicion of lethal osteogenesis imperfecta and one full‐term pregnancy. The proband was a fetus with a lethal skeletal dysplasia and fetal hydrops. WES revealed a homozygous frameshift (c.2770_2773del, p.(Leu924Serfs*)) in MIA3 (also known as TANGO1). Segregation analysis confirmed both parents are heterozygote carriers.

PMID: 40948380 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) was identified in an 3 year old male born to Iranian consanguineous parents. The phenotype consisted of short limbs, short stature, hypotonia at birth and delayed walking.

PMID: 40119123 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) in a 5 year old Egyptian male and homozygous c.113G>T (p.Cys38Phe) in a second Egyptian patient aged 1 year and 9 months old with severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, dentinogenesis imperfecta. Previously reported extra-skeletal manifestations (hearing loss, retinopathy, hydronephrosis, microalbuminuria, diabetes, primary obesity, and intellectual disability) were not observed. Both individuals were born to consanguineous parents.

MIA3 KO mice show neonatal lethality due to insufficient bone mineralization (PMID: 21606205). Skeletal phenotype also seen in dogs with homozygous splice variant (PMID: 34680893).; to: At least four additional cases with biallelic variants in this gene and a severe skeletal dysplasia.

PMID: 33778321 (2021) - Indian family with third degree consanguinity, with a history of three pregnancy terminations due to clinical suspicion of lethal osteogenesis imperfecta and one full‐term pregnancy. The proband was a fetus with a lethal skeletal dysplasia and fetal hydrops. WES revealed a homozygous frameshift c.2770_2773del, p.(Leu924Serfs*) in MIA3 (also known as TANGO1). Segregation analysis confirmed both parents are heterozygote carriers.

PMID: 40948380 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) was identified in an 3 year old male born to Iranian consanguineous parents. The phenotype consisted of short limbs, short stature, hypotonia at birth and delayed walking.

PMID: 40119123 (2025) - Homozygous c.354+2T>G p.(Val90_Asp118del) in a 5 year old Egyptian male and homozygous c.113G>T p.(Cys38Phe) in a second Egyptian patient aged 1 year and 9 months old with severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, dentinogenesis imperfecta. Previously reported extra-skeletal manifestations (hearing loss, retinopathy, hydronephrosis, microalbuminuria, diabetes, primary obesity, and intellectual disability) were not observed. Both individuals were born to consanguineous parents.

PMID: 40130161 (2025) - Homozygous c.2768T>G, p.(Leu923*) was detected in a fetus from a Slovenian family who presented with short bones of extremities (7 percentile), fibular aplasia, bilateral radial aplasia, tibial aplasia, hypoplastic nasal bone, delayed ossification, and congenital contractures.

MIA3 KO mice show neonatal lethality due to insufficient bone mineralization (PMID: 21606205). Skeletal phenotype also seen in dogs with homozygous splice variant (PMID: 34680893).
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163
Skeletal dysplasia v8.24 MIA3 Arina Puzriakova Classified gene: MIA3 as Amber List (moderate evidence)
Skeletal dysplasia v8.24 MIA3 Arina Puzriakova Gene: mia3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Classified gene: MIA3 as Red List (low evidence)
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 5 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Gene: mia3 has been classified as Red List (Low Evidence).
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova edited their review of gene: MIA3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova Tag Q4_25_promote_green tag was added to gene: MIA3.
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32101163, 33778321, 40948380, 40119123, 21606205, 34680893; Phenotypes: Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.121 ZEB1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ZEB1.
Tag Q3_25_NHS_review was removed from gene: ZEB1.
Fetal anomalies v6.121 WDR47 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: WDR47.
Tag Q3_25_NHS_review was removed from gene: WDR47.
Fetal anomalies v6.121 UNC13D Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: UNC13D.
Tag Q3_25_NHS_review was removed from gene: UNC13D.
Fetal anomalies v6.121 TCP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: TCP1.
Tag Q3_25_NHS_review was removed from gene: TCP1.
Fetal anomalies v6.121 STX5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: STX5.
Tag Q3_25_NHS_review was removed from gene: STX5.
Fetal anomalies v6.121 SRPK3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SRPK3.
Tag Q3_25_NHS_review was removed from gene: SRPK3.
Fetal anomalies v6.121 SPTA1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SPTA1.
Tag Q3_25_NHS_review was removed from gene: SPTA1.
Fetal anomalies v6.121 SPOUT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SPOUT1.
Tag Q3_25_NHS_review was removed from gene: SPOUT1.
Fetal anomalies v6.121 SLC35A3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SLC35A3.
Tag Q3_25_NHS_review was removed from gene: SLC35A3.
Fetal anomalies v6.121 SLC12A9 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SLC12A9.
Tag Q3_25_NHS_review was removed from gene: SLC12A9.
Fetal anomalies v6.121 SENP7 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SENP7.
Tag Q3_25_NHS_review was removed from gene: SENP7.
Fetal anomalies v6.121 RPL26 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RPL26.
Tag Q3_25_NHS_review was removed from gene: RPL26.
Fetal anomalies v6.121 RNU5B-1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RNU5B-1.
Tag Q3_25_NHS_review was removed from gene: RNU5B-1.
Fetal anomalies v6.121 RIPPLY2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RIPPLY2.
Tag Q3_25_NHS_review was removed from gene: RIPPLY2.
Fetal anomalies v6.121 RAB11B Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RAB11B.
Tag Q3_25_NHS_review was removed from gene: RAB11B.
Fetal anomalies v6.121 PUS3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PUS3.
Tag Q3_25_NHS_review was removed from gene: PUS3.
Fetal anomalies v6.121 PTEN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PTEN.
Tag Q3_25_NHS_review was removed from gene: PTEN.
Fetal anomalies v6.121 PSKH1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PSKH1.
Tag Q3_25_NHS_review was removed from gene: PSKH1.
Fetal anomalies v6.121 PPFIBP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PPFIBP1.
Tag Q3_25_NHS_review was removed from gene: PPFIBP1.
Fetal anomalies v6.121 PPFIA3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PPFIA3.
Tag Q3_25_NHS_review was removed from gene: PPFIA3.
Fetal anomalies v6.121 PLAA Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PLAA.
Tag Q3_25_NHS_review was removed from gene: PLAA.
Fetal anomalies v6.121 PIGW Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGW.
Tag Q3_25_NHS_review was removed from gene: PIGW.
Optic neuropathy v5.38 NDUFA10 Ida Ertmanska Mode of pathogenicity for gene: NDUFA10 was changed from Other to None
Fetal anomalies v6.121 PIGP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGP.
Tag Q3_25_NHS_review was removed from gene: PIGP.
Optic neuropathy v5.37 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from None to None
Optic neuropathy v5.36 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from None to None
Optic neuropathy v5.35 NDUFA10 Ida Ertmanska Phenotypes for gene: NDUFA10 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243; mitochondrial complex I deficiency, nuclear type 22, MONDO:0032626; Optic neuropathy, HP:0001138
Optic neuropathy v5.34 NDUFA1 Ida Ertmanska edited their review of gene: NDUFA1: Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020, Optic neuropathy, HP:0001138
Optic neuropathy v5.34 NDUFA10 Ida Ertmanska Publications for gene: NDUFA10 were set to PMID: 41234160
Optic neuropathy v5.33 NDUFA10 Ida Ertmanska Classified gene: NDUFA10 as Amber List (moderate evidence)
Optic neuropathy v5.33 NDUFA10 Ida Ertmanska Gene: ndufa10 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NDUFA10.
Tag Q4_25_NHS_review tag was added to gene: NDUFA10.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska changed review comment from: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic).; to: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic). Based on the available evidence, this gene should be promoted to Green for Optic neuropathy.
Fetal anomalies v6.121 PIGG Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGG.
Tag Q3_25_NHS_review was removed from gene: PIGG.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska edited their review of gene: NDUFA10: Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic).; Changed publications to: 31130284, 36270260, 41234160; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243, mitochondrial complex I deficiency, nuclear type 22, MONDO:0032626
Fetal anomalies v6.121 PI4KA Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PI4KA.
Tag Q3_25_NHS_review was removed from gene: PI4KA.
Fetal anomalies v6.121 PHF5A Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PHF5A.
Tag Q3_25_NHS_review was removed from gene: PHF5A.
Fetal anomalies v6.121 PAK2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PAK2.
Tag Q3_25_NHS_review was removed from gene: PAK2.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (PMID: 25356405, PMID: 29506883).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

Authors highlight the clinical variability between LSS patients harbouring the same variant.

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Fetal anomalies v6.121 PAICS Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PAICS.
Tag Q3_25_NHS_review was removed from gene: PAICS.
Fetal anomalies v6.121 ODC1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ODC1.
Tag Q3_25_NHS_review was removed from gene: ODC1.
Fetal anomalies v6.121 NEXN Arina Puzriakova changed review comment from: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; to: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal' as per the review.
Fetal anomalies v6.121 NR2F1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NR2F1.
Tag Q3_25_NHS_review was removed from gene: NR2F1.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.121 NODAL Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: NODAL.
Tag Q3_25_demote_red was removed from gene: NODAL.
Fetal anomalies v6.121 NEXN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NEXN.
Tag Q3_25_NHS_review was removed from gene: NEXN.
Fetal anomalies v6.121 NEPRO Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NEPRO.
Tag Q3_25_NHS_review was removed from gene: NEPRO.
Fetal anomalies v6.121 NDUFB7 Achchuthan Shanmugasundram Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Tag Q3_25_NHS_review was removed from gene: NDUFB7.
Fetal anomalies v6.121 MYH9 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: MYH9.
Tag Q3_25_demote_red was removed from gene: MYH9.
Fetal anomalies v6.121 MSL2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MSL2.
Tag Q3_25_NHS_review was removed from gene: MSL2.
Fetal anomalies v6.121 MIA3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MIA3.
Tag Q3_25_NHS_review was removed from gene: MIA3.
Fetal anomalies v6.121 MED11 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MED11.
Tag Q3_25_NHS_review was removed from gene: MED11.
Fetal anomalies v6.121 MAPK1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MAPK1.
Tag Q3_25_NHS_review was removed from gene: MAPK1.
Fetal anomalies v6.121 MAGED2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MAGED2.
Tag Q3_25_NHS_review was removed from gene: MAGED2.
Fetal anomalies v6.121 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LSS.
Tag Q3_25_NHS_review was removed from gene: LSS.
Fetal anomalies v6.121 LGI3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LGI3.
Tag Q3_25_NHS_review was removed from gene: LGI3.
Fetal anomalies v6.121 LDB1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LDB1.
Tag Q3_25_NHS_review was removed from gene: LDB1.
Fetal anomalies v6.121 LAGE3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LAGE3.
Tag Q3_25_NHS_review was removed from gene: LAGE3.
Fetal anomalies v6.121 ITGAV Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ITGAV.
Tag Q3_25_NHS_review was removed from gene: ITGAV.
Fetal anomalies v6.121 IFT27 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: IFT27.
Tag Q3_25_NHS_review was removed from gene: IFT27.
Fetal anomalies v6.121 HNRNPU Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: HNRNPU.
Tag Q3_25_NHS_review was removed from gene: HNRNPU.
Fetal anomalies v6.121 HDAC3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: HDAC3.
Tag Q3_25_NHS_review was removed from gene: HDAC3.
Fetal anomalies v6.121 GNS Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: GNS.
Tag Q3_25_demote_amber was removed from gene: GNS.
Fetal anomalies v6.121 GNAI2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GNAI2.
Tag Q3_25_NHS_review was removed from gene: GNAI2.
Fetal anomalies v6.121 GEMIN4 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GEMIN4.
Tag Q3_25_NHS_review was removed from gene: GEMIN4.
Fetal anomalies v6.121 GALT Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GALT.
Tag Q3_25_NHS_review was removed from gene: GALT.
Fetal anomalies v6.121 FLVCR1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: FLVCR1.
Fetal anomalies v6.121 FAAP100 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: FAAP100.
Tag Q3_25_NHS_review was removed from gene: FAAP100.
Fetal anomalies v6.121 EXOSC8 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EXOSC8.
Tag Q3_25_NHS_review was removed from gene: EXOSC8.
Fetal anomalies v6.121 EXOC6B Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EXOC6B.
Tag Q3_25_NHS_review was removed from gene: EXOC6B.
Fetal anomalies v6.121 EFL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EFL1.
Tag Q3_25_NHS_review was removed from gene: EFL1.
Fetal anomalies v6.121 EEFSEC Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EEFSEC.
Tag Q3_25_NHS_review was removed from gene: EEFSEC.
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.121 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.120 C1orf127 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: C1orf127.
Tag Q2_25_ NHS_review was removed from gene: C1orf127.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.; to: Comment on list classification: As reviewed by Neringa Jurkute, there are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from Other to None
Optic neuropathy v5.31 NDUFA1 Ida Ertmanska Publications for gene: NDUFA1 were set to PMID: 41234160
Optic neuropathy v5.30 NDUFA1 Ida Ertmanska Phenotypes for gene: NDUFA1 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020; Optic neuropathy, HP:0001138
Optic neuropathy v5.29 NDUFA1 Ida Ertmanska Classified gene: NDUFA1 as Amber List (moderate evidence)
Optic neuropathy v5.29 NDUFA1 Ida Ertmanska Gene: ndufa1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NDUFA1.
Tag Q4_25_NHS_review tag was added to gene: NDUFA1.
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska commented on gene: NDUFA1: Comment on list classification: There are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.
Three probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy ofcerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska reviewed gene: NDUFA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v8.35 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel at the next GMS update.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 16th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.35 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar hypoplasia type 2C, OMIM:612390 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Ataxia and cerebellar anomalies - narrow panel v8.34 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to 18711368; 20952379; 27370523
Intellectual disability v9.198 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Intellectual disability v9.197 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to 0
Intellectual disability v9.196 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. No mention of cognitive ability.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed rating: AMBER
Intellectual disability v9.196 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.
Intellectual disability v9.196 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 20952379, 27370523, 32476018, 37544645; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed publications to: 20952379, 27370523, 32476018, 37544645
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed phenotypes to: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel at the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar hypoplasia type 2C,612390; Pontocerebellar Hypoplasia type 2C; Pontocerebellar hypoplasia 2C (612390); Pontocerebellar Hypoplasia to Pontocerebellar hypoplasia type 2C, OMIM:612390
Ataxia and cerebellar anomalies - narrow panel v8.32 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to PMID: 18711368
Ataxia and cerebellar anomalies - narrow panel v8.31 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed rating: AMBER
Ataxia and cerebellar anomalies - narrow panel v8.31 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 20952379, 27370523; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v6.7 TK2 Ida Ertmanska Publications for gene: TK2 were set to 11687801 18021809 19736010 16831967 36146520
Congenital muscular dystrophy v6.6 TK2 Ida Ertmanska Phenotypes for gene: TK2 were changed from Congenital muscular dystrophy; mitochondrial disease; limb girdle muscular dystrophy to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301
Congenital muscular dystrophy v6.5 TK2 Ida Ertmanska Classified gene: TK2 as Amber List (moderate evidence)
Congenital muscular dystrophy v6.5 TK2 Ida Ertmanska Gene: tk2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TK2.
Tag Q4_25_NHS_review tag was added to gene: TK2.
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska edited their review of gene: TK2: Added comment: Comment on list classification: There are numerous patients reported in literature with biallelic variants in TK2 and mitochondrial myopathy. More than 25 cases have been reported with rapidly progressive infantile-onset (<1year of age) muscle weakness, usually leading to respiratory failure before age 3. Based on available evidence TK2 should be promoted to Green for Congenital muscular dystrophy at the next GMS update.; Changed publications to: 18819985, 38544965, 40098049
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560, mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.28 TK2 Ida Ertmanska Publications for gene: TK2 were set to 22345218 23303857 24198295 31092255 25948719
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.27 TK2 Ida Ertmanska Phenotypes for gene: TK2 were changed from mitochondrial disease; limb girdle muscular dystrophy; congenital muscular dystrophy to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.26 TK2 Ida Ertmanska Classified gene: TK2 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.26 TK2 Ida Ertmanska Gene: tk2 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TK2.
Tag Q4_25_NHS_review tag was added to gene: TK2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska changed review comment from: PMID: 24198295 Alston et al., 2013
A 74-year-old woman with sensorineural hearing loss, progressive muscle weakness and rapidly progressive respiratory failure. Compound het TK2 variants c.103C>T (p.Gln35*) and c.582G>T (p.Lys194Asn).

PMID: 35280287 Manini et al., 2022
55yo Italian woman; ptosis and dysphonia with onset at 8yo, dysphagia at 20yo, slowly progressive limb weakness reported in adulthood; compound het TK2 mutations: c.278A>G, p.Asn93Ser and c.543del, p.Leu182Phefs*11; mtDNA depletion demonstrated by qPCR in muscle tissue.

PMID: 37527940 Morganroth et al., 2023
Report of a 40yo male patient with muscle weakness (limb girdle weakness, chronic progressive external ophthalmoplegia, dysphagia) and respiratory failure; developed limb girdle weakness at 21yo; homozygous for TK2 c.604_606del (p.K202del). Mother confirmed a heterozygous carrier.

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2. 40% of patients presented with disease before 12yo. 50/53 patients had a diagnosis of mitochondrial myopathy based on muscle biopsy findings.

PMID: 40098049 Li et al., 2025
Female patient with early-onset lipid storage myopathy (onset at 8 months old); compound het variatns in TK2: c.311G > A (p.Arg104His) and a deletion spanning TK2 exons 5-10 (g.66545871_66565372del); COX negative fibers and accumulation of lipid droplets noted on biceps biopsy; detected decrease in TK2 protein and mtDNA copy number in patient muscle samples.
Based on literature review of 50 TK2-related myopathy cases, authors note that the same TK2 variant may cause variable onset and severity of disease between patients. Variable presentation of limb girdle muscle weakness, ptosis, respiratory failure, and facial weakness; range of congenital to adult disease onset.

TK2 is associated with AR Mitochondrial DNA depletion syndrome 2 (myopathic type), MIM:609560 and putatively associated with AR Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, MIM:617069 (OMIM accessed 15th Dec 2025).; to: PMID: 24198295 Alston et al., 2013
A 74-year-old woman with sensorineural hearing loss, progressive muscle weakness and rapidly progressive respiratory failure. Compound het TK2 variants c.103C>T (p.Gln35*) and c.582G>T (p.Lys194Asn).

PMID: 35280287 Manini et al., 2022
55yo Italian woman; ptosis and dysphonia with onset at 8yo, dysphagia at 20yo, slowly progressive limb weakness reported in adulthood; compound het TK2 mutations: c.278A>G, p.Asn93Ser and c.543del, p.Leu182Phefs*11; mtDNA depletion demonstrated by qPCR in muscle tissue.

PMID: 37527940 Morganroth et al., 2023
Report of a 40yo male patient with muscle weakness (limb girdle weakness, chronic progressive external ophthalmoplegia, dysphagia) and respiratory failure; developed limb girdle weakness at 21yo; homozygous for TK2 c.604_606del (p.K202del). Mother confirmed to be a heterozygous carrier.

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2. 40% of patients presented with disease before 12yo. 50/53 patients had a diagnosis of mitochondrial myopathy based on muscle biopsy findings.

PMID: 40098049 Li et al., 2025
Female patient with early-onset lipid storage myopathy (onset at 8 months old); compound het variants in TK2: c.311G > A (p.Arg104His) and a deletion spanning TK2 exons 5-10 (g.66545871_66565372del); COX negative fibers and accumulation of lipid droplets noted on biceps biopsy; detected decrease in TK2 protein and mtDNA copy number in patient muscle samples.
Based on literature review of 50 TK2-related myopathy cases, authors note that the same TK2 variant may cause variable onset and severity of disease between patients. Variable presentation of limb girdle muscle weakness, ptosis, respiratory failure, and facial weakness; range of congenital to adult disease onset.

TK2 is associated with AR Mitochondrial DNA depletion syndrome 2 (myopathic type), MIM:609560 and putatively associated with AR Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, MIM:617069 (OMIM accessed 15th Dec 2025).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska commented on gene: TK2: Comment on list classification: There are numerous individuals reported in literature with biallelic TK2 variants and mitochondrial myopathy. Affected individuals may present with disease of variable severity and age of onset. The phenotype range includes progressive muscle weakness, ptosis, chronic progressive external ophthalmoplegia (CPEO), and respiratory failure. Based on available evidence, this gene should be promoted to Green for Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24198295, 35280287, 37527940, 38544965, 40098049; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560, mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.120 DST Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DST.
Tag Q3_25_NHS_review was removed from gene: DST.
Fetal anomalies v6.120 DSE Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DSE.
Tag Q3_25_NHS_review was removed from gene: DSE.
Fetal anomalies v6.120 DHX9 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DHX9.
Tag Q3_25_NHS_review was removed from gene: DHX9.
Fetal anomalies v6.120 DHRSX Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DHRSX.
Tag Q3_25_NHS_review was removed from gene: DHRSX.
Fetal anomalies v6.120 CTGF Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CTGF.
Tag Q3_25_NHS_review was removed from gene: CTGF.
Fetal anomalies v6.120 COQ2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COQ2.
Tag Q3_25_NHS_review was removed from gene: COQ2.
Fetal anomalies v6.120 COMP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COMP.
Tag Q3_25_NHS_review was removed from gene: COMP.
Fetal anomalies v6.120 COL25A1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COL25A1.
Tag Q3_25_NHS_review was removed from gene: COL25A1.
Fetal anomalies v6.120 CELSR1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CELSR1.
Tag Q3_25_NHS_review was removed from gene: CELSR1.
Fetal anomalies v6.120 CDK5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CDK5.
Tag Q3_25_NHS_review was removed from gene: CDK5.
Fetal anomalies v6.120 C12orf66 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: C12orf66.
Tag Q3_25_NHS_review was removed from gene: C12orf66.
Fetal anomalies v6.120 BORCS5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: BORCS5.
Tag Q3_25_NHS_review was removed from gene: BORCS5.
Fetal anomalies v6.120 BHLHE22 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag Q3_25_NHS_review was removed from gene: BHLHE22.
Fetal anomalies v6.120 ARL6IP1 Achchuthan Shanmugasundram Tag Q3_24_NHS_review was removed from gene: ARL6IP1.
Tag Q3_25_promote_green was removed from gene: ARL6IP1.
Fetal anomalies v6.120 ARL2BP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ARL2BP.
Tag Q3_25_NHS_review was removed from gene: ARL2BP.
Fetal anomalies v6.120 AGT Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: AGT.
Tag Q3_25_NHS_review was removed from gene: AGT.
Fetal anomalies v6.120 AGRN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: AGRN.
Tag Q3_25_NHS_review was removed from gene: AGRN.
Bleeding and platelet disorders v4.2 RAP1B Carl Fratter gene: RAP1B was added
gene: RAP1B was added to Bleeding and platelet disorders. Sources: Expert Review
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to PMID: 32627184; 35451551; 37850357
Phenotypes for gene: RAP1B were set to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (OMIM #620654)
Penetrance for gene: RAP1B were set to unknown
Mode of pathogenicity for gene: RAP1B 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: RAP1B was set to GREEN
Added comment: Specific gain-of-function missense variants have been associated with this disorder to date.
RAP1B is already included as a green gene on other panels, including the R91 cytopenia panel.
It would be appropriate to add this gene to the R90 panel, as other syndromic thrombocytopenia associated genes are included on this panel. This opinion is supported by the Central&South GLH haemostasis genomics MDT.
Sources: Expert Review
Fetal anomalies v6.120 ZEB1 Achchuthan Shanmugasundram reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 WDR47 Achchuthan Shanmugasundram reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 UNC13D Achchuthan Shanmugasundram edited their review of gene: UNC13D: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 TCP1 Achchuthan Shanmugasundram reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 STX5 Achchuthan Shanmugasundram edited their review of gene: STX5: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 SRPK3 Achchuthan Shanmugasundram reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SPTA1 Achchuthan Shanmugasundram edited their review of gene: SPTA1: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 SPOUT1 Achchuthan Shanmugasundram reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SLC35A3 Achchuthan Shanmugasundram reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SLC12A9 Achchuthan Shanmugasundram reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SENP7 Achchuthan Shanmugasundram reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RPL26 Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RNU5B-1 Achchuthan Shanmugasundram reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RIPPLY2 Achchuthan Shanmugasundram reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RAB11B Achchuthan Shanmugasundram edited their review of gene: RAB11B: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PUS3 Achchuthan Shanmugasundram reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PTEN Achchuthan Shanmugasundram reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PSKH1 Achchuthan Shanmugasundram reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PPFIBP1 Achchuthan Shanmugasundram reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PPFIA3 Achchuthan Shanmugasundram reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PLAA Achchuthan Shanmugasundram edited their review of gene: PLAA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PIGW Achchuthan Shanmugasundram reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PIGP Achchuthan Shanmugasundram reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PIGG Achchuthan Shanmugasundram edited their review of gene: PIGG: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PI4KA Achchuthan Shanmugasundram edited their review of gene: PI4KA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PHF5A Achchuthan Shanmugasundram reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PDE12 Achchuthan Shanmugasundram edited their review of gene: PDE12: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: The concern from the panel for this one is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal pehnotype and there is not another cuase of these abnormalities in these families.; Changed rating: AMBER
Fetal anomalies v6.120 PAK2 Achchuthan Shanmugasundram reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PAICS Achchuthan Shanmugasundram reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ODC1 Achchuthan Shanmugasundram reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NR2F1 Achchuthan Shanmugasundram reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NODAL Achchuthan Shanmugasundram reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NEXN Achchuthan Shanmugasundram edited their review of gene: NEXN: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 NEPRO Achchuthan Shanmugasundram reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NDUFB7 Achchuthan Shanmugasundram reviewed gene: NDUFB7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MYH9 Achchuthan Shanmugasundram reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MSL2 Achchuthan Shanmugasundram reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MIA3 Achchuthan Shanmugasundram reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MED11 Achchuthan Shanmugasundram reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MAPK1 Achchuthan Shanmugasundram edited their review of gene: MAPK1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 MAGED2 Achchuthan Shanmugasundram reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LGI3 Achchuthan Shanmugasundram reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LDB1 Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LAGE3 Achchuthan Shanmugasundram edited their review of gene: LAGE3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 ITGAV Achchuthan Shanmugasundram edited their review of gene: ITGAV: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 IFT27 Achchuthan Shanmugasundram edited their review of gene: IFT27: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 HNRNPU Achchuthan Shanmugasundram reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 HDAC3 Achchuthan Shanmugasundram reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GNS Achchuthan Shanmugasundram reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GNAI2 Achchuthan Shanmugasundram reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GEMIN4 Achchuthan Shanmugasundram reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GALT Achchuthan Shanmugasundram reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FLVCR1 Achchuthan Shanmugasundram reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FLII Achchuthan Shanmugasundram reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FAAP100 Achchuthan Shanmugasundram reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EXOSC8 Achchuthan Shanmugasundram edited their review of gene: EXOSC8: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 EXOC6B Achchuthan Shanmugasundram reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EFL1 Achchuthan Shanmugasundram reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EEFSEC Achchuthan Shanmugasundram reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DST Achchuthan Shanmugasundram reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DSE Achchuthan Shanmugasundram reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DHX9 Achchuthan Shanmugasundram reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DHRSX Achchuthan Shanmugasundram reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 CTGF Achchuthan Shanmugasundram reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COQ2 Achchuthan Shanmugasundram reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COMP Achchuthan Shanmugasundram reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COL25A1 Achchuthan Shanmugasundram edited their review of gene: COL25A1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 CELSR1 Achchuthan Shanmugasundram edited their review of gene: CELSR1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 CDK5 Achchuthan Shanmugasundram reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 C1orf127 Achchuthan Shanmugasundram reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 C12orf66 Achchuthan Shanmugasundram reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 BORCS5 Achchuthan Shanmugasundram reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 BHLHE22 Achchuthan Shanmugasundram reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ARL6IP1 Achchuthan Shanmugasundram reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ARL2BP Achchuthan Shanmugasundram reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 AGT Achchuthan Shanmugasundram edited their review of gene: AGT: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 AGRN Achchuthan Shanmugasundram reviewed gene: AGRN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska commented on gene: PNPT1: Comment on list classification: There are at least 4 unrelated families with adult-onset Spinocerebellar ataxia and heterozygous PNPT1 variants. While some carriers were very mildly affected or reported unaffected, there is good evidence of PNPT1 variants cosegregating with ataxia, supporting an autosomal dominant inheritance mode. Based on available evidence, this gene should be promoted to Green for Hereditary ataxia with onset in adulthood.
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. The PNPT1 splice variant introduces a premature stop codon (p.Gln672SerfsTer6) - confirmed by RT-PCR. OXPHOS enzyme activities were normal,
Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).
The authors pose that heterozygous variants cause lower penetrance and variable expressivity, which may explain later onset and milder phenotype than in homozygous cases.

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska Phenotypes for gene: PNPT1 were changed from to Spinocerebellar ataxia 25, OMIM:608703
Hereditary ataxia with onset in adulthood v8.14 PNPT1 Ida Ertmanska Publications for gene: PNPT1 were set to
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Classified gene: PNPT1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PNPT1.
Tag Q4_25_NHS_review tag was added to gene: PNPT1.
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35411967, 39924761; Phenotypes: Spinocerebellar ataxia 25, OMIM:608703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.119 ZEB1 Arina Puzriakova Source Expert Review Green was added to ZEB1.
Source NHS GMS was added to ZEB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 WDR47 Arina Puzriakova Source Expert Review Green was added to WDR47.
Source NHS GMS was added to WDR47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 UNC13D Arina Puzriakova Source Expert Review Green was added to UNC13D.
Source NHS GMS was added to UNC13D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 TCP1 Arina Puzriakova Source Expert Review Green was added to TCP1.
Source NHS GMS was added to TCP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 STX5 Arina Puzriakova Source Expert Review Green was added to STX5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SRPK3 Arina Puzriakova Source Expert Review Green was added to SRPK3.
Source NHS GMS was added to SRPK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SPTA1 Arina Puzriakova Source Expert Review Green was added to SPTA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SPOUT1 Arina Puzriakova Source Expert Review Green was added to SPOUT1.
Source NHS GMS was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SLC35A3 Arina Puzriakova Source Expert Review Green was added to SLC35A3.
Source NHS GMS was added to SLC35A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SLC12A9 Arina Puzriakova Source Expert Review Green was added to SLC12A9.
Source NHS GMS was added to SLC12A9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SENP7 Arina Puzriakova Source Expert Review Green was added to SENP7.
Source NHS GMS was added to SENP7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RPL26 Arina Puzriakova Source Expert Review Green was added to RPL26.
Source NHS GMS was added to RPL26.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RNU5B-1 Arina Puzriakova Source Expert Review Green was added to RNU5B-1.
Source NHS GMS was added to RNU5B-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RIPPLY2 Arina Puzriakova Source Expert Review Green was added to RIPPLY2.
Source NHS GMS was added to RIPPLY2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RAB11B Arina Puzriakova Source Expert Review Green was added to RAB11B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PUS3 Arina Puzriakova Source Expert Review Green was added to PUS3.
Source NHS GMS was added to PUS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PTEN Arina Puzriakova Source Expert Review Green was added to PTEN.
Source NHS GMS was added to PTEN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PSKH1 Arina Puzriakova Source Expert Review Green was added to PSKH1.
Source NHS GMS was added to PSKH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PPFIBP1 Arina Puzriakova Source Expert Review Green was added to PPFIBP1.
Source NHS GMS was added to PPFIBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PPFIA3 Arina Puzriakova Source Expert Review Green was added to PPFIA3.
Source NHS GMS was added to PPFIA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PLAA Arina Puzriakova Source Expert Review Green was added to PLAA.
Source NHS GMS was added to PLAA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGW Arina Puzriakova Source Expert Review Green was added to PIGW.
Source NHS GMS was added to PIGW.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGP Arina Puzriakova Source Expert Review Green was added to PIGP.
Source NHS GMS was added to PIGP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGG Arina Puzriakova Source Expert Review Green was added to PIGG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PI4KA Arina Puzriakova Source Expert Review Green was added to PI4KA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PHF5A Arina Puzriakova Source Expert Review Green was added to PHF5A.
Source NHS GMS was added to PHF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PAK2 Arina Puzriakova Source Expert Review Green was added to PAK2.
Source NHS GMS was added to PAK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PAICS Arina Puzriakova Source Expert Review Green was added to PAICS.
Source NHS GMS was added to PAICS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ODC1 Arina Puzriakova Source Expert Review Green was added to ODC1.
Source NHS GMS was added to ODC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NR2F1 Arina Puzriakova Source Expert Review Green was added to NR2F1.
Source NHS GMS was added to NR2F1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NODAL Arina Puzriakova Source Expert Review Red was added to NODAL.
Source NHS GMS was added to NODAL.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Fetal anomalies v6.119 NEXN Arina Puzriakova Source Expert Review Green was added to NEXN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NEPRO Arina Puzriakova Source Expert Review Green was added to NEPRO.
Source NHS GMS was added to NEPRO.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MYH9 Arina Puzriakova Source Expert Review Red was added to MYH9.
Source NHS GMS was added to MYH9.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Fetal anomalies v6.119 MSL2 Arina Puzriakova Source Expert Review Green was added to MSL2.
Source NHS GMS was added to MSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MIA3 Arina Puzriakova Source Expert Review Green was added to MIA3.
Source NHS GMS was added to MIA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MED11 Arina Puzriakova Source Expert Review Green was added to MED11.
Source NHS GMS was added to MED11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MAPK1 Arina Puzriakova Source Expert Review Green was added to MAPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MAGED2 Arina Puzriakova Source Expert Review Green was added to MAGED2.
Source NHS GMS was added to MAGED2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LSS Arina Puzriakova Source Expert Review Green was added to LSS.
Source NHS GMS was added to LSS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LGI3 Arina Puzriakova Source Expert Review Green was added to LGI3.
Source NHS GMS was added to LGI3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LDB1 Arina Puzriakova Source Expert Review Green was added to LDB1.
Source NHS GMS was added to LDB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LAGE3 Arina Puzriakova Source Expert Review Green was added to LAGE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ITGAV Arina Puzriakova Source Expert Review Green was added to ITGAV.
Source NHS GMS was added to ITGAV.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 IFT27 Arina Puzriakova Source Expert Review Green was added to IFT27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 HNRNPU Arina Puzriakova Source Expert Review Green was added to HNRNPU.
Source NHS GMS was added to HNRNPU.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 HDAC3 Arina Puzriakova Source Expert Review Green was added to HDAC3.
Source NHS GMS was added to HDAC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GNS Arina Puzriakova Source Expert Review Amber was added to GNS.
Source NHS GMS was added to GNS.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v6.119 GNAI2 Arina Puzriakova Source Expert Review Green was added to GNAI2.
Source NHS GMS was added to GNAI2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GEMIN4 Arina Puzriakova Source Expert Review Green was added to GEMIN4.
Source NHS GMS was added to GEMIN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GALT Arina Puzriakova Source Expert Review Green was added to GALT.
Source NHS GMS was added to GALT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 FLVCR1 Arina Puzriakova Source Expert Review Green was added to FLVCR1.
Source NHS GMS was added to FLVCR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 FAAP100 Arina Puzriakova Source Expert Review Green was added to FAAP100.
Source NHS GMS was added to FAAP100.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EXOSC8 Arina Puzriakova Source Expert Review Green was added to EXOSC8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EXOC6B Arina Puzriakova Source Expert Review Green was added to EXOC6B.
Source NHS GMS was added to EXOC6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EFL1 Arina Puzriakova Source Expert Review Green was added to EFL1.
Source NHS GMS was added to EFL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EEFSEC Arina Puzriakova Source Expert Review Green was added to EEFSEC.
Source NHS GMS was added to EEFSEC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DST Arina Puzriakova Source Expert Review Green was added to DST.
Source NHS GMS was added to DST.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DSE Arina Puzriakova Source Expert Review Green was added to DSE.
Source NHS GMS was added to DSE.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DHX9 Arina Puzriakova Source Expert Review Green was added to DHX9.
Source NHS GMS was added to DHX9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DHRSX Arina Puzriakova Source Expert Review Green was added to DHRSX.
Source NHS GMS was added to DHRSX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CTGF Arina Puzriakova Source Expert Review Green was added to CTGF.
Source NHS GMS was added to CTGF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COQ2 Arina Puzriakova Source Expert Review Green was added to COQ2.
Source NHS GMS was added to COQ2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COMP Arina Puzriakova Source Expert Review Green was added to COMP.
Source NHS GMS was added to COMP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COL25A1 Arina Puzriakova Source Expert Review Green was added to COL25A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CELSR1 Arina Puzriakova Source Expert Review Green was added to CELSR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CDK5 Arina Puzriakova Source Expert Review Green was added to CDK5.
Source NHS GMS was added to CDK5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 C1orf127 Arina Puzriakova Source Expert Review Green was added to C1orf127.
Source NHS GMS was added to C1orf127.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 C12orf66 Arina Puzriakova Source Expert Review Green was added to C12orf66.
Source NHS GMS was added to C12orf66.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 BORCS5 Arina Puzriakova Source Expert Review Green was added to BORCS5.
Source NHS GMS was added to BORCS5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 BHLHE22 Arina Puzriakova Source Expert Review Green was added to BHLHE22.
Source NHS GMS was added to BHLHE22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ARL6IP1 Arina Puzriakova Source Expert Review Green was added to ARL6IP1.
Source NHS GMS was added to ARL6IP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ARL2BP Arina Puzriakova Source Expert Review Green was added to ARL2BP.
Source NHS GMS was added to ARL2BP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 AGT Arina Puzriakova Source Expert Review Green was added to AGT.
Source NHS GMS was added to AGT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 AGRN Arina Puzriakova Source Expert Review Green was added to AGRN.
Source NHS GMS was added to AGRN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NDUFB7 Arina Puzriakova Source Expert Review Green was added to NDUFB7.
Source NHS GMS was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.118 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Fetal anomalies v6.118 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Fetal anomalies v6.117 DMPK_CTG Arina Puzriakova Tag Q3_25_promote_green was removed from STR: DMPK_CTG.
Tag Q3_25_NHS_review was removed from STR: DMPK_CTG.
Fetal anomalies v6.117 DMPK_CTG Arina Puzriakova commented on STR: DMPK_CTG: The rating of this STR has been updated to Green following NHS Genomic Medicine Service approval.
Fetal anomalies v6.117 XYLT1_GCC Arina Puzriakova commented on STR: XYLT1_GCC: R21 Clinical Oversight Group comment: Agree that this should be approved by the STR group first
Amelogenesis imperfecta v4.24 LTBP3 Ida Ertmanska commented on gene: LTBP3
Intellectual disability v9.196 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from Developmental delay; Intellectual disability; Autism; Speech and language delay to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Classified gene: ANKS1B as Amber List (moderate evidence)
Intellectual disability v9.195 ANKS1B Ida Ertmanska Gene: anks1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a complex neurodevelopmental disorder, with normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).

Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.

9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: Individuals with monogenic heterozygous microdeletions in ANSK1B had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska edited their review of gene: ANKS1B: Added comment: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; Changed rating: AMBER; Changed publications to: 31388001, 38129387; Changed phenotypes to: complex neurodevelopmental disorder, MONDO:0100038; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.194 ANKS1B Ida Ertmanska commented on gene: ANKS1B
Intellectual disability v9.194 LDB1 Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence)
Intellectual disability v9.194 LDB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although ventriculomegaly and/or hydrocephalus are the primary feature of the disorder, at least seven unrelated individuals have been reported with GDD and several also exhibited hypotonia. Taking this into account and the broader syndromic presentation, it would be appropriate to include this gene on the R27 Paediatric disorders and R69 Hypotonic infant super panels, both of which incorporate Intellectual disability as a component panel.
Intellectual disability v9.194 LDB1 Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v5.5 LDB1 Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence)
Hydrocephalus v5.5 LDB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - more than 10 unrelated individuals with de novo variants in this gene and ventriculomegaly and/or hydrocephalus.
Hydrocephalus v5.5 LDB1 Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.193 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: LDB1.
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature
Hydrocephalus v5.4 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Hydrocephalus. Sources: Literature
Q4_25_promote_green tags were added to gene: LDB1.
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature
Possible mitochondrial disorder - nuclear genes v4.17 TOMM7 Ida Ertmanska reviewed gene: TOMM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 NDUFB7 Ida Ertmanska reviewed gene: NDUFB7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 MRPL39 Ida Ertmanska reviewed gene: MRPL39: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 COX14 Ida Ertmanska reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 BTD Ida Ertmanska commented on gene: BTD
Possible mitochondrial disorder - nuclear genes v4.17 ANO10 Ida Ertmanska reviewed gene: ANO10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.16 BTD Ida Ertmanska Tag Q2_25_expert_review was removed from gene: BTD.
Tag Q2_25_ demote_amber was removed from gene: BTD.
Possible mitochondrial disorder - nuclear genes v4.16 ANO10 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: ANO10.
Tag Q2_25_ demote_amber was removed from gene: ANO10.
Possible mitochondrial disorder - nuclear genes v4.16 COX14 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: COX14.
Tag Q2_25_ demote_amber was removed from gene: COX14.
Possible mitochondrial disorder - nuclear genes v4.16 MRPL39 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: MRPL39.
Possible mitochondrial disorder - nuclear genes v4.16 NDUFB7 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Possible mitochondrial disorder - nuclear genes v4.16 TOMM7 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Possible mitochondrial disorder - nuclear genes v4.16 TOMM7 Ida Ertmanska Source Expert Review Green was added to TOMM7.
Source NHS GMS was added to TOMM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 NDUFB7 Ida Ertmanska Source Expert Review Green was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 MRPL39 Ida Ertmanska Source Expert Review Green was added to MRPL39.
Source NHS GMS was added to MRPL39.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 COX14 Ida Ertmanska Source Expert Review Amber was added to COX14.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.16 ANO10 Ida Ertmanska Source Expert Review Amber was added to ANO10.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Non-acute porphyrias v1.33 HMBS Ida Ertmanska commented on gene: HMBS: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the mode of inheritance.
Non-acute porphyrias v1.33 HMBS Ida Ertmanska Tag to_be_confirmed_NHSE tag was added to gene: HMBS.
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TS2.
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TL1.
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TK.
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-CO1.
Monogenic hearing loss v5.49 TUBB4B Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: TUBB4B.
Monogenic hearing loss v5.49 XPA Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: XPA.
Monogenic hearing loss v5.49 RFC4 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: RFC4.
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TS2.
Tag Q2_25_expert_review was removed from gene: MT-TS2.
Tag Q2_25_ NHS_review was removed from gene: MT-TS2.
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: MT-CO1.
Tag Q1_25_ promote_green was removed from gene: MT-CO1.
Tag Q2_25_ NHS_review was removed from gene: MT-CO1.
Monogenic hearing loss v5.49 MRPL49 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MRPL49.
Monogenic hearing loss v5.49 LHX3 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: LHX3.
Monogenic hearing loss v5.49 HGF Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: HGF.
Tag Q1_25_ expert_review was removed from gene: HGF.
Monogenic hearing loss v5.49 GJB6 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: GJB6.
Tag Q2_25_expert_review was removed from gene: GJB6.
Tag Q2_25_ NHS_review was removed from gene: GJB6.
Monogenic hearing loss v5.49 DAP3 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: DAP3.
Monogenic hearing loss v5.49 ATP6V1B1 Ida Ertmanska Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Monogenic hearing loss v5.49 XPA Ida Ertmanska reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 TUBB4B Ida Ertmanska reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 RFC4 Ida Ertmanska reviewed gene: RFC4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska commented on gene: MT-TS2
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska commented on gene: MT-TL1
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska commented on gene: MT-TK
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska commented on gene: MT-CO1
Monogenic hearing loss v5.49 MRPL49 Ida Ertmanska reviewed gene: MRPL49: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 LHX3 Ida Ertmanska reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 HGF Ida Ertmanska reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 GJB6 Ida Ertmanska reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 DAP3 Ida Ertmanska reviewed gene: DAP3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 ATP6V1B1 Ida Ertmanska commented on gene: ATP6V1B1
Monogenic hearing loss v5.48 XPA Ida Ertmanska Source Expert Review Green was added to XPA.
Source NHS GMS was added to XPA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 TUBB4B Ida Ertmanska Source Expert Review Green was added to TUBB4B.
Source NHS GMS was added to TUBB4B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 RFC4 Ida Ertmanska Source Expert Review Green was added to RFC4.
Source NHS GMS was added to RFC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 MRPL49 Ida Ertmanska Source Expert Review Green was added to MRPL49.
Source NHS GMS was added to MRPL49.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 LHX3 Ida Ertmanska Source Expert Review Green was added to LHX3.
Source NHS GMS was added to LHX3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 HGF Ida Ertmanska Source Expert Review Green was added to HGF.
Source NHS GMS was added to HGF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 GJB6 Ida Ertmanska Source Expert Review Green was added to GJB6.
Source NHS GMS was added to GJB6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 DAP3 Ida Ertmanska Source Expert Review Green was added to DAP3.
Source NHS GMS was added to DAP3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 ATP6V1B1 Ida Ertmanska Source NHS GMS was added to ATP6V1B1.
Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. ; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. Heterozygous mother of one homozgyous proband is reported to have had Thrombocytosis from adolescence.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464; 40481232
Thrombocythaemia v1.10 SH2B3 Eleanor Williams commented on gene: SH2B3: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.
Thrombophilia with a likely monogenic cause v2.9 PLG Eleanor Williams Tag Q2_25_expert_review was removed from gene: PLG.
Tag Q2_25_ demote_amber was removed from gene: PLG.
Thrombophilia with a likely monogenic cause v2.9 PLG Eleanor Williams reviewed gene: PLG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombophilia with a likely monogenic cause v2.8 PLG Eleanor Williams Source Expert Review Amber was added to PLG.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Added comment: Comment on phenotypes: Phenotype accessed in OMIM on 11th Dec 2025
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Phenotypes for gene: SH2B3 were changed from Thrombocythemia, somatic, 187950 to Thrombocythemia, somatic, OMIM:187950
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram Tag Q4_24_promote_green was removed from gene: MYMX.
Congenital myopathy v6.43 RFC4 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: RFC4.
Congenital myopathy v6.43 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Congenital myopathy v6.43 MT-TW Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TW.
Tag Q2_25_expert_review was removed from gene: MT-TW.
Tag Q2_25_ NHS_review was removed from gene: MT-TW.
Congenital myopathy v6.43 MT-TN Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TN.
Tag Q2_25_expert_review was removed from gene: MT-TN.
Tag Q2_25_ NHS_review was removed from gene: MT-TN.
Congenital myopathy v6.43 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Congenital myopathy v6.43 MT-TK Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Congenital myopathy v6.43 MT-TE Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TE.
Tag Q2_25_expert_review was removed from gene: MT-TE.
Tag Q2_25_ NHS_review was removed from gene: MT-TE.
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: SH2B3.
Tag Q2_25_expert_review was removed from gene: SH2B3.
Tag Q2_25_ NHS_review was removed from gene: SH2B3.
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Added comment: Comment on publications: Adding the PubMed ID of 40481232 for Leardini et al 2025
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464
Congenital myopathy v6.43 TNNI1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TNNI1.
Thrombocythaemia v1.8 SH2B3 Eleanor Williams changed review comment from: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval. NW : Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?NW: Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?; to: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 TNNI1 Achchuthan Shanmugasundram reviewed gene: TNNI1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital myopathy v6.43 SRPK3 Achchuthan Shanmugasundram reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital myopathy v6.43 RFC4 Achchuthan Shanmugasundram commented on gene: RFC4: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram commented on gene: MYMX: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 MT-TW Achchuthan Shanmugasundram edited their review of gene: MT-TW: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TN Achchuthan Shanmugasundram edited their review of gene: MT-TN: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TK Achchuthan Shanmugasundram edited their review of gene: MT-TK: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TE Achchuthan Shanmugasundram edited their review of gene: MT-TE: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 CIAO1 Achchuthan Shanmugasundram reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombocythaemia v1.8 SH2B3 Eleanor Williams reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombocythaemia v1.7 SH2B3 Eleanor Williams Source Expert Review Green was added to SH2B3.
Mode of inheritance for gene SH2B3 was changed from Other to BIALLELIC, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 TNNI1 Achchuthan Shanmugasundram Source Expert Review Green was added to TNNI1.
Source NHS GMS was added to TNNI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 SRPK3 Achchuthan Shanmugasundram Source Expert Review Green was added to SRPK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 RFC4 Achchuthan Shanmugasundram Source Expert Review Green was added to RFC4.
Source NHS GMS was added to RFC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 MYMX Achchuthan Shanmugasundram Source Expert Review Green was added to MYMX.
Source NHS GMS was added to MYMX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 MT-TW Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TW.
Source NHS GMS was added to MT-TW.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TN Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TN.
Source NHS GMS was added to MT-TN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TL1 Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TL1.
Source NHS GMS was added to MT-TL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TK Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TK.
Source NHS GMS was added to MT-TK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TE Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TE.
Source NHS GMS was added to MT-TE.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 CIAO1 Achchuthan Shanmugasundram Source Expert Review Green was added to CIAO1.
Source NHS GMS was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v4.4 SMAD6 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: SMAD6.
Tag Q2_25_expert_review was removed from gene: SMAD6.
Tag Q2_25_ NHS_review was removed from gene: SMAD6.
Thoracic aortic aneurysm or dissection (GMS) v4.4 SMAD6 Eleanor Williams reviewed gene: SMAD6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v4.3 SMAD6 Eleanor Williams Source Expert Review Red was added to SMAD6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Optic neuropathy v5.28 MT-TS2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TS2.
Tag Q2_25_expert_review was removed from gene: MT-TS2.
Tag Q2_25_ NHS_review was removed from gene: MT-TS2.
Tag technical-limitations tag was added to gene: MT-TS2.
Optic neuropathy v5.28 MT-TL1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Tag technical-limitations tag was added to gene: MT-TL1.
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND2.
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND3.
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND4L.
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND5.
Optic neuropathy v5.28 MT-TK Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Tag technical-limitations tag was added to gene: MT-TK.
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND5.
Tag Q2_25_expert_review was removed from gene: MT-ND5.
Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND4L.
Tag Q2_25_expert_review was removed from gene: MT-ND4L.
Tag Q2_25_ NHS_review was removed from gene: MT-ND4L.
Severe early-onset obesity v5.20 STX16 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: STX16.
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND3.
Tag Q2_25_expert_review was removed from gene: MT-ND3.
Tag Q2_25_ NHS_review was removed from gene: MT-ND3.
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND2.
Tag Q2_25_expert_review was removed from gene: MT-ND2.
Tag Q2_25_ NHS_review was removed from gene: MT-ND2.
Severe early-onset obesity v5.20 STX16 Eleanor Williams reviewed gene: STX16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. The GMS reviewers commented as follows: More appropriate for specialist mitochondrial lab to test for this - 1) Alternative panel test available for this gene (R42.2 - Leber hereditary optic neuropathy). 2). May not be technically feasible for all laboratories to include this gene on the panel.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. The GMS reviewers commented as follows: More appropriate for specialist mitochondrial lab to test for this - 1) Alternative panel test available for this gene (R42.2 - Leber hereditary optic neuropathy); 2). May not be technically feasible for all laboratories to include this gene on the panel.
Severe early-onset obesity v5.19 STX16 Eleanor Williams Source Expert Review Green was added to STX16.
Source NHS GMS was added to STX16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v5.28 MIEF1 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: MIEF1.
Tag Q3_24_NHS_review was removed from gene: MIEF1.
Optic neuropathy v5.28 BORCS8 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: BORCS8.
Optic neuropathy v5.28 MT-TS2 Ida Ertmanska commented on gene: MT-TS2
Optic neuropathy v5.28 MT-TL1 Ida Ertmanska commented on gene: MT-TL1
Optic neuropathy v5.28 MT-TK Ida Ertmanska commented on gene: MT-TK
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska commented on gene: MT-ND5
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska commented on gene: MT-ND4L
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska commented on gene: MT-ND3
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska commented on gene: MT-ND2
Optic neuropathy v5.28 MIEF1 Ida Ertmanska reviewed gene: MIEF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v5.28 BORCS8 Ida Ertmanska reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Segmental overgrowth disorders - Deep sequencing v4.3 PADI6 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: PADI6.
Tag Q2_25_expert_review was removed from gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v4.3 PADI6 Achchuthan Shanmugasundram reviewed gene: PADI6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Segmental overgrowth disorders - Deep sequencing v4.2 PADI6 Eleanor Williams Source Expert Review Red was added to PADI6.
Source NHS GMS was added to PADI6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Optic neuropathy v5.27 MIEF1 Ida Ertmanska Source Expert Review Green was added to MIEF1.
Source NHS GMS was added to MIEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v5.27 BORCS8 Ida Ertmanska Source Expert Review Green was added to BORCS8.
Source NHS GMS was added to BORCS8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Multi locus imprinting disorders v1.14 ZFP57 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: ZFP57.
Tag to_be_confirmed_NHSE tag was added to gene: ZFP57.
Multi locus imprinting disorders v1.14 ZFP57 Ida Ertmanska commented on gene: ZFP57
Non-acute porphyrias v1.33 HMBS Ida Ertmanska Tag Q2_25_ demote_red was removed from gene: HMBS.
Tag Q2_25_ MOI was removed from gene: HMBS.
Tag Q2_25_expert_review was removed from gene: HMBS.
Non-acute porphyrias v1.33 HMBS Ida Ertmanska commented on gene: HMBS
Respiratory ciliopathies including non-CF bronchiectasis v4.50 WFDC2 Eleanor Williams Tag Q3_24_promote_green was removed from gene: WFDC2.
Tag Q3_24_NHS_review was removed from gene: WFDC2.
Tag to_be_confirmed_NHSE tag was added to gene: WFDC2.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TUBB4B Eleanor Williams Tag dd_review was removed from gene: TUBB4B.
Tag Q1_25_ promote_green was removed from gene: TUBB4B.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TTC12 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: TTC12.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TP73 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: TP73.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 NEK10 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 GAS2L2 Eleanor Williams Tag Q3_24_promote_green was removed from gene: GAS2L2.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: EFCAB1.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DNAJB13 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: DNAJB13.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DAW1 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: DAW1.
Tag Q2_25_expert_review was removed from gene: DAW1.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Eleanor Williams Tag Q1_25_ NHS_review was removed from gene: CFAP74.
Tag Q1_25_ promote_green was removed from gene: CFAP74.
Tag Q1_25_ expert_review was removed from gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP54 Eleanor Williams Tag Q1_25_ NHS_review was removed from gene: CFAP54.
Tag Q1_25_ promote_green was removed from gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP221 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CFAP221.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CEP164 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CEP164.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 WFDC2 Eleanor Williams commented on gene: WFDC2
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TUBB4B Eleanor Williams reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TTC12 Eleanor Williams reviewed gene: TTC12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TP73 Eleanor Williams reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 NEK10 Eleanor Williams reviewed gene: NEK10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 GAS2L2 Eleanor Williams edited their review of gene: GAS2L2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Eleanor Williams reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DNAJB13 Eleanor Williams reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DAW1 Eleanor Williams reviewed gene: DAW1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Eleanor Williams reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP54 Eleanor Williams reviewed gene: CFAP54: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP221 Eleanor Williams reviewed gene: CFAP221: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CEP164 Eleanor Williams reviewed gene: CEP164: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TUBB4B Eleanor Williams Source NHS GMS was added to TUBB4B.
Source Expert Review Green was added to TUBB4B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TTC12 Eleanor Williams Source NHS GMS was added to TTC12.
Source Expert Review Green was added to TTC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TP73 Eleanor Williams Source NHS GMS was added to TP73.
Source Expert Review Green was added to TP73.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 NEK10 Eleanor Williams Source NHS GMS was added to NEK10.
Source Expert Review Green was added to NEK10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 GAS2L2 Eleanor Williams Source NHS GMS was added to GAS2L2.
Source Expert Review Green was added to GAS2L2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 EFCAB1 Eleanor Williams Source NHS GMS was added to EFCAB1.
Source Expert Review Green was added to EFCAB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 DNAJB13 Eleanor Williams Source Expert Review Green was added to DNAJB13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 DAW1 Eleanor Williams Source Expert Review Red was added to DAW1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP74 Eleanor Williams Source NHS GMS was added to CFAP74.
Source Expert Review Green was added to CFAP74.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP54 Eleanor Williams Source Expert Review Green was added to CFAP54.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP221 Eleanor Williams Source NHS GMS was added to CFAP221.
Source Expert Review Green was added to CFAP221.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CEP164 Eleanor Williams Source NHS GMS was added to CEP164.
Source Expert Review Green was added to CEP164.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypertrophic cardiomyopathy v5.22 MT-TV Arina Puzriakova commented on gene: MT-TV
Hypertrophic cardiomyopathy v5.22 MT-TL1 Arina Puzriakova commented on gene: MT-TL1
Hypertrophic cardiomyopathy v5.22 MT-ND5 Arina Puzriakova commented on gene: MT-ND5
Hypertrophic cardiomyopathy v5.22 KLHL24 Arina Puzriakova reviewed gene: KLHL24: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypertrophic cardiomyopathy v5.22 ALPK3 Arina Puzriakova commented on gene: ALPK3: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Hypertrophic cardiomyopathy v5.21 MT-TV Arina Puzriakova Classified gene: MT-TV as No list
Hypertrophic cardiomyopathy v5.21 MT-TV Arina Puzriakova Gene: mt-tv has been removed from the panel.
Hypertrophic cardiomyopathy v5.20 MT-TV Arina Puzriakova Tag curated_removed tag was added to gene: MT-TV.
Hypertrophic cardiomyopathy v5.20 MT-TV Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-TV.
Tag Q2_25_expert_review was removed from gene: MT-TV.
Tag Q2_25_ NHS_review was removed from gene: MT-TV.
Hypertrophic cardiomyopathy v5.20 MT-TL1 Arina Puzriakova Classified gene: MT-TL1 as No list
Hypertrophic cardiomyopathy v5.20 MT-TL1 Arina Puzriakova Gene: mt-tl1 has been removed from the panel.
Hypertrophic cardiomyopathy v5.19 MT-TL1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Tag curated_removed tag was added to gene: MT-TL1.
Hypertrophic cardiomyopathy v5.19 MT-ND5 Arina Puzriakova Classified gene: MT-ND5 as No list
Hypertrophic cardiomyopathy v5.19 MT-ND5 Arina Puzriakova Gene: mt-nd5 has been removed from the panel.
Hypertrophic cardiomyopathy v5.18 MT-ND5 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-ND5.
Tag Q2_25_expert_review was removed from gene: MT-ND5.
Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
Tag curated_removed tag was added to gene: MT-ND5.
Renal tubulopathies v5.10 OCRL Eleanor Williams Tag Q2_25_ promote_green was removed from gene: OCRL.
Tag Q2_25_ NHS_review was removed from gene: OCRL.
Monogenic short stature v1.27 SPOUT1 Ida Ertmanska reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SMC5 Ida Ertmanska reviewed gene: SMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SLF2 Ida Ertmanska reviewed gene: SLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SLC13A1 Ida Ertmanska reviewed gene: SLC13A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RSPRY1 Ida Ertmanska reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RNPC3 Ida Ertmanska reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RECQL4 Ida Ertmanska reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 PAPPA2 Ida Ertmanska commented on gene: PAPPA2
Monogenic short stature v1.27 MSTO1 Ida Ertmanska commented on gene: MSTO1
Monogenic short stature v1.27 GH1 Ida Ertmanska reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 FBXO22 Ida Ertmanska reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypertrophic cardiomyopathy v5.18 KLHL24 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: KLHL24.
Tag Q3_24_NHS_review was removed from gene: KLHL24.
Hypertrophic cardiomyopathy v5.18 ALPK3 Arina Puzriakova Tag Q3_24_NHS_review was removed from gene: ALPK3.
Tag Q3_24_MOI was removed from gene: ALPK3.
Hypertrophic cardiomyopathy v5.18 KLHL24 Arina Puzriakova Source Expert Review Green was added to KLHL24.
Source NHS GMS was added to KLHL24.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypertrophic cardiomyopathy v5.18 ALPK3 Arina Puzriakova Mode of inheritance for gene ALPK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.17 NDUFB7 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Mitochondrial disorder with complex I deficiency v3.17 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Mitochondrial disorder with complex I deficiency v3.16 NDUFB7 Arina Puzriakova Source Expert Review Green was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.64 PLA2G16 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: PLA2G16.
Severe insulin resistance and lipodystrophy syndromes v4.64 PLA2G16 Achchuthan Shanmugasundram reviewed gene: PLA2G16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe insulin resistance and lipodystrophy syndromes v4.63 PLA2G16 Arina Puzriakova Source NHS GMS was added to PLA2G16.
Source Expert Review Green was added to PLA2G16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TNNI1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: TNNI1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 SNUPN Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SNUPN.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 JAG2 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: JAG2.
Tag Q2_25_ NHS_review was removed from gene: JAG2.
Intellectual disability v9.192 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital myaesthenic syndrome v5.6 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital myopathy v6.41 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital muscular dystrophy v6.4 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Arthrogryposis v9.15 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 CIAO1 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 ACTN2 Arina Puzriakova Tag Q2_25_ MOI was removed from gene: ACTN2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 TNNI1 Arina Puzriakova commented on gene: TNNI1: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 SNUPN Arina Puzriakova reviewed gene: SNUPN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 JAG2 Arina Puzriakova reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 CIAO1 Arina Puzriakova reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 ACTN2 Arina Puzriakova commented on gene: ACTN2
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 TNNI1 Arina Puzriakova Source NHS GMS was added to TNNI1.
Source Expert Review Green was added to TNNI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 SNUPN Arina Puzriakova Source NHS GMS was added to SNUPN.
Source Expert Review Green was added to SNUPN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 JAG2 Arina Puzriakova Source Expert Review Green was added to JAG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 CIAO1 Arina Puzriakova Source NHS GMS was added to CIAO1.
Source Expert Review Green was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 ACTN2 Arina Puzriakova Mode of inheritance for gene ACTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neonatal diabetes v5.9 RNU4ATAC Anna-Marie Johnson gene: RNU4ATAC was added
gene: RNU4ATAC was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: RNU4ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU4ATAC were set to MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
Phenotypes for gene: RNU4ATAC were set to neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis
Penetrance for gene: RNU4ATAC were set to Complete
Mode of pathogenicity for gene: RNU4ATAC was set to Other
Review for gene: RNU4ATAC was set to GREEN
Added comment: RNU4ATAC is a non-protein-coding gene and a component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Johnson et al report RNU4ATAC as a novel disease gene causing monogenic autoimmune diabetes (median onset: 20 weeks) with additional immune dysregulation; whole genome sequencing of 7 unrelated individuals identified homozygous or compound heterozygous variants in RNU4ATAC, all known causes of monogenic diabetes had already been excluded. Sanger sequencing of the RNU4ATAC gene in patients with neonatal diabetes of unknown cause identified a further 5 unrelated individuals with biallelic variants in RNU4ATAC. RNA-seq from 3 unrelated individuals confirmed intron retention in comparison to controls. Multi-omic analysis of patient samples revealed a profound B cell developmental defect. This is the first report of pathogenic variants in non-coding genes causing monogenic diabetes, and also extends the phenotype of RNU4ATACopathies.
Sources: Literature
Neonatal diabetes v5.9 RNU6ATAC Anna-Marie Johnson gene: RNU6ATAC was added
gene: RNU6ATAC was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to MedRxiv preprint Johnson et al., 2025 https://doi.org/10.1101/2025.09.12.25335567
Phenotypes for gene: RNU6ATAC were set to neonatal diabetes; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia
Penetrance for gene: RNU6ATAC were set to Complete
Mode of pathogenicity for gene: RNU6ATAC was set to Other
Review for gene: RNU6ATAC was set to GREEN
Added comment: RNU6ATAC is a non-protein-coding gene and a component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Johnson et al report RNU6ATAC as a novel disease gene causing monogenic autoimmune diabetes (median onset: 17 weeks) with additional immune dysregulation; whole genome sequencing of 4 individuals from 4 families identified 4 different biallelic pathogenic variants in the RNU6ATAC gene, all known causes of monogenic diabetes had already been excluded. Sanger sequencing of affected siblings from family A and D confirmed co segregation (1 additional case in family A, 2 in family D). RNA-seq from Family D confirmed intron retention in comparison to controls. Multi-omic analysis of patient samples revealed a profound B cell developmental defect.
Sources: Literature
Laterality disorders and isomerism v4.8 C1orf127 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: C1orf127.
Tag Q2_25_ NHS_review was removed from gene: C1orf127.
Laterality disorders and isomerism v4.8 AL117258.1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: AL117258.1.
Laterality disorders and isomerism v4.8 C1orf127 Arina Puzriakova commented on gene: C1orf127: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Laterality disorders and isomerism v4.8 AL117258.1 Arina Puzriakova reviewed gene: AL117258.1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Laterality disorders and isomerism v4.7 C1orf127 Arina Puzriakova Source NHS GMS was added to C1orf127.
Source Expert Review Green was added to C1orf127.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Laterality disorders and isomerism v4.7 AL117258.1 Arina Puzriakova Source NHS GMS was added to AL117258.1.
Source Expert Review Green was added to AL117258.1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Iron metabolism disorders - NOT common HFE mutations v3.3 CYBRD1 Arina Puzriakova Tag Q4_24_expert_review was removed from gene: CYBRD1.
Tag Q4_24_demote_red was removed from gene: CYBRD1.
Iron metabolism disorders - NOT common HFE mutations v3.3 CYBRD1 Arina Puzriakova reviewed gene: CYBRD1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Iron metabolism disorders - NOT common HFE mutations v3.2 CYBRD1 Arina Puzriakova Source Expert Review Red was added to CYBRD1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v3.10 MBD4 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MBD4.
Tag Q2_25_ NHS_review was removed from gene: MBD4.
Inherited polyposis and early onset colorectal cancer - germline testing v3.10 MBD4 Arina Puzriakova edited their review of gene: MBD4: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Inherited polyposis and early onset colorectal cancer - germline testing v3.9 MBD4 Arina Puzriakova Source Expert Review Green was added to MBD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.9 DNMT3A Arina Puzriakova Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome, OMIM: 618724 to Heyn-Sproul-Jackson syndrome, OMIM:618724
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.8 DNMT3A Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.8 DNMT3A Arina Puzriakova reviewed gene: DNMT3A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.7 DNMT3A Arina Puzriakova Source NHS GMS was added to DNMT3A.
Source Expert Review Green was added to DNMT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited ovarian cancer (without breast cancer) v4.8 LLGL2 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: LLGL2.
Tag Q2_25_ NHS_review was removed from gene: LLGL2.
Tag to_be_confirmed_NHSE tag was added to gene: LLGL2.
Inherited ovarian cancer (without breast cancer) v4.8 LLGL2 Arina Puzriakova commented on gene: LLGL2
Monogenic short stature v1.26 SPOUT1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: SPOUT1.
Monogenic short stature v1.26 SMC5 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: SMC5.
Monogenic short stature v1.26 SLF2 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: SLF2.
Monogenic short stature v1.26 SLC13A1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: SLC13A1.
Monogenic short stature v1.26 RSPRY1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: RSPRY1.
Monogenic short stature v1.26 RNPC3 Ida Ertmanska Tag Q2_25_ demote_red was removed from gene: RNPC3.
Tag Q2_25_expert_review was removed from gene: RNPC3.
Tag Q2_25_ phenotype was removed from gene: RNPC3.
Ectodermal dysplasia v4.19 FOSL2 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: FOSL2.
Monogenic short stature v1.26 RECQL4 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: RECQL4.
Tag Q3_24_NHS_review was removed from gene: RECQL4.
Ectodermal dysplasia v4.19 TWIST2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TWIST2.
Monogenic short stature v1.26 MSTO1 Ida Ertmanska Tag Q3_24_NHS_review was removed from gene: MSTO1.
Tag Q3_24_MOI was removed from gene: MSTO1.
Monogenic short stature v1.26 GH1 Ida Ertmanska Tag Q1_25_ NHS_review was removed from gene: GH1.
Tag Q1_25_ promote_green was removed from gene: GH1.
Monogenic short stature v1.26 FBXO22 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: FBXO22.
Ectodermal dysplasia v4.19 TWIST2 Achchuthan Shanmugasundram reviewed gene: TWIST2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Ectodermal dysplasia v4.19 FOSL2 Achchuthan Shanmugasundram commented on gene: FOSL2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Ectodermal dysplasia v4.18 TWIST2 Achchuthan Shanmugasundram Source NHS GMS was added to TWIST2.
Source Expert Review Green was added to TWIST2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v4.18 FOSL2 Achchuthan Shanmugasundram Source NHS GMS was added to FOSL2.
Source Expert Review Green was added to FOSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dilated and arrhythmogenic cardiomyopathy v3.10 MYLK3 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MYLK3.
Tag Q2_25_expert_review was removed from gene: MYLK3.
Tag Q2_25_ NHS_review was removed from gene: MYLK3.
Dilated and arrhythmogenic cardiomyopathy v3.10 MYLK3 Achchuthan Shanmugasundram commented on gene: MYLK3
Mitochondrial disorder with complex IV deficiency v4.11 COX14 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: COX14.
Tag Q2_25_ demote_amber was removed from gene: COX14.
Mitochondrial disorder with complex IV deficiency v4.11 COX14 Ida Ertmanska reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Mitochondrial disorder with complex IV deficiency v4.10 COX14 Ida Ertmanska Source Expert Review Amber was added to COX14.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Rare anaemia v3.15 RPL27 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: RPL27.
Tag Q2_25_ NHS_review was removed from gene: RPL27.
Rare anaemia v3.15 RPL27 Ida Ertmanska reviewed gene: RPL27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare anaemia v3.14 RPL27 Ida Ertmanska Source Expert Review Green was added to RPL27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.30 RPL27 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RPL27.
Tag Q2_25_ NHS_review was removed from gene: RPL27.
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RPL17.
Cytopenia - NOT Fanconi anaemia v4.30 FASLG Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: FASLG.
Cytopenia - NOT Fanconi anaemia v4.30 FAS Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: FAS.
Pigmentary skin disorders v4.10 BLM Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: BLM.
Pigmentary skin disorders v4.10 BLM Ida Ertmanska reviewed gene: BLM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v4.30 RPL27 Achchuthan Shanmugasundram edited their review of gene: RPL27: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram commented on gene: RPL17: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Cytopenia - NOT Fanconi anaemia v4.30 FASLG Achchuthan Shanmugasundram commented on gene: FASLG: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Cytopenia - NOT Fanconi anaemia v4.30 FAS Achchuthan Shanmugasundram commented on gene: FAS: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Pigmentary skin disorders v4.9 BLM Ida Ertmanska Source NHS GMS was added to BLM.
Source Expert Review Green was added to BLM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 RPL27 Achchuthan Shanmugasundram Source Expert Review Green was added to RPL27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 RPL17 Achchuthan Shanmugasundram Source Expert Review Green was added to RPL17.
Source NHS GMS was added to RPL17.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 FASLG Achchuthan Shanmugasundram Source Expert Review Green was added to FASLG.
Source NHS GMS was added to FASLG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 FAS Achchuthan Shanmugasundram Source Expert Review Green was added to FAS.
Source NHS GMS was added to FAS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Primary lymphoedema v4.20 TIE1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: TIE1.
Primary lymphoedema v4.20 TIE1 Ida Ertmanska reviewed gene: TIE1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary lymphoedema v4.19 TIE1 Ida Ertmanska Source NHS GMS was added to TIE1.
Source Expert Review Green was added to TIE1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Osteogenesis imperfecta v5.3 KIF5B Ida Ertmanska Tag Q3_24_promote_green was removed from gene: KIF5B.
Osteogenesis imperfecta v5.3 KIF5B Ida Ertmanska reviewed gene: KIF5B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Osteogenesis imperfecta v5.2 KIF5B Ida Ertmanska Source NHS GMS was added to KIF5B.
Source Expert Review Green was added to KIF5B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v5.4 ATP6V1B1 Ida Ertmanska Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Nephrocalcinosis or nephrolithiasis v5.4 ATP6V1B1 Ida Ertmanska commented on gene: ATP6V1B1
Nephrocalcinosis or nephrolithiasis v5.3 ATP6V1B1 Ida Ertmanska Source NHS GMS was added to ATP6V1B1.
Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v5.5 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Tag to_be_confirmed_NHSE tag was added to gene: CIAO1.
Congenital myaesthenic syndrome v5.5 CIAO1 Achchuthan Shanmugasundram commented on gene: CIAO1
Congenital muscular dystrophy v6.3 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Congenital muscular dystrophy v6.3 CIAO1 Achchuthan Shanmugasundram reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital muscular dystrophy v6.2 CIAO1 Achchuthan Shanmugasundram Source Expert Review Green was added to CIAO1.
Source NHS GMS was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited breast cancer and ovarian cancer v2.17 BARD1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: BARD1.
Tag Q2_25_ NHS_review was removed from gene: BARD1.
Inherited breast cancer and ovarian cancer v2.17 BARD1 Arina Puzriakova edited their review of gene: BARD1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval. Additional comments from reviewing GLHs: Propose that BARD1 are treated in the same way as ATM/CHEK2 (truncating variants only etc); Changed rating: GREEN
Inherited breast cancer and ovarian cancer v2.16 BARD1 Arina Puzriakova Source Expert Review Green was added to BARD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital adrenal hypoplasia v4.8 ABCD1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ABCD1.
Congenital adrenal hypoplasia v4.8 ABCD1 Achchuthan Shanmugasundram reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital adrenal hypoplasia v4.7 ABCD1 Achchuthan Shanmugasundram Source NHS GMS was added to ABCD1.
Source Expert Review Green was added to ABCD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RNF216.
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: FEZF1.
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova reviewed gene: RNF216: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova reviewed gene: FEZF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.2 RNF216 Arina Puzriakova Source Expert Review Green was added to RNF216.
Source NHS GMS was added to RNF216.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.2 FEZF1 Arina Puzriakova Source Expert Review Green was added to FEZF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: PSKH1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red was removed from gene: RINT1.
Tag Q2_25_expert_review was removed from gene: RINT1.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CLCN5.
Tag Q2_25_ NHS_review was removed from gene: CLCN5.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram edited their review of gene: RINT1: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram commented on gene: PSKH1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Cholestasis v3.13 RINT1 Achchuthan Shanmugasundram Source NHS GMS was added to RINT1.
Source Expert Review Red was added to RINT1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Cholestasis v3.13 PSKH1 Achchuthan Shanmugasundram Source NHS GMS was added to PSKH1.
Source Expert Review Green was added to PSKH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: PAPPA2.
Tag Q3_24_NHS_review was removed from gene: PAPPA2.
Tag Q3_24_expert_review was removed from gene: PAPPA2.
Tag to_be_confirmed_NHSE tag was added to gene: PAPPA2.
Monogenic short stature v1.26 SPOUT1 Ida Ertmanska reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SMC5 Ida Ertmanska reviewed gene: SMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLF2 Ida Ertmanska reviewed gene: SLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLC13A1 Ida Ertmanska reviewed gene: SLC13A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RSPRY1 Ida Ertmanska reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RNPC3 Ida Ertmanska reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RECQL4 Ida Ertmanska reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska commented on gene: PAPPA2
Monogenic short stature v1.26 MSTO1 Ida Ertmanska commented on gene: MSTO1
Monogenic short stature v1.26 GH1 Ida Ertmanska reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 FBXO22 Ida Ertmanska reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Renal tubulopathies v5.10 OCRL Eleanor Williams commented on gene: OCRL: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams commented on gene: CLCN5: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams commented on gene: ATP6V1B1: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.9 OCRL Eleanor Williams Source Expert Review Green was added to OCRL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 CLCN5 Eleanor Williams Source Expert Review Green was added to CLCN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 ATP6V1B1 Eleanor Williams Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal