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Congenital hypothyroidism v0.53 NTN1 Zornitza Stark Classified gene: NTN1 as Amber List (moderate evidence)
Congenital hypothyroidism v0.53 NTN1 Zornitza Stark Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.52 JAG1 Zornitza Stark Phenotypes for gene: JAG1 were changed from Alagille syndrome 1 to Alagille syndrome, MIM#118450
Congenital hypothyroidism v0.51 JAG1 Zornitza Stark Classified gene: JAG1 as Green List (high evidence)
Congenital hypothyroidism v0.51 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Mendeliome v1.3098 TRPC4AP Zornitza Stark Marked gene: TRPC4AP as ready
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3098 TRPC4AP Zornitza Stark Classified gene: TRPC4AP as Amber List (moderate evidence)
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3097 TRPC4AP Zornitza Stark gene: TRPC4AP was added
gene: TRPC4AP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC4AP were set to 32428920; 26786105
Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related
Review for gene: TRPC4AP was set to AMBER
Added comment: De novo LoF TRPC4AP variant identified on WES in a child with thyroid dyshormonogenesis.
179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs. Insufficient clinical cases for green. Candidate gene.
Sources: Literature
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Marked gene: TRPC4AP as ready
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.50 TRPC4AP Zornitza Stark Phenotypes for gene: TRPC4AP were changed from Thyroid hypoplasia to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related
Congenital hypothyroidism v0.49 TRPC4AP Zornitza Stark Classified gene: TRPC4AP as Amber List (moderate evidence)
Congenital hypothyroidism v0.49 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Congenital hypothyroidism v0.48 TRPC4AP Zornitza Stark reviewed gene: TRPC4AP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.294 PSMB1 Zornitza Stark Phenotypes for gene: PSMB1 were changed from Intellectual disability; microcephaly to Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Intellectual disability syndromic and non-syndromic v1.293 PSMB1 Zornitza Stark edited their review of gene: PSMB1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Mendeliome v1.3096 PSMB1 Zornitza Stark Phenotypes for gene: PSMB1 were changed from Intellectual disability; microcephaly to Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Mendeliome v1.3095 PSAT1 Zornitza Stark Phenotypes for gene: PSAT1 were changed from Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038 to Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related
Hereditary Neuropathy_CMT - isolated v1.63 PRX Zornitza Stark Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895; HMSN to Charcot-Marie-Tooth disease type 4 MONDO:0018995
Hereditary Neuropathy_CMT - isolated v1.62 PRX Zornitza Stark edited their review of gene: PRX: Changed phenotypes: Charcot-Marie-Tooth disease type 4 MONDO:0018995
Mendeliome v1.3094 PRX Zornitza Stark Phenotypes for gene: PRX were changed from Charcot-Marie-Tooth disease, type 4F, MIM# 614895; Dejerine-Sottas disease, MIM# 145900 to Charcot-Marie-Tooth disease type 4 MONDO:0018995
Paroxysmal Dyskinesia v0.142 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Paroxysmal Dyskinesia v0.141 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Alternating Hemiplegia and Hemiplegic Migraine v0.59 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; Seizures, benign familial infantile, 2, 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia - paediatric v1.51 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Episodic kinesigenic dyskinesia 1 MIM#128200; Convulsions, familial infantile, with paroxysmal choreoathetosis MIM#602066; Seizures, benign familial infantile, 2 MIM#605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia - paediatric v1.50 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia - adult onset v1.54 PRRT2 Zornitza Stark Marked gene: PRRT2 as ready
Ataxia - adult onset v1.54 PRRT2 Zornitza Stark Gene: prrt2 has been classified as Green List (High Evidence).
Ataxia - adult onset v1.54 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Familial infantile convulsions with paroxysmal dyskinesia 1, 602066; CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS; episodic kinesigenic dyskinesia; dystonia and occasionally hemiplegic migraine and epilepsy; episodic kinesigenic dyskinesia, 128200; EPISODIC KINESIGENIC DYSKINESIA 1; SEIZURES, BENIGN FAMILIAL INFANTILE, 2 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Ataxia - adult onset v1.53 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Genetic Epilepsy v1.202 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Genetic Epilepsy v1.201 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Brain Channelopathies v1.4 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Brain Channelopathies v1.3 PRRT2 Zornitza Stark edited their review of gene: PRRT2: Changed phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556
Mendeliome v1.3093 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Deafness_IsolatedAndComplex v1.222 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from Deafness, X-linked 1, MIM# 304500; Charcot-Marie-Tooth disease, X-linked recessive, 5, MIM# 311070; Arts syndrome, MIM# 301835 to PRPS1 deficiency disorder MONDO:0100061
Deafness_IsolatedAndComplex v1.221 PRPS1 Zornitza Stark edited their review of gene: PRPS1: Changed phenotypes: PRPS1 deficiency disorder MONDO:0100061
Mendeliome v1.3092 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from Arts syndrome MIM#301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070; Deafness, X-linked 1 MIM#304500; Gout, PRPS-related MIM#300661; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661 to PRPS1 deficiency disorder MONDO:0100061; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Marked gene: PRPH2 as ready
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Gene: prph2 has been classified as Green List (High Evidence).
Macular Dystrophy/Stargardt Disease v0.56 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Leber congenital amaurosis 18, MIM#608133; Macular dystrophy, vitelliform, 3, MIM#608161; Retinitis pigmentosa 7 and digenic form, MIM#608133; Choroidal dystrophy, central areolar 2, MIM#613105; Macular dystrophy, patterned, 1, MIM#169150; Retinitis punctata albescens, MIM#136880 to PRPH2-related retinopathy MONDO:1040055
Macular Dystrophy/Stargardt Disease v0.55 PRPH2 Zornitza Stark Mode of inheritance for gene: PRPH2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Macular Dystrophy/Stargardt Disease v0.54 PRPH2 Zornitza Stark reviewed gene: PRPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPH2-related retinopathy MONDO:1040055; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Dominant v0.80 PRPH2 Zornitza Stark Marked gene: PRPH2 as ready
Retinitis pigmentosa_Autosomal Dominant v0.80 PRPH2 Zornitza Stark Gene: prph2 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Dominant v0.80 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Retinitis pigmentosa 7 to PRPH2-related retinopathy MONDO:1040055
Mendeliome v1.3091 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Leber congenital amaurosis 18, MIM#608133; Macular dystrophy, vitelliform, 3, MIM#608161; Retinitis pigmentosa 7 and digenic form, MIM#608133; Choroidal dystrophy, central areolar 2, MIM#613105; Macular dystrophy, patterned, 1, MIM#169150; Retinitis punctata albescens, MIM#136880 to PRPH2-related retinopathy MONDO:1040055
Mendeliome v1.3090 PROM1 Zornitza Stark Phenotypes for gene: PROM1 were changed from Inherited retinal dystrophy, MONDO:0019118; Cone-rod dystrophy 12, MIM# 612657; Macular dystrophy, retinal, 2, MI# 608051; Retinitis pigmentosa 41, MIM# 612095; Stargardt disease 4, MIM# 603786 to PROM1-related dominant retinopathy MONDO:1040053; Cone-rod dystrophy 12, MIM# 612657; Retinitis pigmentosa 41, MIM# 612095
Mendeliome v1.3089 PRKAG3 Zornitza Stark Phenotypes for gene: PRKAG3 were changed from increased glycogen content in skeletal muscle to Skeletal muscle glycogen content and metabolism QTL MIM#619030
Mendeliome v1.3088 PSMB1 Lucy Spencer reviewed gene: PSMB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PSMB1-related; Mode of inheritance: None
Mendeliome v1.3088 PSAT1 Lucy Spencer reviewed gene: PSAT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related; Mode of inheritance: None
Mendeliome v1.3088 PRX Lucy Spencer reviewed gene: PRX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease type 4 MONDO:0018995; Mode of inheritance: None
Mendeliome v1.3088 PRRT2 Lucy Spencer reviewed gene: PRRT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556; Mode of inheritance: None
Mendeliome v1.3088 PRPS1 Lucy Spencer reviewed gene: PRPS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPS1 deficiency disorder MONDO:0100061; Mode of inheritance: None
Mendeliome v1.3088 PRPH2 Lucy Spencer reviewed gene: PRPH2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPH2-related retinopathy MONDO:1040055; Mode of inheritance: None
Mendeliome v1.3088 PROM1 Lucy Spencer reviewed gene: PROM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PROM1-related dominant retinopathy MONDO:1040053; Mode of inheritance: None
Mendeliome v1.3088 PRKAG3 Lucy Spencer reviewed gene: PRKAG3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal muscle glycogen content and metabolism QTL MIM#619030; Mode of inheritance: None
Ataxia - paediatric v1.50 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from Cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Ataxia - paediatric v1.49 PRDX3 Zornitza Stark Deleted their comment
Ataxia - paediatric v1.49 PRDX3 Zornitza Stark edited their review of gene: PRDX3: Changed phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related
Ataxia - adult onset v1.53 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from Cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Ataxia - adult onset v1.52 PRDX3 Zornitza Stark Deleted their comment
Ataxia - adult onset v1.52 PRDX3 Zornitza Stark edited their review of gene: PRDX3: Changed phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related
Mitochondrial disease v0.1005 PRDX3 Zornitza Stark Deleted their comment
Mitochondrial disease v0.1005 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from Cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Mitochondrial disease v0.1004 PRDX3 Zornitza Stark edited their review of gene: PRDX3: Changed phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related
Mendeliome v1.3088 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Mendeliome v1.3087 PRDX3 Lucy Spencer reviewed gene: PRDX3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related; Mode of inheritance: None
Mendeliome v1.3087 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart disease MONDO:0005453; thoracic aortic aneurysms to Congenital heart disease, MONDO:0005453, HEY2-related; thoracic aortic aneurysms
Mendeliome v1.3086 HEY2 Zornitza Stark Publications for gene: HEY2 were set to 32820247
Mendeliome v1.3085 HEY2 Zornitza Stark Deleted their comment
Mendeliome v1.3085 HEY2 Zornitza Stark commented on gene: HEY2: Further family reported segregating a missense variant and Tetralogy of Fallot.
Mendeliome v1.3085 HEY2 Zornitza Stark edited their review of gene: HEY2: Added comment: Further family reported segregating a missense variant and Tetralogy of Fallot.; Changed publications: 32820247, 40481234; Changed phenotypes: Congenital heart disease, MONDO:0005453, HEY2-related
Congenital Heart Defect v0.461 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart defects and thoracic aortic aneurysms to Congenital heart disease, MONDO:0005453, HEY2-related
Congenital Heart Defect v0.460 HEY2 Zornitza Stark Publications for gene: HEY2 were set to PMID: 32820247
Congenital Heart Defect v0.459 HEY2 Zornitza Stark reviewed gene: HEY2: Rating: RED; Mode of pathogenicity: None; Publications: 40481234; Phenotypes: Congenital heart disease, MONDO:0005453, HEY2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3085 ENPP5 Zornitza Stark Marked gene: ENPP5 as ready
Mendeliome v1.3085 ENPP5 Zornitza Stark Gene: enpp5 has been classified as Red List (Low Evidence).
Mendeliome v1.3085 ENPP5 Zornitza Stark gene: ENPP5 was added
gene: ENPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENPP5 were set to 40457511
Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related
Review for gene: ENPP5 was set to RED
Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts.
Sources: Literature
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark Marked gene: ENPP5 as ready
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark Gene: enpp5 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.318 ENPP5 Zornitza Stark gene: ENPP5 was added
gene: ENPP5 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENPP5 were set to 40457511
Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related
Review for gene: ENPP5 was set to RED
Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts.
Sources: Literature
Mendeliome v1.3084 AXDND1 Zornitza Stark Marked gene: AXDND1 as ready
Mendeliome v1.3084 AXDND1 Zornitza Stark Gene: axdnd1 has been classified as Red List (Low Evidence).
Mendeliome v1.3084 AXDND1 Zornitza Stark gene: AXDND1 was added
gene: AXDND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXDND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXDND1 were set to 40457935
Phenotypes for gene: AXDND1 were set to Spermatogenic failure, MONDO:0004983, AXDND1-related
Review for gene: AXDND1 was set to RED
Added comment: Single family reported with bi-allelic LoF variant.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark Marked gene: AXDND1 as ready
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark Gene: axdnd1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.31 AXDND1 Zornitza Stark gene: AXDND1 was added
gene: AXDND1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AXDND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXDND1 were set to 40457935
Phenotypes for gene: AXDND1 were set to Spermatogenic failure, MONDO:0004983, AXDND1-related
Review for gene: AXDND1 was set to RED
Added comment: Single family reported with bi-allelic LoF variant.
Sources: Literature
Mendeliome v1.3083 KDF1 Zornitza Stark Marked gene: KDF1 as ready
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3083 KDF1 Zornitza Stark Classified gene: KDF1 as Green List (high evidence)
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3082 KDF1 Zornitza Stark gene: KDF1 was added
gene: KDF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDF1 were set to 27838789; 40463401; 38501196
Phenotypes for gene: KDF1 were set to Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337
Review for gene: KDF1 was set to GREEN
Added comment: Three families reported.
Sources: Literature
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Marked gene: KDF1 as ready
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.102 KDF1 Zornitza Stark Phenotypes for gene: KDF1 were changed from ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type to Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337
Ectodermal Dysplasia v0.101 KDF1 Zornitza Stark reviewed gene: KDF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27838789, 40463401, 38501196; Phenotypes: Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3081 KCNA4 Zornitza Stark Marked gene: KCNA4 as ready
Mendeliome v1.3081 KCNA4 Zornitza Stark Gene: kcna4 has been classified as Red List (Low Evidence).
Mendeliome v1.3081 KCNA4 Zornitza Stark gene: KCNA4 was added
gene: KCNA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA4 were set to 40472070
Phenotypes for gene: KCNA4 were set to Epilepsy, MONDO:0005027, KCNA4-related
Review for gene: KCNA4 was set to RED
Added comment: Single individual with de novo missense variant reported.
Sources: Literature
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark Marked gene: KCNA4 as ready
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark Gene: kcna4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.201 KCNA4 Zornitza Stark gene: KCNA4 was added
gene: KCNA4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA4 were set to 40472070
Phenotypes for gene: KCNA4 were set to Epilepsy, MONDO:0005027, KCNA4-related
Review for gene: KCNA4 was set to RED
Added comment: Single individual with de novo missense variant reported.
Sources: Literature
Mendeliome v1.3080 LIMK1 Zornitza Stark Marked gene: LIMK1 as ready
Mendeliome v1.3080 LIMK1 Zornitza Stark Gene: limk1 has been classified as Red List (Low Evidence).
Mendeliome v1.3080 LIMK1 Zornitza Stark gene: LIMK1 was added
gene: LIMK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LIMK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LIMK1 were set to 40491492
Phenotypes for gene: LIMK1 were set to Endocrine system disorder, MONDO:0005151, LIMK1-related
Review for gene: LIMK1 was set to RED
Added comment: Two individuals reported with divergent phenotypes and divergent underlying mechanisms postulated.

One individual exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. Actin polymerization was significantly decreased in individual 1, whereas it was increased in individual 2. Insulin-secreting cell lines expressing the LIMK1 variant of individual 1 exhibited significantly slower exocytosis, contrasting the rapid and uncontrolled exocytosis in individual 2. Intriguingly, both variants led to increased overall insulin secretion.

Hold off further panel distribution until phenotypic associations clarified through further case reports.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.293 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Mendeliome v1.3079 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Mendeliome v1.3079 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Mendeliome v1.3079 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Genetic Epilepsy v1.200 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Genetic Epilepsy v1.200 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.200 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Congenital Heart Defect v0.459 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.458 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Fetal anomalies v1.413 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Fetal anomalies v1.413 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.413 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Fetal anomalies v1.413 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.412 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Mendeliome v1.3078 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3078 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3077 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Craniosynostosis v1.71 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Craniosynostosis v1.71 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.71 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Craniosynostosis v1.71 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.70 DHRS3 Zornitza Stark edited their review of gene: DHRS3: Changed rating: AMBER
Craniosynostosis v1.70 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to GREEN
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Mendeliome v1.3076 DMRTA2 Zornitza Stark Marked gene: DMRTA2 as ready
Mendeliome v1.3076 DMRTA2 Zornitza Stark Gene: dmrta2 has been classified as Red List (Low Evidence).
Mendeliome v1.3076 DMRTA2 Zornitza Stark gene: DMRTA2 was added
gene: DMRTA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DMRTA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRTA2 were set to 40541527; 26757254
Phenotypes for gene: DMRTA2 were set to Microcephaly, MONDO:0001149, DMRTA2-related
Review for gene: DMRTA2 was set to RED
Added comment: Single family reported with three affected siblings and bi-allelic LoF variant. Newly published functional data but no further reports.
Sources: Literature
Microcephaly v1.335 DMRTA2 Zornitza Stark Marked gene: DMRTA2 as ready
Microcephaly v1.335 DMRTA2 Zornitza Stark Gene: dmrta2 has been classified as Red List (Low Evidence).
Microcephaly v1.335 DMRTA2 Zornitza Stark gene: DMRTA2 was added
gene: DMRTA2 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: DMRTA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRTA2 were set to 40541527; 26757254
Phenotypes for gene: DMRTA2 were set to Microcephaly, MONDO:0001149, DMRTA2-related
Review for gene: DMRTA2 was set to RED
Added comment: Single family reported with three affected siblings and bi-allelic LoF variant. Newly published functional data but no further reports.
Sources: Literature
Congenital hypothyroidism v0.48 TRPC4AP Chris Richmond gene: TRPC4AP was added
gene: TRPC4AP was added to Congenital hypothyroidism. Sources: Expert Review,Literature
Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC4AP were set to 32428920; 26786105
Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia
Review for gene: TRPC4AP was set to AMBER
Added comment: De novo TRPC4AP variant has been identified on WES in a child with thyroid dyshormonogenesis. Next, 179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs.

Insufficient clinical cases for green. Candidate gene. Propose amber.
Sources: Expert Review, Literature
Congenital hypothyroidism v0.48 JAG1 Chris Richmond gene: JAG1 was added
gene: JAG1 was added to Congenital hypothyroidism. Sources: Expert Review,Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 26760175; 28653287
Phenotypes for gene: JAG1 were set to Alagille syndrome 1
Review for gene: JAG1 was set to GREEN
Added comment: Het LoF cause Alagille. Notch pathway involved in thyroid development. Disruption causes hypothyroidism in zebrafish. PMID 28653287

Thyroid function in 21 patients with JAG1 mutations was analyzed and genetic analysis of JAG1 was carried out in an Italian cohort of 100 CH patients. De Filippis et al. reported the predominance of CH in 6/21 patients with Alagille syndrome, two of which had thyroid hypoplasia. PMID 26760175
Sources: Expert Review, Literature
Congenital hypothyroidism v0.48 NTN1 Chris Richmond gene: NTN1 was added
gene: NTN1 was added to Congenital hypothyroidism. Sources: Literature
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 35774517; 25353184
Phenotypes for gene: NTN1 were set to Thyroid ectopia with hypothyroidism
Review for gene: NTN1 was set to AMBER
Added comment: Only 1x family (de novo NTN1 deletion) with animal model. Propose Amber.

NTN1 codes for Netrin 1, which is involved in regulating various developmental processes, such as angiogenesis, the migration of non-neuronal cells, and epithelial morphogenesis. Known to be associated with congenital mirror movts (OMIM 618264)

A patient with a congenital heart defect and TD (ectopia) has been described with a de novo deletion of NTN1. Embryos of the zebrafish with the ntn1a gene disabled have abnormal morphogenesis of the thyroid, probablydue to abnormal vascularisation not enabling the thyroid progenitor cells
Sources: Literature
Angelman Rett like syndromes v1.13 DYRK1A Zornitza Stark Marked gene: DYRK1A as ready
Angelman Rett like syndromes v1.13 DYRK1A Zornitza Stark Gene: dyrk1a has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Marked gene: ICK as ready
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.101 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Cranioectodermal dysplasia MONDO:0009032 to Cranioectodermal dysplasia 6, MIM# 621337
Ectodermal Dysplasia v0.100 ICK Zornitza Stark reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cranioectodermal dysplasia 6, MIM# 621337; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.37 ICK Zornitza Stark Publications for gene: ICK were set to 19185282; 27069622
Renal Ciliopathies and Nephronophthisis v1.36 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Endocrine-cerebroosteodysplasia, MIM# 612651 to Endocrine-cerebroosteodysplasia, MIM# 612651; Cranioectodermal dysplasia 6, MIM# 621337
Ciliopathies v1.85 ICK Zornitza Stark Phenotypes for gene: ICK were changed from Endocrine-cerebroosteodysplasia (MIM#612651) to Endocrine-cerebroosteodysplasia (MIM#612651); Cranioectodermal dysplasia 6, MIM# 621337
Ciliopathies v1.84 ICK Zornitza Stark edited their review of gene: ICK: Added comment: 5 children from two families homozygous for the same 2bp deletion. Uncertain if this is a distinct disorder or represents spectrum of abnormalities within the ciliopathies.; Changed rating: GREEN; Changed publications: 40615527; Changed phenotypes: Cranioectodermal dysplasia 6, MIM# 621337; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3075 RCC1 Zornitza Stark Phenotypes for gene: RCC1 were changed from Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related to Infection-induced acute-onset axonal neuropathy, MIM# 621333
Mendeliome v1.3074 RCC1 Zornitza Stark edited their review of gene: RCC1: Changed phenotypes: Infection-induced acute-onset axonal neuropathy, MIM# 621333
Hereditary Neuropathy_CMT - isolated v1.62 RCC1 Zornitza Stark Phenotypes for gene: RCC1 were changed from Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related to Infection-induced acute-onset axonal neuropathy, MIM# 621333
Hereditary Neuropathy_CMT - isolated v1.61 RCC1 Zornitza Stark edited their review of gene: RCC1: Changed phenotypes: Infection-induced acute-onset axonal neuropathy, MIM# 621333
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Classified gene: DYRK1A as Green List (high evidence)
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Gene: dyrk1a has been classified as Green List (High Evidence).
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Classified gene: DYRK1A as Green List (high evidence)
Angelman Rett like syndromes v1.13 DYRK1A Chirag Patel Gene: dyrk1a has been classified as Green List (High Evidence).
Angelman Rett like syndromes v1.12 DYRK1A Chirag Patel gene: DYRK1A was added
gene: DYRK1A was added to Angelman Rett like syndromes. Sources: Expert list
Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DYRK1A were set to PMID: 26677511
Phenotypes for gene: DYRK1A were set to DYRK1A-related intellectual disability syndrome MONDO:0013578
Review for gene: DYRK1A was set to GREEN
Added comment: Established gene-disease association.
Presentation overlaps Angelman-Rett like syndromes with: intellectual disability, autism spectrum disorder, stereotypic behaviour problems, microcephaly, epilepsy, hypertonia, gait disturbances, feeding problems, short stature, ophthalmologic anomalies, urogenital anomalies, cardiac anomalies, dental anomalies, foot anomalies, and typical facial gestalt.
Sources: Expert list
Ciliopathies v1.84 ICK Chirag Patel reviewed gene: ICK: Rating: ; Mode of pathogenicity: None; Publications: PMID: 40615527; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.35 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.100 ICK Chirag Patel Classified gene: ICK as Amber List (moderate evidence)
Ectodermal Dysplasia v0.100 ICK Chirag Patel Gene: ick has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.99 ICK Chirag Patel gene: ICK was added
gene: ICK was added to Ectodermal Dysplasia. Sources: Literature
Mode of inheritance for gene: ICK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ICK were set to PMID: 40615527, 24797473
Phenotypes for gene: ICK were set to Cranioectodermal dysplasia MONDO:0009032
Review for gene: ICK was set to AMBER
Added comment: 5 individuals from 2 families (from the same city - Tal Afar) with disproportionately short stature, skeletal abnormalities (short limbs, relative macrocephaly, digit anomalies), ectodermal dysplasia (dental/nail/hair issues), renal issues (hyperechogenic kidneys, dilated renal pelvis, CKD/kidney failure), and liver complications (abnormal enzymes, liver failure). All the patients survived into childhood. Exome sequencing identified the same homozygous frameshift variant (p.(Tyr555Cysfs*48) in ICK (CILK1) gene in the distal part of the non-catalytic domain.

Functional data from patient-derived cells and the C. elegans model indicate that the variant reduces cilia number, increases cilia length, and disrupts the localization of IFT components. In contrast, the ciliary localization of CILK1 bearing the variant itself remains unaffected. They rescued the majority of these abnormalities by reintroducing CILK1 into patient-derived cells.

Note ICK gene is green on multiple panels for Endocrine-cerebro-osteodysplasia syndrome MONDO:0012980 (3 families reported, homozygous missense variants in catalytic domain, supportive functional studies and animal models).

PMID: 24797473 - Ick deficient mice showed ciliary defects. Authors concluded that ICK is required for normal ciliogenesis.
Sources: Literature
Renal Ciliopathies and Nephronophthisis v1.34 ICK Chirag Patel reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 40615527, 24797473; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3074 ICK Chirag Patel reviewed gene: ICK: Rating: ; Mode of pathogenicity: None; Publications: PMID: 40615527; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.292 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.291 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.3074 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3074 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3073 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Mitochondrial disease v0.1004 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.1003 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.3072 KCNJ15 Zornitza Stark Marked gene: KCNJ15 as ready
Mendeliome v1.3072 KCNJ15 Zornitza Stark Gene: kcnj15 has been classified as Red List (Low Evidence).
Mendeliome v1.3072 KCNJ15 Zornitza Stark gene: KCNJ15 was added
gene: KCNJ15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNJ15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ15 were set to 40566643
Phenotypes for gene: KCNJ15 were set to Parkinson disease, MONDO:0005180, KCNJ15-related
Review for gene: KCNJ15 was set to RED
Added comment: Single multiplex family reported with a missense variant and functional data.
Sources: Literature
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark Marked gene: KCNJ15 as ready
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark Gene: kcnj15 has been classified as Red List (Low Evidence).
Early-onset Parkinson disease v2.38 KCNJ15 Zornitza Stark gene: KCNJ15 was added
gene: KCNJ15 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: KCNJ15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ15 were set to 40566643
Phenotypes for gene: KCNJ15 were set to Parkinson disease, MONDO:0005180, KCNJ15-related
Review for gene: KCNJ15 was set to RED
Added comment: Single multiplex family reported with a missense variant and functional data.
Sources: Literature
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Marked gene: TFCP2L1 as ready
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Classified gene: TFCP2L1 as Amber List (moderate evidence)
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3070 TFCP2L1 Zornitza Stark gene: TFCP2L1 was added
gene: TFCP2L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 40569305; 33097957
Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis.

PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant.

TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.
Sources: Literature
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Marked gene: TFCP2L1 as ready
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Classified gene: TFCP2L1 as Amber List (moderate evidence)
Renal Tubulopathies and related disorders v1.20 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Renal Tubulopathies and related disorders v1.19 TFCP2L1 Zornitza Stark gene: TFCP2L1 was added
gene: TFCP2L1 was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 40569305; 33097957
Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis.

PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant.

TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.
Sources: Literature
Prepair 1000+ v2.13 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Fetal anomalies v1.411 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Interstitial Lung Disease v1.2 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Heterotaxy v1.41 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Ciliary Dyskinesia v1.55 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Mendeliome v1.3069 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Mendeliome v1.3069 BCAS2 Zornitza Stark Marked gene: BCAS2 as ready
Mendeliome v1.3069 BCAS2 Zornitza Stark Gene: bcas2 has been classified as Red List (Low Evidence).
Mendeliome v1.3069 BCAS2 Zornitza Stark gene: BCAS2 was added
gene: BCAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BCAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCAS2 were set to 40585763
Phenotypes for gene: BCAS2 were set to Hyper IgM syndrome, MONDO:0003947, BCAS2-related
Review for gene: BCAS2 was set to RED
Added comment: Extensive functional work, however a single individual reported with non-coding variant, 3'UTR.
Sources: Literature
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark Marked gene: BCAS2 as ready
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark Gene: bcas2 has been classified as Red List (Low Evidence).
Predominantly Antibody Deficiency v1.4 BCAS2 Zornitza Stark gene: BCAS2 was added
gene: BCAS2 was added to Predominantly Antibody Deficiency. Sources: Literature
Mode of inheritance for gene: BCAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCAS2 were set to 40585763
Phenotypes for gene: BCAS2 were set to Hyper IgM syndrome, MONDO:0003947, BCAS2-related
Review for gene: BCAS2 was set to RED
Added comment: Extensive functional work, however a single individual reported with non-coding variant, 3'UTR.
Sources: Literature
Polydactyly v0.291 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Polydactyly v0.291 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Polydactyly v0.291 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Polydactyly v0.291 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Polydactyly v0.290 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Polydactyly. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Clefting disorders v0.270 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Clefting disorders v0.270 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Clefting disorders v0.270 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Clefting disorders v0.270 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Clefting disorders v0.269 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Mendeliome v1.3068 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3068 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3067 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Fetal anomalies v1.411 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Fetal anomalies v1.411 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.411 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Fetal anomalies v1.411 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.410 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Fetal anomalies v1.410 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Fetal anomalies v1.409 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Mendeliome v1.3066 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Mendeliome v1.3066 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Heterotaxy v1.41 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Heterotaxy v1.41 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Heterotaxy v1.40 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Congenital Heart Defect v0.457 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Congenital Heart Defect v0.457 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Macrocephaly_Megalencephaly v0.150 PPP2R1A Lucy Spencer reviewed gene: PPP2R1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Houge-Janssens syndrome 2 MIM#616362; Mode of inheritance: None
Mendeliome v1.3065 PPP1R12A Lucy Spencer reviewed gene: PPP1R12A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Genitourinary and/or/brain malformation syndrome MIM#618820; Mode of inheritance: None
Mendeliome v1.3065 PPM1F Lucy Spencer reviewed gene: PPM1F: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis MONDO:0001751, PPM1F-related; Mode of inheritance: None
Fetal anomalies v1.409 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Fetal anomalies v1.409 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Fetal anomalies v1.408 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Ciliopathies v1.84 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Ciliopathies v1.84 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Ciliopathies v1.84 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Ciliopathies v1.84 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Ciliopathies v1.83 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Ciliopathies. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Mendeliome v1.3065 ICK Zornitza Stark Marked gene: ICK as ready
Mendeliome v1.3065 ICK Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is CILK1
Mendeliome v1.3065 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Mendeliome v1.3065 ICK Zornitza Stark Tag new gene name tag was added to gene: ICK.
Ciliopathies v1.82 ICK Zornitza Stark Marked gene: ICK as ready
Ciliopathies v1.82 ICK Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is CILK1
Ciliopathies v1.82 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Ciliopathies v1.82 ICK Zornitza Stark Tag new gene name tag was added to gene: ICK.
Heterotaxy v1.40 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Fetal anomalies v1.407 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Congenital Heart Defect v0.456 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.406 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Congenital Heart Defect v0.455 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Heterotaxy v1.40 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Heterotaxy v1.40 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Heterotaxy v1.40 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3064 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Heterotaxy v1.39 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Heterotaxy. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Mendeliome v1.3063 ZNF319 Zornitza Stark Marked gene: ZNF319 as ready
Mendeliome v1.3063 ZNF319 Zornitza Stark Gene: znf319 has been classified as Red List (Low Evidence).
Mendeliome v1.3063 ZNF319 Zornitza Stark gene: ZNF319 was added
gene: ZNF319 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF319 were set to 40820230
Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related
Review for gene: ZNF319 was set to RED
Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser.

18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy.
Sources: Literature
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark Marked gene: ZNF319 as ready
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark Gene: znf319 has been classified as Red List (Low Evidence).
Leukodystrophy - adult onset v0.151 ZNF319 Zornitza Stark gene: ZNF319 was added
gene: ZNF319 was added to Leukodystrophy - adult onset. Sources: Literature
Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF319 were set to 40820230
Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related
Review for gene: ZNF319 was set to RED
Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser.

18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy.
Sources: Literature
Congenital Disorders of Glycosylation v1.73 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155 to Myopathy caused by variation in POMT1 MONDO:0700070
Congenital Disorders of Glycosylation v1.72 POMT1 Zornitza Stark edited their review of gene: POMT1: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3062 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308 to Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3061 POMT1 Zornitza Stark edited their review of gene: POMT1: Changed phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070
Congenital Disorders of Glycosylation v1.72 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 618135 to Myopathy caused by variation in POMGNT2 MONDO:0700069
Congenital Disorders of Glycosylation v1.71 POMGNT2 Zornitza Stark edited their review of gene: POMGNT2: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMGNT2 MONDO:0700069
Mendeliome v1.3061 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135 to Myopathy caused by variation in POMGNT2 MONDO:0700069
Congenital Disorders of Glycosylation v1.71 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, 253280; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B3, 613151; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 613157 to Myopathy caused by variation in POMGNT1 MONDO:0700068
Congenital Disorders of Glycosylation v1.70 POMGNT1 Zornitza Stark edited their review of gene: POMGNT1: Added comment: Lumped by ClinGen.; Changed phenotypes: Myopathy caused by variation in POMGNT1 MONDO:0700068
Mendeliome v1.3060 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 MIM#614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135; Retinitis pigmentosa 76 617123 to Myopathy caused by variation in POMGNT1 MONDO:0700068; Retinitis pigmentosa 76 617123
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.151 NR6A1 Zornitza Stark Publications for gene: NR6A1 were set to 39606382
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.150 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Added comment: PMID: 40774958 - Additional 10x individuals identified from a CAKUT cohort with kidney, eye, and other congenital anomalies.; Changed publications: 40774958
Mendeliome v1.3059 NR6A1 Zornitza Stark Publications for gene: NR6A1 were set to 39606382
Mendeliome v1.3058 ARID3A Zornitza Stark Phenotypes for gene: ARID3A were changed from Cornelia de Lange syndrome - MONDO:0016033 to Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Cornelia de Lange syndrome - MONDO:0016033
Mendeliome v1.3057 ARID3A Zornitza Stark Publications for gene: ARID3A were set to PMID: 40677927
Mendeliome v1.3056 ARID3A Zornitza Stark Classified gene: ARID3A as Amber List (moderate evidence)
Mendeliome v1.3056 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Marked gene: MIR184 as ready
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Gene: mir184 has been classified as Green List (High Evidence).
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Classified gene: MIR184 as Green List (high evidence)
Corneal Dystrophy v1.13 MIR184 Zornitza Stark Gene: mir184 has been classified as Green List (High Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Marked gene: MED14 as ready
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Classified gene: MED14 as Red List (low evidence)
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Marked gene: NXT2 as ready
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Classified gene: NXT2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.30 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Marked gene: NXT2 as ready
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Classified gene: NXT2 as Amber List (moderate evidence)
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Marked gene: ARID3A as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Classified gene: ARID3A as Amber List (moderate evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.126 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Dystonia - complex v0.285 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Dystonia - complex v0.284 ATP5A1 Zornitza Stark gene: ATP5A1 was added
gene: ATP5A1 was added to Dystonia - complex. Sources: Literature
new gene name tags were added to gene: ATP5A1.
Mode of inheritance for gene: ATP5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5A1 were set to 34483339; 34954817; 40859057
Phenotypes for gene: ATP5A1 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD
Review for gene: ATP5A1 was set to GREEN
Added comment: At least 12 individuals reported with de novo missense variants in this gene, several recurrent.

PMIDs: 34483339, 34954817: 6xde novo patients 4 with Arg207His, 1 Arg182Gln 1 Ser346Phe. All Arg207His patients were neonates with failure to thrive, hyperammonemia, lactic acidosis, and respiratory defects in fibroblasts, major symptoms remitted with treatment by late infancy, and at age 14mo to 3yrs growth and development were normal. Other 2 patients are 17yo with ID, ataxia, spastic paraparesis and dystonia, and a 12yo with psychomotor retardation, spastic tetraparesis, generalised dystonia, absent speech, swallowing problems, and increased blood lactate concentrations.

And an internal VCGS patient Arg182Gln (variant also seen in a different patient above) with ID, muscular hypotonia, clinodactyly of the 5th finger, and dysmorphic facial features, proteomics showed decreased ATP5F1A and a complex V deficiency. There is also an alternative change at this residue in the DECIPHER cohort Arg182Pro de novo in an individual with a neurodevelopmental disorder.

PMID: 40672495: 6x de novo individuals - 4 variants p.Arg182Gln, p.Ser346Phe, p.Pro331Leu, and p.Leu109Ser - with complex but overlapping neurological phenotypes including developmental delays, intellectual disability, pyramidal tract dysfunction, and dystonia.

In vivo functional studies in C. elegans were performed for three of the variants, showing growth defects and disruption of mitochondrial function (measured by mitochondrial stress). Authors suggest a dominant negative mechanism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Tag new gene name tag was added to gene: ATP5A1.
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.290 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.289 ATP5A1 Zornitza Stark gene: ATP5A1 was added
gene: ATP5A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5A1 were set to 34483339; 34954817; 40859057
Phenotypes for gene: ATP5A1 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD
Review for gene: ATP5A1 was set to GREEN
Added comment: At least 12 individuals reported with de novo missense variants in this gene, several recurrent.

PMIDs: 34483339, 34954817: 6xde novo patients 4 with Arg207His, 1 Arg182Gln 1 Ser346Phe. All Arg207His patients were neonates with failure to thrive, hyperammonemia, lactic acidosis, and respiratory defects in fibroblasts, major symptoms remitted with treatment by late infancy, and at age 14mo to 3yrs growth and development were normal. Other 2 patients are 17yo with ID, ataxia, spastic paraparesis and dystonia, and a 12yo with psychomotor retardation, spastic tetraparesis, generalised dystonia, absent speech, swallowing problems, and increased blood lactate concentrations.

And an internal VCGS patient Arg182Gln (variant also seen in a different patient above) with ID, muscular hypotonia, clinodactyly of the 5th finger, and dysmorphic facial features, proteomics showed decreased ATP5F1A and a complex V deficiency. There is also an alternative change at this residue in the DECIPHER cohort Arg182Pro de novo in an individual with a neurodevelopmental disorder.

PMID: 40672495: 6x de novo individuals - 4 variants p.Arg182Gln, p.Ser346Phe, p.Pro331Leu, and p.Leu109Ser - with complex but overlapping neurological phenotypes including developmental delays, intellectual disability, pyramidal tract dysfunction, and dystonia.

In vivo functional studies in C. elegans were performed for three of the variants, showing growth defects and disruption of mitochondrial function (measured by mitochondrial stress). Authors suggest a dominant negative mechanism.
Sources: Literature
Mendeliome v1.3053 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Mendeliome v1.3052 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390, 34954817, 34483339
Mendeliome v1.3051 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 ATP5A1 Zornitza Stark changed review comment from: Two unrelated families.; to: Two unrelated families with biallelic disease. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Genetic Epilepsy v1.199 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A MIM#620358; Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Genetic Epilepsy v1.198 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390
Genetic Epilepsy v1.197 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v1.196 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed publications: 23599390, 23596069
Genetic Epilepsy v1.196 ATP5A1 Zornitza Stark changed review comment from: Two unrelated families.; to: Two unrelated families. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Mitochondrial disease v0.1002 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mitochondrial disorder, autosomal dominant to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mitochondrial disorder, autosomal dominant
Mitochondrial disease v0.1001 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390; 34483339
Mitochondrial disease v0.1000 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed rating: RED
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed publications: 23599390, 23596069
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark changed review comment from: One family described with each of these mitochondrial conditions.; to: One family described with each of these mitochondrial conditions. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Mitochondrial disease v0.999 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Mendeliome v1.3050 POMT2 Lucy Spencer reviewed gene: POMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT2 MONDO:0700071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMT1 Lucy Spencer reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT2 Lucy Spencer reviewed gene: POMGNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT2 MONDO:0700069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT1 Lucy Spencer reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT1 MONDO:0700068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 NR6A1 Rylee Peters reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Oculovertebral syndrome MIM# 621277; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.125 ARID3A Rylee Peters gene: ARID3A was added
gene: ARID3A was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to 40774958
Phenotypes for gene: ARID3A were set to Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related
Review for gene: ARID3A was set to AMBER
Added comment: PMID: 40774958: 7x individuals from a CAKUT cohort - 5 individuals with unilateral renal agenesis and two individuals with hydronephrosis, extra-renal anomalies were also identified.

Variants identified include 3x stopgain, 1xframeshift, 3x splice site – inheritance includes 2x de novo, 4x unknown inheritance, 1x maternally inherited (unknown clinical status).
Sources: Literature
Mendeliome v1.3050 ARID3A Rylee Peters reviewed gene: ARID3A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Corneal Dystrophy v1.12 MIR184 Rylee Peters gene: MIR184 was added
gene: MIR184 was added to Corneal Dystrophy. Sources: Literature
Mode of inheritance for gene: MIR184 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR184 were set to 40852795; 21996275; 22131394; 25373792; 24138095
Phenotypes for gene: MIR184 were set to EDICT syndrome (MIM#614303)
Review for gene: MIR184 was set to GREEN
Added comment: PMID: 40852795: Four individuals with Fuchs Endothelial Corneal Dystrophy (FECD) – three harboured n.58G>A and one with n.73G>T. No segregation testing was performed in this cohort.

At least 5 other families reported for EDICT syndrome (autosomal dominant syndromal anterior segment dysgenesis characterised by endothelial dystrophy, iris hypoplasia, congenital cataract, and thinning of the corneal stroma). Three had the same variant, (+57C>T). However, it has been suggested that his arose independently rather than being a founder variant (PMIDs: 21996275, 22131394, 25373792, 24138095).
Sources: Literature
Mendeliome v1.3050 MED14 Rylee Peters gene: MED14 was added
gene: MED14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED14 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MED14 were set to PMID: 40597352
Phenotypes for gene: MED14 were set to Neurodevelopmental disorder (MONDO:0700092), MED14-related
Review for gene: MED14 was set to RED
Added comment: PMID: 40597352: 1x male with clinical VLCAD, developmental delay, microcephaly, hypotonia and brain anomalies. Identified a hemizygous, maternally inherited splice variant c.2365+2T>C, classified as VUS. RNA studies show that the variant results in an out-of-frame loss of the C-terminal end of exon 18 due to novel splice donor use in 1.72 percent of reads.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.29 NXT2 Rylee Peters gene: NXT2 was added
gene: NXT2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NXT2 were set to PMID: 40624043; 35013161
Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related
Review for gene: NXT2 was set to AMBER
Added comment: PMID: 40624043
- 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis.
- 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis.
- Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene.
Sources: Literature
Mendeliome v1.3050 NXT2 Rylee Peters gene: NXT2 was added
gene: NXT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NXT2 were set to PMID: 40624043; 35013161
Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related
Review for gene: NXT2 was set to AMBER
Added comment: PMID: 40624043
- 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis.
- 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis.
- Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene.
Sources: Literature
Mendeliome v1.3050 ATP5A1 Rylee Peters reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40672495; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.998 ATP5A1 Rylee Peters reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40672495; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 LDHD Zornitza Stark Marked gene: LDHD as ready
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Mendeliome v1.3050 LDHD Zornitza Stark Classified gene: LDHD as Green List (high evidence)
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Marked gene: LDHD as ready
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Classified gene: LDHD as Green List (high evidence)
Miscellaneous Metabolic Disorders v1.51 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Cone-rod Dystrophy v0.57 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Cone-rod Dystrophy v0.56 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.176 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.176 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.176 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.176 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3049 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3049 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3048 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Mendeliome v1.3048 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3048 XPO1 Zornitza Stark Marked gene: XPO1 as ready
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Mendeliome v1.3048 XPO1 Zornitza Stark Classified gene: XPO1 as Green List (high evidence)
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Marked gene: XPO1 as ready
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Classified gene: XPO1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.288 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Atrial Fibrillation v1.4 NPPA Zornitza Stark Publications for gene: NPPA were set to 18614783; 20064500; 31034774; 31077706
Atrial Fibrillation v1.3 NPPA Zornitza Stark Mode of inheritance for gene: NPPA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Atrial Fibrillation v1.2 NPPA Zornitza Stark edited their review of gene: NPPA: Added comment: PMID 40838933: young adult with AF and homozygous missense variant in this gene p.Arg150Gln. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; Changed rating: AMBER; Changed publications: 23275345, 40838933; Changed phenotypes: Atrial fibrillation, familial, 6, (MIM#612201); Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3047 NPPA Zornitza Stark Publications for gene: NPPA were set to 18614783; 20064500; 31034774; 31077706
Mendeliome v1.3046 NPPA Zornitza Stark Mode of inheritance for gene: NPPA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3045 NPPA Zornitza Stark changed review comment from: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; to: PMID 40838933: young adult with AF and homozygous missense variant in this gene p.Arg150Gln. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.
Mendeliome v1.3045 NPPA Zornitza Stark edited their review of gene: NPPA: Added comment: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; Changed publications: 18614783, 20064500, 31034774, 31077706, 40838933, 23275345; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Marked gene: PNLIP as ready
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Gene: pnlip has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Classified gene: PNLIP as Amber List (moderate evidence)
Congenital Diarrhoea v1.23 PNLIP Zornitza Stark Gene: pnlip has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.22 PNLIP Zornitza Stark gene: PNLIP was added
gene: PNLIP was added to Congenital Diarrhoea. Sources: Expert Review
Mode of inheritance for gene: PNLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308; 40840699
Phenotypes for gene: PNLIP were set to Pancreatic lipase deficiency MIM#614338
Review for gene: PNLIP was set to AMBER
Added comment: PMID 40840699: Six children from four Amish families with novel homozygous PNLIP variant, c.869G>A (p.S290N) and CPLD symptoms. Computational modeling showed that p.Ser290 is highly conserved across species and the variant causes steric hindrance resulting in protein misfolding. Functional assays revealed that the PNLIP variant had a complete loss of activity compared to the wild type (WT), with defects in catalytic function and secretion. Immunoblotting showed reduced PNLIP variant in the medium and increased accumulation in the detergent-insoluble fraction consistent with protein misfolding. Variant-expressing cells had elevated levels of BiP, an ER stress marker, and increased Xbp1 mRNA splicing, suggesting an elevated ER stress and unfolded protein response (UPR).

Previous reports: 4 cases from 2 unrelated families, with supporting biochemical assays in patient cells and cellular-based assays. The cases have decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health.

AMBER rating as not quite as severe as the other conditions included in this panel.
Sources: Expert Review
Dyslipidaemia v0.46 PNLIP Zornitza Stark Classified gene: PNLIP as Green List (high evidence)
Dyslipidaemia v0.46 PNLIP Zornitza Stark Gene: pnlip has been classified as Green List (High Evidence).
Dyslipidaemia v0.45 PNLIP Zornitza Stark reviewed gene: PNLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40840699; Phenotypes: Pancreatic lipase deficiency MIM#614338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3045 PNLIP Zornitza Stark Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308
Mendeliome v1.3044 PNLIP Zornitza Stark Classified gene: PNLIP as Green List (high evidence)
Mendeliome v1.3044 PNLIP Zornitza Stark Gene: pnlip has been classified as Green List (High Evidence).
Mendeliome v1.3043 PNLIP Zornitza Stark reviewed gene: PNLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40840699; Phenotypes: Pancreatic lipase deficiency MIM#614338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3043 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Mendeliome v1.3043 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Added comment: PMID 40859057: 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. Functional data.; Changed rating: GREEN; Changed publications: 23599390, 40859057
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Disorders of immune dysregulation v1.25 PLCG1 Zornitza Stark Publications for gene: PLCG1 were set to PMID: 37422272
Disorders of immune dysregulation v1.24 PLCG1 Zornitza Stark Classified gene: PLCG1 as Green List (high evidence)
Disorders of immune dysregulation v1.24 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.23 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Added comment: PMID 40862571: seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] presenting with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). Further functional work in Drosophila on some of the variants investigating GoF effect.; Changed rating: GREEN; Changed publications: 37422272, 40862571
Mendeliome v1.3042 PLCG1 Zornitza Stark Publications for gene: PLCG1 were set to 37422272
Mendeliome v1.3041 PLCG1 Zornitza Stark Classified gene: PLCG1 as Green List (high evidence)
Mendeliome v1.3041 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Green List (High Evidence).
Mendeliome v1.3040 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Added comment: PMID 40862571: seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] presenting with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). Further functional work in Drosophila on some of the variants investigating GoF effect.; Changed rating: GREEN; Changed publications: 37422272, 40862571
Mendeliome v1.3040 KNG1 Zornitza Stark Classified gene: KNG1 as Green List (high evidence)
Mendeliome v1.3040 KNG1 Zornitza Stark Gene: kng1 has been classified as Green List (High Evidence).
Mendeliome v1.3039 KNG1 Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 40848077: Two more individuals reported with LoF variants as part of a large angioedema cohort.; Changed rating: GREEN; Changed publications: 31087670, 33114181, 40848077
Hereditary angioedema v1.11 KNG1 Zornitza Stark Classified gene: KNG1 as Green List (high evidence)
Hereditary angioedema v1.11 KNG1 Zornitza Stark Gene: kng1 has been classified as Green List (High Evidence).
Hereditary angioedema v1.10 KNG1 Zornitza Stark edited their review of gene: KNG1: Changed rating: GREEN
Hereditary angioedema v1.10 KNG1 Zornitza Stark Publications for gene: KNG1 were set to 31087670; 33114181
Hereditary angioedema v1.9 KNG1 Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 40848077: Two more individuals reported with LoF variants as part of a large angioedema cohort.; Changed publications: 31087670, 33114181, 40848077
Mendeliome v1.3039 MYOF Zornitza Stark Classified gene: MYOF as Amber List (moderate evidence)
Mendeliome v1.3039 MYOF Zornitza Stark Gene: myof has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3038 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: PMID 40848077: four more missense variants reported as part of a cohort, no further supportive data. Upgrade to Amber.; Changed rating: AMBER; Changed publications: 32542751, 40797221, 40848077
Hereditary angioedema v1.9 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751; 40797221
Hereditary angioedema v1.8 MYOF Zornitza Stark Classified gene: MYOF as Amber List (moderate evidence)
Hereditary angioedema v1.8 MYOF Zornitza Stark Gene: myof has been classified as Amber List (Moderate Evidence).
Hereditary angioedema v1.7 MYOF Zornitza Stark edited their review of gene: MYOF: Changed rating: AMBER
Hereditary angioedema v1.7 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: PMID 40848077: four more missense variants reported as part of a cohort, no further supportive data. Upgrade to Amber.; Changed publications: 32542751, 40797221, 40848077
Hereditary angioedema v1.7 HS3ST6 Zornitza Stark Publications for gene: HS3ST6 were set to 33508266
Hereditary angioedema v1.6 HS3ST6 Zornitza Stark edited their review of gene: HS3ST6: Added comment: PMID 40848077: reports additional patient with missense variant but no further supportive data.; Changed publications: 33508266, 40848077
Mendeliome v1.3038 ETS1 Zornitza Stark Phenotypes for gene: ETS1 were changed from Neurodevelopmental disorder, MONDO:0700092, ETS1-related to Neurodevelopmental disorder, MONDO:0700092, ETS1-related; Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Mendeliome v1.3037 ETS1 Zornitza Stark edited their review of gene: ETS1: Added comment: PMID 40870883: Single multiplex family reported with LoF variant and DCM.; Changed publications: 31160359, 40870883; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ETS1-related, Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark Marked gene: ETS1 as ready
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark Gene: ets1 has been classified as Red List (Low Evidence).
Dilated Cardiomyopathy v1.44 ETS1 Zornitza Stark gene: ETS1 was added
gene: ETS1 was added to Dilated Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: ETS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ETS1 were set to 40870883
Phenotypes for gene: ETS1 were set to Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Review for gene: ETS1 was set to RED
Added comment: Single multiplex family reported with LoF variant and DCM.
Sources: Literature
Mendeliome v1.3037 SCN3B Zornitza Stark Marked gene: SCN3B as ready
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3037 SCN3B Zornitza Stark Classified gene: SCN3B as Amber List (moderate evidence)
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Marked gene: SCN3B as ready
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Classified gene: SCN3B as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.287 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.355 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.354 POLR3H Zornitza Stark reviewed gene: POLR3H: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR3H-related; Mode of inheritance: None
Mendeliome v1.3036 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.354 POU5F1 Zornitza Stark Phenotypes for gene: POU5F1 were changed from Premature ovarian failure to Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.353 POU5F1 Zornitza Stark edited their review of gene: POU5F1: Changed phenotypes: Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Mendeliome v1.3035 POU5F1 Zornitza Stark Phenotypes for gene: POU5F1 were changed from Premature ovarian failure to Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Mendeliome v1.3034 PPARA Zornitza Stark Phenotypes for gene: PPARA were changed from {Hyperapobetalipoproteinemia, susceptibility to} to Cholesterol metabolism disease MONDO:0045008, PPARA-related
Mendeliome v1.3033 TCFL5 Zornitza Stark Marked gene: TCFL5 as ready
Mendeliome v1.3033 TCFL5 Zornitza Stark Gene: tcfl5 has been classified as Red List (Low Evidence).
Mendeliome v1.3033 TCFL5 Zornitza Stark Phenotypes for gene: TCFL5 were changed from Oligoasthenoteratozoospermia MONDO:0850098 to Oligoasthenoteratozoospermia MONDO:0850098, TCFL5-related
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.99 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.454 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Mitochondrial disease v0.998 MT-TT Zornitza Stark Phenotypes for gene: MT-TT were changed from Mitochondrial disease (MONDO:0044970), MT-TT-related to Mitochondrial disease (MONDO:0044970), MT-TT-related
Mitochondrial disease v0.998 MT-TT Zornitza Stark Phenotypes for gene: MT-TT were changed from to Mitochondrial disease (MONDO:0044970), MT-TT-related
Mitochondrial disease v0.997 MT-TT Zornitza Stark Classified gene: MT-TT as Amber List (moderate evidence)
Mitochondrial disease v0.997 MT-TT Zornitza Stark Gene: mt-tt has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.286 UPF1 Zornitza Stark Classified gene: UPF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.286 UPF1 Zornitza Stark Gene: upf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.285 UPF1 Zornitza Stark edited their review of gene: UPF1: Added comment: Additional reports identified:

PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs)

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.; Changed rating: GREEN; Changed publications: 33057194, 28135719, 28539120, 39571789, 39993774; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, UPF1-related
Mendeliome v1.3031 UPF1 Zornitza Stark Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092, UPF1-related
Mendeliome v1.3030 UPF1 Zornitza Stark Publications for gene: UPF1 were set to 33057194
Mendeliome v1.3029 UPF1 Zornitza Stark Classified gene: UPF1 as Green List (high evidence)
Mendeliome v1.3029 UPF1 Zornitza Stark Gene: upf1 has been classified as Green List (High Evidence).
Mendeliome v1.3028 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022, https://doi.org/10.1016/j.ymgme.2024.108362.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia changed review comment from: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; to: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm pathogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia edited their review of gene: GAMT: Added comment: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023.

The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014.

There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc.

Only in RED in Cerebral Palsy, Fetal anomalies.

Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship.

There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine.

There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; Changed publications: PMID: 36856349, PMID: 28055022; Changed phenotypes: Creberal creatine deficiency syndrome 2 (MIM 612736), global developmental delay, intellectual disability, epilepsy, behavioral disturbance, movement disorder, markedly low brain creatine and elevated guanidinoacetate.
Genomic newborn screening: ICoNS v0.7 GAMT Judit Garcia gene: GAMT was added
gene: GAMT was added to Genomic newborn screening: ICoNS. Sources: Expert Review
Mode of inheritance for gene: GAMT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GAMT were set to Creberal creatine deficiency syndrome 2 (MIM 612736)
Penetrance for gene: GAMT were set to Complete
Review for gene: GAMT was set to GREEN
gene: GAMT was marked as current diagnostic
Added comment: Sources: Expert Review
Mitochondrial disease v0.996 MT-TT Chern Lim reviewed gene: MT-TT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL; Current diagnostic: yes
Mendeliome v1.3028 COMMD9 Krithika Murali Marked gene: COMMD9 as ready
Mendeliome v1.3028 COMMD9 Krithika Murali Gene: commd9 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali Marked gene: COMMD9 as ready
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali Gene: commd9 has been classified as Red List (Low Evidence).
Mendeliome v1.3028 COMMD9 Krithika Murali gene: COMMD9 was added
gene: COMMD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD9 were set to PMID: 40601774
Phenotypes for gene: COMMD9 were set to Neurodevelopmental disorder, MONDO:0700092, COMMD9-related
Review for gene: COMMD9 was set to RED
Added comment: PMID: 40601774 report a cohort ascertained through GeneMatcher with phenotypic features overlapping with Ritscher-Schinzel syndrome.

Homozygous fs variant in COMMD9 [NM_014186.3:c.208_209del, p.Leu70Glyfs*5] identified in a 4 yo M with dev delay, dysmorphism, skeletal changes including brachydactyly and radioulnar dysostosis, hypotonia, MRI-B anomalies - dysgyria, dilated
lateral ventricles, deep white matter periventricular demyelination, thin corpus callosum, cerebellar vermis hypoplasia and malrotation.

Consanguineous parents confirmed to be heterozygous carriers. No information provided regarding segregation of these variants in unaffected siblings.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.285 COMMD9 Krithika Murali gene: COMMD9 was added
gene: COMMD9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COMMD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD9 were set to PMID: 40601774
Phenotypes for gene: COMMD9 were set to Neurodevelopmental disorder, MONDO:0700092, COMMD9-related
Review for gene: COMMD9 was set to RED
Added comment: PMID: 40601774 report a cohort ascertained through GeneMatcher with phenotypic features overlapping with Ritscher-Schinzel syndrome.

Homozygous fs variant in COMMD9 [NM_014186.3:c.208_209del, p.Leu70Glyfs*5] identified in a 4 yo M with dev delay, dysmorphism, skeletal changes including brachydactyly and radioulnar dysostosis, hypotonia, MRI-B anomalies - dysgyria, dilated
lateral ventricles, deep white matter periventricular demyelination, thin corpus callosum, cerebellar vermis hypoplasia and malrotation.

Consanguineous parents confirmed to be heterozygous carriers. No information provided regarding segregation of these variants in unaffected siblings.
Sources: Literature
Autism v0.215 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Autism v0.215 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Autism v0.214 TBCB Krithika Murali Marked gene: TBCB as ready
Autism v0.214 TBCB Krithika Murali Gene: tbcb has been classified as Red List (Low Evidence).
Autism v0.214 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Autism. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Callosome v0.558 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Callosome v0.558 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Callosome v0.557 TBCB Krithika Murali Marked gene: TBCB as ready
Callosome v0.557 TBCB Krithika Murali Gene: tbcb has been classified as Red List (Low Evidence).
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Marked gene: TBCB as ready
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Marked gene: TBCB as ready
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.95 TBCB Krithika Murali Marked gene: TBCB as ready
Hereditary Spastic Paraplegia - paediatric v1.95 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Leukodystrophy - paediatric v0.327 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.95 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Hereditary Spastic Paraplegia - paediatric v1.95 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.284 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Callosome v0.557 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Callosome. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Leukodystrophy - paediatric v0.326 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Hereditary Spastic Paraplegia - paediatric v1.94 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.283 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Mendeliome v1.3027 TBCB Krithika Murali Marked gene: TBCB as ready
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3027 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3026 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Mendeliome v1.3025 NPSR1 Zornitza Stark Phenotypes for gene: NPSR1 were changed from {Asthma, susceptibility to, 2} 608584 to Short sleep, familial natural, 3, MIM# 621336; {Asthma, susceptibility to, 2} 608584
Mendeliome v1.3024 NPSR1 Zornitza Stark Publications for gene: NPSR1 were set to
Mendeliome v1.3023 NPSR1 Zornitza Stark reviewed gene: NPSR1: Rating: RED; Mode of pathogenicity: None; Publications: 31619542; Phenotypes: Short sleep, familial natural, 3, MIM# 621336; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3023 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3023 KRT32 Bryony Thompson Classified gene: KRT32 as Green List (high evidence)
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3022 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 40814173; 39048559
Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908; Pityriasis rubra pilaris MONDO:0100017
Review for gene: KRT32 was set to GREEN
Added comment: Sufficient evidence for Pityriasis rubra pilaris association, but limited for association with loose anagen syndrome.
PMID: 39048559 - Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype.
PMID: 40814173 - a single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition. In vitro functional assay showing the variant alters interaction with KRT82, however, only WT & the variant were assessed (no positive control).
Sources: Literature
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Classified gene: KRT32 as Green List (high evidence)
Palmoplantar Keratoderma and Erythrokeratoderma v0.136 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Palmoplantar Keratoderma and Erythrokeratoderma v0.135 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Palmoplantar Keratoderma and Erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 39048559
Phenotypes for gene: KRT32 were set to Pityriasis rubra pilaris MONDO:0100017
Review for gene: KRT32 was set to GREEN
Added comment: Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype.
Sources: Literature
Hair disorders v0.81 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Hair disorders v0.81 KRT32 Bryony Thompson Gene: krt32 has been classified as Red List (Low Evidence).
Hair disorders v0.81 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Hair disorders. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 40814173
Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908
Review for gene: KRT32 was set to RED
Added comment: A single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition and it would be expected that this phenotype has been reported in association with the variant/gene previously. In vitro functional assay showing the variant alters interaction with KRT82; however, only WT & the variant were assessed (no positive control).
Sources: Literature
Mendeliome v1.3021 CCDC89 Bryony Thompson Marked gene: CCDC89 as ready
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Marked gene: CCDC89 as ready
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Classified gene: CCDC89 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.29 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.28 CCDC89 Bryony Thompson gene: CCDC89 was added
gene: CCDC89 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC89 were set to 40591933
Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983
Review for gene: CCDC89 was set to AMBER
Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile.
Sources: Literature
Mendeliome v1.3021 CCDC89 Bryony Thompson Classified gene: CCDC89 as Amber List (moderate evidence)
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3020 CCDC89 Bryony Thompson gene: CCDC89 was added
gene: CCDC89 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC89 were set to 40591933
Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983
Review for gene: CCDC89 was set to AMBER
Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile.
Sources: Literature
Mendeliome v1.3019 TULP2 Bryony Thompson Marked gene: TULP2 as ready
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Marked gene: TULP2 as ready
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Classified gene: TULP2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.27 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.26 TULP2 Bryony Thompson gene: TULP2 was added
gene: TULP2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP2 were set to 35619658: 33763418; 40613306
Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372
Review for gene: TULP2 was set to AMBER
Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility.
Sources: Literature
Mendeliome v1.3019 TULP2 Bryony Thompson Classified gene: TULP2 as Amber List (moderate evidence)
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3018 TULP2 Bryony Thompson gene: TULP2 was added
gene: TULP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP2 were set to 35619658: 33763418; 40613306
Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372
Review for gene: TULP2 was set to AMBER
Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility.
Sources: Literature
Leukodystrophy - paediatric v0.325 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694 to POLR3A-related disorder MONDO:0700276
Leukodystrophy - paediatric v0.324 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Dystonia - complex v0.283 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; Striatal abnormalities; Dystonia to POLR3A-related disorder MONDO:0700276
Dystonia - complex v0.282 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Ataxia - paediatric v1.49 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Autosomal Recessive Ataxia; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism; Hypomyelinating leukodystrophy 7 with or without oligodontia and/or hypogonadotrophic hypogonadism, 607694 to POLR3A-related disorder MONDO:0700276
Ataxia - paediatric v1.48 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Differences of Sex Development v1.16 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM#607694 to POLR3A-related disorder MONDO:0700276
Differences of Sex Development v1.15 POLR3A Zornitza Stark reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: POLR3A-related disorder MONDO:0700276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v2.37 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; POLR3A Leukoencephalopathy; Parkinsonism; Ocular and dental abnormality; Hypogonadism to POLR3A-related disorder MONDO:0700276
Early-onset Parkinson disease v2.36 POLR3A Zornitza Stark edited their review of gene: POLR3A: Changed phenotypes: POLR3A-related disorder MONDO:0700276
Mendeliome v1.3017 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; Wiedemann-Rautenstrauch syndrome, MIM# 264090; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia to POLR3A-related disorder MONDO:0700276; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.353 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 POLR2C Zornitza Stark reviewed gene: POLR2C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR2C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3016 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
Growth failure v1.81 ZPR1 Zornitza Stark Phenotypes for gene: ZPR1 were changed from Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies, MIM# 619321 to Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, MIM# 619321
Growth failure v1.80 ZPR1 Zornitza Stark Classified gene: ZPR1 as Amber List (moderate evidence)
Growth failure v1.80 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Amber List (Moderate Evidence).
Growth failure v1.79 ZPR1 Zornitza Stark edited their review of gene: ZPR1: Changed rating: AMBER
Growth failure v1.79 ZPR1 Zornitza Stark changed review comment from: PMID 40776660: new family reported with two sibs, same homozygous founder variant.; to: PMID 40776660: new family reported with two sibs, same homozygous founder variant.

This paper also summarizes functional studies from the previous paper PMID: 29851065 - cultured skin fibroblasts from the patient homozygous for c.587 T>C showed significantly fewer cells in late S and G2/M phases of the cell cycle compared to control fibroblasts suggesting a disruption of cell-cycle progression past the G1 phase. ZPR1 protein was undetectable in fibroblasts from the affected individual.
Mendeliome v1.3015 ZPR1 Zornitza Stark Classified gene: ZPR1 as Amber List (moderate evidence)
Mendeliome v1.3015 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.282 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Callosome v0.556 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Callosome v0.556 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Callosome v0.556 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Callosome v0.556 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.453 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Congenital Heart Defect v0.453 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.98 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.98 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3013 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Mendeliome v1.3013 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.452 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Mendeliome v1.3012 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.97 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Mendeliome v1.3011 TCFL5 Chirag Patel gene: TCFL5 was added
gene: TCFL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCFL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCFL5 were set to PMID: 40711600
Phenotypes for gene: TCFL5 were set to Oligoasthenoteratozoospermia MONDO:0850098
Review for gene: TCFL5 was set to RED
Added comment: 2 brothers from non-consanguineous family with oligoasthenoteratozoospermia (OAT). WES identified missense variant in TCFL5 gene (c.1207G>A, p.E403K). Western blotting and immunofluorescence showed no significant effect on the expression of 'mutant' TCFL5. Dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function.
The variant disrupted the normal transcription of crucial genes involved in spermatogenesis (DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6). Tcfl5+/- male mice manifest infertile due to OAT, while Tcfl5-/- mice can not be generated.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.25 TCFL5 Chirag Patel gene: TCFL5 was added
gene: TCFL5 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TCFL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCFL5 were set to PMID: 40711600
Phenotypes for gene: TCFL5 were set to Oligoasthenoteratozoospermia MONDO:0850098
Review for gene: TCFL5 was set to RED
Added comment: 2 brothers from non-consanguineous family with oligoasthenoteratozoospermia (OAT). WES identified missense variant in TCFL5 gene (c.1207G>A, p.E403K). Western blotting and immunofluorescence showed no significant effect on the expression of 'mutant' TCFL5. Dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function.
The variant disrupted the normal transcription of crucial genes involved in spermatogenesis (DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6). Tcfl5+/- male mice manifest infertile due to OAT, while Tcfl5-/- mice can not be generated.
Sources: Literature
Heterotaxy v1.38 NPHP4 Chirag Patel Classified gene: NPHP4 as Red List (low evidence)
Heterotaxy v1.38 NPHP4 Chirag Patel Gene: nphp4 has been classified as Red List (Low Evidence).
Mendeliome v1.3010 PPARA Lucy Spencer reviewed gene: PPARA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholesterol metabolism disease MONDO:0045008, PPARA-related; Mode of inheritance: None
Mendeliome v1.3010 POU5F1 Lucy Spencer reviewed gene: POU5F1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POU5F1-related; Mode of inheritance: None
Mendeliome v1.3010 POPDC2 Lucy Spencer reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39006410, 32535041; Phenotypes: Cardiac conduction defect MONDO:0100042, POPDC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3010 POLR3H Lucy Spencer reviewed gene: POLR3H: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR3H-related; Mode of inheritance: None
Mendeliome v1.3010 POLR3A Lucy Spencer reviewed gene: POLR3A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: POLR3A-related disorder MONDO:0700276; Mode of inheritance: None
Mendeliome v1.3010 POLR2C Lucy Spencer reviewed gene: POLR2C: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR2C-related; Mode of inheritance: None
Mendeliome v1.3010 ZPR1 Lucy Spencer reviewed gene: ZPR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40776660; Phenotypes: Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies MIM#619321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.281 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Callosome v0.555 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Callosome. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Mendeliome v1.3010 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.281 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Callosome v0.555 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Callosome v0.555 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Callosome v0.555 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Callosome v0.555 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Genetic Epilepsy v1.196 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3010 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3010 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Mendeliome v1.3009 C4orf26 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is ODAPH.
Mendeliome v1.3009 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Tag new gene name tag was added to gene: C4orf26.
Callosome v0.554 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Callosome. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Genetic Epilepsy v1.195 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.280 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Mendeliome v1.3009 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Marked gene: PHLPP2 as ready
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Classified gene: PHLPP2 as Red List (low evidence)
Hypertrophic cardiomyopathy_HCM v1.9 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3009 PHLPP2 Zornitza Stark Marked gene: PHLPP2 as ready
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3009 PHLPP2 Zornitza Stark Classified gene: PHLPP2 as Red List (low evidence)
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Marked gene: MYO19 as ready
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Classified gene: MYO19 as Red List (low evidence)
Cardiomyopathy_Paediatric v0.201 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Marked gene: MYO19 as ready
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Classified gene: MYO19 as Red List (low evidence)
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3007 C4orf26 Sangavi Sivagnanasundram reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: Other; Publications: 40680053; Phenotypes: Amelogenesis imperfecta, type IIA4 MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3007 MYO19 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Cardiomyopathy_Paediatric v0.200 MYO19 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Hypertrophic cardiomyopathy_HCM v1.8 PHLPP2 Lucy Spencer gene: PHLPP2 was added
gene: PHLPP2 was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature
Mode of inheritance for gene: PHLPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHLPP2 were set to 40634996; 29628444
Phenotypes for gene: PHLPP2 were set to Hypertrophic cardiomyopathy MONDO:0005045, PHLPP2-related
Review for gene: PHLPP2 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444.
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer gene: PHLPP2 was added
gene: PHLPP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHLPP2 were set to 40634996; 29628444
Phenotypes for gene: PHLPP2 were set to Hypertrophic cardiomyopathy MONDO:0005045, PHLPP2-related
Review for gene: PHLPP2 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Cardiomyopathy_Paediatric v0.200 MYO19 Lucy Spencer gene: MYO19 was added
gene: MYO19 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO19 were set to 40634996
Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related
Review for gene: MYO19 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 MYO19 Lucy Spencer gene: MYO19 was added
gene: MYO19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO19 were set to 40634996
Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related
Review for gene: MYO19 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.280 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Mendeliome v1.3007 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Mendeliome v1.3007 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Mendeliome v1.3007 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Leukodystrophy - paediatric v0.324 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Marked gene: STAB2 as ready
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Classified gene: STAB2 as Red List (low evidence)
Bleeding and Platelet Disorders v1.58 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3006 STAB2 Zornitza Stark Marked gene: STAB2 as ready
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3006 STAB2 Zornitza Stark Classified gene: STAB2 as Red List (low evidence)
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.50 LDHD Lucy Spencer gene: LDHD was added
gene: LDHD was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 40678184
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout MIM#245450
Review for gene: LDHD was set to GREEN
Added comment: 8 patients summarized in PMID: 40678184 with D-Lactate Dehydrogenase Deficiency. 5 homozygous missense, 1 homozygous frameshift, 1 compound heterozygous canonical splice and missense, and 1 homozygous deletion encompassing CTRB2, ZFP1 (neither of which have a disease association) and the first 7 exons of LDHD. Three of these patients had additional variants of interest in other genes that were thought to explain extra phenotypes they had out of the typical spectrum for this disorder.

Some patients only have increased plasma urate/gout however 4 also had delayed development, ataxia or epilepsy. 2 of these individuals had other genetic variants that likely explained the neurodevelopmental phenotype (11p deletion syndrome, CACNA1B), and 1 had the deletion that also affected 2 other genes of uncertain significance. So its unclear whether this gene is actually associated with a neurodevelopmental phenotype.

"Patients diagnosed with the disease human D-lactate dehydrogenase deficiency present with elevated plasma D-lactate, causing D-lactic acidosis"
Sources: Literature
Mendeliome v1.3005 LDHD Lucy Spencer gene: LDHD was added
gene: LDHD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 40678184
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout MIM#245450
Review for gene: LDHD was set to GREEN
Added comment: 8 patients summarized in PMID: 40678184 with D-Lactate Dehydrogenase Deficiency. 5 homozygous missense, 1 homozygous frameshift, 1 compound heterozygous canonical splice and missense, and 1 homozygous deletion encompassing CTRB2, ZFP1 (neither of which have a disease association) and the first 7 exons of LDHD. Three of these patients had additional variants of interest in other genes that were thought to explain extra phenotypes they had out of the typical spectrum for this disorder.

Some patients only have increased plasma urate/gout however 4 also had delayed development, ataxia or epilepsy. 2 of these individuals had other genetic variants that likely explained the neurodevelopmental phenotype (11p deletion syndrome, CACNA1B), and 1 had the deletion that also affected 2 other genes of uncertain significance. So its unclear whether this gene is actually associated with a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer changed review comment from: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature; to: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Bleeding and Platelet Disorders v1.57 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: PMID: 40726512 In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Wilms Tumour v1.1 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumor, MONDO:0006058; Wilms tumor predisposition, no MIM# to Wilms tumor 7, MIM# 621332
Wilms Tumour v1.0 TRIM28 Zornitza Stark reviewed gene: TRIM28: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Wilms tumor 7, MIM# 621332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.137 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumour, MONDO:0006058, TRIM28-related to Wilms tumor 7, MIM# 621332
Genomic newborn screening: BabyScreen+ v1.136 TRIM28 Zornitza Stark edited their review of gene: TRIM28: Changed phenotypes: Wilms tumor 7, MIM# 621332
Cancer Predisposition_Paediatric v0.132 TRIM28 Zornitza Stark Phenotypes for gene: TRIM28 were changed from Wilms tumour, MONDO:0006058, TRIM28-related to Wilms tumor 7, MIM# 621332
Cancer Predisposition_Paediatric v0.131 TRIM28 Zornitza Stark edited their review of gene: TRIM28: Changed phenotypes: Wilms tumor 7, MIM# 621332
Stroke v1.26 ARHGEF15 Zornitza Stark Marked gene: ARHGEF15 as ready
Stroke v1.26 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Stroke v1.26 ARHGEF15 Zornitza Stark Classified gene: ARHGEF15 as Green List (high evidence)
Stroke v1.26 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Stroke v1.25 ARHGEF15 Zornitza Stark gene: ARHGEF15 was added
gene: ARHGEF15 was added to Stroke. Sources: Literature
Mode of inheritance for gene: ARHGEF15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGEF15 were set to 36929019
Phenotypes for gene: ARHGEF15 were set to Brain small vessel disease 5 with osteoporosis, MIM# 621331
Review for gene: ARHGEF15 was set to GREEN
Added comment: 7 individuals, ranging from 42 to 60 years of age and from 4 unrelated Chinese families, who presented between 38 and 46 years of age, with cognitive and memory decline, psychiatric disturbances, and small-vessel cerebral infarction and/or intracerebral hemorrhage on brain imaging. Features included irritability, mania, anxiety, depression, and suicidal tendencies. Four different missense variants identified. Supportive functional data, including mouse model.
Sources: Literature
Mendeliome v1.3005 ARHGEF15 Zornitza Stark Phenotypes for gene: ARHGEF15 were changed from to Brain small vessel disease 5 with osteoporosis, MIM# 621331
Mendeliome v1.3004 ARHGEF15 Zornitza Stark Publications for gene: ARHGEF15 were set to
Mendeliome v1.3003 ARHGEF15 Zornitza Stark Mode of inheritance for gene: ARHGEF15 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Classified gene: ARHGEF15 as Green List (high evidence)
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Mendeliome v1.3001 ARHGEF15 Zornitza Stark edited their review of gene: ARHGEF15: Added comment: 7 individuals, ranging from 42 to 60 years of age and from 4 unrelated Chinese families, who presented between 38 and 46 years of age, with cognitive and memory decline, psychiatric disturbances, and small-vessel cerebral infarction and/or intracerebral hemorrhage on brain imaging. Features included irritability, mania, anxiety, depression, and suicidal tendencies.

Four different missense variants identified. Supportive functional data, including mouse model.; Changed rating: GREEN; Changed publications: 36929019; Changed phenotypes: Brain small vessel disease 5 with osteoporosis, MIM# 621331; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Marked gene: TDRD9 as ready
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Classified gene: TDRD9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.24 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.23 TDRD9 Bryony Thompson gene: TDRD9 was added
gene: TDRD9 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TDRD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD9 were set to 28536242; 40645105; 20059948; 39267058; 39174853; 35172124
Phenotypes for gene: TDRD9 were set to spermatogenic failure MONDO:0004983
Review for gene: TDRD9 was set to GREEN
Added comment: At least 5 families with biallelic variants (homozygous and compound heterozygous) were identified in males with spermatogenic failure (azoospermia and oligoazoospermia). Also, supporting infertile mouse model.
Sources: Literature
Mendeliome v1.3001 TDRD9 Bryony Thompson Classified gene: TDRD9 as Green List (high evidence)
Mendeliome v1.3001 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Mendeliome v1.3000 TDRD9 Bryony Thompson gene: TDRD9 was added
gene: TDRD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD9 were set to 28536242; 40645105; 20059948; 39267058; 39174853; 35172124
Phenotypes for gene: TDRD9 were set to spermatogenic failure MONDO:0004983
Review for gene: TDRD9 was set to GREEN
Added comment: At least 5 families with biallelic variants (homozygous and compound heterozygous) were identified in males with spermatogenic failure (azoospermia and oligoazoospermia). Also, supporting infertile mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Marked gene: HS6ST2 as ready
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Classified gene: HS6ST2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.279 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.278 HS6ST2 Bryony Thompson gene: HS6ST2 was added
gene: HS6ST2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HS6ST2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HS6ST2 were set to 40686562; 30471091; 36993824; 38015989
Phenotypes for gene: HS6ST2 were set to X-linked syndromic intellectual disability MONDO:0020119
Review for gene: HS6ST2 was set to GREEN
Added comment: 4 males with a neurodevelopmental phenotype from 3 families (1 set monozygotic twins) hemizygous for rare missense variants and a supporting mouse model.
PMID: 40686562 - a Chinese male child with a syndromic neurodevelopmental phenotype hemizygous c.764C>A (p.Pro255Glu) and in vitro assays showing the variant alters function. Parents were unaffected and variant was maternally inherited.

PMID: 38015989 - knockout mouse model impairs dendritic spines of hippocampal neurons, and affects memory.

PMID: 36993824 - an Iranian male child with a syndromic neurodevelopmental phenotype hemizygouc.979C>T p.Pro327Ser.

PMID: 30471091 - Italian monozygotic male twins with a syndromic neurodevelopmental phenotype hemizygous c.916G>C (p.G306R - inherited from unaffected mother) and functional assay showing altered enzyme activity.
Sources: Literature
Mendeliome v1.2999 HS6ST2 Bryony Thompson Marked gene: HS6ST2 as ready
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2999 HS6ST2 Bryony Thompson Classified gene: HS6ST2 as Green List (high evidence)
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2998 HS6ST2 Bryony Thompson gene: HS6ST2 was added
gene: HS6ST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HS6ST2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HS6ST2 were set to 40686562; 30471091; 36993824; 38015989
Phenotypes for gene: HS6ST2 were set to X-linked syndromic intellectual disability MONDO:0020119
Review for gene: HS6ST2 was set to GREEN
Added comment: 4 males with a neurodevelopmental phenotype from 3 families (1 set monozygotic twins) hemizygous for rare missense variants and a supporting mouse model.
PMID: 40686562 - a Chinese male child with a syndromic neurodevelopmental phenotype hemizygous c.764C>A (p.Pro255Glu) and in vitro assays showing the variant alters function. Parents were unaffected and variant was maternally inherited.

PMID: 38015989 - knockout mouse model impairs dendritic spines of hippocampal neurons, and affects memory.

PMID: 36993824 - an Iranian male child with a syndromic neurodevelopmental phenotype hemizygouc.979C>T p.Pro327Ser.

PMID: 30471091 - Italian monozygotic male twins with a syndromic neurodevelopmental phenotype hemizygous c.916G>C (p.G306R - inherited from unaffected mother) and functional assay showing altered enzyme activity.
Sources: Literature
Ataxia - paediatric v1.48 ATXN2_SCA2_CAG Bryony Thompson Marked STR: ATXN2_SCA2_CAG as ready
Ataxia - paediatric v1.48 ATXN2_SCA2_CAG Bryony Thompson Str: atxn2_sca2_cag has been classified as Green List (High Evidence).
Ataxia - paediatric v1.48 ATXN2_SCA2_CAG Bryony Thompson Classified STR: ATXN2_SCA2_CAG as Green List (high evidence)
Ataxia - paediatric v1.48 ATXN2_SCA2_CAG Bryony Thompson Str: atxn2_sca2_cag has been classified as Green List (High Evidence).
Ataxia - paediatric v1.47 ATXN2_SCA2_CAG Bryony Thompson STR: ATXN2_SCA2_CAG was added
STR: ATXN2_SCA2_CAG was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for STR: ATXN2_SCA2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: ATXN2_SCA2_CAG were set to 40741828
Phenotypes for STR: ATXN2_SCA2_CAG were set to Spinocerebellar ataxia type 2 MONDO:0008458
Review for STR: ATXN2_SCA2_CAG was set to GREEN
STR: ATXN2_SCA2_CAG was marked as clinically relevant
STR: ATXN2_SCA2_CAG was marked as current diagnostic
Added comment: Cohort of paediatric-onset SCA2 cases. The infantile onset group (n=9) had expansions ≥88 repeats, and the juvenile onset group (n=13) had expansions ≥43 repeats. Paediatric SCA2 phenotype includes developmental delay and seizures (infantile-onset) and cerebellar degeneration similar to adults in the juvenile group.
Sources: Literature
Mendeliome v1.2997 SPNS1 Zornitza Stark Marked gene: SPNS1 as ready
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2997 SPNS1 Zornitza Stark Classified gene: SPNS1 as Amber List (moderate evidence)
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Marked gene: SPNS1 as ready
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Classified gene: SPNS1 as Amber List (moderate evidence)
Lysosomal Storage Disorder v1.22 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.277 CSMD2 Zornitza Stark Deleted their review
Intellectual disability syndromic and non-syndromic v1.277 CSMD2 Zornitza Stark reviewed gene: CSMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal epilepsy - MONDO:0005384, CSMD2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.326 SDHD Zornitza Stark Marked gene: SDHD as ready
Incidentalome v0.326 SDHD Zornitza Stark Gene: sdhd has been classified as Green List (High Evidence).
Incidentalome v0.326 SDHD Zornitza Stark Phenotypes for gene: SDHD were changed from to Paragangliomas 1, with or without deafness, MIM# 168000; Pheochromocytoma, MIM# 171300
Incidentalome v0.325 SDHD Zornitza Stark Mode of inheritance for gene: SDHD was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Incidentalome v0.324 SDHAF2 Zornitza Stark Marked gene: SDHAF2 as ready
Incidentalome v0.324 SDHAF2 Zornitza Stark Gene: sdhaf2 has been classified as Green List (High Evidence).
Incidentalome v0.324 SDHAF2 Zornitza Stark Phenotypes for gene: SDHAF2 were changed from to Paragangliomas 2, MIM# 601650
Incidentalome v0.323 SDHAF2 Zornitza Stark Mode of inheritance for gene: SDHAF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Fetal anomalies v1.405 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Fetal anomalies v1.404 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Ciliopathies and Nephronophthisis v1.34 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Polydactyly v0.289 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Polydactyly v0.289 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Polydactyly v0.289 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Polydactyly v0.288 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2996 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Mendeliome v1.2995 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: Meckel syndrome MONDO:0018921, TMEM17-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliopathies v1.82 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to 40841990
Ciliopathies v1.82 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Incidentalome v0.322 SDHAF2 Anna Le Fevre reviewed gene: SDHAF2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Ciliopathies v1.81 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: Meckel syndrome MONDO:0018921, TMEM17-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2995 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Incidentalome v0.322 SDHD Anna Le Fevre commented on gene: SDHD: Would you like this gene added to the imprinted gene list?
Note gene in incidentalome.
Mendeliome v1.2995 TEX44 Zornitza Stark Classified gene: TEX44 as Green List (high evidence)
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Mendeliome v1.2994 TEX44 Zornitza Stark gene: TEX44 was added
gene: TEX44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEX44 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX44 were set to 40849303
Phenotypes for gene: TEX44 were set to Spermatogenic failure, MONDO:0004983, TEX44-related
Review for gene: TEX44 was set to GREEN
Added comment: Six individuals with biallelic variants, mouse model and other functional data support this gene-disease relationship.
Sources: Literature
Incidentalome v0.322 SDHD Anna Le Fevre reviewed gene: SDHD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.22 TEX44 Zornitza Stark Publications for gene: TEX44 were set to
Infertility and Recurrent Pregnancy Loss v1.21 TEX44 Zornitza Stark Classified gene: TEX44 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.21 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.20 TEX44 Zornitza Stark edited their review of gene: TEX44: Changed publications: 40849303
Infertility and Recurrent Pregnancy Loss v1.20 TEX44 Zornitza Stark gene: TEX44 was added
gene: TEX44 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TEX44 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TEX44 were set to Spermatogenic failure, MONDO:0004983, TEX44-related
Review for gene: TEX44 was set to GREEN
Added comment: Six individuals with biallelic variants, mouse model and other functional data support this gene-disease relationship.
Sources: Literature
IBMDx study v0.37 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
IBMDx study v0.37 ADA2 Zornitza Stark Marked gene: ADA2 as ready
IBMDx study v0.37 ADA2 Zornitza Stark Gene: ada2 has been classified as Green List (High Evidence).
IBMDx study v0.37 ADA2 Zornitza Stark Publications for gene: ADA2 were set to
IBMDx study v0.36 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory Disorders v2.15 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285
Autoinflammatory Disorders v2.14 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory Disorders v2.13 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bone Marrow Failure v1.125 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Bone Marrow Failure v1.124 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bone Marrow Failure v1.123 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Vasculitis v0.89 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Vasculitis v0.88 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Vasculitis v0.87 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.277 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Intellectual disability syndromic and non-syndromic v1.277 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Mendeliome v1.2993 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Mendeliome v1.2992 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 FSCN1 Zornitza Stark Marked gene: FSCN1 as ready
Mendeliome v1.2991 FSCN1 Zornitza Stark Gene: fscn1 has been classified as Red List (Low Evidence).
Mendeliome v1.2991 FSCN1 Zornitza Stark gene: FSCN1 was added
gene: FSCN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FSCN1 were set to 40874942
Phenotypes for gene: FSCN1 were set to Neurodevelopmental disorder, MONDO:0700092, FSCN1-related
Review for gene: FSCN1 was set to RED
Added comment: Two individuals reported in an Iranian cohort with same missense variant, c.665C>A; p.Ala222Asp, plus other circumstantial data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark Marked gene: FSCN1 as ready
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark Gene: fscn1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.277 FSCN1 Zornitza Stark gene: FSCN1 was added
gene: FSCN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FSCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FSCN1 were set to 40874942
Phenotypes for gene: FSCN1 were set to Neurodevelopmental disorder, MONDO:0700092, FSCN1-related
Review for gene: FSCN1 was set to RED
Added comment: Two individuals reported from an Iranian cohort with same missense variant, c.665C>A; p.Ala222Asp plus other circumstantial data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.276 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Mendeliome v1.2990 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Mendeliome v1.2990 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Mendeliome v1.2990 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Microcephaly v1.334 MAEA Zornitza Stark Marked gene: MAEA as ready
Microcephaly v1.334 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.87 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Microcephaly v1.334 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Microcephaly v1.334 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Microcephaly v1.333 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Mendeliome v1.2989 MAEA Zornitza Stark Marked gene: MAEA as ready
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2989 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2988 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark changed review comment from: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands.
Sources: Literature; to: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Marked gene: MAEA as ready
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.275 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.274 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands.
Sources: Literature
Mendeliome v1.2987 NIN Zornitza Stark Publications for gene: NIN were set to 22933543
Mendeliome v1.2986 NIN Zornitza Stark edited their review of gene: NIN: Added comment: PMID 40751525: second affected individual but homozygous inframe deletion.; Changed publications: 22933543, 40751525
Microcephaly v1.332 NIN Zornitza Stark Publications for gene: NIN were set to 22933543
Microcephaly v1.331 NIN Zornitza Stark edited their review of gene: NIN: Added comment: PMID 40751525: second affected individual but homozygous inframe deletion.; Changed publications: 22933543, 40751525
Mendeliome v1.2986 SYNE2 Zornitza Stark Publications for gene: SYNE2 were set to 32184094; 17761684
Mendeliome v1.2985 SYNE2 Zornitza Stark Mode of inheritance for gene: SYNE2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 SYNE2 Zornitza Stark reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 40757551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 EMP2 Zornitza Stark Phenotypes for gene: EMP2 were changed from nephrotic syndrome, type 10 MONDO:0014373 to nephrotic syndrome, type 10 MONDO:0014373; Ichthyosis, MONDO:0019269, EMP2-related
Mendeliome v1.2983 EMP2 Zornitza Stark Mode of inheritance for gene: EMP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2982 EMP2 Zornitza Stark reviewed gene: EMP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40758889; Phenotypes: Ichthyosis, MONDO:0019269, EMP2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis v1.13 EMP2 Zornitza Stark Marked gene: EMP2 as ready
Ichthyosis v1.13 EMP2 Zornitza Stark Gene: emp2 has been classified as Amber List (Moderate Evidence).
Ichthyosis v1.13 EMP2 Zornitza Stark Classified gene: EMP2 as Amber List (moderate evidence)
Ichthyosis v1.13 EMP2 Zornitza Stark Gene: emp2 has been classified as Amber List (Moderate Evidence).
Ichthyosis v1.12 EMP2 Zornitza Stark gene: EMP2 was added
gene: EMP2 was added to Ichthyosis. Sources: Literature
Mode of inheritance for gene: EMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMP2 were set to 40758889
Phenotypes for gene: EMP2 were set to Ichthyosis, MONDO:0019269, EMP2-related
Review for gene: EMP2 was set to AMBER
Added comment: Recurrent de novo missense variant associated with progressive symmetric erythrokeratoderma, mechanism appears GoF.
Sources: Literature
Growth failure v1.79 ZPR1 Zornitza Stark Publications for gene: ZPR1 were set to 29851065
Growth failure v1.78 ZPR1 Zornitza Stark edited their review of gene: ZPR1: Added comment: PMID 40776660: new family reported with two sibs, same homozygous founder variant.; Changed publications: 29851065, 40776660
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark Marked gene: TTL as ready
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark Gene: ttl has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v1.8 TTL Zornitza Stark gene: TTL was added
gene: TTL was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature
Mode of inheritance for gene: TTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTL were set to 40779454
Phenotypes for gene: TTL were set to Hypertrophic cardiomyopathy, MONDO:0005045, TTL-related
Review for gene: TTL was set to RED
Added comment: Single case report, missense variant with functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.273 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2982 C4A Zornitza Stark Publications for gene: C4A were set to 22387014; 22737222; 15998580; 10529130; 15294999; 32048120
Mendeliome v1.2981 C4A Zornitza Stark reviewed gene: C4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40788338; Phenotypes: C4a deficiency MIM#614380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Complement Deficiencies v1.1 C4A Zornitza Stark Publications for gene: C4A were set to 22387014; 22737222; 15998580; 10529130; 15294999; 32048120
Complement Deficiencies v1.0 C4A Zornitza Stark reviewed gene: C4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40788338; Phenotypes: C4a deficiency MIM#614380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2981 NDNF Zornitza Stark Publications for gene: NDNF were set to 31883645
Mendeliome v1.2980 NDNF Zornitza Stark edited their review of gene: NDNF: Added comment: PMID 40788466: two sisters with compound het variants and CHH. RED for this MOI.; Changed rating: AMBER; Changed publications: 31883645, 40788466
Differences of Sex Development v1.15 NDNF Zornitza Stark Publications for gene: NDNF were set to 31883645
Differences of Sex Development v1.14 NDNF Zornitza Stark changed review comment from: PMID 40788466: two sisters with compound het variants and CHH.; to: PMID 40788466: two sisters with compound het variants and CHH. RED for this MOI.
Differences of Sex Development v1.14 NDNF Zornitza Stark edited their review of gene: NDNF: Changed rating: AMBER
Differences of Sex Development v1.14 NDNF Zornitza Stark edited their review of gene: NDNF: Added comment: PMID 40788466: two sisters with compound het variants and CHH.; Changed publications: 31883645, 40788466
Mendeliome v1.2980 REPS1 Zornitza Stark Publications for gene: REPS1 were set to 29395073
Mendeliome v1.2979 REPS1 Zornitza Stark edited their review of gene: REPS1: Added comment: Additional family reported in PMID 40788509, but homozygous missense variant with no further supporting information.; Changed publications: 29395073, 40788509
Neurodegeneration with brain iron accumulation v1.1 REPS1 Zornitza Stark Publications for gene: REPS1 were set to 29395073
Neurodegeneration with brain iron accumulation v1.0 REPS1 Zornitza Stark edited their review of gene: REPS1: Added comment: Additional family reported in PMID 40788509, but homozygous missense variant with no further supporting information.; Changed publications: 29395073, 40788509; Changed phenotypes: Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Mendeliome v1.2979 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751
Mendeliome v1.2978 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: Two further families reported but with missense variants, which did not completely segregate with disease. No other supportive information provided.; Changed publications: 32542751, 40797221
Hereditary angioedema v1.6 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751
Hereditary angioedema v1.5 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: Two further families reported but with missense variants, which did not completely segregate with disease. No other supportive information provided.; Changed publications: 32542751, 40797221
Intellectual disability syndromic and non-syndromic v1.273 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Intellectual disability syndromic and non-syndromic v1.272 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Second family reported, but same homozygous missense variant, likely founder.; Changed publications: 23918663, 40801391
Microcephaly v1.331 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Microcephaly v1.330 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Report of a second family but same homozygous variant, likely founder.; Changed publications: 23918663, 40801391
Mendeliome v1.2978 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Mendeliome v1.2977 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Report of a second family, but same homozygous missense variant, suggestive of founder effect.; Changed publications: 23918663, 40801391
Incidentalome v0.322 DNAJC7 Zornitza Stark Publications for gene: DNAJC7 were set to 31768050
Incidentalome v0.321 DNAJC7 Zornitza Stark edited their review of gene: DNAJC7: Added comment: PMID 40802071: single family with three affected sibs and bi-allelic variants associated with ALS.; Changed publications: 31768050, 40802071
Motor Neurone Disease v1.34 DNAJC7 Zornitza Stark Publications for gene: DNAJC7 were set to 31768050
Motor Neurone Disease v1.33 DNAJC7 Zornitza Stark edited their review of gene: DNAJC7: Added comment: PMID 40802071: report of bi-allelic LoF variants in three sibs with ALS.; Changed publications: 40802071
Genetic Epilepsy v1.195 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Genetic Epilepsy v1.195 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Intellectual disability syndromic and non-syndromic v1.272 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Genetic Epilepsy v1.195 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Genetic Epilepsy v1.195 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.272 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Genetic Epilepsy v1.195 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 31068362; 38649688
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD2-related
Review for gene: CSMD2 was set to RED
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Sources: Literature
Mendeliome v1.2977 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Mendeliome v1.2977 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Mendeliome v1.2977 CSMD2 Krithika Murali reviewed gene: CSMD2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40632521, 31068362, 38649688; Phenotypes: Focal epilepsy - MONDO:0005384, CSMD2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.271 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.271 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.270 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Genetic Epilepsy v1.194 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Genetic Epilepsy v1.194 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Genetic Epilepsy v1.193 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Genetic Epilepsy v1.193 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Genetic Epilepsy v1.192 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Mendeliome v1.2977 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Mendeliome v1.2977 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Mendeliome v1.2976 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Mendeliome v1.2976 CSMD2 Krithika Murali Deleted their review
Intellectual disability syndromic and non-syndromic v1.270 HIRA Zornitza Stark Phenotypes for gene: HIRA were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, HIRA-related
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 38649688; 31068362
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD1-related
Review for gene: CSMD2 was set to AMBER
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2975 PTCH2 Zornitza Stark Phenotypes for gene: PTCH2 were changed from Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic to Duplication of pituitary gland; Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic
Mendeliome v1.2974 PTCH2 Zornitza Stark Publications for gene: PTCH2 were set to 30820324; 23479190; 18285427
Mendeliome v1.2973 PTCH2 Zornitza Stark edited their review of gene: PTCH2: Added comment: PMID 40803816: novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids identified in individual with duplication of the pituitary gland. Unclear how this relates to previously reported variants and phenotypes.; Changed publications: 30820324, 23479190, 18285427, 40803816; Changed phenotypes: Basal cell nevus syndrome, MIM#109400, Duplication of pituitary gland
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Marked gene: SLC10A2 as ready
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Haem degradation and bilirubin metabolism defects v0.19 SLC10A2 Zornitza Stark Publications for gene: SLC10A2 were set to 9109432
Haem degradation and bilirubin metabolism defects v0.18 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Haem degradation and bilirubin metabolism defects v0.18 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Haem degradation and bilirubin metabolism defects v0.17 SLC10A2 Zornitza Stark reviewed gene: SLC10A2: Rating: AMBER; Mode of pathogenicity: None; Publications: 9109432, 40814585; Phenotypes: Bile acid malabsorption, primary, MIM# 613291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2973 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Mendeliome v1.2973 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2972 SLC10A2 Zornitza Stark edited their review of gene: SLC10A2: Added comment: Second individual reported homozygous missense, but quite a specific phenotype so upgrade to Amber.; Changed rating: AMBER; Changed publications: 9109432, 40814585
Congenital Diarrhoea v1.21 SLC10A2 Zornitza Stark Publications for gene: SLC10A2 were set to 9109432
Congenital Diarrhoea v1.20 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Congenital Diarrhoea v1.20 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.19 SLC10A2 Zornitza Stark edited their review of gene: SLC10A2: Added comment: Second individual reported homozygous missense, but quite a specific phenotype so upgrade to Amber.; Changed rating: AMBER; Changed publications: 9109432, 40814585
Mendeliome v1.2972 KLHL9 Zornitza Stark Publications for gene: KLHL9 were set to 20554658
Mendeliome v1.2971 KLHL9 Zornitza Stark reviewed gene: KLHL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 40818927; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.61 KLHL9 Zornitza Stark Publications for gene: KLHL9 were set to 20554658
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 KLHL9 Zornitza Stark reviewed gene: KLHL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 40818927; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2971 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982; 36458887
Mendeliome v1.2970 UHRF1 Zornitza Stark Classified gene: UHRF1 as Amber List (moderate evidence)
Mendeliome v1.2970 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2969 UHRF1 Zornitza Stark edited their review of gene: UHRF1: Added comment: Second family reported with homozygous missense variant.; Changed rating: AMBER; Changed publications: 29574422, 28976982, 40825131; Changed phenotypes: Imprinting disorder
Imprinting disorders v1.8 UHRF1 Zornitza Stark commented on gene: UHRF1: Second family reported with homozygous missense variant.
Imprinting disorders v1.8 UHRF1 Zornitza Stark Phenotypes for gene: UHRF1 were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; Imprinting disorder
Imprinting disorders v1.7 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Imprinting disorders v1.6 UHRF1 Zornitza Stark Classified gene: UHRF1 as Amber List (moderate evidence)
Imprinting disorders v1.6 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Amber List (Moderate Evidence).
Imprinting disorders v1.5 UHRF1 Zornitza Stark edited their review of gene: UHRF1: Changed rating: AMBER; Changed publications: 40825131; Changed phenotypes: Imprinting disorder; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.269 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.269 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.268 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 33864376, 40831499
Genetic Epilepsy v1.192 RNF2 Zornitza Stark Publications for gene: RNF2 were set to 33864376
Genetic Epilepsy v1.191 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Genetic Epilepsy v1.191 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.190 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 33864376, 40831499
Mendeliome v1.2969 RNF2 Zornitza Stark Publications for gene: RNF2 were set to 33864376
Mendeliome v1.2968 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Mendeliome v1.2968 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Mendeliome v1.2967 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 40831499
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.267 CCDC93 Zornitza Stark reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.554 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Callosome v0.554 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Callosome v0.554 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Callosome v0.554 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2967 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2967 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Marked gene: COX18 as ready
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.30 COX18 Zornitza Stark gene: COX18 was added
gene: COX18 was added to Hereditary Neuropathy - complex. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to 37468577; 40830826
Phenotypes for gene: COX18 were set to Mitochondrial disease (MONDO:0044970), COX18-related
Review for gene: COX18 was set to GREEN
Added comment: PMID 40830826: Two sibs presenting with early onset progressive axonal sensory-motor peripheral neuropathy Family 1 (consanguineous) - two sibs affected with axonal CMT and homozygous c.435-6A>G - NFE AF - 0.001531% Family 2 - 4 sibs affected with axonal CMT and homozygous Leu72Arg - MID PopMax AF - 0.07120% Family 3 - two sibs with axonal CMT and compound het variants confirmed in trans - Ala110Pro; Arg297Pro Functional assay on c.435-6A>G showed stable but defective COX18 isoform - impairs CIV assembly and activity resulting in the reduction of mitochondrial membrane potential.

Note earlier case report with multi-system mitochondrial disease, hence placing in this panel.
Sources: Literature
Mendeliome v1.2966 COX18 Zornitza Stark Publications for gene: COX18 were set to PMID:37468577
Mendeliome v1.2965 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Mendeliome v1.2965 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Mitochondrial disease v0.996 COX18 Zornitza Stark Publications for gene: COX18 were set to PMID:37468577
Lysosomal Storage Disorder v1.21 SPNS1 Sangavi Sivagnanasundram gene: SPNS1 was added
gene: SPNS1 was added to Lysosomal Storage Disorder. Sources: Literature
Mode of inheritance for gene: SPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPNS1 were set to 40608416
Phenotypes for gene: SPNS1 were set to Lysosomal disorder, SPNS1-related, MONDO:0002561
Review for gene: SPNS1 was set to AMBER
Added comment: Patient 1 and 2 - Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram changed review comment from: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature; to: Patient 1 and 2 - Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram gene: SPNS1 was added
gene: SPNS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPNS1 were set to 40608416
Phenotypes for gene: SPNS1 were set to Lysosomal disorder, SPNS1-related, MONDO:0002561
Review for gene: SPNS1 was set to AMBER
Added comment: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali Marked gene: WDR18 as ready
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali Gene: wdr18 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali gene: WDR18 was added
gene: WDR18 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: WDR18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR18 were set to PMID: 40677927
Phenotypes for gene: WDR18 were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: WDR18 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali Marked gene: MIS18BP1 as ready
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali Gene: mis18bp1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali gene: MIS18BP1 was added
gene: MIS18BP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MIS18BP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIS18BP1 were set to PMID: 40677927
Phenotypes for gene: MIS18BP1 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: MIS18BP1 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2964 MIS18BP1 Krithika Murali Marked gene: MIS18BP1 as ready
Mendeliome v1.2964 MIS18BP1 Krithika Murali Gene: mis18bp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali Marked gene: WDR18 as ready
Mendeliome v1.2964 WDR18 Krithika Murali Gene: wdr18 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali gene: WDR18 was added
gene: WDR18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR18 were set to PMID: 40677927
Phenotypes for gene: WDR18 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: WDR18 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2963 MIS18BP1 Krithika Murali gene: MIS18BP1 was added
gene: MIS18BP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIS18BP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIS18BP1 were set to PMID: 40677927
Phenotypes for gene: MIS18BP1 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: MIS18BP1 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mitochondrial disease v0.995 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Mitochondrial disease v0.995 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark Marked gene: HYPK as ready
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark Gene: hypk has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark gene: HYPK was added
gene: HYPK was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: HYPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HYPK were set to Clinical Genetics Early View
Phenotypes for gene: HYPK were set to Neurodevelopmental disorder, MONDO:0700092, HYPK-related
Review for gene: HYPK was set to RED
Added comment: Single case report - Patel, R. et al 2025 Clinical Genetics Early View

Male proband with developmental delay, autism and facial dysmorphism with a de novo missense HYPK variant (p. R70I). Variant-specific biochemical analyses demonstrates enhanced inhibitory activity of HYPK on NatA-mediated N-terminal protein acetylation.

GestaltMatcher analysis indicates that the proband's facial phenotype closely resembles Ogden syndrome (NAA10) and some resemblance to NAA15-NDS - both associated genes are also involved in the N-terminal acetylation pathway.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark Marked gene: DDX39A as ready
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark Gene: ddx39a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark gene: DDX39A was added
gene: DDX39A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DDX39A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX39A were set to 40726340
Phenotypes for gene: DDX39A were set to Neurodevelopmental disorder, MONDO:0700092, DDX39A-related
Review for gene: DDX39A was set to RED
Added comment: PMID: 40726340 Ahmed et al 2025 (Clinical Genetics) report a 7 month old F with GDD, seizures, microcephaly, hypotonia, corpus callosum thinning and homozygous missense variant (p.Lys137Gln) in DDX39A on trio WES with both non-consanguineous parents confirmed to be heterozygous carriers. DDX39A is involved in mRNA splicing and export. Patient-derived fibroblast studies showed that mutant protein resulted in aberrant nuclear clumping and failure to interact with the TREX complex.

Of note, closely-related paralogue DDX39B is also a component of the TREX complex and has a definitive monoallelic association with neurodevelopmental disorder.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark Marked gene: ARID3A as ready
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark Gene: arid3a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark gene: ARID3A was added
gene: ARID3A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to 40677927
Phenotypes for gene: ARID3A were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: ARID3A was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark Marked gene: PIK3C3 as ready
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark Gene: pik3c3 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark gene: PIK3C3 was added
gene: PIK3C3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C3 were set to 40677927
Phenotypes for gene: PIK3C3 were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: PIK3C3 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Marked gene: MED29 as ready
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.330 MED29 Zornitza Stark Marked gene: MED29 as ready
Microcephaly v1.330 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.330 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Microcephaly v1.330 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2962 MED29 Zornitza Stark Marked gene: MED29 as ready
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2962 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.86 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.86 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.85 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.85 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: GLYAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYAT were set to 40747359
Phenotypes for gene: GLYAT were set to Neurodevelopmental disorder, MONDO:0700092, GLYAT-related
Review for gene: GLYAT was set to RED
Added comment: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of oedema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Mendeliome v1.2961 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Mendeliome v1.2961 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Mendeliome v1.2961 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GLYAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYAT were set to 40747359
Phenotypes for gene: GLYAT were set to Neurodevelopmental disorder, MONDO:0700092, GLYAT-related
Review for gene: GLYAT was set to RED
Added comment: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of oedema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark changed review comment from: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of edema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature; to: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of oedema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GLYAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYAT were set to 40747359
Phenotypes for gene: GLYAT were set to Neurodevelopmental disorder, MONDO:0700092, GLYAT-related
Review for gene: GLYAT was set to RED
Added comment: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of edema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Mendeliome v1.2960 TDRD12 Zornitza Stark Marked gene: TDRD12 as ready
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2960 TDRD12 Zornitza Stark Classified gene: TDRD12 as Amber List (moderate evidence)
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2959 TDRD12 Zornitza Stark gene: TDRD12 was added
gene: TDRD12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD12 were set to 40750267
Phenotypes for gene: TDRD12 were set to Spermatogenic failure, MONDO:0004983, TDRD12-related
Review for gene: TDRD12 was set to AMBER
Added comment: Two novel homozygous TDRD12 variants (c.3378dupG and c.2463C>G) reported in two unrelated infertile men, respectively. Patient 1 had a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This individual presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 had a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This individual exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Marked gene: TDRD12 as ready
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Classified gene: TDRD12 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.18 TDRD12 Zornitza Stark gene: TDRD12 was added
gene: TDRD12 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TDRD12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD12 were set to 40750267
Phenotypes for gene: TDRD12 were set to Spermatogenic failure, MONDO:0004983, TDRD12-related
Review for gene: TDRD12 was set to AMBER
Added comment: Two novel homozygous TDRD12 variants (c.3378dupG and c.2463C>G) reported in two unrelated infertile men, respectively. Patient 1 had a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This individual presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 had a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This individual exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage.
Sources: Literature
Mendeliome v1.2958 CCDC189 Zornitza Stark Marked gene: CCDC189 as ready
Mendeliome v1.2958 CCDC189 Zornitza Stark Gene: ccdc189 has been classified as Red List (Low Evidence).
Mendeliome v1.2958 CCDC189 Zornitza Stark gene: CCDC189 was added
gene: CCDC189 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: CCDC189.
Mode of inheritance for gene: CCDC189 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC189 were set to 40759592
Phenotypes for gene: CCDC189 were set to Spermatogenic failure, MONDO:0004983, CCDC189-related
Review for gene: CCDC189 was set to RED
Added comment: Single individual with biallelic variants. Limited functional data.

New HGNC approved name CFAP119.
Sources: Literature
Mendeliome v1.2957 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Mendeliome v1.2957 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Marked gene: CCDC189 as ready
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name CFAP119.
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Gene: ccdc189 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Tag new gene name tag was added to gene: CCDC189.
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark gene: CCDC189 was added
gene: CCDC189 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCDC189 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC189 were set to 40759592
Phenotypes for gene: CCDC189 were set to Spermatogenic failure, MONDO:0004983, CCDC189-related
Review for gene: CCDC189 was set to RED
Added comment: Single individual with biallelic variants. Limited functional data.
Sources: Literature
Mendeliome v1.2956 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features. Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Microcephaly v1.329 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Microcephaly v1.329 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Microcephaly v1.329 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Microcephaly v1.329 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.189 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features. Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Microcephaly v1.328 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features. Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.258 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features.

Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Mendeliome v1.2955 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2955 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2954 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160
Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related
Review for gene: ASAP2 was set to AMBER
Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development. Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.256 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160
Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related
Review for gene: ASAP2 was set to AMBER
Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development. Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants.
Sources: Literature
Microcephaly v1.327 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Microcephaly v1.327 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.327 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Microcephaly v1.327 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.326 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160
Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related
Review for gene: ASAP2 was set to AMBER
Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development.

Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark changed review comment from: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Supportive functional data.
Sources: Literature; to: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark changed review comment from: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature; to: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development.
Sources: Literature
Microcephaly v1.325 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Microcephaly v1.325 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Microcephaly v1.325 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Microcephaly v1.325 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Microcephaly v1.324 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196
Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related
Review for gene: RTF1 was set to GREEN
Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2953 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2952 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196
Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related
Review for gene: RTF1 was set to GREEN
Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.254 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196
Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related
Review for gene: RTF1 was set to GREEN
Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Supportive functional data.
Sources: Literature
Genomic newborn screening: BabyScreen+ v1.136 SNTA1 Lilian Downie reviewed gene: SNTA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 12 MIM#612955; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.404 DAW1 Zornitza Stark Marked gene: DAW1 as ready
Fetal anomalies v1.404 DAW1 Zornitza Stark Gene: daw1 has been classified as Green List (High Evidence).
Fetal anomalies v1.404 DAW1 Zornitza Stark Classified gene: DAW1 as Green List (high evidence)
Fetal anomalies v1.404 DAW1 Zornitza Stark Gene: daw1 has been classified as Green List (High Evidence).
Fetal anomalies v1.403 DAW1 Zornitza Stark gene: DAW1 was added
gene: DAW1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, with or without heterotaxy, MIM#620570
Review for gene: DAW1 was set to GREEN
Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype.
Sources: Expert Review
Mendeliome v1.2951 PIK3C3 Krithika Murali Marked gene: PIK3C3 as ready
Mendeliome v1.2951 PIK3C3 Krithika Murali Gene: pik3c3 has been classified as Red List (Low Evidence).
Mendeliome v1.2951 PIK3C3 Krithika Murali gene: PIK3C3 was added
gene: PIK3C3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C3 were set to PMID:40677927
Phenotypes for gene: PIK3C3 were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: PIK3C3 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2950 ARID3A Krithika Murali Marked gene: ARID3A as ready
Mendeliome v1.2950 ARID3A Krithika Murali Gene: arid3a has been classified as Red List (Low Evidence).
Mendeliome v1.2950 ARID3A Krithika Murali gene: ARID3A was added
gene: ARID3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to PMID: 40677927
Phenotypes for gene: ARID3A were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: ARID3A was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2949 DDX39A Krithika Murali Marked gene: DDX39A as ready
Mendeliome v1.2949 DDX39A Krithika Murali Gene: ddx39a has been classified as Red List (Low Evidence).
Mendeliome v1.2949 DDX39A Krithika Murali gene: DDX39A was added
gene: DDX39A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX39A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX39A were set to PMID: 40726340
Phenotypes for gene: DDX39A were set to Neurodevelopmental disorder, MONDO:0700092, DDX39A-related
Review for gene: DDX39A was set to RED
Added comment: PMID: 40726340 Ahmed et al 2025 (Clinical Genetics) report a 7 month old F with GDD, seizures, microcephaly, hypotonia, corpus callosum thinning and homozygous missense variant (p.Lys137Gln) in DDX39A on trio WES with both non-consanguineous parents confirmed to be heterozygous carriers. DDX39A is involved in mRNA splicing and export. Patient-derived fibroblast studies showed that mutant protein resulted in aberrant nuclear clumping and failure to interact with the TREX complex.

Of note, closely-related paralogue DDX39B is also a component of the TREX complex and has a definitive monoallelic association with neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.2948 HYPK Krithika Murali Marked gene: HYPK as ready
Mendeliome v1.2948 HYPK Krithika Murali Gene: hypk has been classified as Red List (Low Evidence).
Mendeliome v1.2948 HYPK Krithika Murali gene: HYPK was added
gene: HYPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HYPK were set to Clinical Genetics Early View
Phenotypes for gene: HYPK were set to Neurodevelopmental disorder, MONDO:0700092, HYPK-related
Review for gene: HYPK was set to RED
Added comment: Single case report - Patel, R. et al 2025 Clinical Genetics Early View

Male proband with developmental delay, autism and facial dysmorphism with a de novo missense HYPK variant (p. R70I). Variant-specific biochemical analyses demonstrates enhanced inhibitory activity of HYPK on NatA-mediated N-terminal protein acetylation.

GestaltMatcher analysis indicates that the proband's facial phenotype closely resembles Ogden syndrome (NAA10) and some resemblance to NAA15-NDS - both associated genes are also involved in the N-terminal acetylation pathway.
Sources: Literature
Microcephaly v1.323 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.253 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.84 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Mendeliome v1.2947 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Mitochondrial disease v0.994 COX18 Sangavi Sivagnanasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 40830826; Phenotypes: Mitochondrial disease (MONDO:0044970), COX18-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 COX18 Sangavi Sivagnanasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 40830826; Phenotypes: Mitochondrial disease (MONDO:0044970), COX18-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.553 CCDC93 Sarah Milton reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40601774; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.553 CCDC93 Sarah Milton Deleted their review
Mendeliome v1.2947 CCDC93 Sarah Milton reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40601774; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 CCDC93 Sarah Milton Deleted their review
Callosome v0.553 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Callosome. Sources: Literature
Mode of inheritance for gene: CCDC93 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC93 were set to PMID: 40601774
Phenotypes for gene: CCDC93 were set to Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related
Review for gene: CCDC93 was set to AMBER
Added comment: CCDC93 encodes the coiled coil domain containing subunit of commander complex involved in recycling of integral membrane proteins.

PMID: 40601774 describes 1 affected individual with compound heterozygous variants in CCDC93 who presented with Ritscher Schinzel like phenotype. Features included hypoplasia of cerebellar hemispheres, hypoplasia of the brainstem and of the corpus callosum, distinctive facial features and multiple small renal cysts.
Variants were missense and nonsense.

No homozygous LOF variants in gnomAD v4.

Some supportive functional data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.253 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC93 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC93 were set to PMID: 40601774
Phenotypes for gene: CCDC93 were set to Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related
Review for gene: CCDC93 was set to AMBER
Added comment: CCDC93 encodes the coiled coil domain containing subunit of commander complex involved in recycling of integral membrane proteins.

PMID: 40601774 describes 1 affected individual with compound heterozygous variants in CCDC93 who presented with Ritscher Schinzel like phenotype. Features included hypoplasia of cerebellar hemispheres, hypoplasia of the brainstem and of the corpus callosum, distinctive facial features and multiple small renal cysts.
Variants were missense and nonsense.

No homozygous LOF variants in gnomAD v4.

Some supportive functional data.
Sources: Literature
Mendeliome v1.2947 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC93 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC93 were set to PMID: 40601774
Phenotypes for gene: CCDC93 were set to Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related
Review for gene: CCDC93 was set to AMBER
Added comment: CCDC93 encodes the coiled coil domain containing subunit of commander complex involved in recycling of integral membrane proteins.

PMID: 40601774 describes 1 affected individual with compound heterozygous variants in CCDC93 who presented with Ritscher Schinzel like phenotype. Features included hypoplasia of cerebellar hemispheres, hypoplasia of the brainstem and of the corpus callosum, distinctive facial features and multiple small renal cysts.
Variants were missense and nonsense.

No homozygous LOF variants in gnomAD v4.

Some supportive functional data.
Sources: Literature
Pulmonary Arterial Hypertension v1.43 ATP13A3 Zornitza Stark Mode of inheritance for gene: ATP13A3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2947 ATP13A3 Zornitza Stark Mode of inheritance for gene: ATP13A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2946 ATP13A3 Zornitza Stark edited their review of gene: ATP13A3: Added comment: Biallelic variants reported in childhood onset. DEFINITIVE by ClinGen.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2946 DLGAP5 Zornitza Stark Marked gene: DLGAP5 as ready
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2946 DLGAP5 Zornitza Stark Classified gene: DLGAP5 as Green List (high evidence)
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2945 DLGAP5 Zornitza Stark gene: DLGAP5 was added
gene: DLGAP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLGAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLGAP5 were set to 40796344
Phenotypes for gene: DLGAP5 were set to Infertility disorder, MONDO:0005047, DLGAP5-related
Review for gene: DLGAP5 was set to GREEN
Added comment: 3 individuals with biallelic variants identified as part of a large cohort (N=488) of women experiencing recurrent early embryonic arrest. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Marked gene: DLGAP5 as ready
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Classified gene: DLGAP5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.15 DLGAP5 Zornitza Stark gene: DLGAP5 was added
gene: DLGAP5 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DLGAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLGAP5 were set to 40796344
Phenotypes for gene: DLGAP5 were set to Infertility disorder, MONDO:0005047, DLGAP5-related
Review for gene: DLGAP5 was set to GREEN
Added comment: 3 individuals with biallelic variants identified as part of a large cohort (N=488) of women experiencing recurrent early embryonic arrest. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
Sources: Literature
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: CREB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CREB3 were set to PMID: 40674075
Phenotypes for gene: CREB3 were set to Retinal degeneration, MONDO:0004580, CREB3-related
Review for gene: CREB3 was set to GREEN
Added comment: CREB3 encodes Cyclic AMP response element binding protein-3 which is an endoplasmic reticulum–membrane-bound transcription factor.

PMID: 40674075 describes 13 individuals from 4 families with the same homozygous nonsense variant (CREB:c.881G>A|p.Trp294). Affected individuals had retinal degeneration presenting initially with slowly progressive decreased visual acuity – significant variability in age of onset and severity – age 8-65.
2 different haplotypes identified on which the variant was found.

Homozygous LOF variants not present in CREB3 in gnomad v4.

Functional studies performed only demonstrated that mRNA transcript doesn't undergo NMD and that protein is expressed in retina. No variant specific or downstream effects investigated.
Sources: Literature
Cone-rod Dystrophy v0.56 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Cone-rod Dystrophy. Sources: Literature
Mode of inheritance for gene: CREB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CREB3 were set to PMID: 40674075
Phenotypes for gene: CREB3 were set to Retinal degeneration, MONDO:0004580, CREB3-related
Review for gene: CREB3 was set to GREEN
Added comment: CREB3 encodes Cyclic AMP response element binding protein-3 which is an endoplasmic reticulum–membrane-bound transcription factor.

PMID: 40674075 describes 13 individuals from 4 families with the same homozygous nonsense variant (CREB:c.881G>A|p.Trp294). Affected individuals had retinal degeneration presenting initially with slowly progressive decreased visual acuity – significant variability in age of onset and severity – age 8-65.
2 different haplotypes identified on which the variant was found.

Homozygous LOF variants not present in CREB3 in gnomad v4.

Functional studies performed only demonstrated that mRNA transcript doesn't undergo NMD and that protein is expressed in retina. No variant specific or downstream effects investigated.
Sources: Literature
Fetal anomalies v1.402 ISPD Zornitza Stark Marked gene: ISPD as ready
Fetal anomalies v1.402 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Fetal anomalies v1.402 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Fetal anomalies v1.402 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Marked gene: ISPD as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v1.2944 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CREB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CREB3 were set to PMID: 40674075
Phenotypes for gene: CREB3 were set to Retinal degeneration, MONDO:0004580, CREB3-related
Review for gene: CREB3 was set to GREEN
Added comment: CREB3 encodes Cyclic AMP response element binding protein-3 which is an endoplasmic reticulum–membrane-bound transcription factor.

PMID: 40674075 describes 13 individuals from 4 families with the same homozygous nonsense variant (CREB:c.881G>A|p.Trp294). Affected individuals had retinal degeneration presenting initially with slowly progressive decreased visual acuity – significant variability in age of onset and severity – age 8-65.
2 different haplotypes identified on which the variant was found.

Homozygous LOF variants not present in CREB3 in gnomad v4.

Functional studies performed only demonstrated that mRNA transcript doesn't undergo NMD and that protein is expressed in retina. No variant specific or downstream effects investigated.
Sources: Literature
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Genetic Epilepsy v1.188 ISPD Zornitza Stark Marked gene: ISPD as ready
Genetic Epilepsy v1.188 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Genetic Epilepsy v1.188 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Genetic Epilepsy v1.188 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Marked gene: ISPD as ready
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Mendeliome v1.2944 ISPD Zornitza Stark Marked gene: ISPD as ready
Mendeliome v1.2944 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Mendeliome v1.2944 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v1.2944 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Marked gene: ISPD as ready
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Marked gene: ISPD as ready
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Marked gene: ISPD as ready
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Cataract v0.374 ISPD Zornitza Stark Marked gene: ISPD as ready
Cataract v0.374 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Cataract v0.374 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Cataract v0.374 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Marked gene: ISPD as ready
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Mendeliome v1.2944 TRIM72 Zornitza Stark Marked gene: TRIM72 as ready
Mendeliome v1.2944 TRIM72 Zornitza Stark Gene: trim72 has been classified as Red List (Low Evidence).
Mendeliome v1.2944 TRIM72 Zornitza Stark gene: TRIM72 was added
gene: TRIM72 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM72 were set to 40804694
Phenotypes for gene: TRIM72 were set to Limb girdle muscular dystrophy MONDO:0016971, TRIM72-related
Review for gene: TRIM72 was set to RED
Added comment: Single affected individual, homozygous LoF variant, c.891delT; p.Ala298ArgfsTer64. However note two homozygous individuals are present in gnomAD.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Marked gene: TRIM74 as ready
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Classified gene: TRIM74 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2943 TRIM74 Zornitza Stark Marked gene: TRIM74 as ready
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2943 TRIM74 Zornitza Stark Classified gene: TRIM74 as Red List (low evidence)
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark Marked gene: TRIM72 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark Gene: trim72 has been classified as Red List (Low Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark gene: TRIM72 was added
gene: TRIM72 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: TRIM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM72 were set to 40804694
Phenotypes for gene: TRIM72 were set to Limb girdle muscular dystrophy MONDO:0016971, TRIM72-related
Review for gene: TRIM72 was set to RED
Added comment: Single affected individual, homozygous LoF variant, c.891delT; p.Ala298ArgfsTer64. However note two homozygous individuals are present in gnomAD.
Sources: Literature
Mendeliome v1.2942 ZNF496 Zornitza Stark Marked gene: ZNF496 as ready
Mendeliome v1.2942 ZNF496 Zornitza Stark Gene: znf496 has been classified as Red List (Low Evidence).
Mendeliome v1.2942 ZNF496 Zornitza Stark gene: ZNF496 was added
gene: ZNF496 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF496 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF496 were set to 40806714
Phenotypes for gene: ZNF496 were set to Neurodevelopmental disorder, MONDO:0700092, ZNF496-related
Review for gene: ZNF496 was set to RED
Added comment: Single individual with NDD and de novo LoF variant, no other supportive data.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark Marked gene: ZNF496 as ready
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark Gene: znf496 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.252 SCN3B Sarah Milton gene: SCN3B was added
gene: SCN3B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SCN3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN3B were set to PMID: 40879121
Phenotypes for gene: SCN3B were set to Neurodevelopmental disorder, MONDO:0700092, SCN3B-related
Review for gene: SCN3B was set to AMBER
Added comment: SCN3B Encodes b3 auxiliary subunit of the sodium channel.

4 affected individuals from 2 consanguineous families reported in PMID: 40879121 with biallelic variants in this gene with neurodevelopmental phenotypes. Presentation included GDD, ID of variable severity, autism, seizures.
One variant was nonsense, one canonical splice site in the penultimate exon.

No homozygous LOF variants in gnomAD v4.

Some functional studies performed with loss of function of channel demonstrated for one variant.
Sources: Literature
Mendeliome v1.2941 SCN3B Sarah Milton gene: SCN3B was added
gene: SCN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN3B were set to PMID: 40879121
Phenotypes for gene: SCN3B were set to Neurodevelopmental disorder, MONDO:0700092, SCN3B-related
Review for gene: SCN3B was set to AMBER
Added comment: SCN3B Encodes b3 auxiliary subunit of the sodium channel.

4 affected individuals from 2 consanguineous families reported in PMID: 40879121 with biallelic variants in this gene with neurodevelopmental phenotypes. Presentation included GDD, ID of variable severity, autism, seizures.
One variant was nonsense, one canonical splice site in the penultimate exon.

No homozygous LOF variants in gnomAD v4.

Some functional studies performed with loss of function of channel demonstrated for one variant.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.252 XPO1 Sangavi Sivagnanasundram gene: XPO1 was added
gene: XPO1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: XPO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPO1 were set to 40819229
Phenotypes for gene: XPO1 were set to Neurodevelopmental disorder, XPO1-related, MONDO:0700092
Review for gene: XPO1 was set to GREEN
Added comment: Established gene-disease association
22 probands with de novo XPO1 variants presenting with phenotypes associated with NDD (DD, ID, motor delay, behavioral problems, facial dysmorphisms, microcephaly and organ anomalies) along with supportive Drosophila knockdown model reported.
Sources: Literature
Mendeliome v1.2941 XPO1 Sangavi Sivagnanasundram gene: XPO1 was added
gene: XPO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: XPO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPO1 were set to 40819229
Phenotypes for gene: XPO1 were set to Neurodevelopmental disorder, XPO1-related, MONDO:0700092
Review for gene: XPO1 was set to GREEN
Added comment: Established gene-disease association
22 probands with de novo XPO1 variants presenting with phenotypes associated with NDD (DD, ID, motor delay, behavioral problems, facial dysmorphisms, microcephaly and organ anomalies) along with supportive Drosophila knockdown model reported.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.96 TLN1 Elena Savva Publications for gene: TLN1 were set to 30888838; 39163585; 33092471
Aortopathy_Connective Tissue Disorders v1.96 TLN1 Elena Savva Publications for gene: TLN1 were set to 30888838
Aortopathy_Connective Tissue Disorders v1.95 TLN1 Elena Savva changed review comment from: Azizi (2024):
- describes missense variants and functionally analyzes only a SINGLE missense finding a measurable defect in features such as cell behaviour and movement.
- Missense that were analysed were the same variants described in the previous submission (Turley 2019). Functional studies showed some effects in wound healing assay, but not cell monolayer integrity - weak functional evidence; to: Azizi (2024):
- describes missense variants and functionally analyzes only a SINGLE missense finding a measurable defect in features such as cell behaviour and movement.
- Missense that were analysed were the same variants described in the previous submission (Turley 2019). Functional studies showed some effects in wound healing assay, but not cell monolayer integrity - weak functional evidence

Li (2021): Additional SNPs observed in a cohort with thoracic aortic aneurysm, no follow analysis of the variants (MAF, in silicos, functional etc.)
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark gene: ZNF496 was added
gene: ZNF496 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNF496 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF496 were set to 40806714
Phenotypes for gene: ZNF496 were set to Neurodevelopmental disorder, MONDO:0700092, ZNF496-related
Review for gene: ZNF496 was set to RED
Added comment: Single individual with NDD and de novo LoF variant, no other supportive data.
Sources: Literature
Mendeliome v1.2941 MKL1 Zornitza Stark Phenotypes for gene: MKL1 were changed from Neutropaenia with combined immune deficiency to Inborn error of immunity, MONDO:0003778, MKL1-related
Mendeliome v1.2940 MKL1 Zornitza Stark Publications for gene: MKL1 were set to 32128589; 26224645
Mendeliome v1.2939 MKL1 Zornitza Stark Classified gene: MKL1 as Green List (high evidence)
Mendeliome v1.2939 MKL1 Zornitza Stark Gene: mkl1 has been classified as Green List (High Evidence).
Mendeliome v1.2938 MKL1 Zornitza Stark edited their review of gene: MKL1: Added comment: Third individual reported with compound het LoF variants and some supportive functional data. Neutrophils from the affected individual showed impaired F-actin polymerization, decreased migration ability, reduced ROS production, increased apoptosis, diminished NETs formation, and decreased MPO levels. Transcriptome profiling revealed neutrophil-specific downregulation of cytoskeletal genes with concomitant upregulation of antimicrobial peptide/inflammatory pathways, while PBMCs presented upregulated adhesion/migration-related genes.; Changed rating: GREEN; Changed publications: 32128589, 26224645, 40808667; Changed phenotypes: Inborn error of immunity, MONDO:0003778, MKL1-related
Phagocyte Defects v1.42 MKL1 Zornitza Stark Phenotypes for gene: MKL1 were changed from Neutropaenia with combined immune deficiency to Inborn error of immunity, MONDO:0003778, MKL1-related
Phagocyte Defects v1.41 MKL1 Zornitza Stark edited their review of gene: MKL1: Changed phenotypes: Inborn error of immunity, MONDO:0003778, MKL1-related
Phagocyte Defects v1.41 MKL1 Zornitza Stark Publications for gene: MKL1 were set to 32128589; 26224645
Phagocyte Defects v1.40 MKL1 Zornitza Stark Classified gene: MKL1 as Green List (high evidence)
Phagocyte Defects v1.40 MKL1 Zornitza Stark Gene: mkl1 has been classified as Green List (High Evidence).
Phagocyte Defects v1.39 MKL1 Zornitza Stark edited their review of gene: MKL1: Added comment: Third individual reported with compound het LoF variants and some supportive functional data. Neutrophils from the affected individual showed impaired F-actin polymerization, decreased migration ability, reduced ROS production, increased apoptosis, diminished NETs formation, and decreased MPO levels. Transcriptome profiling revealed neutrophil-specific downregulation of cytoskeletal genes with concomitant upregulation of antimicrobial peptide/inflammatory pathways, while PBMCs presented upregulated adhesion/migration-related genes.; Changed rating: GREEN; Changed publications: 32128589, 26224645, 40808667
Mendeliome v1.2938 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043; 24482476; 34585293
Mendeliome v1.2937 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Second individual with homozygous variant and trichothiodystorphy reported in PMID 40820264; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293, 40820264, 33909043
Chromosome Breakage Disorders v1.23 MARS Zornitza Stark Publications for gene: MARS were set to 33909043
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark edited their review of gene: MARS: Changed publications: 40820264, 33909043
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark Classified gene: MARS as Amber List (moderate evidence)
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark Gene: mars has been classified as Amber List (Moderate Evidence).
Chromosome Breakage Disorders v1.21 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Second individual reported with this phenotype and a homozygous variant in this gene.; Changed rating: AMBER
Mendeliome v1.2937 TECTB Zornitza Stark Marked gene: TECTB as ready
Mendeliome v1.2937 TECTB Zornitza Stark Gene: tectb has been classified as Red List (Low Evidence).
Mendeliome v1.2937 TECTB Zornitza Stark gene: TECTB was added
gene: TECTB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TECTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TECTB were set to 40832383
Phenotypes for gene: TECTB were set to Hearing loss disorder, MONDO:0005365, TECTB-related
Review for gene: TECTB was set to RED
Added comment: Single multigenerational family segregating a missense variant and a mouse model.
Sources: Literature
Deafness_Isolated v1.74 TECTB Zornitza Stark Marked gene: TECTB as ready
Deafness_Isolated v1.74 TECTB Zornitza Stark Gene: tectb has been classified as Red List (Low Evidence).
Deafness_Isolated v1.74 TECTB Zornitza Stark gene: TECTB was added
gene: TECTB was added to Deafness_Isolated. Sources: Literature
Mode of inheritance for gene: TECTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TECTB were set to 40832383
Phenotypes for gene: TECTB were set to Hearing loss disorder, MONDO:0005365, TECTB-related
Review for gene: TECTB was set to RED
Added comment: Single multigenerational family segregating a missense variant and a mouse model.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.251 TRIM74 Sangavi Sivagnanasundram gene: TRIM74 was added
gene: TRIM74 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRIM74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM74 were set to 40735933
Phenotypes for gene: TRIM74 were set to Neurodevelopmental disorder, TRIM74-related, MONDO:0700092
Review for gene: TRIM74 was set to RED
Added comment: Only one reported case with DD.

PMID: 40735933
5yr M presenting from non consanguineous parents with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Parents of the proband were found to be carriers of the variant.
Homozygous variant c.562C > T (p.Pro121Leu) - NFE AF 0.0188% - rare enough for AR

Supportive functional analysis on human fibroblast showed protein function disruption leading to protein aggregation, proteostasis collapse, and cell death.
Sources: Literature
Mendeliome v1.2936 TRIM74 Sangavi Sivagnanasundram gene: TRIM74 was added
gene: TRIM74 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TRIM74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM74 were set to 40735933
Phenotypes for gene: TRIM74 were set to Neurodevelopmental disorder, TRIM74-related, MONDO:0700092
Review for gene: TRIM74 was set to RED
Added comment: Only one reported case with supportive functional assay

PMID: 40735933
5yr M presenting from non consanguineous parents with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Parents of the proband were found to be carriers of the variant.
Homozygous variant c.562C > T (p.Pro121Leu) - NFE AF 0.0188% - rare enough for AR

Supportive functional analysis on human fibroblast showed protein function disruption leading to protein aggregation, proteostasis collapse, and cell death.
Sources: Other
Mendeliome v1.2936 BAZ2B Zornitza Stark Classified gene: BAZ2B as Amber List (moderate evidence)
Mendeliome v1.2936 BAZ2B Zornitza Stark Gene: baz2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2935 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Autism v0.213 BAZ2B Zornitza Stark Classified gene: BAZ2B as Amber List (moderate evidence)
Autism v0.213 BAZ2B Zornitza Stark Gene: baz2b has been classified as Amber List (Moderate Evidence).
Autism v0.212 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.251 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Intellectual disability syndromic and non-syndromic v1.250 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Autism v0.212 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Autism v0.211 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2935 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2934 BBS2 Sarah Milton reviewed gene: BBS2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: BBS2-related ciliopathy, MONDO:1040048; Mode of inheritance: None
Mendeliome v1.2934 BAZ2B Sarah Milton reviewed gene: BAZ2B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related; Mode of inheritance: None
Vasculitis v0.87 TRAP1 Zornitza Stark Marked gene: TRAP1 as ready
Vasculitis v0.87 TRAP1 Zornitza Stark Gene: trap1 has been classified as Red List (Low Evidence).
Vasculitis v0.87 TRAP1 Zornitza Stark Classified gene: TRAP1 as Red List (low evidence)
Vasculitis v0.87 TRAP1 Zornitza Stark Gene: trap1 has been classified as Red List (Low Evidence).
Vasculitis v0.86 TRAP1 Zornitza Stark reviewed gene: TRAP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.402 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to Syndromic disease, MONDO:0002254, TRAP1-related
Fetal anomalies v1.401 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2934 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from CAKUT; VACTERL to Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2933 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.125 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from CAKUT; VACTERL to Syndromic disease, MONDO:0002254, TRAP1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.124 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Hand and foot malformations v0.77 TP63 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen, lumped multiple entities together.; to: DEFINITIVE by ClinGen, lumped multiple entities together. Limb anomalies are a key feature.
Hand and foot malformations v0.77 TP63 Zornitza Stark Marked gene: TP63 as ready
Hand and foot malformations v0.77 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Hand and foot malformations v0.77 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Hay-Wells syndrome 106260; Rapp-Hodgkin syndrome 129400; Limb-mammary syndrome 603543; Split-hand/foot malformation 4 605289; Orofacial cleft 8 129400; ULT syndrome 103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Hand and foot malformations v0.76 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.401 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Fetal anomalies v1.400 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Clefting disorders v0.268 TP63 Zornitza Stark Marked gene: TP63 as ready
Clefting disorders v0.268 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Clefting disorders v0.268 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Orofacial cleft 8, EEC SYNDROME 3, Rapp Hodgkins syndrome, 129400; EEC3; Limb-mammary syndrome, 603543; AEC (Ankyloblepharon filiforme adnatum, Ectodermal defects and Clefting), Hay Wells syndrome 106260; EEC syndrome (Ectrodactyly, Ectodermal dysplasia and Clefting); ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3; Cleft lip; Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3, 604292 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Clefting disorders v0.267 TP63 Zornitza Stark commented on gene: TP63: DEFINITIVE by ClinGen, lumped multiple disorders.
Clefting disorders v0.267 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hair disorders v0.80 TP63 Zornitza Stark Marked gene: TP63 as ready
Hair disorders v0.80 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Hair disorders v0.80 TP63 Zornitza Stark Publications for gene: TP63 were set to 31332722
Hair disorders v0.79 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Hair disorders v0.78 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Marked gene: TP63 as ready
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Ectodermal Dysplasia v0.97 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v0.317 TP63 Zornitza Stark Marked gene: TP63 as ready
Skeletal dysplasia v0.317 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.317 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Hay-Wells syndrome 106260; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292; Limb-mammary syndrome 603543; Rapp-Hodgkin syndrome 129400; Orofacial cleft 8 129400; ULT syndrome 103285; Split-hand/foot malformation 4 605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Skeletal dysplasia v0.316 TP63 Zornitza Stark Publications for gene: TP63 were set to
Skeletal dysplasia v0.315 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Intellectual disability syndromic and non-syndromic v1.250 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Intellectual disability syndromic and non-syndromic v1.249 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe Combined Immunodeficiency (absent T present B cells) v1.11 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, MIM# 604292; lymphopaenia to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Severe Combined Immunodeficiency (absent T present B cells) v1.10 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Mendeliome v1.2933 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Premature ovarian failure 21, MIM#620311
Mendeliome v1.2932 TP63 Zornitza Stark edited their review of gene: TP63: Added comment: DEFINITIVE by ClinGen.

Lumped EEC3 syndrome (MIM:604292), ADULT syndrome (MIM:103285), AEC syndrome (MIM:106260), Rapp-Hodgkin syndrome (MIM:129400), Limb-mammary syndrome (MIM:603543), Split-hand/foot malformation 4 (MIM:605289), and Orofacial cleft 8 (MIM:618149).

Association with POF considered separate.; Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001, Premature ovarian failure 21, MIM#620311
Leukodystrophy - paediatric v0.323 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from White matter abnormalities; Developmental delay; Regression; Movement disorder to Leukodystrophy, MONDO:0019046, TOMM70-related
Leukodystrophy - paediatric v0.322 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Leukodystrophy, MONDO:0019046, TOMM70-related
Mitochondrial disease v0.994 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from Severe anaemia; Lactic acidosis; Developmental delay to Mitochondrial disease, MONDO:0044970, TOMM70-related
Mitochondrial disease v0.993 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TOMM70-related
Mendeliome v1.2932 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder to Mitochondrial disease, MONDO:0044970, TOMM70-related; Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TOMM70-related, Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 ARNTL Zornitza Stark Marked gene: ARNTL as ready
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2931 ARNTL Zornitza Stark Classified gene: ARNTL as Green List (high evidence)
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2930 ARNTL Zornitza Stark Tag new gene name tag was added to gene: ARNTL.
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Marked gene: ARNTL as ready
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Classified gene: ARNTL as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.248 ARNTL Zornitza Stark Tag new gene name tag was added to gene: ARNTL.
Mendeliome v1.2930 CSMD3 Zornitza Stark Marked gene: CSMD3 as ready
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2930 CSMD3 Zornitza Stark Classified gene: CSMD3 as Green List (high evidence)
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Marked gene: CSMD3 as ready
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Classified gene: CSMD3 as Green List (high evidence)
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Marked gene: TMPRSS7 as ready
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Gene: tmprss7 has been classified as Red List (Low Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark gene: TMPRSS7 was added
gene: TMPRSS7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMPRSS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS7 were set to 40796295
Phenotypes for gene: TMPRSS7 were set to Neurodevelopmental disorder, TMPRSS7-related
Review for gene: TMPRSS7 was set to RED
Added comment: PMID 40796295: individual with compound het variants, p.R479H and p.S685Kfs*26 and neurodevelopmental disorder. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus.
Sources: Literature
Genomic newborn screening: BabyScreen+ v1.136 TNFSF11 Lilian Downie commented on gene: TNFSF11: This type of osteopetrosis is particularly difficult to treat PMID: 36031188
Intellectual disability syndromic and non-syndromic v1.248 TMPRSS7 Zornitza Stark gene: TMPRSS7 was added
gene: TMPRSS7 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TMPRSS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS7 were set to 40796295
Phenotypes for gene: TMPRSS7 were set to Neurodevelopmental disorder, TMPRSS7-related
Review for gene: TMPRSS7 was set to RED
Added comment: PMID 40796295: individual with compound het variants, p.R479H and p.S685Kfs*26 and neurodevelopmental disorder. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark Marked gene: PPP1R2 as ready
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark Gene: ppp1r2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark gene: PPP1R2 was added
gene: PPP1R2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PPP1R2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R2 were set to 40597352; 26558779
Phenotypes for gene: PPP1R2 were set to Neurodevelopmental disorder, PPP1R2-related
Review for gene: PPP1R2 was set to RED
Added comment: Single individual reported with homozygous splicing variant c.403 + 3 A >T. Abnormal splicing demonstrated but leaky. Clinical features included pre and postnatal growth restriction, ventricular septal defect, dysmorphic features (proptosis, long eye lashes, thick eyebrows, low-set ears), microcephaly, sensorineural hearing loss, cortical cataracts, retinal defects, intellectual disability with limited speech, and autism spectrum disorder. Note mouse model is embryonically lethal, leading the authors to speculate survival may be due to fraction of normally spliced transcripts.
Sources: Literature
Mendeliome v1.2928 PPP1R2 Zornitza Stark gene: PPP1R2 was added
gene: PPP1R2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R2 were set to 40597352; 26558779
Phenotypes for gene: PPP1R2 were set to Neurodevelopmental disorder, PPP1R2-related
Review for gene: PPP1R2 was set to RED
Added comment: Single individual reported with homozygous splicing variant c.403 + 3 A >T. Abnormal splicing demonstrated but leaky. Clinical features included pre and postnatal growth restriction, ventricular septal defect, dysmorphic features (proptosis, long eye lashes, thick eyebrows, low-set ears), microcephaly, sensorineural hearing loss, cortical cataracts, retinal defects, intellectual disability with limited speech, and autism spectrum disorder. Note mouse model is embryonically lethal, leading the authors to speculate survival may be due to fraction of normally spliced transcripts.
Sources: Literature
Optic Atrophy v1.49 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Optic Atrophy v1.49 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Optic Atrophy v1.49 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Optic Atrophy v1.49 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Optic Atrophy v1.48 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Optic Atrophy. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Microcephaly v1.323 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Microcephaly v1.323 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.186 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Microcephaly v1.323 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Microcephaly v1.323 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Microcephaly v1.322 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Fetal anomalies v1.400 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Fetal anomalies v1.400 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Arthrogryposis v0.424 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Arthrogryposis v0.424 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Arthrogryposis v0.424 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Arthrogryposis v0.424 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Fetal anomalies v1.400 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Fetal anomalies v1.400 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Fetal anomalies v1.399 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Arthrogryposis v0.423 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Mendeliome v1.2927 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2927 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2926 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Regression v0.585 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Regression v0.585 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Regression v0.585 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Regression v0.585 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Regression v0.584 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Regression. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.245 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Lysosomal Storage Disorder v1.20 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Lysosomal Storage Disorder. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Osteopetrosis v0.38 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Osteopetrosis v0.38 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Red List (Low Evidence).
Osteopetrosis v0.38 BORCS5 Zornitza Stark Publications for gene: BORCS5 were set to 40621786; 7577667
Osteopetrosis v0.37 BORCS5 Zornitza Stark edited their review of gene: BORCS5: Changed publications: 40621786, 7577667, 40385417
Osteopetrosis v0.37 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Osteopetrosis. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40621786; 7577667
Phenotypes for gene: BORCS5 were set to Neuroaxonal dystrophy (NAD) with osteopetrosis syndrome (OMIM # 600329)
Review for gene: BORCS5 was set to RED
Added comment: Disease entity originally described in 1995 but genetic basis unknown. Report of consanguineous family with two affected fetuses, homozygous for same missense variant, p. Arg301His.

However, note preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Genetic Epilepsy v1.185 CSMD3 Sarah Milton gene: CSMD3 was added
gene: CSMD3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CSMD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD3 were set to PMID: 40632521
Phenotypes for gene: CSMD3 were set to Epilepsy, MONDO:0005027, CSMD3-related
Review for gene: CSMD3 was set to GREEN
Added comment: CSMD3 encodes a synaptic membrane proteins and play a role in neuronal maturation/growth dendrites. A related protein CSMD1 has been previously associated with a complex neurodevelopmental disorder.

PMID: 40632521 describes 8 individuals with seizures. 4 with focal epilepsy, 3 with febrile seizures and 1 individual with infantile spasms. 1 individual described had a de novo missense variant with remainder having comp het/biallelic variants. Mild ID in 1 individual only.

Variant type mostly missense variants with 1 nonsense, all appropriately rare in gnomAD v4 for recessive disorder.

No variant specific functional studies performed, no clear discussion in paper about postulated mechanism for disease. No discussion around difference in mechanism for de novo monoallelic variant.

Previous studies showed homozygous knockout mice display abnormal neuronal proliferation and growth retardation.
Sources: Literature
Mendeliome v1.2925 CSMD3 Sarah Milton gene: CSMD3 was added
gene: CSMD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD3 were set to PMID: 40632521
Phenotypes for gene: CSMD3 were set to Epilepsy, MONDO:0005027, CSMD3-related
Review for gene: CSMD3 was set to GREEN
Added comment: CSMD3 encodes a synaptic membrane proteins and play a role in neuronal maturation/growth dendrites. A related protein CSMD1 has been previously associated with a complex neurodevelopmental disorder.

PMID: 40632521 describes 8 individuals with seizures. 4 with focal epilepsy, 3 with febrile seizures and 1 individual with infantile spasms. 1 individual described had a de novo missense variant with remainder having comp het/biallelic variants. Mild ID in 1 individual only.

Variant type mostly missense variants with 1 nonsense, all appropriately rare in gnomAD v4 for recessive disorder.

No variant specific functional studies performed, no clear discussion in paper about postulated mechanism for disease. No discussion around difference in mechanism for de novo monoallelic variant.

Previous studies showed homozygous knockout mice display abnormal neuronal proliferation and growth retardation.
Sources: Literature
Phagocyte Defects v1.39 MMD2 Zornitza Stark Marked gene: MMD2 as ready
Phagocyte Defects v1.39 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.39 MMD2 Zornitza Stark edited their review of gene: MMD2: Changed rating: AMBER
Phagocyte Defects v1.39 MMD2 Zornitza Stark Classified gene: MMD2 as Amber List (moderate evidence)
Phagocyte Defects v1.39 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.38 MMD2 Zornitza Stark gene: MMD2 was added
gene: MMD2 was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: MMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMD2 were set to 40663042
Phenotypes for gene: MMD2 were set to Periodontitis, MONDO:0005076, MMD2-related
Review for gene: MMD2 was set to GREEN
Added comment: Two multigenerational families with aggressive periodontitis segregating missense variants, plus supportive functional data. Abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 variants.
Sources: Literature
Mendeliome v1.2925 MMD2 Zornitza Stark Marked gene: MMD2 as ready
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2925 MMD2 Zornitza Stark Classified gene: MMD2 as Amber List (moderate evidence)
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2924 MMD2 Zornitza Stark gene: MMD2 was added
gene: MMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMD2 were set to 40663042
Phenotypes for gene: MMD2 were set to Periodontitis, MONDO:0005076, MMD2-related
Review for gene: MMD2 was set to AMBER
Added comment: Two multigenerational families with aggressive periodontitis segregating missense variants, plus supportive functional data. Abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.244 ARNTL Sarah Milton gene: ARNTL was added
gene: ARNTL was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARNTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARNTL were set to PMID: 40720646
Phenotypes for gene: ARNTL were set to Neurodevelopmental disorder, MONDO:0700092, BMAL1-related
Review for gene: ARNTL was set to GREEN
Added comment: Note has new HGNC approved name - BMAL1

BMAL1 encodes a transcription factor that plays a role in the mammalian molecular clock, binds to promoter of PER and CRY family genes to promote transcription. Other circardian genes have sleep phase disorder assoc but not neurodevelopmental phenotype.

10 affected individuals described in PMID: 40455867 with variable developmental delay/ID from average IQ to severe ID, seizures in 50%, autism, some had sleep disturbance and marfanoid habitus.
Variants were LOF & missense and very rare or absent in gnomAD v4.
5 confirmed de novo, 2 confirmed inherited (one from apparently unaffected mother).

Functional studies using luciferase reporter assay of downstream target PER showed reduced luminescence for most variants with presumed LOF mechanism. One variant p.(Ile201Thr) led to increased luminescence with author's postulating GOF mechanism for this variant. Drosophilia studies for 2 of the variants demonstrated altered circadian rhythm. ?needs more studies to further define mechanism.
Sources: Literature
Mendeliome v1.2923 ARNTL Sarah Milton gene: ARNTL was added
gene: ARNTL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARNTL were set to PMID: 40720646
Phenotypes for gene: ARNTL were set to Neurodevelopmental disorder, MONDO:0700092, BMAL1-related
Review for gene: ARNTL was set to GREEN
Added comment: Note has new HGNC approved name - BMAL1

BMAL1 encodes a transcription factor that plays a role in the mammalian molecular clock, binds to promoter of PER and CRY family genes to promote transcription. Other circardian genes have sleep phase disorder assoc but not neurodevelopmental phenotype.

10 affected individuals described in PMID: 40455867 with variable developmental delay/ID from average IQ to severe ID, seizures in 50%, autism, some had sleep disturbance and marfanoid habitus.
Variants were LOF & missense and very rare or absent in gnomAD v4.
5 confirmed de novo, 2 confirmed inherited (one from apparently unaffected mother).

Functional studies using luciferase reporter assay of downstream target PER showed reduced luminescence for most variants with presumed LOF mechanism. One variant p.(Ile201Thr) led to increased luminescence with author's postulating GOF mechanism for this variant. Drosophilia studies for 2 of the variants demonstrated altered circadian rhythm. ?needs more studies to further define mechanism.
Sources: Literature
Mendeliome v1.2923 FAM136A Zornitza Stark Marked gene: FAM136A as ready
Mendeliome v1.2923 FAM136A Zornitza Stark Gene: fam136a has been classified as Red List (Low Evidence).
Mendeliome v1.2923 FAM136A Zornitza Stark gene: FAM136A was added
gene: FAM136A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM136A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM136A were set to 40714634
Phenotypes for gene: FAM136A were set to Meniere's disease
Review for gene: FAM136A was set to RED
Added comment: Single family reported with high impact variant, supportive functional data.
Sources: Literature
Mitochondrial disease v0.993 FAM136A Zornitza Stark Marked gene: FAM136A as ready
Mitochondrial disease v0.993 FAM136A Zornitza Stark Gene: fam136a has been classified as Red List (Low Evidence).
Mitochondrial disease v0.993 FAM136A Zornitza Stark gene: FAM136A was added
gene: FAM136A was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: FAM136A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM136A were set to 40714634
Phenotypes for gene: FAM136A were set to Meniere's disease
Review for gene: FAM136A was set to RED
Added comment: Single family reported with high impact variant, supportive functional data.
Sources: Literature
Mendeliome v1.2922 NCOA7 Zornitza Stark Marked gene: NCOA7 as ready
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2922 NCOA7 Zornitza Stark Classified gene: NCOA7 as Green List (high evidence)
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2921 NCOA7 Zornitza Stark gene: NCOA7 was added
gene: NCOA7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NCOA7 were set to 40745099
Phenotypes for gene: NCOA7 were set to Inherited premature ovarian failure MONDO:0019852, NCOA7-related
Review for gene: NCOA7 was set to GREEN
Added comment: 7 individuals with POI and heterozygous variants in this gene. Two of the variants led to NMD; 3 were missense. Functional data supports role in cell senescence.
Sources: Literature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Marked gene: NCOA7 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Classified gene: NCOA7 as Green List (high evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.351 NCOA7 Zornitza Stark gene: NCOA7 was added
gene: NCOA7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature
Mode of inheritance for gene: NCOA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NCOA7 were set to 40745099
Phenotypes for gene: NCOA7 were set to Inherited premature ovarian failure MONDO:0019852, NCOA7-related
Review for gene: NCOA7 was set to GREEN
Added comment: 7 individuals with POI and heterozygous variants in this gene. Two of the variants led to NMD; 3 were missense. Functional data supports role in cell senescence.
Sources: Literature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.350 POU5F1 Zornitza Stark edited their review of gene: POU5F1: Added comment: Additional individual reported in PMID 40744326 with rare high impact variant, maintain Red rating for now.; Changed publications: 21273125, 40744326
Mendeliome v1.2920 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029 to Spermatogenic failure, MONDO:0004983, DNAH6-related
Mendeliome v1.2919 DNAH6 Zornitza Stark Publications for gene: DNAH6 were set to PMID: 26918822
Mendeliome v1.2918 DNAH6 Zornitza Stark Classified gene: DNAH6 as Green List (high evidence)
Mendeliome v1.2918 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Mendeliome v1.2917 DNAH6 Zornitza Stark Deleted their comment
Mendeliome v1.2917 DNAH6 Zornitza Stark edited their review of gene: DNAH6: Added comment: More than 5 unrelated individuals reported with spermatogenic failure and bi-allelic variants in this gene.; Changed rating: GREEN; Changed publications: 37594300, 39192248, 37424858, 31676830, 29356036, 40592014
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Marked gene: DNAH6 as ready
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Classified gene: DNAH6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.13 DNAH6 Zornitza Stark gene: DNAH6 was added
gene: DNAH6 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH6 were set to 37594300; 39192248; 37424858; 31676830; 29356036; 40592014
Phenotypes for gene: DNAH6 were set to Spermatogenic failure, MONDO:0004983, DNAH6-related
Review for gene: DNAH6 was set to GREEN
Added comment: More than 5 unrelated individuals reported with spermatogenic failure and bi-allelic variants in this gene.
Sources: Literature
Mendeliome v1.2917 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Heterotaxy, Azoospermia to Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029
Mendeliome v1.2916 DNAH6 Zornitza Stark reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 40592014; Phenotypes: Spermatogenic failure, MONDO:0004983, DNAH6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Marked gene: DNAH2 as ready
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Publications for gene: DNAH2 were set to 30811583; 32732226; 40592014
Infertility and Recurrent Pregnancy Loss v1.11 DNAH2 Zornitza Stark Classified gene: DNAH2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.11 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.10 DNAH2 Zornitza Stark gene: DNAH2 was added
gene: DNAH2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH2 were set to 30811583; 32732226; 40592014
Phenotypes for gene: DNAH2 were set to Spermatogenic failure 45, MIM# 619094
Review for gene: DNAH2 was set to GREEN
Added comment: At least 3 unrelated families reported with biallelic variants and spermatogenic failure.
Sources: Literature
Mendeliome v1.2916 PAX4 Zornitza Stark edited their review of gene: PAX4: Changed phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2916 PAX4 Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225; Diabetes mellitus, type 2, MIM# 125853 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2915 PAX4 Zornitza Stark Publications for gene: PAX4 were set to 17426099; 14561778; 25951767; 21263211
Mendeliome v1.2914 PAX4 Zornitza Stark Mode of inheritance for gene: PAX4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2913 PAX4 Zornitza Stark edited their review of gene: PAX4: Added comment: Homozygous PAX4 loss-of-function variants in 2 individuals with transient NDM: a p.(Arg126∗) stop-gain variant and a c.-352_104del deletion affecting the first 4 PAX4 exons. This is a separate association to the refuted association with MODY but maintaining the RED rating overall.; Changed rating: RED; Changed publications: 17426099, 14561778, 25951767, 21263211, 40614820; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic Diabetes v0.145 PAX4 Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Monogenic Diabetes v0.144 PAX4 Zornitza Stark Publications for gene: PAX4 were set to 17426099; 14561778; 25951767; 21263211
Monogenic Diabetes v0.143 PAX4 Zornitza Stark Mode of inheritance for gene: PAX4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic Diabetes v0.142 PAX4 Zornitza Stark edited their review of gene: PAX4: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic Diabetes v0.142 PAX4 Zornitza Stark reviewed gene: PAX4: Rating: RED; Mode of pathogenicity: None; Publications: 40614820; Phenotypes: Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.244 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Intellectual disability syndromic and non-syndromic v1.243 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.243 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.242 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.242 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Added comment: PMID 40628855: second unrelated individual reported, presenting with ID/autism and with bi-allelic variants, one missense and the other LoF. Abnormal glycosylation patterns observed consistent with CDG.; Changed publications: 36357165, 40628855
Mendeliome v1.2913 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Mendeliome v1.2912 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Mendeliome v1.2912 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.70 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Mendeliome v1.2911 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Added comment: PMID 40628855: second unrelated individual reported, presenting with ID/autism and with bi-allelic variants, one missense and the other LoF. Abnormal glycosylation patterns observed consistent with CDG.; Changed rating: AMBER; Changed publications: 36357165, 40628855
Congenital Disorders of Glycosylation v1.69 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Congenital Disorders of Glycosylation v1.69 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.68 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Changed rating: AMBER
Congenital Disorders of Glycosylation v1.68 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Added comment: PMID 40628855: second unrelated individual reported, presenting with ID/autism and with bi-allelic variants, one missense and the other LoF. Abnormal glycosylation patterns observed consistent with CDG.; Changed publications: 36357165, 40628855
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Marked gene: CCDC186 as ready
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.241 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146; 37569695; 40633195
Phenotypes for gene: CCDC186 were set to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Review for gene: CCDC186 was set to GREEN
Added comment: At least 3 unrelated families reported with bi-allelic LoF variants and a neurodevelopmental phenotype comprising ID and seizures, plus other more variable features.
Sources: Literature
Genetic Epilepsy v1.185 CCDC186 Zornitza Stark Phenotypes for gene: CCDC186 were changed from Epileptic encephalopathy to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Genetic Epilepsy v1.184 CCDC186 Zornitza Stark Publications for gene: CCDC186 were set to 33259146
Genetic Epilepsy v1.183 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Genetic Epilepsy v1.183 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.182 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID 40633195: Individual with another bi-allelic LoF variant reported, NM_018017.4:c.535C>T (p.Arg179Ter), presenting with seizures, ID and microcephaly.

PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter. EE was part of the phenotype, although the phenotype was broader.; Changed rating: GREEN; Changed publications: 33259146, 37569695, 40633195; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2911 CCDC186 Zornitza Stark Phenotypes for gene: CCDC186 were changed from Epileptic encephalopathy to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2910 CCDC186 Zornitza Stark Publications for gene: CCDC186 were set to 33259146
Mendeliome v1.2909 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Mendeliome v1.2909 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed rating: GREEN
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID 40633195: Individual with another bi-allelic LoF variant reported, NM_018017.4:c.535C>T (p.Arg179Ter), presenting with seizures, ID and microcephaly.; Changed publications: 33259146, 37569695, 40633195
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; to: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter. EE was part of the phenotype, although the phenotype was broader.
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature; to: One individual reported with bi-allelic truncating variant p.(Ser256Ter) and EE.
Sources: Literature
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; Changed publications: 33259146, 37569695
Mendeliome v1.2908 VWA8 Zornitza Stark Publications for gene: VWA8 were set to PMID: 37012052
Mendeliome v1.2907 VWA8 Zornitza Stark Classified gene: VWA8 as Green List (high evidence)
Mendeliome v1.2907 VWA8 Zornitza Stark Gene: vwa8 has been classified as Green List (High Evidence).
Mendeliome v1.2906 VWA8 Zornitza Stark edited their review of gene: VWA8: Added comment: PMID 40638000: additional individual reported with LoF variant and RP, upgrade to Green.; Changed rating: GREEN; Changed publications: 37012052, 40638000
Retinitis pigmentosa_Autosomal Dominant v0.79 VWA8 Zornitza Stark Publications for gene: VWA8 were set to PMID: 37012052; 40638000
Retinitis pigmentosa_Autosomal Dominant v0.78 VWA8 Zornitza Stark Publications for gene: VWA8 were set to PMID: 37012052
Retinitis pigmentosa_Autosomal Dominant v0.77 VWA8 Zornitza Stark Classified gene: VWA8 as Green List (high evidence)
Retinitis pigmentosa_Autosomal Dominant v0.77 VWA8 Zornitza Stark Gene: vwa8 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Dominant v0.76 VWA8 Zornitza Stark edited their review of gene: VWA8: Changed rating: GREEN
Retinitis pigmentosa_Autosomal Dominant v0.76 VWA8 Zornitza Stark edited their review of gene: VWA8: Added comment: PMID 40638000: additional individual reported with LoF variant and RP, upgrade to Green.; Changed publications: 40638000
Intellectual disability syndromic and non-syndromic v1.240 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Intellectual disability syndromic and non-syndromic v1.239 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.239 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.238 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 40661989: additional case report of a Thai patient with PCH and compound het LoF variants in this gene. PMID 32122952: rat model consistent with human phenotype. PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 25832664, 40661989, 32122952, 30287594
Mendeliome v1.2906 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Mendeliome v1.2905 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Mendeliome v1.2905 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Mendeliome v1.2904 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 40661989: additional case report of a Thai patient with PCH and compound het LoF variants in this gene.
PMID 32122952: rat model consistent with human phenotype.
PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 25832664, 40661989, 32122952, 30287594
Cerebellar and Pontocerebellar Hypoplasia v1.84 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Cerebellar and Pontocerebellar Hypoplasia v1.83 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.83 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Changed rating: GREEN
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed publications: 25832664, 40661989, 32122952, 30287594
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 32122952: rat model consistent with human phenotype.; Changed publications: 25832664, 40661989, 32122952
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 40661989: additional case report of a Thai patient with PCH and compound het LoF variants in this gene.; Changed publications: 25832664, 40661989
Mendeliome v1.2904 LSR Zornitza Stark Phenotypes for gene: LSR were changed from transient neonatal cholestasis; intellectual disability; short stature to Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related; transient neonatal cholestasis; intellectual disability; short stature
Mendeliome v1.2903 LSR Zornitza Stark Publications for gene: LSR were set to 30250217; 32303357
Mendeliome v1.2902 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Mendeliome v1.2902 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Mendeliome v1.2901 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40846272: further two patients with homozygous missense variants.
PMID 40679108: additional case report, compound het LoF and missense variant in a 4yo with cholestasis and mild liver fibrosis.
We are aware of a further case internally, upgrade to GREEN.; Changed rating: GREEN; Changed publications: 32303357, 30250217, 40679108, 40846272; Changed phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related, transient neonatal cholestasis, intellectual disability, short stature
Cholestasis v1.4 LSR Zornitza Stark Phenotypes for gene: LSR were changed from transient neonatal cholestasis; intellectual disability; short stature to Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related; transient neonatal cholestasis; intellectual disability; short stature
Cholestasis v1.3 LSR Zornitza Stark Publications for gene: LSR were set to 32303357; 30250217
Cholestasis v1.2 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Cholestasis v1.2 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Cholestasis v1.1 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40846272: further two patients with homozygous missense variants.; Changed publications: 32303357, 30250217, 40679108, 40846272
Cholestasis v1.1 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40679108: additional case report, compound het LoF and missense variant in a 4yo with cholestasis and mild liver fibrosis. We are aware of a further case internally, upgrade to GREEN.; Changed rating: GREEN; Changed publications: 32303357, 30250217, 40679108; Changed phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related, transient neonatal cholestasis, intellectual disability, short stature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.350 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism to Disorder of sex differentiation, MONDO:0002145, IGSF10-related; delayed puberty; hypogonadotropic hypogonadism
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.349 IGSF10 Zornitza Stark reviewed gene: IGSF10: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related; Mode of inheritance: None
Fetal anomalies v1.398 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432; Microcephaly to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Fetal anomalies v1.397 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Fetal anomalies v1.396 TAF13 Zornitza Stark edited their review of gene: TAF13: Added comment: Two more families reported, but with same homozygous missense variant as previous, c.119T>A p.Met40Lys, suggestive of founder effect. In addition to ID and microcephaly, DSD reported, which may also be relevant to this panel.; Changed publications: 28257693, 40679298; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Intellectual disability syndromic and non-syndromic v1.238 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432 to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Intellectual disability syndromic and non-syndromic v1.237 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Intellectual disability syndromic and non-syndromic v1.236 TAF13 Zornitza Stark edited their review of gene: TAF13: Changed publications: 28257693, 40679298; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2901 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432 to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2900 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Added comment: Two more families reported, but with same homozygous missense variant as previous, c.119T>A p.Met40Lys, suggestive of founder effect. In addition to ID and microcephaly, DSD reported.; Changed publications: 28257693, 40679298
Mendeliome v1.2899 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency to Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Mendeliome v1.2898 IGSF10 Zornitza Stark Publications for gene: IGSF10 were set to 27137492; 31042289
Mendeliome v1.2897 IGSF10 Zornitza Stark Mode of inheritance for gene: IGSF10 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2896 IGSF10 Zornitza Stark reviewed gene: IGSF10: Rating: AMBER; Mode of pathogenicity: None; Publications: 27137492, 31042289, 40700020; Phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v1.14 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency to Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Differences of Sex Development v1.13 IGSF10 Zornitza Stark edited their review of gene: IGSF10: Changed phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Differences of Sex Development v1.13 IGSF10 Zornitza Stark Publications for gene: IGSF10 were set to 27137492; 31042289
Differences of Sex Development v1.12 IGSF10 Zornitza Stark edited their review of gene: IGSF10: Added comment: PMID 40700020 provides some functional data to support pathogenicity of R156L and E161K, maintain AMBER rating.; Changed publications: 27137492, 31042289, 40700020
Mendeliome v1.2896 TXNRD2 Zornitza Stark Classified gene: TXNRD2 as Green List (high evidence)
Mendeliome v1.2896 TXNRD2 Zornitza Stark Gene: txnrd2 has been classified as Green List (High Evidence).
Mendeliome v1.2895 TXNRD2 Zornitza Stark edited their review of gene: TXNRD2: Added comment: PMID 40726908: further family reported with compound het missense variants, some supportive data (reduced protein levels).

Two further case reports identified in PMIDs 38011841 and 39097530. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 34258490, 40726908, 38011841, 39097530
Intellectual disability syndromic and non-syndromic v1.236 FAAH2 Zornitza Stark Phenotypes for gene: FAAH2 were changed from Neuropsychiatric disorder to Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Intellectual disability syndromic and non-syndromic v1.235 FAAH2 Zornitza Stark Publications for gene: FAAH2 were set to 25885783
Intellectual disability syndromic and non-syndromic v1.234 FAAH2 Zornitza Stark edited their review of gene: FAAH2: Added comment: Further case report of novel missense variant in an individual with a neurodevelopmental disorder, no supportive evidence.; Changed publications: 25885783, 40744325; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Mendeliome v1.2895 FAAH2 Zornitza Stark Phenotypes for gene: FAAH2 were changed from autism spectrum disorder MONDO:0005258 to Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Mendeliome v1.2894 FAAH2 Zornitza Stark Publications for gene: FAAH2 were set to 34645488; 25885783
Mendeliome v1.2893 FAAH2 Zornitza Stark edited their review of gene: FAAH2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2893 FAAH2 Zornitza Stark reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: 40744325; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, FAAH2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v1.3 TNFSF12 Zornitza Stark Publications for gene: TNFSF12 were set to 23493554
Predominantly Antibody Deficiency v1.2 TNFSF12 Zornitza Stark Phenotypes for gene: TNFSF12 were changed from Recurrent infections, poor antibody responses, decreased immunoglobulins to Inborn error of immunity, MONDO:0003778, TNFSF12-related
Predominantly Antibody Deficiency v1.1 TNFSF12 Zornitza Stark edited their review of gene: TNFSF12: Changed phenotypes: Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2893 TNFSF12 Zornitza Stark Phenotypes for gene: TNFSF12 were changed from Recurrent infections, poor antibody responses, decreased immunoglobulins to Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2892 TNFSF12 Zornitza Stark edited their review of gene: TNFSF12: Changed phenotypes: Inborn error of immunity, MONDO:0003778, TNFSF12-related
Hereditary Neuropathy - complex v1.29 NDC1 Zornitza Stark Phenotypes for gene: NDC1 were changed from triple-A syndrome MONDO:0009279 to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328
Hereditary Neuropathy - complex v1.28 NDC1 Zornitza Stark reviewed gene: NDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.234 NDC1 Zornitza Stark Phenotypes for gene: NDC1 were changed from triple-A syndrome MONDO:0009279 to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328
Intellectual disability syndromic and non-syndromic v1.233 NDC1 Zornitza Stark reviewed gene: NDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2892 NDC1 Zornitza Stark Phenotypes for gene: NDC1 were changed from triple-A syndrome MONDO:0009279 to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328
Mendeliome v1.2891 NDC1 Zornitza Stark reviewed gene: NDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.233 SEPHS1 Zornitza Stark Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related to Ververi-Brady syndrome 2, MIM# 621325
Intellectual disability syndromic and non-syndromic v1.232 SEPHS1 Zornitza Stark edited their review of gene: SEPHS1: Changed phenotypes: Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2891 SEPHS1 Zornitza Stark Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related to Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 SEPHS1 Zornitza Stark edited their review of gene: SEPHS1: Changed phenotypes: Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 TNFRSF21 Zornitza Stark Phenotypes for gene: TNFRSF21 were changed from high myopia to Myopia, MONDO:0001384, TNFRSF21-related
Mendeliome v1.2889 TNFRSF21 Zornitza Stark reviewed gene: TNFRSF21: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopia, MONDO:0001384, TNFRSF21-related; Mode of inheritance: None
Deafness_Isolated v1.73 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Deafness_Isolated v1.73 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Deafness_Isolated v1.72 TMTC2 Zornitza Stark Tag disputed tag was added to gene: TMTC2.
Deafness_Isolated v1.72 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED
Mendeliome v1.2889 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Mendeliome v1.2889 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Mendeliome v1.2888 TMTC2 Zornitza Stark Tag disputed tag was added to gene: TMTC2.
Mendeliome v1.2888 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED
Deafness_IsolatedAndComplex v1.221 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Deafness_IsolatedAndComplex v1.221 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Deafness_IsolatedAndComplex v1.220 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED
Autism v0.211 TMPRSS9 Zornitza Stark Phenotypes for gene: TMPRSS9 were changed from autism spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, TMPRSS9-related
Autism v0.210 TMPRSS9 Zornitza Stark edited their review of gene: TMPRSS9: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TMPRSS9-related
Mitochondrial disease v0.992 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial disease, MONDO:0044970, TMEM65-related to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mitochondrial disease v0.992 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial encephalomyopathy to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mitochondrial disease v0.991 TMEM65 Zornitza Stark edited their review of gene: TMEM65: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2888 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial encephalomyopathy to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2887 TMEM65 Zornitza Stark edited their review of gene: TMEM65: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TMEM65-related
Combined Immunodeficiency v1.126 POLE2 Zornitza Stark Phenotypes for gene: POLE2 were changed from Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism to Combined immunodeficiency MONDO:0015131, POLE2-related
Combined Immunodeficiency v1.125 POLE2 Zornitza Stark edited their review of gene: POLE2: Changed phenotypes: Combined immunodeficiency MONDO:0015131, POLE2-related
Mendeliome v1.2887 POLE2 Zornitza Stark Phenotypes for gene: POLE2 were changed from Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism to Combined immunodeficiency MONDO:0015131, POLE2-related
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Marked gene: PNPLA6 as ready
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Publications for gene: PNPLA6 were set to
Syndromic Retinopathy v0.229 PNPLA6 Zornitza Stark Phenotypes for gene: PNPLA6 were changed from to Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155
Syndromic Retinopathy v0.228 PNPLA6 Zornitza Stark Mode of inheritance for gene: PNPLA6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Syndromic Retinopathy v0.227 PNPLA6 Zornitza Stark edited their review of gene: PNPLA6: Changed phenotypes: Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155
Mendeliome v1.2886 PNPLA6 Zornitza Stark Phenotypes for gene: PNPLA6 were changed from Boucher-Neuhauser syndrome, 215470; ?Laurence-Moon syndrome, 245800; Oliver-McFarlane syndrome, 275400; Spastic paraplegia 39, autosomal recessive, 612020 to Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155; Spastic paraplegia 39, autosomal recessive MIM#612020
Mitochondrial disease v0.991 PNPLA4 Zornitza Stark Phenotypes for gene: PNPLA4 were changed from to Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mitochondrial disease v0.990 PNPLA4 Zornitza Stark edited their review of gene: PNPLA4: Changed phenotypes: Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mendeliome v1.2885 PNPLA4 Zornitza Stark Phenotypes for gene: PNPLA4 were changed from to Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mendeliome v1.2884 PNPLA3 Zornitza Stark Phenotypes for gene: PNPLA3 were changed from Susceptibility to nonalcoholic fatty liver disease to Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related
Mendeliome v1.2883 POLE2 Lucy Spencer reviewed gene: POLE2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined immunodeficiency MONDO:0015131, POLE2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA6 Lucy Spencer reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155, Spastic paraplegia 39, autosomal recessive MIM#612020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA4 Lucy Spencer reviewed gene: PNPLA4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disease (MONDO:0044970), PNPLA4-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2883 PNPLA3 Lucy Spencer reviewed gene: PNPLA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2883 TMEM173 Zornitza Stark Marked gene: TMEM173 as ready
Mendeliome v1.2883 TMEM173 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is STING1
Mendeliome v1.2883 TMEM173 Zornitza Stark Gene: tmem173 has been classified as Green List (High Evidence).
Mendeliome v1.2883 TMEM173 Zornitza Stark Tag new gene name tag was added to gene: TMEM173.
Interstitial Lung Disease v1.2 TMEM173 Zornitza Stark Tag new gene name tag was added to gene: TMEM173.
Mendeliome v1.2883 PMM2 Lucy Spencer changed review comment from: Adding HIPKD MONDO term specific for this gene; to: Adding HIPKD MONDO term specific for this gene
Mendeliome v1.2883 PMM2 Lucy Spencer reviewed gene: PMM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinaemic Hypoglycaemia with polycystic kidney disease MONDO:1030000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PMFBP1 Lucy Spencer reviewed gene: PMFBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 31 MIM#618112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PLXNC1 Lucy Spencer reviewed gene: PLXNC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral cortical dysplasia MONDO:0017094, PLXNC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2883 PLXNA3 Lucy Spencer reviewed gene: PLXNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0018555, PLXNA3-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mitochondrial disease v0.990 TIMM22 Zornitza Stark Phenotypes for gene: TIMM22 were changed from hypotonia; gastroesophageal reflux disease to Mitochondrial disease, MONDO:0044970, TIMM22-related
Mitochondrial disease v0.989 TIMM22 Zornitza Stark edited their review of gene: TIMM22: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2883 TIMM22 Zornitza Stark Phenotypes for gene: TIMM22 were changed from mitochondrial myopathy; hypotonia; gastroesophageal reflux disease to Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 TIMM22 Zornitza Stark edited their review of gene: TIMM22: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 THOC1 Zornitza Stark Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Hearing loss disorder, MONDO:0005365, THOC1-related
Mendeliome v1.2881 THOC1 Zornitza Stark reviewed gene: THOC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hearing loss disorder, MONDO:0005365, THOC1-related; Mode of inheritance: None
Deafness_IsolatedAndComplex v1.220 THOC1 Zornitza Stark Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Hearing loss disorder, MONDO:0005365, THOC1-related
Deafness_IsolatedAndComplex v1.219 THOC1 Zornitza Stark reviewed gene: THOC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hearing loss disorder, MONDO:0005365, THOC1-related; Mode of inheritance: None
Genomic newborn screening: BabyScreen+ v1.136 TPM1 Lilian Downie reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33642254; Phenotypes: Cardiomyopathy, hypertrophic, 3 MIM#115196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.232 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Intellectual disability syndromic and non-syndromic v1.231 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed rating: RED; Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2881 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from Forebrain abnormalities to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2880 TDGF1 Zornitza Stark Tag disputed tag was added to gene: TDGF1.
Mendeliome v1.2880 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Holoprosencephaly and septo-optic dysplasia v1.21 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from Forebrain abnormalities to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Holoprosencephaly and septo-optic dysplasia v1.20 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Intellectual disability syndromic and non-syndromic v1.231 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system to Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Intellectual disability syndromic and non-syndromic v1.230 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2880 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system to Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2879 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Marked gene: TCF7L1 as ready
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from No OMIM number; pituitary hormone deficiency to Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related
Pituitary hormone deficiency v0.36 TCF7L1 Zornitza Stark Classified gene: TCF7L1 as Red List (low evidence)
Pituitary hormone deficiency v0.36 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v0.35 TCF7L1 Zornitza Stark reviewed gene: TCF7L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2879 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from Congenital hypopituitarism to Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related
Mendeliome v1.2878 TCF7L1 Zornitza Stark reviewed gene: TCF7L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.136 VCL Lilian Downie reviewed gene: VCL: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32516855; Phenotypes: Cardiomyopathy, dilated, 1W MIM#611407; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2878 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Mendeliome v1.2877 NIT1 Zornitza Stark reviewed gene: NIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 4, MIM# 621313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia - isolated/combined v1.41 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Dystonia - isolated/combined v1.40 NIT1 Zornitza Stark reviewed gene: NIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 4, MIM# 621313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Stroke v1.24 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Stroke v1.23 NIT1 Zornitza Stark reviewed gene: NIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 4, MIM# 621313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Marked gene: NLRP1 as ready
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Gene: nlrp1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Phenotypes for gene: NLRP1 were changed from Autoinflammation with arthritis and dyskeratosis to Autoinflammation with arthritis and dyskeratosis, MIM# 617388
Disorders of immune dysregulation v1.22 NLRP1 Zornitza Stark Classified gene: NLRP1 as Green List (high evidence)
Disorders of immune dysregulation v1.22 NLRP1 Zornitza Stark Gene: nlrp1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.21 NLRP1 Zornitza Stark reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation with arthritis and dyskeratosis, MIM# 617388; Mode of inheritance: None
Genetic Epilepsy v1.182 NALCN Zornitza Stark Phenotypes for gene: NALCN were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419) to Congenital contractures of the limbs and face, hypotonia, and developmental delay - MIM#616266; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 - MIM#615419
Genetic Epilepsy v1.181 NALCN Zornitza Stark Publications for gene: NALCN were set to 30167850
Genetic Epilepsy v1.180 NALCN Zornitza Stark Mode of inheritance for gene: NALCN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.179 NALCN Zornitza Stark reviewed gene: NALCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25683120, 35388452, 28327206, 27473021, 27558372; Phenotypes: Congenital contractures of the limbs and face, hypotonia, and developmental delay - MIM#616266, Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 - MIM#615419; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.21 NLRP1 Peter McNaughton gene: NLRP1 was added
gene: NLRP1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: NLRP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NLRP1 were set to PMID: 27965258
Phenotypes for gene: NLRP1 were set to Autoinflammation with arthritis and dyskeratosis
Review for gene: NLRP1 was set to GREEN
Added comment: Given overlap autoinflammatory / auto-immune phenotype with arthritis, thyroiditis, cytopaenias, hepatosplenomegaly should be included in immune dysregulation panel in addition to autoinflammatory panel.
Sources: Literature
Ataxia - paediatric v1.46 CSNK2B Zornitza Stark Marked gene: CSNK2B as ready
Ataxia - paediatric v1.46 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Ataxia - paediatric v1.46 CSNK2B Zornitza Stark Phenotypes for gene: CSNK2B were changed from intellectual disability; ataxia; epilepsy to Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732
Ataxia - paediatric v1.45 CSNK2B Zornitza Stark Classified gene: CSNK2B as Green List (high evidence)
Ataxia - paediatric v1.45 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Ataxia - paediatric v1.44 CSNK2B Boris Keren gene: CSNK2B was added
gene: CSNK2B was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for gene: CSNK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2B were set to PMID: 34041744
Phenotypes for gene: CSNK2B were set to intellectual disability; ataxia; epilepsy
Penetrance for gene: CSNK2B were set to Complete
Review for gene: CSNK2B was set to GREEN
Added comment: PMID: 34041744. 25 patients with mostly de novo LoF or missenses and NDD. 25% have ataxia
Sources: Literature
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Marked gene: PDE4D as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Gene: pde4d has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Phenotypes for gene: PDE4D were changed from to Acrodysostosis 2, with or without hormone resistance, MIM# 614613
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.32 PDE4D Zornitza Stark Publications for gene: PDE4D were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.31 PDE4D Zornitza Stark Mode of inheritance for gene: PDE4D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Marked gene: PRKAR1A as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis 1, with or without hormone resistance, MIM# 101800
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.29 PRKAR1A Zornitza Stark Publications for gene: PRKAR1A were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.28 PRKAR1A Zornitza Stark Mode of inheritance for gene: PRKAR1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Marked gene: GNAS as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Gene: gnas has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Phenotypes for gene: GNAS were changed from to Pseudohypoparathyroidism Ia (103580) AD; Pseudohypoparathyroidism Ib (603233) AD; Pseudohypoparathyroidism Ic (612462) AD; Pseudopseudohypoparathyroidism (612463); Osseous heteroplasia, progressive (166350) AD; Pituitary adenoma 3, multiple types, somatic (617686)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.26 GNAS Zornitza Stark Mode of inheritance for gene: GNAS was changed from Unknown to Other
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Marked gene: PTHLH as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Gene: pthlh has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Phenotypes for gene: PTHLH were changed from to Brachydactyly, type E2, MIM# 613382
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.24 PTHLH Zornitza Stark Publications for gene: PTHLH were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Marked gene: HOXD13 as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Phenotypes for gene: HOXD13 were changed from to Brachydactyly, type E, 113300
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.22 HOXD13 Zornitza Stark Publications for gene: HOXD13 were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.21 HOXD13 Zornitza Stark Mode of inheritance for gene: HOXD13 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Marked gene: TBCE as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Phenotypes for gene: TBCE were changed from to Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.19 TBCE Zornitza Stark Mode of inheritance for gene: TBCE was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.48 CDKN1C Zornitza Stark Marked gene: CDKN1C as ready
Hyperinsulinism v1.48 CDKN1C Zornitza Stark Gene: cdkn1c has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 ADK Zornitza Stark Marked gene: ADK as ready
Hyperinsulinism v1.48 ADK Zornitza Stark Gene: adk has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 FAH Zornitza Stark Marked gene: FAH as ready
Hyperinsulinism v1.48 FAH Zornitza Stark Gene: fah has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 EIF2S3 Zornitza Stark Publications for gene: EIF2S3 were set to
Hyperinsulinism v1.47 HRAS Zornitza Stark Marked gene: HRAS as ready
Hyperinsulinism v1.47 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Hyperinsulinism v1.47 TRMT10A Zornitza Stark Publications for gene: TRMT10A were set to
Hyperinsulinism v1.46 YARS Zornitza Stark Marked gene: YARS as ready
Hyperinsulinism v1.46 YARS Zornitza Stark Gene: yars has been classified as Red List (Low Evidence).
Retinitis pigmentosa_Autosomal Dominant v0.76 ACTG1 Zornitza Stark Marked gene: ACTG1 as ready
Retinitis pigmentosa_Autosomal Dominant v0.76 ACTG1 Zornitza Stark Gene: actg1 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Dominant v0.76 ACTG1 Zornitza Stark Phenotypes for gene: ACTG1 were changed from Retinitis pigmentosa to Retinitis pigmentosa MONDO:0019200, ACTG1-related
Retinitis pigmentosa_Autosomal Dominant v0.75 ACTG1 Zornitza Stark Classified gene: ACTG1 as Amber List (moderate evidence)
Retinitis pigmentosa_Autosomal Dominant v0.75 ACTG1 Zornitza Stark Gene: actg1 has been classified as Amber List (Moderate Evidence).
Hereditary Neuropathy_CMT - isolated v1.61 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from HMSN, dHMN/dSMA; Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067 to hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
Hereditary Neuropathy_CMT - isolated v1.60 PLEKHG5 Zornitza Stark edited their review of gene: PLEKHG5: Added comment: Lumped by ClinGen.; Changed phenotypes: hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
Mendeliome v1.2877 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067 to hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Marked gene: TBX1 as ready
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Gene: tbx1 has been classified as Green List (High Evidence).
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Publications for gene: TBX1 were set to PMID: 20301696, 16684884, 14585638, 30137364
Pain syndromes v0.36 PLEKHN1 Zornitza Stark Phenotypes for gene: PLEKHN1 were changed from Sensory Neuropathy to Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related
Pain syndromes v0.35 PLEKHN1 Zornitza Stark edited their review of gene: PLEKHN1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pain syndromes v0.35 PLEKHN1 Zornitza Stark reviewed gene: PLEKHN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related; Mode of inheritance: None
Mendeliome v1.2876 PLEKHN1 Zornitza Stark Phenotypes for gene: PLEKHN1 were changed from Sensory Neuropathy to Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related
Mendeliome v1.2875 CYP3A4 Zornitza Stark Publications for gene: CYP3A4 were set to 29461981
Genetic Epilepsy v1.179 TRIO Zornitza Stark Mode of inheritance for gene: TRIO was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Susceptibility to Viral Infections v1.1 TAOK2 Zornitza Stark Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation to Inborn error of immunity, MONDO:0003778, TAOK2-related
Susceptibility to Viral Infections v1.0 TAOK2 Zornitza Stark reviewed gene: TAOK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, TAOK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mackenzie's Mission_Reproductive Carrier Screening v0.110 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96, 300802 (3) to Intellectual developmental disorder, X-linked 96, MIM# 300802
Mackenzie's Mission_Reproductive Carrier Screening v0.109 SYP Zornitza Stark reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v1.230 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96 MIM#300802 to Intellectual developmental disorder, X-linked 96, MIM# 300802
Intellectual disability syndromic and non-syndromic v1.229 SYP Zornitza Stark edited their review of gene: SYP: Changed phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802
Mendeliome v1.2874 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96 MIM#300802 to Intellectual developmental disorder, X-linked 96, MIM# 300802
Mendeliome v1.2873 SYP Zornitza Stark reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2873 SYNCRIP Zornitza Stark Phenotypes for gene: SYNCRIP were changed from Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology to Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYNCRIP Zornitza Stark edited their review of gene: SYNCRIP: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYCP2 Zornitza Stark Phenotypes for gene: SYCP2 were changed from Male infertility to Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SYCP2 Zornitza Stark edited their review of gene: SYCP2: Changed phenotypes: Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental syndrome; Basal cell nevus syndrome, MIM# 109400 to Joubert syndrome 32, MIM#617757; Neurodevelopmental disorder, MONDO:0700092, SUFU-related; Basal cell nevus syndrome, MIM# 109400
Mendeliome v1.2870 SUFU Zornitza Stark edited their review of gene: SUFU: Changed phenotypes: Joubert syndrome 32, MIM#617757, Neurodevelopmental disorder, MONDO:0700092, SUFU-related, Basal cell nevus syndrome, MIM# 109400
Ciliopathies v1.81 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental disorder, Joubert-like to Joubert syndrome 32, MIM#617757; Neurodevelopmental disorder, MONDO:0700092, SUFU-related
Osteogenesis Imperfecta and Osteoporosis v1.8 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, SUCO-related
Osteogenesis Imperfecta and Osteoporosis v1.7 SUCO Zornitza Stark reviewed gene: SUCO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, MONDO:0019019, SUCO-related; Mode of inheritance: None
Mendeliome v1.2870 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, SUCO-related
Mendeliome v1.2869 SUCO Zornitza Stark reviewed gene: SUCO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, MONDO:0019019, SUCO-related; Mode of inheritance: None
Autoinflammatory Disorders v2.13 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Autoinflammatory Disorders v2.12 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Deafness_IsolatedAndComplex v1.219 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Deafness_IsolatedAndComplex v1.218 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2869 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2868 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Inflammatory bowel disease v0.125 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Inflammatory bowel disease v0.124 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Polydactyly v0.288 RBM10 Zornitza Stark Mode of inheritance for gene: RBM10 was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v1.178 TRIO Chris Ciotta reviewed gene: TRIO: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32109419, 28796471; Phenotypes: Intellectual developmental disorder, autosomal dominant 44, with microcephaly (MIM#617061), Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (MIM#618825), Syndromic intellectual disability (MONDO:0000508), TRIO-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v1.396 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from congenital anomalies of the kidney and urinary tract to CAKUT, MONDO:0019719, SRGAP1-related
Fetal anomalies v1.395 SRGAP1 Zornitza Stark reviewed gene: SRGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: CAKUT, MONDO:0019719, SRGAP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2868 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from CAKUT to CAKUT, MONDO:0019719, SRGAP1-related
Mendeliome v1.2867 SRGAP1 Zornitza Stark edited their review of gene: SRGAP1: Changed rating: AMBER; Changed phenotypes: CAKUT, MONDO:0019719, SRGAP1-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.124 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from CAKUT to CAKUT, MONDO:0019719, SRGAP1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.123 SRGAP1 Zornitza Stark edited their review of gene: SRGAP1: Changed phenotypes: CAKUT, MONDO:0019719, SRGAP1-related
Aortopathy_Connective Tissue Disorders v1.95 TLN1 Elena Savva reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39163585, 30888838; Phenotypes: Idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Marked gene: NOTCH3 as ready
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Amber List (Moderate Evidence).
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Classified gene: NOTCH3 as Amber List (moderate evidence)
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Amber List (Moderate Evidence).
Lipodystrophy_Lipoatrophy v1.23 NOTCH3 Zornitza Stark gene: NOTCH3 was added
gene: NOTCH3 was added to Lipodystrophy_Lipoatrophy. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 39652711
Phenotypes for gene: NOTCH3 were set to Lipodystrophy, familial partial, type 1, MIM#608600
Review for gene: NOTCH3 was set to AMBER
Added comment: Three families reported with novel missense variants in NOTCH3 and partial lipodystrophy. Variant segregated with phenotype in 4 affected individuals of one family but no additional supportive data presented. Some functional data to suggest GoF mechanism.
Sources: Literature
Hyperthyroidism v0.24 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Osteopetrosis v0.36 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital
Osteopetrosis v0.35 SGMS2 Chirag Patel Classified gene: SGMS2 as Red List (low evidence)
Osteopetrosis v0.35 SGMS2 Chirag Patel Gene: sgms2 has been classified as Red List (Low Evidence).
Osteopetrosis v0.35 SGMS2 Chirag Patel Classified gene: SGMS2 as Red List (low evidence)
Osteopetrosis v0.35 SGMS2 Chirag Patel Gene: sgms2 has been classified as Red List (Low Evidence).
Osteopetrosis v0.34 SGMS2 Chirag Patel reviewed gene: SGMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2867 COPZ1 Zornitza Stark Marked gene: COPZ1 as ready
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2867 COPZ1 Zornitza Stark Classified gene: COPZ1 as Amber List (moderate evidence)
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2866 COPZ1 Zornitza Stark gene: COPZ1 was added
gene: COPZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COPZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPZ1 were set to 39642330
Phenotypes for gene: COPZ1 were set to Severe congenital neutropenia, autosomal recessive, MONDO:0028226, COPZ1-related
Review for gene: COPZ1 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported. A pair of siblings with homozygous LoF variant and a more severe phenotype, comprising other immune defects, neurological and skeletal features. An additional individual with homozygous missense variant and a milder phenotype of isolated neutropenia. Some supportive functional data. AMBER rating as only two families and homozygous variants.
Sources: Literature
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Marked gene: COPZ1 as ready
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Classified gene: COPZ1 as Amber List (moderate evidence)
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.36 COPZ1 Zornitza Stark gene: COPZ1 was added
gene: COPZ1 was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: COPZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPZ1 were set to 39642330
Phenotypes for gene: COPZ1 were set to Severe congenital neutropenia, autosomal recessive, MONDO:0028226, COPZ1-related
Review for gene: COPZ1 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported. A pair of siblings with homozygous LoF variant and a more severe phenotype, comprising other immune defects, neurological and skeletal features. An additional individual with homozygous missense variant and a milder phenotype of isolated neutropenia. Some supportive functional data.

AMBER rating as only two families and homozygous variants.
Sources: Literature
Mendeliome v1.2865 CYP3A4 Chirag Patel Classified gene: CYP3A4 as Amber List (moderate evidence)
Mendeliome v1.2865 CYP3A4 Chirag Patel Gene: cyp3a4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2864 CYP3A4 Chirag Patel reviewed gene: CYP3A4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38179381, 29461981, 36656330; Phenotypes: Vitamin D-dependent rickets, type 3, MIM#619073; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2864 PLEKHN1 Lucy Spencer reviewed gene: PLEKHN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial hypoparathyroidism v1.6 Chirag Patel Panel types changed to Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Familial hypoparathyroidism v1.5 TBX1 Chirag Patel Classified gene: TBX1 as Green List (high evidence)
Familial hypoparathyroidism v1.5 TBX1 Chirag Patel Gene: tbx1 has been classified as Green List (High Evidence).
Familial hypoparathyroidism v1.4 TBX1 Chirag Patel gene: TBX1 was added
gene: TBX1 was added to Familial hypoparathyroidism. Sources: Expert list,Literature
Mode of inheritance for gene: TBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX1 were set to PMID: 20301696, 16684884, 14585638, 30137364
Phenotypes for gene: TBX1 were set to DiGeorge syndrome MIM# 188400; Velocardiofacial syndrome MIM# 192430; Decreased T cells; Hypoparathyroidism; Conotruncal cardiac malformation; velopalatal insufficiency; abnormal facies (cleft palate, prominent tubular nose etc); intellectual disability; Immunodeficiency; thymic hypoplasia or aplasia with resultant T‐cell dysfunction; renal anomalies; autoimmunity
Review for gene: TBX1 was set to GREEN
Added comment: Well-established disease-gene association with DiGeorge syndrome and Velocardiofacial syndrome; multiple mouse models Most common micro-deletion syndrome (22q11.2 Deletion Syndrome) which can lead to diverse clinical features comprising a triad of immunodeficiency, hypoparathyroidism, and congenital heart defect in addition to renal anomalies, autoimmunity.

Hypoparathyroidism and subsequent hypocalcemia is present in 17%-60% of persons with 22q11.2DS and is typically most serious in the neonatal period.
Sources: Expert list, Literature
Mendeliome v1.2864 PLEKHG5 Lucy Spencer changed review comment from: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition; to: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition
Mendeliome v1.2864 PLEKHG5 Lucy Spencer reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: ICoNS v0.7 F9 Jorune Balciuniene gene: F9 was added
gene: F9 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: F9 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: F9 were set to Hemophilia B
Penetrance for gene: F9 were set to Complete
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark changed review comment from: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025.

Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and subsequently upgraded.

Therefore there is full consensus to include this gene in gNBS studies.; to: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025.

Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and gene subsequently included in the study.

Therefore there is full consensus to include this gene in gNBS studies.
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Marked gene: CBS as ready
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Publications for gene: CBS were set to
Genomic newborn screening: ICoNS v0.6 CBS Zornitza Stark Classified gene: CBS as Green List (high evidence)
Genomic newborn screening: ICoNS v0.6 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.5 CBS Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27778219; Phenotypes: Homocystinuria, B6-responsive and nonresponsive types MIM#236200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Dominant v0.74 ACTG1 Eleanor Ludington gene: ACTG1 was added
gene: ACTG1 was added to Retinitis pigmentosa_Autosomal Dominant. Sources: Literature
Mode of inheritance for gene: ACTG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTG1 were set to PMID: 28000701, PMID 34448047, PMID 39734360
Phenotypes for gene: ACTG1 were set to Retinitis pigmentosa
Mode of pathogenicity for gene: ACTG1 was set to Other
Review for gene: ACTG1 was set to AMBER
Added comment: The ACTG1:c.773C>T;p.(Pro258Leu) variant has been reported in 2 individuals with retinitis pigmentosa, and one with night time vision impairment (see above PMIDs).

An RMH patient with retinitis pigmentosa and examination and history findings consistent with Baraitser-Winter syndrome also has this variant.

Collectively, these patients provide evidence that retinitis pigmentosa may be part of the Baraitser-Winter syndrome type 2 phenotype for individuals with this specific variant.
Sources: Literature
Hyperinsulinism v1.43 YARS Chirag Patel gene: YARS was added
gene: YARS was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to PMID: 33490854
Phenotypes for gene: YARS were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Review for gene: YARS was set to RED
Added comment: Multisystemic disorder characterized by cholestatic hepatitis, poor feeding, poor overall growth, and hypoglycemia apparent from infancy. Most have variable global developmental delay. Additional common features include sensorineural deafness and retinal abnormalities with visual defects. Some patients have pancreatic dysfunction, hypothyroidism, and primary amenorrhea.

PMID: 33490854- only 1 case of hyperinsulinaemic hypoglycaemia,
Sources: Literature
Hyperinsulinism v1.42 TRMT10A Chirag Patel Classified gene: TRMT10A as Red List (low evidence)
Hyperinsulinism v1.42 TRMT10A Chirag Patel Gene: trmt10a has been classified as Red List (Low Evidence).
Hyperinsulinism v1.41 TRMT10A Chirag Patel reviewed gene: TRMT10A: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 25053765; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.41 MPI Chirag Patel Classified gene: MPI as Red List (low evidence)
Hyperinsulinism v1.41 MPI Chirag Patel Gene: mpi has been classified as Red List (Low Evidence).
Hyperinsulinism v1.40 MPI Chirag Patel reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29531722; Phenotypes: ; Mode of inheritance: None
Hyperinsulinism v1.40 HRAS Chirag Patel Classified gene: HRAS as Green List (high evidence)
Hyperinsulinism v1.40 HRAS Chirag Patel Gene: hras has been classified as Green List (High Evidence).
Hyperinsulinism v1.39 HRAS Chirag Patel gene: HRAS was added
gene: HRAS was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HRAS were set to PMID: 16278907, 25668678, 33224014, 37454648, 37065762
Phenotypes for gene: HRAS were set to Costello syndrome MONDO:0009026
Review for gene: HRAS was set to GREEN
Added comment: Well established gene-disease association.

Neonatal hypoglycemia is quite common (44%), but hyperinsulinemic hypoglycemia has only occasionally been documented.
Sources: Literature
Hyperinsulinism v1.38 EIF2S3 Chirag Patel reviewed gene: EIF2S3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30878599; Phenotypes: MEHMO syndrome, MIM# 300148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hyperinsulinism v1.38 FAH Chirag Patel Classified gene: FAH as Green List (high evidence)
Hyperinsulinism v1.38 FAH Chirag Patel Gene: fah has been classified as Green List (High Evidence).
Hyperinsulinism v1.37 FAH Chirag Patel gene: FAH was added
gene: FAH was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAH were set to PMID: 15877201
Phenotypes for gene: FAH were set to Tyrosinemia type I MONDO:0010161
Review for gene: FAH was set to GREEN
Added comment: Well established gene-disease association.

PMID: 15877201 reported 3 individuals with Tyrosinaemia type I and acute liver dysfunction. Hyperinsulinemic hypoglycemia was seen in early infancy and all were successfully treated with diazoxide and chlorthiazide, with treatment gradually withdrawn. The mechanism of pancreatic dysfunction is unknown but may be related to accumulation of toxic metabolites.
Sources: Literature
Hyperinsulinism v1.36 ADK Chirag Patel Publications for gene: ADK were set to PMID: 26642971, 21963049
Hyperinsulinism v1.35 CDKN1C Chirag Patel Publications for gene: CDKN1C were set to
Hyperinsulinism v1.34 CDKN1C Chirag Patel Classified gene: CDKN1C as Green List (high evidence)
Hyperinsulinism v1.34 CDKN1C Chirag Patel Gene: cdkn1c has been classified as Green List (High Evidence).
Hyperinsulinism v1.33 CDKN1C Chirag Patel gene: CDKN1C was added
gene: CDKN1C was added to Hyperinsulinism. Sources: Expert list
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 due to CDKN1C mutation MONDO:0016476
Review for gene: CDKN1C was set to GREEN
Added comment: Well established gene-disease association.
Hyperinsulinaemic hypoglycemia well documented.
Sources: Expert list
Hyperinsulinism v1.32 ADK Chirag Patel Classified gene: ADK as Green List (high evidence)
Hyperinsulinism v1.32 ADK Chirag Patel Gene: adk has been classified as Green List (High Evidence).
Hyperinsulinism v1.31 ADK Chirag Patel gene: ADK was added
gene: ADK was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: ADK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADK were set to PMID: 26642971, 21963049
Phenotypes for gene: ADK were set to Adenosine kinase deficiency MONDO:0100255
Review for gene: ADK was set to GREEN
Added comment: A rare inborn error of metabolism characterized by persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine which manifests with encephalopathy, severe global developmental delay, mild to severe liver dysfunction, hypotonia and facial dysmorphism. Epileptic seizures, hypoglycemia and/or cardiac defects may be associated.

PMID: 26642971 reported 11 patients from 8 families.
9/11 had recurrent hypoglycemia (4 in neonatal period).
-3/9 had hyperinsulinism as the underlying cause (not studied in most other cases).
-2/11 were treated with diazoxide with good response.
Sources: Literature
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.18 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Classified gene: TBCE as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Classified gene: TBCE as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 TBCE Chirag Patel reviewed gene: TBCE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Classified gene: HOXD13 as Green List (high evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Classified gene: HOXD13 as Green List (high evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.15 HDAC4 Chirag Patel Classified gene: HDAC4 as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.15 HDAC4 Chirag Patel Gene: hdac4 has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HDAC4 Chirag Patel reviewed gene: HDAC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel reviewed gene: HOXD13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34777468, 12649808; Phenotypes: Brachydactyly, type E, 113300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Deleted their review
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PTHLH Chirag Patel changed review comment from: Type E brachydactyly with shortening mainly of the metacarpals and metatarsals, but in some cases the phalanges as well. Some individuals have moderate short stature and round facies but do not have ectopic ossification or intellectual disability.

Phenotype similar to Albright Hereditary Osteodystrophy but no hormone resistance.; to: Established gene-disease association, multiple families reported.

Type E brachydactyly with shortening mainly of the metacarpals and metatarsals, but in some cases the phalanges as well. Some individuals have moderate short stature and round facies but do not have ectopic ossification or intellectual disability.

Phenotype similar to Albright Hereditary Osteodystrophy but no hormone resistance.
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PTHLH Chirag Patel reviewed gene: PTHLH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20015959, 34897794, 29947179, 28211986; Phenotypes: Brachydactyly, type E2, MIM# 613382; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PRMT7 Chirag Patel reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26437029, 27718516, 30513135; Phenotypes: Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel changed review comment from: Not associated with Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy; to: Not associated with Pseudohypoparathyroidism or Albright Hereditary Osteodystrophy
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 GNAS Chirag Patel reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudohypoparathyroidism Ia (103580) AD, Pseudohypoparathyroidism Ib (603233) AD, Pseudohypoparathyroidism Ic (612462) AD, Pseudopseudohypoparathyroidism (612463), Osseous heteroplasia, progressive (166350) AD, Pituitary adenoma 3, multiple types, somatic (617686); Mode of inheritance: Other
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PRKAR1A Chirag Patel reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21651393, 22464250; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PDE4D Chirag Patel reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22464250, 22464252, 23033274, 24203977; Phenotypes: Acrodysostosis 2, with or without hormone resistance, MIM# 614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Classified gene: HOXD13 as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.13 HOXD13 Chirag Patel reviewed gene: HOXD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type E 113300, Brachydactyly, type D, MIM# 113200, Syndactyly, type V, MIM# 186300 Synpolydactyly 1, MIM# 186000, Brachydactyly-syndactyly syndrome, MIM# 610713; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2864 TRIM33 Zornitza Stark Phenotypes for gene: TRIM33 were changed from to Developmental dysplasia of the hip 4, MIM# 621311
Mendeliome v1.2863 TRIM33 Zornitza Stark Publications for gene: TRIM33 were set to
Mendeliome v1.2862 TRIM33 Zornitza Stark Mode of inheritance for gene: TRIM33 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 TRIM33 Zornitza Stark edited their review of gene: TRIM33: Added comment: Four siblings with homozygous single aa insertion reported.; Changed publications: 39054052; Changed phenotypes: Developmental dysplasia of the hip 4, MIM# 621311; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataract v0.374 SRD5A3 Rachel Wong reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34925443; Phenotypes: nystagmus, retinal dystrophy, autism, anxiety, ataxia, learning difficulties; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 SPOP Zornitza Stark Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1 MIM#618828; Nabais Sa-de Vries syndrome, type 2, MIM#618829
Mendeliome v1.2860 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Nabais Sa-de Vries syndrome, type 1 MIM#618828, Nabais Sa-de Vries syndrome, type 2, MIM#618829
Intellectual disability syndromic and non-syndromic v1.229 SPOP Zornitza Stark Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1 MIM#618828; Nabais Sa-de Vries syndrome, type 2, MIM#618829
Intellectual disability syndromic and non-syndromic v1.228 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Nabais Sa-de Vries syndrome, type 1 MIM#618828, Nabais Sa-de Vries syndrome, type 2, MIM#618829
Intellectual disability syndromic and non-syndromic v1.228 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPOP-related
Deafness_Isolated v1.72 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
Deafness_IsolatedAndComplex v1.218 SPATC1L Zornitza Stark Phenotypes for gene: SPATC1L were changed from Deafness to Hearing loss disorder, MONDO:0005365 SPATC1L-related
Deafness_IsolatedAndComplex v1.217 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2860 SPATC1L Zornitza Stark Phenotypes for gene: SPATC1L were changed from Deafness to Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SOHLH2 Zornitza Stark Phenotypes for gene: SOHLH2 were changed from Premature ovarian failure to Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOHLH2 Zornitza Stark edited their review of gene: SOHLH2: Changed phenotypes: Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.349 SOHLH2 Zornitza Stark Phenotypes for gene: SOHLH2 were changed from Premature ovarian failure to Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.348 SOHLH2 Zornitza Stark edited their review of gene: SOHLH2: Changed phenotypes: Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from {Microvascular complications of diabetes 6} 612634; Lethal neonatal dilated cardiomyopathy to {Microvascular complications of diabetes 6} 612634; Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Dilated Cardiomyopathy v1.43 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from Lethal neonatal dilated cardiomyopathy to Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Dilated Cardiomyopathy v1.42 SOD2 Zornitza Stark edited their review of gene: SOD2: Changed phenotypes: Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Intellectual disability syndromic and non-syndromic v1.228 SOBP Zornitza Stark Phenotypes for gene: SOBP were changed from Mental retardation, anterior maxillary protrusion, and strabismus, MIM# 613671 to Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Intellectual disability syndromic and non-syndromic v1.227 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2857 SOBP Zornitza Stark Phenotypes for gene: SOBP were changed from Mental retardation, anterior maxillary protrusion, and strabismus, MIM# 613671 to Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: mpaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Intellectual disability syndromic and non-syndromic v1.227 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Intellectual disability syndromic and non-syndromic v1.226 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Genetic Epilepsy v1.178 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Genetic Epilepsy v1.177 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2856 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2855 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Pain syndromes v0.35 SMPDL3A Zornitza Stark Phenotypes for gene: SMPDL3A were changed from Sensory Neuropathy to Sensory Neuropathy MONDO:0002321, SMPDL3A-related
Pain syndromes v0.34 SMPDL3A Zornitza Stark reviewed gene: SMPDL3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sensory Neuropathy MONDO:0002321, SMPDL3A-related; Mode of inheritance: None
Mendeliome v1.2855 SMPDL3A Zornitza Stark Phenotypes for gene: SMPDL3A were changed from Sensory Neuropathy to Sensory Neuropathy MONDO:0002321, SMPDL3A-related
Mendeliome v1.2854 SMPDL3A Zornitza Stark reviewed gene: SMPDL3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sensory Neuropathy MONDO:0002321, SMPDL3A-related; Mode of inheritance: None
Mendeliome v1.2854 SMPD4 Zornitza Stark Phenotypes for gene: SMPD4 were changed from Severe neurodevelopmental delay, microcephaly, arthrogryposis to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Mendeliome v1.2853 SMPD4 Zornitza Stark edited their review of gene: SMPD4: Changed phenotypes: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Intellectual disability syndromic and non-syndromic v1.226 SMARCD1 Zornitza Stark Phenotypes for gene: SMARCD1 were changed from no OMIM number yet to Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Intellectual disability syndromic and non-syndromic v1.225 SMARCD1 Zornitza Stark reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCD1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2853 SMARCD1 Zornitza Stark Phenotypes for gene: SMARCD1 were changed from Intellectual disability; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Mendeliome v1.2852 SMARCD1 Zornitza Stark edited their review of gene: SMARCD1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Intellectual disability syndromic and non-syndromic v1.225 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Intellectual disability syndromic and non-syndromic v1.224 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Microcephaly v1.321 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Microcephaly v1.320 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2852 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMAD1 Zornitza Stark Phenotypes for gene: SMAD1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, SMAD1-related
Fetal anomalies v1.395 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Fetal anomalies v1.394 SLIT3 Zornitza Stark reviewed gene: SLIT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related; Mode of inheritance: None
Mendeliome v1.2850 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Mendeliome v1.2849 SLIT3 Zornitza Stark edited their review of gene: SLIT3: Changed phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Congenital diaphragmatic hernia v1.17 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Congenital diaphragmatic hernia v1.16 SLIT3 Zornitza Stark edited their review of gene: SLIT3: Changed phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Fetal anomalies v1.394 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT; vesicoureteric reflux to CAKUT MONDO:0019719, SLIT2-related
Fetal anomalies v1.393 SLIT2 Zornitza Stark reviewed gene: SLIT2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: CAKUT MONDO:0019719, SLIT2-related; Mode of inheritance: None
Mendeliome v1.2849 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT to CAKUT MONDO:0019719, SLIT2-related
Mendeliome v1.2848 SLIT2 Zornitza Stark edited their review of gene: SLIT2: Changed phenotypes: CAKUT MONDO:0019719, SLIT2-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.123 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT to CAKUT MONDO:0019719, SLIT2-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.122 SLIT2 Zornitza Stark edited their review of gene: SLIT2: Changed phenotypes: CAKUT MONDO:0019719, SLIT2-related
Mitochondrial disease v0.989 SLIRP Zornitza Stark reviewed gene: SLIRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2848 SLIRP Zornitza Stark Phenotypes for gene: SLIRP were changed from Mitochondrial encephalomyopathy with complex I and IV deficiency to Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related
Mendeliome v1.2847 SLIRP Zornitza Stark reviewed gene: SLIRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.393 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from Mental retardation, autosomal recessive 48, MIM# 616269 to Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Intellectual disability syndromic and non-syndromic v1.224 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from Mental retardation, autosomal recessive 48, MIM# 616269 to Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Intellectual disability syndromic and non-syndromic v1.223 SLC6A17 Zornitza Stark edited their review of gene: SLC6A17: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2847 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from Mental retardation, autosomal recessive 48, MIM# 616269 to Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2846 SLC6A17 Zornitza Stark edited their review of gene: SLC6A17: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Added comment: Comment when marking as ready: Downgraded to RED as only one plausible family.
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Gene: daam2 has been classified as Red List (Low Evidence).
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Classified gene: DAAM2 as Red List (low evidence)
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Gene: daam2 has been classified as Red List (Low Evidence).
Mendeliome v1.2846 WNT1 Zornitza Stark Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, MIM# 615220 to Osteogenesis imperfecta, type XV, MIM# 615220; Osteoporosis MONDO:0005298
Mendeliome v1.2845 WNT1 Zornitza Stark Publications for gene: WNT1 were set to 23499309; 23499310; 23656646; 26671912
Mendeliome v1.2844 WNT1 Zornitza Stark edited their review of gene: WNT1: Added comment: Multiple families with milder monoallelic disease reported.; Changed publications: 23499309, 23499310, 23656646, 26671912, 27005318, 25010833, 30246918, 30283887; Changed phenotypes: Osteogenesis imperfecta, type XV, MIM# 615220, Osteoporosis MONDO:0005298; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v1.7 WNT1 Zornitza Stark Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, MIM# 615220 to Osteogenesis imperfecta, type XV, MIM# 615220; Osteoporosis MONDO:0005298
Osteogenesis Imperfecta and Osteoporosis v1.6 WNT1 Zornitza Stark Publications for gene: WNT1 were set to 23499309; 23499310; 23656646; 26671912
Callosome v0.553 MAP1B Zornitza Stark Marked gene: MAP1B as ready
Callosome v0.553 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Callosome v0.553 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from corpus callosum to Periventricular nodular heterotopia 9, MIM# 618918
Callosome v0.552 MAP1B Zornitza Stark Classified gene: MAP1B as Green List (high evidence)
Callosome v0.552 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Callosome v0.551 MAP1B Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Periventricular nodular heterotopia 9, MIM# 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2844 MAP4K1 Zornitza Stark Marked gene: MAP4K1 as ready
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2844 MAP4K1 Zornitza Stark Classified gene: MAP4K1 as Green List (high evidence)
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2843 MAP4K1 Zornitza Stark gene: MAP4K1 was added
gene: MAP4K1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K1 were set to 40716650
Phenotypes for gene: MAP4K1 were set to Inborn error of immunity, MONDO:0003778, MAP4K1-related
Review for gene: MAP4K1 was set to GREEN
Added comment: Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. Functional analysis of primary patient T cells, transcriptomics, and CRISPR-Cas9 editing demonstrated that HPK1 deficiency heightened T cell activation and inflammatory cytokine production. Penetrance was incomplete.

One of the families was multiplex (8 affected individuals) and the other had single individual affected, extensive functional data. Borderline Amber/Green.
Sources: Expert Review
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Marked gene: MAP4K1 as ready
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Phenotypes for gene: MAP4K1 were changed from Immune dysregulation to Inborn error of immunity, MONDO:0003778, MAP4K1-related
Disorders of immune dysregulation v1.20 MAP4K1 Zornitza Stark Classified gene: MAP4K1 as Green List (high evidence)
Disorders of immune dysregulation v1.20 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.19 MAP4K1 Zornitza Stark changed review comment from: One multiplex family with 8 affected individuals and one family with single individual affected, extensive functional data.; to: One multiplex family with 8 affected individuals and one family with single individual affected, extensive functional data. Borderline Amber/Green.
Disorders of immune dysregulation v1.19 MAP4K1 Zornitza Stark reviewed gene: MAP4K1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, MAP4K1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Marked gene: MN1 as ready
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Gene: mn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Phenotypes for gene: MN1 were changed from to Cleft palate; CEBALID syndrome, MIM# 618774
Pierre Robin Sequence v0.51 MN1 Zornitza Stark Publications for gene: MN1 were set to
Pierre Robin Sequence v0.50 MN1 Zornitza Stark Mode of inheritance for gene: MN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pierre Robin Sequence v0.49 MN1 Zornitza Stark reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33351141, 31834374, 33351070, 15870292; Phenotypes: Cleft palate, CEBALID syndrome, MIM# 618774; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2842 MN1 Zornitza Stark commented on gene: MN1: Recently discussed at Clingen syndromic GCEP. Noted well described C terminal truncating variants to result in GOF and CEBALID syndrome. Defined a milder phenotype with LOF mechanism for NMD predicted variants and whole gene deletions to result in a non specific craniofacial phenotype involving cleft palate.
Clefting disorders v0.267 MN1 Zornitza Stark Publications for gene: MN1 were set to 33351141; 31834374; 33351070
Clefting disorders v0.266 MN1 Zornitza Stark Classified gene: MN1 as Green List (high evidence)
Clefting disorders v0.266 MN1 Zornitza Stark Gene: mn1 has been classified as Green List (High Evidence).
Clefting disorders v0.265 MN1 Sarah Milton reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33351070, 31834374, 31834374, 15870292; Phenotypes: Cleft palate, MONDO:0016064, MN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Transplant Co-Morbidity Superpanel v0.19 CHST14 Zornitza Stark Marked gene: CHST14 as ready
Transplant Co-Morbidity Superpanel v0.19 CHST14 Zornitza Stark Gene: chst14 has been classified as Green List (High Evidence).
Transplant Co-Morbidity Superpanel v0.19 CHST14 Zornitza Stark Mode of inheritance for gene: CHST14 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.57 CHST14 Zornitza Stark Mode of inheritance for gene: CHST14 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.56 CHST14 Zornitza Stark edited their review of gene: CHST14: Changed phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, MIM# 601776; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.19 MAP4K1 Peter McNaughton gene: MAP4K1 was added
gene: MAP4K1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K1 were set to PMID: 40716650
Phenotypes for gene: MAP4K1 were set to Immune dysregulation
Penetrance for gene: MAP4K1 were set to Incomplete
Review for gene: MAP4K1 was set to GREEN
Added comment: Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. Functional analysis of primary patient T cells, transcriptomics, and CRISPR-Cas9 editing demonstrated that HPK1 deficiency heightened T cell activation and inflammatory cytokine production. Penetrance was incomplete.
Sources: Literature
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.96 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Ectodermal Dysplasia. Sources: Expert Review
SV/CNV, regulatory region tags were added to gene: ARHGAP36.
Mode of inheritance for gene: ARHGAP36 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ARHGAP36 were set to 35986704; 40015599
Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845
Mode of pathogenicity for gene: ARHGAP36 was set to Other
Review for gene: ARHGAP36 was set to AMBER
Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.
Sources: Expert Review
Genomic newborn screening: ICoNS v0.5 CBS Lilian Downie gene: CBS was added
gene: CBS was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: CBS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CBS were set to Homocystinuria, B6-responsive and nonresponsive types MIM#236200
Added comment: Well established gene-disease association.

Multi-system disorder, onset can be in infancy - highly variable.
In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature.

Homozygous for the p.I278T can be asymptomatic throughout life or have isolated thromboembolism.

Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219.

Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids

Paediatric actionable gene by ClinGen.
Sources: Expert list
Genomic newborn screening: ICoNS v0.4 AK2 Lilian Downie reviewed gene: AK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19043416, 19043417, 40654267; Phenotypes: Reticular dysgenesis MIM#267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2841 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Mendeliome. Sources: Expert Review
SV/CNV, regulatory region tags were added to gene: ARHGAP36.
Mode of inheritance for gene: ARHGAP36 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ARHGAP36 were set to 35986704; 40015599
Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845
Mode of pathogenicity for gene: ARHGAP36 was set to Other
Review for gene: ARHGAP36 was set to AMBER
Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.
Sources: Expert Review
Hair disorders v0.78 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Hair disorders v0.78 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Hair disorders v0.78 ARHGAP36 Zornitza Stark Publications for gene: ARHGAP36 were set to
Hair disorders v0.77 ARHGAP36 Zornitza Stark changed review comment from: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.

Sources: Expert Review; to: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.

Sources: Expert Review
Hair disorders v0.77 ARHGAP36 Zornitza Stark edited their review of gene: ARHGAP36: Changed publications: 35986704, 40015599; Changed phenotypes: Bazex-Dupre-Christol syndrome, MIM# 301845
Hair disorders v0.77 ARHGAP36 Zornitza Stark changed review comment from: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.
Sources: Expert Review; to: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.

Sources: Expert Review
Hair disorders v0.77 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Hair disorders v0.77 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Hair disorders v0.76 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Hair disorders. Sources: Expert Review
SV/CNV, regulatory region tags were added to gene: ARHGAP36.
Mode of inheritance for gene: ARHGAP36 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845
Mode of pathogenicity for gene: ARHGAP36 was set to Other
Review for gene: ARHGAP36 was set to AMBER
Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.
Sources: Expert Review
Callosome v0.551 MAP1B Boris Keren edited their review of gene: MAP1B: Changed publications: PMID: 31317654, PMID: 30150678
Callosome v0.551 MAP1B Boris Keren reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31317654, 30150678; Phenotypes: intellectual disability, corpus callosum dysgenesis, corpus callosum hypoplasia, seizures, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Callosome v0.551 MAP1B Boris Keren gene: MAP1B was added
gene: MAP1B was added to Callosome. Sources: Literature
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to PMID: 30150678; PMID: 31317654
Phenotypes for gene: MAP1B were set to corpus callosum
Penetrance for gene: MAP1B were set to Incomplete
Mode of pathogenicity for gene: MAP1B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Osteogenesis Imperfecta and Osteoporosis v1.5 WNT1 Chirag Patel reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27005318, 25010833, 30246918, 30283887; Phenotypes: Osteoporosis MONDO:0005298; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.136 GFAP Lilian Downie reviewed gene: GFAP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Alexander disease, MIM#203450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2840 YWHAZ Zornitza Stark Phenotypes for gene: YWHAZ were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Mendeliome v1.2839 YWHAZ Zornitza Stark Publications for gene: YWHAZ were set to 36001342
Mendeliome v1.2838 YWHAZ Zornitza Stark Classified gene: YWHAZ as Amber List (moderate evidence)
Mendeliome v1.2838 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2837 YWHAZ Zornitza Stark edited their review of gene: YWHAZ: Added comment: PMID 31024343: 5 individuals with de novo variants in this gene, two had a clinical diagnosis of Rasopathy. 3 missense variants and 2 high impact variants (one is NMD escape). Parentage not confirmed in 3. Two had other possible variants of interest.

Used Xenopus to investigate the effect of one of the missense variants, S230W, and demonstrated activation of the Raf-MEK-Erk pathway and embryonic defects when expressed at high levels. Suggests GoF as mechanism.

Further de novo missense identified in a large cohort of NDDs, PMID 35143101.

PMID 35501409: knockout Zebrafish, altered brain activity and behaviour.

PMID 22124272, 26207352: two mouse models also support role in brain development.

MODERATE by ClinGen, but note this is mostly driven by experimental data points. Also note there is evidence for both GoF and LoF mechanism, potentially two distinct disorders?; Changed rating: AMBER; Changed publications: 36001342, 31024343, 35143101, 35501409, 22124272, 26207352; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Intellectual disability syndromic and non-syndromic v1.223 YWHAZ Zornitza Stark Phenotypes for gene: YWHAZ were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Intellectual disability syndromic and non-syndromic v1.222 YWHAZ Zornitza Stark Classified gene: YWHAZ as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.222 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.221 YWHAZ Zornitza Stark reviewed gene: YWHAZ: Rating: AMBER; Mode of pathogenicity: None; Publications: 31024343, 35143101, 35501409, 22124272, 26207352; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.123 THRA Zornitza Stark Marked gene: THRA as ready
Bone Marrow Failure v1.123 THRA Zornitza Stark Gene: thra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.123 THRA Zornitza Stark Classified gene: THRA as Amber List (moderate evidence)
Bone Marrow Failure v1.123 THRA Zornitza Stark Gene: thra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.122 THRA Zornitza Stark gene: THRA was added
gene: THRA was added to Bone Marrow Failure. Sources: Expert Review
Mode of inheritance for gene: THRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: THRA were set to Hypothyroidism, congenital, nongoitrous, 6, MIM# 614450
Review for gene: THRA was set to AMBER
Added comment: Over 10 sequence variants (including truncating nonsense and frameshift as well as missense) have been reported in the literature in association with consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia, delayed dentition and constipation) and specific facial features. Milder outcomes for missense variants and more severe phenotype manifestations for truncating variants have been observed.

Most of the variants are located in the last exon of the THRA isoform 1 (NM_199334.5; a shorter isoform) affecting the C-terminal ligand binding domain with nonsense and frameshift variants predicted to escape nonsense mediated decay. These variants are either de novo or inherited from an affected parent. A few pedigrees are also available with segregation data. Truncating variants appear to have near complete penetrance whereas missense variants may be associated with variable expressivity (Family C - PMID: 27144938).

Note routine TFTs can be normal.

We have identified multiple individuals internally with pathogenic de novo variants in this gene and macrocytic anaemia.

AMBER rating as only one lineage affected. However, the above patients tested through haematology.
Sources: Expert Review
Red cell disorders v1.33 THRA Zornitza Stark Marked gene: THRA as ready
Red cell disorders v1.33 THRA Zornitza Stark Gene: thra has been classified as Green List (High Evidence).
Red cell disorders v1.33 THRA Zornitza Stark Classified gene: THRA as Green List (high evidence)
Red cell disorders v1.33 THRA Zornitza Stark Gene: thra has been classified as Green List (High Evidence).
Red cell disorders v1.32 THRA Zornitza Stark gene: THRA was added
gene: THRA was added to Red cell disorders. Sources: Expert Review
Mode of inheritance for gene: THRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: THRA were set to Hypothyroidism, congenital, nongoitrous, 6, MIM# 614450
Review for gene: THRA was set to GREEN
Added comment: Over 10 sequence variants (including truncating nonsense and frameshift as well as missense) have been reported in the literature in association with consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia, delayed dentition and constipation) and specific facial features. Milder outcomes for missense variants and more severe phenotype manifestations for truncating variants have been observed.

Most of the variants are located in the last exon of the THRA isoform 1 (NM_199334.5; a shorter isoform) affecting the C-terminal ligand binding domain with nonsense and frameshift variants predicted to escape nonsense mediated decay. These variants are either de novo or inherited from an affected parent. A few pedigrees are also available with segregation data. Truncating variants appear to have near complete penetrance whereas missense variants may be associated with variable expressivity (Family C - PMID: 27144938).

Note routine TFTs can be normal.

We have identified multiple individuals internally with pathogenic de novo variants in this gene and macrocytic anaemia.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.221 THRA Zornitza Stark reviewed gene: THRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypothyroidism congenital nongoitrous 6 (MIM 614450); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2837 RUSC2 Zornitza Stark commented on gene: RUSC2: LIMITED by ClinGen but note multiple P/LP ClinVar submissions
Callosome v0.551 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
Callosome v0.550 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566
Callosome v0.549 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Callosome v0.549 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Callosome v0.548 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly, anencephaly and ACC, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.

Note previous reports of individuals characterised as having OFD, similarly affected by midline brain abnormalities, including ACC, again supporting the notion of a spectrum.; Changed rating: GREEN; Changed publications: 24285566, 31130284, 36826837, 32573025; Changed phenotypes: Alsahan-Harris syndrome, MIM#621307, Orofaciodigital syndrome type IX, MIM#258865
Ciliopathies v1.80 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865 to Orofaciodigital syndrome type IX, MIM#258865; Alsahan-Harris syndrome, MIM#621307; Retinitis pigmentosa 100, MIM# 621280
Ciliopathies v1.79 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Ciliopathies v1.78 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.

At the milder end of the spectrum, note PMIDs 37768732 and 39930170, associating variants in this gene and RP.; Changed publications: 24285566, 32573025, 32060556, 31130284, 36826837, 40319332, 31130284, 36826837, 37768732, 39930170; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, Alsahan-Harris syndrome, MIM#621307, Retinitis pigmentosa 100, MIM# 621280
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.220 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Phenotypes for gene: TBC1D32 were set to Orofacial digital syndrome type IX, MIM#258865
Review for gene: TBC1D32 was set to GREEN
Added comment: Multiple affected individuals reported from unrelated families. Midline brain abnormalities are a feature and DD/ID is variable.
Sources: Expert Review
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.19 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed rating: GREEN
Holoprosencephaly and septo-optic dysplasia v1.19 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Holoprosencephaly and septo-optic dysplasia. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 31130284; 36826837; 32573025
Phenotypes for gene: TBC1D32 were set to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.

Note previous reports of individuals characterised as having OFD, similarly affected by midline brain abnormalities, again supporting the notion of a spectrum.
Sources: Expert Review
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Anophthalmia_Microphthalmia_Coloboma v1.49 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Anophthalmia_Microphthalmia_Coloboma. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 31130284; 36826837; 32573025
Phenotypes for gene: TBC1D32 were set to Alsahan-Harris syndrome, MIM#621307
Review for gene: TBC1D32 was set to GREEN
Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.
Sources: Expert Review
Mendeliome v1.2837 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170; 36826837; 40319332
Mendeliome v1.2836 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; Alsahan-Harris syndrome, MIM#621307; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2835 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332, 31130284, 36826837; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, Retinitis pigmentosa 100, MIM# 621280, Alsahan-Harris syndrome, MIM#621307
Fetal anomalies v1.392 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865 to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.391 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed publications: 31130284, 32573025, 36826837, 24285566, 32060556, 31130284, 39930170, 36826837, 40319332
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed phenotypes: Alsahan-Harris syndrome, MIM#621307, Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: In addition, 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by severe brain defects, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.; Changed publications: 31130284, 32573025, 36826837; Changed phenotypes: Alsahan-Harris syndrome, MIM#621307
Fetal anomalies v1.390 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofacial digital syndrome type IX to Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.389 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 32573025; 32060556; 31130284
Fetal anomalies v1.388 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported with OFD phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 36826837, 40319332; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865
Mendeliome v1.2835 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2834 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170
Mendeliome v1.2833 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported with OFD phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Ciliopathies v1.78 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX to Orofaciodigital syndrome type IX, MIM#258865
Ciliopathies v1.77 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284
Ciliopathies v1.76 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported.; Changed publications: 24285566, 32573025, 32060556, 31130284, 36826837, 40319332
Ciliopathies v1.76 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865
Callosome v0.548 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Callosome v0.548 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.315 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Skeletal dysplasia v0.315 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Polydactyly v0.287 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Polydactyly v0.287 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Hydrocephalus_Ventriculomegaly v0.128 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Hydrocephalus_Ventriculomegaly v0.128 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Skeletal Dysplasia_Fetal v0.233 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Skeletal Dysplasia_Fetal v0.233 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Fetal anomalies v1.388 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal Dysplasia_Fetal v0.232 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus_Ventriculomegaly v0.127 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Polydactyly v0.286 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.314 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting disorders v0.265 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.547 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.217 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.217 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.216 SLC9A1 Chirag Patel reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lichtenstein-Knorr syndrome MONDO:0014572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2833 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Mendeliome v1.2833 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Ataxia - paediatric v1.44 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Ataxia - paediatric v1.44 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Mendeliome v1.2832 SLC9A1 Chirag Patel reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lichtenstein-Knorr syndrome MONDO:0014572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia - paediatric v1.43 SLC9A1 Chirag Patel reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lichtenstein-Knorr syndrome MONDO:0014572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2832 PSMB10 Chirag Patel commented on gene: PSMB10
Mendeliome v1.2832 PSMB10 Chirag Patel Deleted their review
Mendeliome v1.2832 PSMB10 Chirag Patel reviewed gene: PSMB10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Combined Immunodeficiency (absent T absent B cells) v1.9 PSMB10 Chirag Patel Classified gene: PSMB10 as Red List (low evidence)
Severe Combined Immunodeficiency (absent T absent B cells) v1.9 PSMB10 Chirag Patel Gene: psmb10 has been classified as Red List (Low Evidence).
Severe Combined Immunodeficiency (absent T absent B cells) v1.8 PSMB10 Chirag Patel reviewed gene: PSMB10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Deafness_Isolated v1.72 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Deafness_Isolated v1.72 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Deafness_Isolated v1.71 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Deafness_Isolated v1.71 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Deafness_Isolated v1.70 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2832 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Mendeliome v1.2832 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2831 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Deafness_IsolatedAndComplex v1.216 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Deafness_IsolatedAndComplex v1.216 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Deafness_IsolatedAndComplex v1.215 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pulmonary Fibrosis_Interstitial Lung Disease v0.90 NHP2 Chirag Patel gene: NHP2 was added
gene: NHP2 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Expert Review
Mode of inheritance for gene: NHP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NHP2 were set to Dyskeratosis congenita, autosomal recessive 2 MONDO:0013519
Review for gene: NHP2 was set to RED
Added comment: ClinGen 'limited' classification.

NHP2 ribonucleoprotein (NHP2) was first reported in relation to autosomal recessive dyskeratosis congenita in 2008 (Vulliamy et al., PMID 18523010). NHP2 biallelic variant carriers present with features common to other monogenic telomere biology disorders (TBD) like: oral leukoplakia, reticular skin pigmentation, nail dystrophy, bone marrow failure, intellectual disability, and short telomeres. Variation in other telomere related genes like TERT and TERC have been shown to be related to interstitial lung disease (ILD), but to date ILD has not been observed for this gene-disease entity (PMID 38718684). Seven variants (6 missense, and 1 stop-loss extension) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data from 3 different publications describing a total of 4 probands with ages of onset being reported in both childhood and adulthood. Additionally, 4 families have been reported with heterozygous variant carriers that have presented with features consistent with TBD. The ClinGen Interstitial Lung Disease GCEP has decided to exclude heterozygous cases from this curation due to high population frequencies and/or lack of sufficient detail regarding genotyping. If, however, more convincing data of autosomal dominant inheritance becomes available, the curated entity and classification will be revisited. This gene-disease relationship is supported by protein interaction data, a yeast model and functional alteration in non-patient cells; PMID 11160879, 11074001, 37440454). Experimental data demonstrated that variant NHP2 is related to a decrease in the expression of TERC, and that expression of variant NHP2 and interaction with NOP10 and DKC1 were reduced. The mechanism is unclear but thought to be LOF. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date April 15, 2025 (SOP 11). This gene-disease pair was originally evaluated by the General GCEP on June 1, 2017. It was reevaluated on August 1, 2025. Although additional case and experimental evidence (PMIDs: 37440454, 31985013) was published, the classification did not change.
Sources: Expert Review
Hypertrophic cardiomyopathy_HCM v1.7 JPH2 Chirag Patel Classified gene: JPH2 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.7 JPH2 Chirag Patel Gene: jph2 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.6 JPH2 Chirag Patel reviewed gene: JPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertrophic cardiomyopathy MONDO:0005045; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Classified gene: SLC25A4 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Gene: slc25a4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Classified gene: SLC25A4 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Gene: slc25a4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.5 SLC25A4 Chirag Patel reviewed gene: SLC25A4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive MONDO:0014175; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy_HCM v1.5 FXN Chirag Patel Classified gene: FXN as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.5 FXN Chirag Patel Gene: fxn has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.4 FXN Chirag Patel reviewed gene: FXN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Friedreich ataxia MIM#229300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Marked gene: MYL2 as ready
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Gene: myl2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Phenotypes for gene: MYL2 were changed from Cardiomyopathy, familial hypertrophic, 10 to Cardiomyopathy, hypertrophic, 10, MIM# 608758
Genomic newborn screening: BabyScreen+ v1.135 MYL2 Zornitza Stark reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic, 10, MIM# 608758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Marked gene: LMNA as ready
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Gene: lmna has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Charcot-Marie-Tooth disease; Emery-Dreifuss muscular dystrophy 2; Dilated cardiomyopathy to Cardiomyopathy, dilated, 1A, MIM# 115200
Genomic newborn screening: BabyScreen+ v1.134 LMNA Zornitza Stark Classified gene: LMNA as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.134 LMNA Zornitza Stark Gene: lmna has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.133 LMNA Zornitza Stark reviewed gene: LMNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1A, MIM# 115200; Mode of inheritance: None
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Marked gene: KRIT1 as ready
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Gene: krit1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Publications for gene: KRIT1 were set to PMID: 30061145, 20301470, 27561926
Genomic newborn screening: BabyScreen+ v1.132 KRIT1 Zornitza Stark Classified gene: KRIT1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.132 KRIT1 Zornitza Stark Gene: krit1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.131 KRIT1 Zornitza Stark reviewed gene: KRIT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral cavernous malformations-1 MIM#116860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2831 IGKC Bryony Thompson Classified gene: IGKC as Amber List (moderate evidence)
Mendeliome v1.2831 IGKC Bryony Thompson Added comment: Comment on list classification: Gene does not have a NCBI transcript, therefore variants in this gene may not be annotated by some curation tools
Mendeliome v1.2831 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2830 IGKC Bryony Thompson Tag technically challenging tag was added to gene: IGKC.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, therefore some curation tools will not annotate variants in this gene.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2829 TRU-TCA1-1 Bryony Thompson Tag technically challenging tag was added to gene: TRU-TCA1-1.
Mendeliome v1.2829 IGHM Bryony Thompson Classified gene: IGHM as Green List (high evidence)
Mendeliome v1.2829 IGHM Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, so it may have annotation issues in some curation tools
Mendeliome v1.2829 IGHM Bryony Thompson Gene: ighm has been classified as Green List (High Evidence).
Mendeliome v1.2828 IGHM Bryony Thompson Tag technically challenging tag was added to gene: IGHM.
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Marked gene: KCNE1 as ready
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Gene: kcne1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Phenotypes for gene: KCNE1 were changed from Long QT syndrome-5; Jervell and Lange-Nielsen syndrome to Long QT syndrome 5, MIM# 613695
Genomic newborn screening: BabyScreen+ v1.130 KCNE1 Zornitza Stark Classified gene: KCNE1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.130 KCNE1 Zornitza Stark Gene: kcne1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.129 KCNE1 Zornitza Stark reviewed gene: KCNE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 5, MIM# 613695; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Marked gene: GPD1L as ready
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Gene: gpd1l has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Phenotypes for gene: GPD1L were changed from Brugada syndrome to Brugada syndrome 2, MIM# 611777
Genomic newborn screening: BabyScreen+ v1.128 GPD1L Zornitza Stark Classified gene: GPD1L as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.128 GPD1L Zornitza Stark Gene: gpd1l has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.127 GPD1L Zornitza Stark reviewed gene: GPD1L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brugada syndrome 2, MIM# 611777; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Marked gene: GJA5 as ready
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Gene: gja5 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Phenotypes for gene: GJA5 were changed from Atrial fibrillation to Atrial fibrillation, familial, 11, MIM# 614049
Genomic newborn screening: BabyScreen+ v1.126 GJA5 Zornitza Stark Classified gene: GJA5 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.126 GJA5 Zornitza Stark Gene: gja5 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.125 GJA5 Zornitza Stark reviewed gene: GJA5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Marked gene: DES as ready
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Gene: des has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Phenotypes for gene: DES were changed from Myopathy, myofibrillar; Cardiomyopathy, dilated to Cardiomyopathy, dilated, 1I, MIM# 604765
Genomic newborn screening: BabyScreen+ v1.124 DES Zornitza Stark Classified gene: DES as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.124 DES Zornitza Stark Gene: des has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.123 DES Zornitza Stark reviewed gene: DES: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Marked gene: CRYAB as ready
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Gene: cryab has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Phenotypes for gene: CRYAB were changed from Myofibrillar myopathy; Cardiomyopathy, dilated to Cardiomyopathy, dilated, 1II MIM#615184
Genomic newborn screening: BabyScreen+ v1.122 CRYAB Zornitza Stark Classified gene: CRYAB as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.122 CRYAB Zornitza Stark Gene: cryab has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.121 CRYAB Zornitza Stark reviewed gene: CRYAB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1II MIM#615184; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark Marked gene: CACNA1C as ready
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark reviewed gene: CACNA1C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 8, MIM# 618447, Timothy syndrome, MIM# 601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2828 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Haemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2827 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2826 RC3H1 Zornitza Stark Publications for gene: RC3H1 were set to 31636267
Mendeliome v1.2825 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Added comment: PMID 40769319: 3 individuals (heterozygous c.T674C (p.F225S)) from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations (upper respiratory infections, otitis media, sinusitis, abscess formation, pneumonia, and bacteremia, psoriasis, cytopenias, and liver disease. hyper-inflammation and lymphoproliferation manifesting with exaggerated generalized lymphadenopathy and splenomegaly. Transfected cell model provided functional support.

RED for mono-allelic association, single family.; Changed publications: 31636267, 15917799, 40769319; Changed phenotypes: Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Marked gene: RC3H1 as ready
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from to Inborn error of immunity, MONDO:0003778, RC3H1-related
Disorders of immune dysregulation v1.18 RC3H1 Zornitza Stark Classified gene: RC3H1 as Red List (low evidence)
Disorders of immune dysregulation v1.18 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.17 RC3H1 Zornitza Stark reviewed gene: RC3H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, RC3H1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.989 PMPCA Zornitza Stark Marked gene: PMPCA as ready
Mitochondrial disease v0.989 PMPCA Zornitza Stark Gene: pmpca has been classified as Green List (High Evidence).
Mitochondrial disease v0.989 PMPCA Zornitza Stark Phenotypes for gene: PMPCA were changed from to Spinocerebellar ataxia, autosomal recessive 2, MIM# 213200
Mitochondrial disease v0.988 PMPCA Zornitza Stark Publications for gene: PMPCA were set to
Mitochondrial disease v0.987 PMPCA Zornitza Stark Mode of inheritance for gene: PMPCA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.219 RNU5B-1 Zornitza Stark Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related to Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Intellectual disability syndromic and non-syndromic v1.218 RNU5B-1 Zornitza Stark Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Intellectual disability syndromic and non-syndromic v1.217 RNU5B-1 Zornitza Stark edited their review of gene: RNU5B-1: Changed publications: 40442284; Changed phenotypes: Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2825 RNU5B-1 Zornitza Stark Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related to Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2824 RNU5B-1 Zornitza Stark Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Mendeliome v1.2823 RNU5B-1 Zornitza Stark edited their review of gene: RNU5B-1: Changed publications: 40442284; Changed phenotypes: Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Intellectual disability syndromic and non-syndromic v1.217 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related to Developmental and epileptic encephalopathy 119, MIM# 621304
Intellectual disability syndromic and non-syndromic v1.216 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Intellectual disability syndromic and non-syndromic v1.215 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284; Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Genetic Epilepsy v1.177 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related to Developmental and epileptic encephalopathy 119, MIM# 621304
Genetic Epilepsy v1.176 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Genetic Epilepsy v1.175 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284; Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2823 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related to Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2822 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Disorders of immune dysregulation v1.17 RC3H1 Peter McNaughton gene: RC3H1 was added
gene: RC3H1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RC3H1 were set to PMID: 40769319
Review for gene: RC3H1 was set to AMBER
Added comment: 3 individuals (heterozygous c.T674C (p.F225S)) from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations (upper respiratory infections, otitis media, sinusitis, abscess formation, pneumonia, and bacteremia, psoriasis, cytopenias, and liver disease. hyper-inflammation and lymphoproliferation manifesting with exaggerated generalized lymphadenopathy and splenomegaly. Transfected cell model provided functional support.
Previous single case of HLH in PMID: 31636267 though this patient was homozygous nonsense.
Sources: Literature
Fetal anomalies v1.388 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Fetal anomalies v1.387 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2821 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2820 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.150 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Anophthalmia_Microphthalmia_Coloboma v1.48 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Anophthalmia_Microphthalmia_Coloboma v1.47 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Fetal anomalies v1.387 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Fetal anomalies v1.387 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2820 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Mendeliome v1.2820 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Ciliopathies v1.76 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Ciliopathies v1.76 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.321 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Optic Atrophy v1.46 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Optic Atrophy v1.46 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Optic Atrophy v1.45 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Genetic Epilepsy v1.174 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Genetic Epilepsy v1.174 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.173 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2820 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Mendeliome v1.2820 ST5 Zornitza Stark Marked gene: ST5 as ready
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Mendeliome v1.2820 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Marked gene: ST5 as ready
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.214 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Genetic Epilepsy v1.173 ST5 Zornitza Stark Marked gene: ST5 as ready
Genetic Epilepsy v1.173 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.173 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Genetic Epilepsy v1.173 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Fetal anomalies v1.387 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Fetal anomalies v1.387 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.386 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
Congenital Heart Defect v0.451 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Congenital Heart Defect v0.451 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.450 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.214 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.214 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.213 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
Mendeliome v1.2819 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Mendeliome v1.2819 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark Marked gene: OGFRL1 as ready
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark gene: OGFRL1 was added
gene: OGFRL1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to 38699440
Phenotypes for gene: OGFRL1 were set to Cherubism (MONDO:0007315), OGFRL1-related
Review for gene: OGFRL1 was set to RED
Added comment: 3x individuals from 2 unrelated families with cherubism and homozygous NMD-predicted variants in OGFRL1. In one family, the NMD-predicted OGFRL1 variant was identified in 2x affected individuals and was either heterozygous or absent in 7x unaffected family members tested. OGFRL1 knockout mice and mice carrying a patient frameshift mutation were generated, however, neither mouse model recapitulated human cherubism. Absence of homozygous LoF variants in gnomAD v4.
Sources: Literature
Mendeliome v1.2818 OGFRL1 Zornitza Stark Marked gene: OGFRL1 as ready
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2818 OGFRL1 Zornitza Stark Classified gene: OGFRL1 as Red List (low evidence)
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2817 OGFRL1 Rylee Peters gene: OGFRL1 was added
gene: OGFRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to PMID: 38699440
Phenotypes for gene: OGFRL1 were set to Cherubism (MONDO:0007315), OGFRL1-related
Review for gene: OGFRL1 was set to RED
Added comment: 3x individuals from 2 unrelated families with cherubism and homozygous NMD-predicted variants in OGFRL1.

In one family, the NMD-predicted OGFRL1 variant was identified in 2x affected individuals and was either heterozygous or absent in 7x unaffected family members tested.

OGFRL1 knockout mice and mice carrying a patient frameshift mutation were generated, however, neither mouse model recapitulated human cherubism.

Absence of homozygous LoF variants in gnomAD v4.
Sources: Literature
Mendeliome v1.2817 FRYL Sarah Milton reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38479391; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v1.172 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to PMID: 40717498
Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related
Review for gene: ST5 was set to GREEN
Added comment: HGNC: DENND2B
Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10.

Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment).

In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.213 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to 40717498
Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related
Review for gene: ST5 was set to GREEN
Added comment: HGNC: DENND2B
Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10.

Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment).

In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect.
Sources: Literature
Mendeliome v1.2817 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to PMID: 40717498
Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related
Review for gene: ST5 was set to GREEN
Added comment: HGNC: DENND2B
Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10.

Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment).

In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect.
Sources: Literature
Genetic Epilepsy v1.172 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Optic Atrophy v1.45 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Leukodystrophy - paediatric v0.321 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.213 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Optic Atrophy v1.45 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Optic Atrophy. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Leukodystrophy - paediatric v0.321 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.213 BLOC1S1 Rylee Peters reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2817 BLOC1S1 Rylee Peters reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Repeat Disorders v0.267 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830, 37148549
Repeat Disorders v0.267 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319; 40459937; 39651830
Ataxia - adult onset v1.52 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319; 40459937; 39651830
Ataxia - adult onset v1.51 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830, 37148549
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Polydactyly v0.286 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Polydactyly v0.286 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Ciliopathies v1.76 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Ciliopathies v1.76 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2817 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Mendeliome v1.2817 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal Ciliopathies and Nephronophthisis v1.32 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Renal Ciliopathies and Nephronophthisis. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Polydactyly v0.285 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Polydactyly. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Ciliopathies v1.75 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Fetal anomalies v1.386 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Fetal anomalies v1.386 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2816 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Fetal anomalies v1.385 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.8 IKZF1 Peter McNaughton gene: IKZF1 was added
gene: IKZF1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF1 were set to PMID: 32654692
Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation
Review for gene: IKZF1 was set to GREEN
Added comment: ~30% of patients present with ALPS like autoimmunity +/- lymphoproliferation.
Sources: Literature
Mendeliome v1.2815 CHTF18 Zornitza Stark Marked gene: CHTF18 as ready
Mendeliome v1.2815 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2815 CHTF18 Zornitza Stark Phenotypes for gene: CHTF18 were changed from complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465 to Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Mendeliome v1.2814 CHTF18 Zornitza Stark Classified gene: CHTF18 as Green List (high evidence)
Mendeliome v1.2814 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2813 CHTF18 Zornitza Stark reviewed gene: CHTF18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO#0700092, CHTF18-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.213 CHTF18 Zornitza Stark Marked gene: CHTF18 as ready
Intellectual disability syndromic and non-syndromic v1.213 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.213 CHTF18 Zornitza Stark Phenotypes for gene: CHTF18 were changed from complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465 to Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Intellectual disability syndromic and non-syndromic v1.212 CHTF18 Zornitza Stark Classified gene: CHTF18 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.212 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.211 CHTF18 Zornitza Stark edited their review of gene: CHTF18: Changed phenotypes: Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Intellectual disability syndromic and non-syndromic v1.211 CHTF18 Zornitza Stark reviewed gene: CHTF18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Marked gene: PIK3R1 as ready
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Phenotypes for gene: PIK3R1 were changed from APDS to Immunodeficiency 36, MIM# 616005
Autoimmune Lymphoproliferative Syndrome v1.7 PIK3R1 Zornitza Stark Classified gene: PIK3R1 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.7 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Marked gene: PIK3CD as ready
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Gene: pik3cd has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Phenotypes for gene: PIK3CD were changed from APDS to Immunodeficiency 14B, autosomal recessive, MIM# 619281; Immunodeficiency 14A, autosomal dominant, MIM# 615513
Autoimmune Lymphoproliferative Syndrome v1.5 PIK3CD Zornitza Stark Classified gene: PIK3CD as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.5 PIK3CD Zornitza Stark Gene: pik3cd has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Marked gene: NFKB1 as ready
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576
Autoimmune Lymphoproliferative Syndrome v1.3 NFKB1 Zornitza Stark Classified gene: NFKB1 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.3 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Marked gene: NFKB2 as ready
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577
Autoimmune Lymphoproliferative Syndrome v1.1 NFKB2 Zornitza Stark Classified gene: NFKB2 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.1 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.211 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Intellectual disability syndromic and non-syndromic v1.210 KDM2B Zornitza Stark reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40420380; Phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2813 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Marked gene: KDM2B as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Gene: kdm2b has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Classified gene: KDM2B as Green List (high evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Gene: kdm2b has been classified as Green List (High Evidence).
Callosome v0.547 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Callosome v0.547 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Callosome v0.547 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Callosome v0.547 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2812 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2812 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Microcephaly v1.320 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Microcephaly v1.320 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Microcephaly v1.320 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Microcephaly v1.320 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Callosome v0.546 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Callosome. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Fetal anomalies v1.384 PDCD6IP Zornitza Stark Publications for gene: PDCD6IP were set to 32286682
Fetal anomalies v1.383 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Fetal anomalies v1.383 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Fetal anomalies v1.382 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Added comment: Additional individual with homozygous truncating variant, mild ID, microcephaly and mild thrombocytopenia.
p.Arg322* - present in gnomAD (NFE AF - 0.0006%).; Changed rating: GREEN; Changed publications: https://doi.org/10.1111/cge.70025
Microcephaly v1.319 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.209 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Genetic Epilepsy v1.171 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.209 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.209 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.208 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Added comment: Additional individual with homozygous truncating variant, mild ID, microcephaly and mild thrombocytopenia.
p.Arg322* - present in gnomAD (NFE AF - 0.0006%).; Changed rating: GREEN; Changed publications: https://doi.org/10.1111/cge.70025
Mendeliome v1.2811 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Microcephaly v1.319 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Microcephaly v1.319 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.148 KDM2B Lucy Spencer gene: KDM2B was added
gene: KDM2B was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 40420380; 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#0700092, KDM2B-related
Review for gene: KDM2B was set to GREEN
Added comment: 5/19 patients with variants in the CxxC domain were reported to have unilateral renal agenesis along with the typical syndromic ID phenotype associated with this gene.
Sources: Literature
Mendeliome v1.2811 KDM2B Lucy Spencer reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40420380; Phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2811 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Mendeliome v1.2811 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.0 NFKB2 Peter McNaughton gene: NFKB2 was added
gene: NFKB2 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: NFKB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFKB2 were set to PMID: 39644063
Review for gene: NFKB2 was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 NFKB1 Peter McNaughton gene: NFKB1 was added
gene: NFKB1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: NFKB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFKB1 were set to PMID: 39644063
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 PIK3CD Peter McNaughton gene: PIK3CD was added
gene: PIK3CD was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: PIK3CD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PIK3CD were set to PMID: 39644063
Phenotypes for gene: PIK3CD were set to APDS
Review for gene: PIK3CD was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 PIK3R1 Peter McNaughton gene: PIK3R1 was added
gene: PIK3R1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: PIK3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3R1 were set to PMID: 39644063
Phenotypes for gene: PIK3R1 were set to APDS
Review for gene: PIK3R1 was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Cardiac conduction disease v1.0 POPDC2 Bryony Thompson Marked gene: POPDC2 as ready
Cardiac conduction disease v1.0 POPDC2 Bryony Thompson Gene: popdc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.208 CHTF18 Sangavi Sivagnanasundram gene: CHTF18 was added
gene: CHTF18 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CHTF18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHTF18 were set to 40717333
Phenotypes for gene: CHTF18 were set to complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465
Review for gene: CHTF18 was set to AMBER
Added comment: Only two individuals reported with ID/DD:
1 - 9M with DD, autism and seizures. De novo variant identified - p.Leu355Val
2 - 23month F with congenital bilateral ventriculomegaly status post ventriculoperitoneal shunt placement, epilepsy, right eye optic nerve hypoplasia, hypotonic cerebral palsy complicated by left hip subluxation, and G-tube dependence. De novo variant identified - p.His645Pro
3 - 3F presenting with global DD, hypotonia, seizure and abnormal brain MRI. De novo variant identified - p.Leu676Arg
Sources: Literature
Mendeliome v1.2810 CHTF18 Sangavi Sivagnanasundram gene: CHTF18 was added
gene: CHTF18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHTF18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHTF18 were set to 40717333
Phenotypes for gene: CHTF18 were set to complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465
Review for gene: CHTF18 was set to GREEN
Added comment: >5 unrelated individuals with a rare missense variant in the gene have been identified by the authors however the clinical details were presented on three.
3 different de novo missense variants were identified

3 individuals - neurodevelopment delay, epilepsy, de novo:
1 - 9M with DD, autism and seizures. De novo variant identified - p.Leu355Val
2 - 23month F with congenital bilateral ventriculomegaly status post ventriculoperitoneal shunt placement, epilepsy, right eye optic nerve hypoplasia, hypotonic cerebral palsy complicated by left hip subluxation, and G-tube dependence. De novo variant identified - p.His645Pro
3 - 3F presenting with global DD, hypotonia, seizure and abnormal brain MRI. De novo variant identified - p.Leu676Arg
Sources: Literature
Microcephaly v1.318 PDCD6IP Sangavi Sivagnanasundram reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1111/cge.70025; Phenotypes: Neurodevelopmental disorder with microcephaly MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2810 PDCD6IP Sangavi Sivagnanasundram reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1111/cge.70025; Phenotypes: Neurodevelopmental disorder with microcephaly MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2810 SLC44A1 Zornitza Stark Phenotypes for gene: SLC44A1 were changed from progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria to Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868
Mendeliome v1.2809 SLC44A1 Zornitza Stark edited their review of gene: SLC44A1: Changed rating: GREEN; Changed phenotypes: Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Disorders of Glycosylation v1.68 SLC37A4 Zornitza Stark Publications for gene: SLC37A4 were set to 32884905; 33728255
Intellectual disability syndromic and non-syndromic v1.208 SV2A Zornitza Stark Publications for gene: SV2A were set to PMID: 37985816
Intellectual disability syndromic and non-syndromic v1.207 SV2A Ava Stevenson reviewed gene: SV2A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36350923, 37861890; Phenotypes: Developmental and epileptic encephalopathy 113 (MIM#620772), AR, Neurodevelopmental disorder, MONDO:0700092, SV2A-related, AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Repeat Disorders v0.266 THAP11_SCA51_CAG Bryony Thompson changed review comment from: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual. A 46/29 CAG THAP11 genotype has also been identified in an individual with ataxia of European ancestry, that also had a CACNA1A pathogenic expansion which causes SCA6. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease.
Further probands/families are required to confirm the gene-disease association.
Sources: Other; to: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual and the number of CAA interruptions had been reduced from 5/6 to 3. Expanded alleles have been identified in individuals with neurodevelopmental phenotypes, other neurodegenerative phenotypes, and an individual with ataxia who also had a CACNA1A (SCA6) pathogenic expansion. However, all these individuals had 5/6 CAA interruptions instead of 3 that were reported in the initial Chinese families. Suggesting the number of CAA interruptions is associated with pathogenicity of the repeat expansion. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease. Further probands/families are required to confirm the gene-disease association.
Sources: Other
Repeat Disorders v0.266 THAP11_SCA51_CAG Bryony Thompson Phenotypes for STR: THAP11_SCA51_CAG were changed from Spinocerebellar ataxia 51, MIM# 620947 to Spinocerebellar ataxia 51 MONDO:0975800
Repeat Disorders v0.265 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830; Changed phenotypes: Spinocerebellar ataxia 51 MONDO:0975800
Ataxia - adult onset v1.51 THAP11_SCA51_CAG Bryony Thompson Phenotypes for STR: THAP11_SCA51_CAG were changed from Spinocerebellar ataxia 51, MIM# 620947 to Spinocerebellar ataxia 51 MONDO:0975800
Repeat Disorders v0.265 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319; 37148549; 39651830
Ataxia - adult onset v1.50 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319
Ataxia - adult onset v1.49 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830; Changed phenotypes: Spinocerebellar ataxia 51 MONDO:0975800
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Liver Failure_Paediatric v1.25 ERCC1 Zornitza Stark gene: ERCC1 was added
gene: ERCC1 was added to Liver Failure_Paediatric. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
Ataxia - adult onset v1.49 THAP11_SCA51_CAG Bryony Thompson changed review comment from: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual. A 46/29 CAG THAP11 genotype has also been identified in an individual with ataxia of European ancestry, that also had a CACNA1A pathogenic expansion which causes SCA6. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease. Further probands/families are required to confirm the gene-disease association.
Sources: Literature; to: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual and the number of CAA interruptions had been reduced from 5/6 to 3. Expanded alleles have been identified in individuals with neurodevelopmental phenotypes, other neurodegenerative phenotypes, and an individual with ataxia who also had a CACNA1A (SCA6) pathogenic expansion. However, all these individuals had 5/6 CAA interruptions instead of 3 that were reported in the initial Chinese families. Suggesting the number of CAA interruptions is associated with pathogenicity of the repeat expansion. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease. Further probands/families are required to confirm the gene-disease association.
Sources: Literature
Growth failure v1.78 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Growth failure v1.78 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Growth failure v1.78 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Growth failure v1.78 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Mendeliome v1.2809 ERCC1 Zornitza Stark Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554 to Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554; Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Mendeliome v1.2808 ERCC1 Zornitza Stark Publications for gene: ERCC1 were set to 17273966; 23623389; 33315086
Cholestasis v1.1 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Cholestasis v1.1 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Cholestasis v1.1 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Cholestasis v1.1 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.171 ATG2A Zornitza Stark Marked gene: ATG2A as ready
Genetic Epilepsy v1.171 ATG2A Zornitza Stark Gene: atg2a has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.171 ATG2A Zornitza Stark commented on gene: ATG2A: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence.
Genetic Epilepsy v1.171 ATG2A Zornitza Stark gene: ATG2A was added
gene: ATG2A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to 40631414
Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038
Review for gene: ATG2A was set to RED
Added comment: Sources: Literature
Regression v0.583 ATG2A Zornitza Stark Marked gene: ATG2A as ready
Regression v0.583 ATG2A Zornitza Stark Gene: atg2a has been classified as Red List (Low Evidence).
Regression v0.583 ATG2A Zornitza Stark gene: ATG2A was added
gene: ATG2A was added to Regression. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to 40631414
Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038
Review for gene: ATG2A was set to RED
Added comment: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence.
Sources: Literature
Fetal anomalies v1.382 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Fetal anomalies v1.382 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Fetal anomalies v1.382 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Fetal anomalies v1.382 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Fetal anomalies v1.381 SMAD5 Zornitza Stark gene: SMAD5 was added
gene: SMAD5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
Review for gene: SMAD5 was set to GREEN
Added comment: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2807 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Mendeliome v1.2807 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.449 SMAD5 Sarah Milton gene: SMAD5 was added
gene: SMAD5 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to PMID: 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
Penetrance for gene: SMAD5 were set to Incomplete
Review for gene: SMAD5 was set to GREEN
Added comment: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton gene: SMAD5 was added
gene: SMAD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to PMID: 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
Penetrance for gene: SMAD5 were set to Incomplete
Review for gene: SMAD5 was set to GREEN
Added comment: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Marked gene: TNFRSF11B as ready
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Marked gene: TNFRSF11B as ready
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Classified gene: TNFRSF11B as Green List (high evidence)
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.4 TNFRSF11B Bryony Thompson gene: TNFRSF11B was added
gene: TNFRSF11B was added to Osteogenesis Imperfecta and Osteoporosis. Sources: Literature
Mode of inheritance for gene: TNFRSF11B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TNFRSF11B were set to 24743232; 40735895; 29578045; 33559312; 33989379; 35412619; 14672344
Phenotypes for gene: TNFRSF11B were set to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Review for gene: TNFRSF11B was set to GREEN
gene: TNFRSF11B was marked as current diagnostic
Added comment: Fractures and osteoporosis can be a features of both Paget disease and chondrocalcinosis. Biallelic loss-of-function variants cause Paget disease, and a single monoallelic recurrent stoploss variant is associated with chondrocalcinosis.
Sources: Literature
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Phenotypes for gene: TNFRSF11B were changed from Paget disease of bone 5, juvenile-onset 239000; Paget disease of bone 5, juvenile-onset 239000 to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Skeletal dysplasia v0.312 TNFRSF11B Bryony Thompson Publications for gene: TNFRSF11B were set to
Skeletal dysplasia v0.311 TNFRSF11B Bryony Thompson Mode of inheritance for gene: TNFRSF11B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v0.310 TNFRSF11B Bryony Thompson reviewed gene: TNFRSF11B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24743232, 40735895, 29578045, 33559312, 33989379, 35412619; Phenotypes: chondrocalcinosis 1 MONDO:0010917; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2806 TNFRSF11B Bryony Thompson Publications for gene: TNFRSF11B were set to 14672344
Mendeliome v1.2805 TNFRSF11B Bryony Thompson Phenotypes for gene: TNFRSF11B were changed from Paget disease of bone 5, juvenile-onset, MIM# 239000 to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Mendeliome v1.2804 TNFRSF11B Bryony Thompson Mode of inheritance for gene: TNFRSF11B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2803 TNFRSF11B Bryony Thompson reviewed gene: TNFRSF11B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24743232, 40735895, 29578045, 33559312, 33989379, 35412619; Phenotypes: chondrocalcinosis 1 MONDO:0010917; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal Tubulopathies and related disorders v1.18 ATP6V0A4 Krithika Murali Marked gene: ATP6V0A4 as ready
Renal Tubulopathies and related disorders v1.18 ATP6V0A4 Krithika Murali Gene: atp6v0a4 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.18 ATP6V0A4 Krithika Murali reviewed gene: ATP6V0A4: Rating: RED; Mode of pathogenicity: None; Publications: PMID:40299568; Phenotypes: Renal tubular acidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATP6V0A4 Krithika Murali reviewed gene: ATP6V0A4: Rating: RED; Mode of pathogenicity: None; Publications: PMID:40299568; Phenotypes: Renal tubular acidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATG2A Krithika Murali Marked gene: ATG2A as ready
Mendeliome v1.2803 ATG2A Krithika Murali Gene: atg2a has been classified as Red List (Low Evidence).
Mendeliome v1.2803 ATG2A Krithika Murali gene: ATG2A was added
gene: ATG2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to PMID:40631414
Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038
Review for gene: ATG2A was set to RED
Added comment: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence.
Sources: Literature
Mendeliome v1.2802 CFAP43 Zornitza Stark Classified gene: CFAP43 as Amber List (moderate evidence)
Mendeliome v1.2802 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 CFAP43 Zornitza Stark edited their review of gene: CFAP43: Added comment: DISPUTED by ClinGen for biallelic association with PCD.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliary Dyskinesia v1.55 CFAP43 Zornitza Stark Classified gene: CFAP43 as Amber List (moderate evidence)
Ciliary Dyskinesia v1.55 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Amber List (Moderate Evidence).
Ciliary Dyskinesia v1.54 CFAP43 Zornitza Stark Tag disputed tag was added to gene: CFAP43.
Ciliary Dyskinesia v1.54 CFAP43 Zornitza Stark edited their review of gene: CFAP43: Added comment: DISPUTED by ClinGen for biallelic disease.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliary Dyskinesia v1.54 DNAH6 Zornitza Stark Classified gene: DNAH6 as Red List (low evidence)
Ciliary Dyskinesia v1.54 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Red List (Low Evidence).
Ciliary Dyskinesia v1.53 DNAH6 Zornitza Stark commented on gene: DNAH6: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH6 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:008758.
Ciliary Dyskinesia v1.53 DNAH6 Zornitza Stark edited their review of gene: DNAH6: Added comment: DISPUTED by ClinGen.; Changed rating: RED
Ciliary Dyskinesia v1.53 DNAH8 Zornitza Stark Classified gene: DNAH8 as Red List (low evidence)
Ciliary Dyskinesia v1.53 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Red List (Low Evidence).
Ciliary Dyskinesia v1.52 DNAH8 Zornitza Stark Tag disputed tag was added to gene: DNAH8.
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Marked gene: NFIA as ready
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Classified gene: NFIA as Green List (high evidence)
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.196 NFIA Zornitza Stark gene: NFIA was added
gene: NFIA was added to Polymicrogyria and Schizencephaly. Sources: Expert Review
Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIA were set to 27081522; 28452798; 33973697; 36553517
Phenotypes for gene: NFIA were set to Brain malformations with or without urinary tract defects, MIM#613735
Review for gene: NFIA was set to GREEN
Added comment: Spectrum of brain malformations reported in multiple inviduals including polymicrogyria.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Marked gene: RNU5A-1 as ready
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Marked gene: RNU5A-1 as ready
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Classified gene: RNU5A-1 as Amber List (moderate evidence)
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Classified gene: RNU5A-1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2800 RNU5A-1 Zornitza Stark gene: RNU5A-1 was added
gene: RNU5A-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder (MONDO:0700092), RNU5A-1 related
Review for gene: RNU5A-1 was set to AMBER
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.206 RNU5A-1 Zornitza Stark gene: RNU5A-1 was added
gene: RNU5A-1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder (MONDO:0700092), RNU5A-1 related
Review for gene: RNU5A-1 was set to AMBER
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Mendeliome v1.2799 AMFR Zornitza Stark Phenotypes for gene: AMFR were changed from Spastic paraplegia 89, autosomal recessive, MIM# 620379 to Spastic paraplegia 89, autosomal recessive, MIM# 620379; Inborn error of immunity, MONDO:0003778, AMFR-related
Mendeliome v1.2798 AMFR Zornitza Stark Publications for gene: AMFR were set to 37119330
Mendeliome v1.2797 AMFR Zornitza Stark edited their review of gene: AMFR: Added comment: PMID 38277122:

Single case report of 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, haemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. HLH was the working diagnosis. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy.

Rare monoallelic variant in autocrine motility factor receptor (AMFR) identified. AMFR encodes a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway.

Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans.

RED for this association.; Changed publications: 38277122; Changed phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379, Inborn error of immunity, MONDO:0003778, AMFR-related
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark Marked gene: AMFR as ready
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark Gene: amfr has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark gene: AMFR was added
gene: AMFR was added to Disorders of immune dysregulation. Sources: Expert Review
Mode of inheritance for gene: AMFR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMFR were set to 38277122
Phenotypes for gene: AMFR were set to Inborn error of immunity, MONDO:0003778, AMFR-related
Review for gene: AMFR was set to RED
Added comment: Single case report of 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, haemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. HLH was the working diagnosis. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy.

Rare monoallelic variant in autocrine motility factor receptor (AMFR) identified. AMFR encodes a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway.

Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans.
Sources: Expert Review
Mendeliome v1.2797 ASXL1 Zornitza Stark Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome , MIM#605039 to Bohring-Opitz syndrome , MIM#605039; Combined immunodeficiency, MONDO:0015131, ASXL1-related
Mendeliome v1.2796 ASXL1 Zornitza Stark Publications for gene: ASXL1 were set to 29446906; 21706002
Mendeliome v1.2795 ASXL1 Zornitza Stark edited their review of gene: ASXL1: Added comment: PMID 40742536. Single individual with biallelic variants reported. The patient had a history of haematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction.

Note mono allelic variants are associated with Bohring Opitz syndrome and somatic variants are associated with clonal haematopoiesis.

RED for biallelic association.; Changed publications: 29446906, 21706002, 40742536; Changed phenotypes: Bohring-Opitz syndrome , MIM#605039, Combined immunodeficiency, MONDO:0015131, ASXL1-related
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark Marked gene: ASXL1 as ready
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark Gene: asxl1 has been classified as Red List (Low Evidence).
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark gene: ASXL1 was added
gene: ASXL1 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: ASXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASXL1 were set to 40742536
Phenotypes for gene: ASXL1 were set to Combined immunodeficiency, MONDO:0015131, ASXL1-related
Review for gene: ASXL1 was set to RED
Added comment: Single individual with biallelic variants reported. The patient had a history of haematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction.

Note mono allelic variants are associated with Bohring Opitz syndrome and somatic variants are associated with clonal haematopoiesis.
Sources: Literature
Mendeliome v1.2795 RCC1 Zornitza Stark Marked gene: RCC1 as ready
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2795 RCC1 Zornitza Stark Classified gene: RCC1 as Green List (high evidence)
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2794 RCC1 Zornitza Stark gene: RCC1 was added
gene: RCC1 was added to Mendeliome. Sources: Expert Review
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 Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related
Review for gene: RCC1 was set to GREEN
Added comment: 24 individuals from 12 families reported with severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]).

Eight biallelic missense variants in RCC1 identified.

Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients.

The RCC1 variants coded for proteins that alter GDP-to-GTP exchange activity and had reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.
Sources: Expert Review
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Marked gene: RCC1 as ready
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Classified gene: RCC1 as Green List (high evidence)
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Hereditary Neuropathy_CMT - isolated v1.59 RCC1 Zornitza Stark gene: RCC1 was added
gene: RCC1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Expert list
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 Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related
Review for gene: RCC1 was set to GREEN
Added comment: 24 individuals from 12 families reported with severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]).

Eight biallelic missense variants in RCC1 identified.

Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients.

The RCC1 variants coded for proteins that alter GDP-to-GTP exchange activity and had reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.
Sources: Expert list
Growth failure v1.77 ERCC1 Sarah Milton gene: ERCC1 was added
gene: ERCC1 was added to Growth failure. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to PMID: 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
Cholestasis v1.0 ERCC1 Sarah Milton gene: ERCC1 was added
gene: ERCC1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to PMID: 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
Mendeliome v1.2793 ERCC1 Sarah Milton reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40684071; Phenotypes: Hepatorenal syndrome, MONDO:0001382, ERCC1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2793 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism to Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2792 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284
Mendeliome v1.2791 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: Association with RP:
PMID 37768732: 4 individuals from three unrelated families with bi-allelic variants as per review by Achchuthan Shamugasundram. Some supportive functional data. PMID 39930170: fourth family reported.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170; Changed phenotypes: Orofaciodigital syndrome type IX, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.175 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.174 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 37768732; 39930170
Phenotypes for gene: TBC1D32 were set to Retinitis pigmentosa 100, MIM# 621280
Review for gene: TBC1D32 was set to GREEN
Added comment: PMID 37768732: 4 individuals from three unrelated families with bi-allelic variants. Some supportive functional data.
PMID 39930170: fourth family reported.

Biallelic variants in this gene are also associated with a multi-system ciliopathy.
Sources: Expert Review
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Marked gene: DNHD1 as ready
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Classified gene: DNHD1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark edited their review of gene: DNHD1: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark gene: DNHD1 was added
gene: DNHD1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNHD1 were set to 34932939
Phenotypes for gene: DNHD1 were set to Spermatogenic failure 65, MIM# 619712
Added comment: Biallelic DNHD1 variants identified in 8 unrelated probands with asthenoteratozoospermia, reduced sperm motility and abnormal sperm morphology. DNHD1 knockout mice were infertile and had significantly reduced sperm concentration and motility rates, consistent with human individuals.
Sources: Literature
Genetic Epilepsy v1.170 BSN Zornitza Stark Phenotypes for gene: BSN were changed from Epilepsy MONDO:0005027 to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Genetic Epilepsy v1.169 BSN Zornitza Stark edited their review of gene: BSN: Added comment: Guzman et al 2025: Described 12 additional patients with missense (3/12) and premature termination variants (9/12) which included de novo and inherited variants, suggesting incomplete penetrance.

They assessed all reported patients (n=29) which revealed common clinical characteristics including epilepsy(13/29), febrile seizures (7/29), generalised tonic-clonic seizures (5/29), and focal-onset seizures (3/29). Behavioural phenotypes were present in almost half of all individuals (14/29), which included ADHD (7/29) and autistic behaviour (5/29). Additional common features included developmental delay (11/29), obesity (10/29), and delayed speech (8/29). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29).; Changed rating: GREEN; Changed publications: 40393460; Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), BSN-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2791 BSN Zornitza Stark Phenotypes for gene: BSN were changed from Epilepsy MONDO:0005027 to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Mendeliome v1.2790 BSN Zornitza Stark edited their review of gene: BSN: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), BSN-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Marked gene: BSN as ready
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.204 BSN Zornitza Stark gene: BSN was added
gene: BSN was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: BSN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BSN were set to 40393460
Phenotypes for gene: BSN were set to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Review for gene: BSN was set to GREEN
Added comment: Guzman et al 2025: Described 12 additional patients with missense (3/12) and premature termination variants (9/12) which included de novo and inherited variants, suggesting incomplete penetrance.

They assessed all reported patients (n=29) which revealed common clinical characteristics including epilepsy(13/29), febrile seizures (7/29), generalised tonic-clonic seizures (5/29), and focal-onset seizures (3/29). Behavioural phenotypes were present in almost half of all individuals (14/29), which included ADHD (7/29) and autistic behaviour (5/29). Additional common features included developmental delay (11/29), obesity (10/29), and delayed speech (8/29). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29).
Sources: Expert Review
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Marked gene: FGF10 as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Gene: fgf10 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Classified gene: FGF10 as Green List (high evidence)
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Gene: fgf10 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.88 FGF10 Zornitza Stark gene: FGF10 was added
gene: FGF10 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Expert list
Mode of inheritance for gene: FGF10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF10 were set to 30639323; 30429870; 9916808
Phenotypes for gene: FGF10 were set to Lacrimoauriculodentodigital (LAAD) syndrome - pulmonary hypoplasia
Review for gene: FGF10 was set to GREEN
Added comment: Association with pulmonary hypoplasia and interstitial lung disease reported in multiple families.
Sources: Expert list
Mendeliome v1.2790 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Mendeliome v1.2789 NR6A1 Zornitza Stark reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, NR6A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.148 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.147 NR6A1 Zornitza Stark reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, NR6A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Anophthalmia_Microphthalmia_Coloboma v1.47 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Anophthalmia_Microphthalmia_Coloboma v1.46 NR6A1 Zornitza Stark reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, NR6A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.380 NR6A1 Zornitza Stark Marked gene: NR6A1 as ready
Fetal anomalies v1.380 NR6A1 Zornitza Stark Gene: nr6a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.380 NR6A1 Zornitza Stark Classified gene: NR6A1 as Green List (high evidence)
Fetal anomalies v1.380 NR6A1 Zornitza Stark Gene: nr6a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.379 NR6A1 Zornitza Stark gene: NR6A1 was added
gene: NR6A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 39606382
Phenotypes for gene: NR6A1 were set to Syndromic disease, MONDO:0002254, NR6A1-related
Review for gene: NR6A1 was set to GREEN
Added comment: 6 unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) with incomplete penetrance and variable expressivity. Colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities characterised the phenotype of the families. Also, supporting zebrafish model. Loss of function is the expected mechanism of disease.
Sources: Literature
Mendeliome v1.2789 BSN Lauren Rogers reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 40393460; Phenotypes: Epilepsy (MONDO:0005027), BSN-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Stroke v1.23 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Stroke v1.23 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Stroke v1.23 NOTCH2 Zornitza Stark Classified gene: NOTCH2 as Green List (high evidence)
Stroke v1.23 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Stroke v1.22 NOTCH2 Zornitza Stark gene: NOTCH2 was added
gene: NOTCH2 was added to Stroke. Sources: Expert Review
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to 30761079; 38400955; 25465847
Phenotypes for gene: NOTCH2 were set to Alagille syndrome 2 610205
Review for gene: NOTCH2 was set to GREEN
Added comment: Multiple reports of vascular abnormalities and stroke in Alagille syndrome, can be difficult to diagnose clinically.
Sources: Expert Review
Stroke v1.21 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Stroke v1.21 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Stroke v1.21 JAG1 Zornitza Stark Classified gene: JAG1 as Green List (high evidence)
Stroke v1.21 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Stroke v1.20 JAG1 Zornitza Stark gene: JAG1 was added
gene: JAG1 was added to Stroke. Sources: Expert Review
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 30761079; 38400955; 25465847
Phenotypes for gene: JAG1 were set to Alagille syndrome 1, MIM# 118450
Review for gene: JAG1 was set to GREEN
Added comment: Multiple reports of vascular abnormalities and stroke in Alagille syndrome, can be difficult to diagnose clinically.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Marked gene: SMAD6 as ready
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Gene: smad6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Classified gene: SMAD6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Gene: smad6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Marked gene: DNAH10 as ready
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Classified gene: DNAH10 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.6 DNAH10 Zornitza Stark gene: DNAH10 was added
gene: DNAH10 was added to Infertility and Recurrent Pregnancy Loss. Sources: Expert list
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to Spermatogenic failure 56, MIM# 619515
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Expert list
Intellectual disability syndromic and non-syndromic v1.202 CRBN Elena Savva Phenotypes for gene: CRBN were changed from Intellectual developmental disorder, autosomal recessive 2, MIM# 607417 to Intellectual developmental disorder, autosomal recessive 2, MIM# 607417
Intellectual disability syndromic and non-syndromic v1.202 CRBN Elena Savva Phenotypes for gene: CRBN were changed from Mental retardation, autosomal recessive 2, MIM# 607417 to Intellectual developmental disorder, autosomal recessive 2, MIM# 607417
Intellectual disability syndromic and non-syndromic v1.201 CRBN Elena Savva Mode of inheritance for gene: CRBN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy - adult onset v0.150 C1R Zornitza Stark Classified gene: C1R as Green List (high evidence)
Leukodystrophy - adult onset v0.150 C1R Zornitza Stark Gene: c1r has been classified as Green List (High Evidence).
Mendeliome v1.2789 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Mendeliome v1.2789 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Mendeliome v1.2789 ZNF597 Zornitza Stark gene: ZNF597 was added
gene: ZNF597 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 19968752; 28157578; 32576657
Phenotypes for gene: ZNF597 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: ZNF597 was set to RED
Added comment: ZNF597 is an imprinted gene- maternally expressed and paternally imprinted.
- ZNF597 is highly expressed in the placenta and proposed to have an important role in placental development.
- Knockout ZNF597 mice (homozygous -/-) is embryonic lethal due to failed embryonic organization before cardiogenesis at embryonic day 7.5. This period is equivalent to human Carnegie Stage 9 that occurs during week 3 between 19 to 21 days (5 weeks' gestation).
- Literature associated with ZNF597 including maternal uniparental disomy of chromosome 16 (UPD(16)mat) or loss of paternal imprinting of ZNF59, resulting in an overexpression of ZNF597.
- Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy loss at 5-8 weeks' gestation.
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Classified gene: ZNF597 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Marked gene: ZFP36L2 as ready
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Classified gene: ZFP36L2 as Green List (high evidence)
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2787 ZFP36L2 Zornitza Stark gene: ZFP36L2 was added
gene: ZFP36L2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZFP36L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFP36L2 were set to 34611029; 38829516; 37211617
Phenotypes for gene: ZFP36L2 were set to Oocyte/zygote/embryo maturation arrest 13, MIM# 620154
Review for gene: ZFP36L2 was set to GREEN
Added comment: i) Literature in OMIM- PMID:34611029- x2 unrelated infertile Chinese women with defective oocyte maturation carrying different biallelic variants and functional analysis suggested that the variants cause maternal mRNA decay defects that result in female infertility.

ii) New papers reporting biallelic variants in conjunction with female infertility due to oocyte maturation defect+/- embryonic development arrest
- PMID: 38829516: Novel compound heterozygous variant (p.His62Gln and p.Pro290Leu) in a patient with oocyte maturation defect. These variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes.
- PMID: 37211617: Novel homozygous variant c.853_861del (p.285_287del) in the affected individual with oocyte maturation defect from a consanguineous family. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs
Sources: Expert list
Mendeliome v1.2786 WNT6 Zornitza Stark Marked gene: WNT6 as ready
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2786 WNT6 Zornitza Stark Classified gene: WNT6 as Amber List (moderate evidence)
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2785 WNT6 Zornitza Stark gene: WNT6 was added
gene: WNT6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: WNT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT6 were set to 36385415; 25750203
Phenotypes for gene: WNT6 were set to recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: WNT6 was set to AMBER
Added comment: i) PMID: 36385415- heterozygous missense variant (p.Arg70Gly) in a female with recurrent pregnancy loss (C21)

ii) PMID: 25750203- four novel heterozygous (checked Sanger traces) variants (i.e, one missense P.Leu148Arg, one synonymous c. 522C>T, one variant in intron 1 c. 297+40G>A, and one variant in the 3′UTR c. 1127G>A ) in 4 women with unexplained recurrent miscarriages (RM), but only the missense variant was shown to affect the functional region of WNT6 that might explain the unexplained RM

In effect, only 2 cases with limited other supporting data, hence Amber.
Sources: Expert list
Mendeliome v1.2784 USP26 Zornitza Stark Marked gene: USP26 as ready
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2784 USP26 Zornitza Stark Classified gene: USP26 as Amber List (moderate evidence)
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2783 USP26 Zornitza Stark edited their review of gene: USP26: Changed rating: AMBER
Mendeliome v1.2783 USP26 Zornitza Stark gene: USP26 was added
gene: USP26 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: USP26 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: USP26 were set to 34202084; 27089915
Phenotypes for gene: USP26 were set to Spermatogenic failure, X-linked 6, MIM# 301101
Added comment: i) PMID: 34202084- hemizygous missense variants in 2 unrelated affected Chinese men with infertility due to asthenoteratozoospermia (R825G in proband H002, and N799S in proband H042) and functional analysis showed markedly reduced USP26 mRNA and protein levels in patient sperm.

ii) PMID: 27089915- a novel hemizygous missense variant R344W in two affected Chinese men with non-obstructive azoospermia, which has been shown functionally to have reduce binding affinity and deubiquitinating activity of USP26 to androgen receptors.

Rated Amber as missense variants with little other supporting data.
Sources: Expert list
Mendeliome v1.2782 UBE2B Zornitza Stark Marked gene: UBE2B as ready
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2782 UBE2B Zornitza Stark Classified gene: UBE2B as Green List (high evidence)
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2781 UBE2B Zornitza Stark gene: UBE2B was added
gene: UBE2B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: UBE2B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UBE2B were set to 23378580; 26223869; 12784252
Phenotypes for gene: UBE2B were set to Male infertility, MONDO:0005372
Review for gene: UBE2B was set to GREEN
Added comment: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): Reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patients in the Chinese population, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Expert list
Mendeliome v1.2780 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2780 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2779 TIMP2 Zornitza Stark gene: TIMP2 was added
gene: TIMP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TIMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIMP2 were set to 20847186; 34756330
Phenotypes for gene: TIMP2 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: TIMP2 was set to AMBER
Added comment: i) PMID: 20847186- In family 6, TIMP2 partial duplication (involves Ex1-2) in mother and 4 out of 5 miscarriages. They have not yet been associated with RPL in humans, however, overexpression of TIMP2 was detected in a mouse model of RPL (Dixon et al., 2006). The TIMP2 disruption in miscarriages in Family 6 may have affected the placental development, but the possibility remains that maternal disruption of TIMP2 may contribute to RPL by impairing the remodeling of the endometrium in early pregnancy. Functional study was performed by PMID: 25674159, which showed reduced RNA and protein expression in chorionic villi cultures from miscarriages with the CNV.

ii) PMID: 34756330- de novo damaging heterozygous missense TIMP2 variant, c.[553G>A]; p.[Gly185Arg] in an eight-week euploid embryonic loss. The MMP2/TIMP2 complex is involved in several gestational processes including implantation and placentation.

iii) PMID: 11912288- The disruption of the TIMP2 gene was considered to be relevant for recurrent miscarriage due to its critical role in modulating invasion of the trophoblast into maternal endometrium and in vascular remodeling and angiogenesis of maternal and placenta tissues in the first trimester.
Sources: Expert list
Mendeliome v1.2778 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2778 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2777 TBPL2 Zornitza Stark gene: TBPL2 was added
gene: TBPL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TBPL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBPL2 were set to 37804378; 33966269; 33893736; 33541821
Phenotypes for gene: TBPL2 were set to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Review for gene: TBPL2 was set to GREEN
Added comment: New papers reporting biallelic variants in infertile women:
i) PMID: 37804378- Compound heterozygous novel p.Arg268Ter and recurrent p.Arg233Ter in a female with impaired ovarian folliculogenesis. Structure prediction by molecular modeling demonstrated that three-dimensional structure of TBPL2 was destabilized in mutant proteins.

ii) PMID: 33966269- Homozygous missense mutation p.C299R in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family. Functional assays showed that the transcriptional level of ZP3 was not completely blocked but severely reduced by the regulation of the mutant TBPL2, while the transcriptional level of H2Bc was significantly reduced but to a less severe extent compared with that of ZP3, suggesting that the missense had a damage to the transcription initiation function of TBPL2 and its downstream targeted genes got involved in different degrees. The mutant protein also has less stability, which contributes to the lower activity of transcription initiation in the mutant form.

iii) PMID: 33893736- Homozygous splicing variant (c.788 + 3A>G) in two unrelated families characterized by oocyte maturation defects. Functional assays showed that the variant disrupted the integrity of TBPL2 mRNA and affected oocytes showed that vital genes for oocyte maturation and fertilization were widely and markedly downregulated, suggesting that a mutation in TBPL2, led to global gene alterations in oocytes; the same variant reported before in PMID: 33541821 in three affected females with diminished ovarian reserve from 3 independent families.
Sources: Expert list
Mendeliome v1.2776 TACC3 Zornitza Stark Marked gene: TACC3 as ready
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2776 TACC3 Zornitza Stark Classified gene: TACC3 as Amber List (moderate evidence)
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2775 TACC3 Zornitza Stark gene: TACC3 was added
gene: TACC3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TACC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACC3 were set to 36395215
Phenotypes for gene: TACC3 were set to Female infertility due to oocyte meiotic arrest, MONDO:0044626
Review for gene: TACC3 was set to AMBER
Added comment: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Classified gene: SYCP3 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.3 SYCP3 Zornitza Stark reviewed gene: SYCP3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2774 RXFP2 Zornitza Stark Phenotypes for gene: RXFP2 were changed from Cryptorchidism to Infertility; cryptorchidism; non-obstructive azoospermia
Mendeliome v1.2773 RXFP2 Zornitza Stark Publications for gene: RXFP2 were set to 31167797; 20963592
Mendeliome v1.2772 RXFP2 Zornitza Stark Classified gene: RXFP2 as Green List (high evidence)
Mendeliome v1.2772 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Mendeliome v1.2771 RXFP2 Zornitza Stark edited their review of gene: RXFP2: Added comment: New literature PMID: 39222519- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.; Changed rating: GREEN; Changed publications: 31167797, 20963592, 39222519
Mendeliome v1.2771 PABPC1L Zornitza Stark Marked gene: PABPC1L as ready
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2771 PABPC1L Zornitza Stark Classified gene: PABPC1L as Green List (high evidence)
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2770 PABPC1L Zornitza Stark gene: PABPC1L was added
gene: PABPC1L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PABPC1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PABPC1L were set to 37052235; 37723834; 38177974; 32172300
Phenotypes for gene: PABPC1L were set to Oocyte/zygote/embryo maturation arrest 22, #MIM 621093
Review for gene: PABPC1L was set to GREEN
Added comment: i) Literature in OMIM (PMID: 37052235;37723834;38177974)- >3 unrelated infertile women (due to a mixed phenotype including oocyte maturation abnormalities, fertilization failure, and embryonic development arrest) with different biallelic variants

ii) Additional paper (PMID: 32172300)- Homozygous likely deleterious variant in PABPC1L p.(Met26Lys) in a woman whose infertility phenotype resembles that of Pabpc1l−/− mouse. During her IVF cycles, 18 oocytes were retrieved and subjected to IVF and ICSI. Nine oocytes were assigned to ICSI, but eight were at germinal vesicle stage and only one showed polar body and failed to fertilize following ICSI. Similarly, nine oocytes were assigned to IVF, and only two showed polar body on the next day without any sign of fertilization. The remaining oocytes were at germinal vesicle stage.
Sources: Expert list
Mendeliome v1.2769 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2769 NLRP14 Zornitza Stark Classified gene: NLRP14 as Amber List (moderate evidence)
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2768 NLRP14 Zornitza Stark gene: NLRP14 was added
gene: NLRP14 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NLRP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP14 were set to 38060382
Phenotypes for gene: NLRP14 were set to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Review for gene: NLRP14 was set to AMBER
Added comment: PMID: 38060382- Compound heterozygous variants (p.Cys428Profs∗28/p.Leu887delinsArgTyr) reported in an infertile woman with oocyte maturation defects and early embryo arrest (EEA).
- Functional analysis showed comparable protein levels compared with the wild-type control, although a truncated band of the expected size (47 kDa) was observed for the p.Cys428Profs∗28 variant.
-The truncated variant, p.Cys428Profs∗28, is lacking the LRR domain and, hence, completely loses the ability to bind with UHRF1. The p.Leu887delinsArgTyr variant results in significant alteration in binding modes with decreased binding area and binding free energy, which introduced regional instability in the NLRP14-UHRF1 interaction. The interaction of both variants and UHRF1 was disrupted and might lead to increased UHRF1 protein degradation in oocytes.
Sources: Expert list
Mendeliome v1.2767 MEI1 Zornitza Stark Marked gene: MEI1 as ready
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2767 MEI1 Zornitza Stark Classified gene: MEI1 as Green List (high evidence)
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2766 MEI1 Zornitza Stark gene: MEI1 was added
gene: MEI1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MEI1 were set to 30388401; 38416203; 34037756; 36759719; 32741963; 36017582
Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia
Review for gene: MEI1 was set to GREEN
Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others: PMID: 32741963;36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Expert list
Mendeliome v1.2765 MAJIN Zornitza Stark Marked gene: MAJIN as ready
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2765 MAJIN Zornitza Stark Classified gene: MAJIN as Amber List (moderate evidence)
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2764 MAJIN Zornitza Stark gene: MAJIN was added
gene: MAJIN was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MAJIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAJIN were set to 39545410; 33211200
Phenotypes for gene: MAJIN were set to Recurrent hydatidiform mole, non-obstructive azoospermia
Review for gene: MAJIN was set to AMBER
Added comment: New papers (biallelic variant for HM/male infertility):
i) PMID: 39545410- Novel homozygous splice donor site variant c.349+1G>T in patient 1824 (Italian) with 2 HMs followed by secondary infertility and substantially reduced bilateral ovarian volumes. MAJIN codes for a junction protein that forms a complex with TERB1 and TERB2, which together bind to telomeres and anchor them to the inner nuclear membrane components KASH5 and SUN1. This attachment of chromosomes to the nuclear envelope is essential for homologous chromosome movement and synapsis. In mice, both male and female null mutants Majin are infertile (PMID: 26548954). In humans, biallelic mutations in MAJIN have been reported in infertile males.

ii) PMID: 33211200- A homozygous p.Arg53His in NOA-affected male (Individual 4- M1646) with high CADD scores and low gnomad freq. Mice disrupted for either Majin or Terb2 display impaired synapsis, zygotene arrest, a lack of postmeiotic cells and infertility (Shibuya et al. 2015; Zhang et al. 2017).
Sources: Expert list
Mendeliome v1.2763 LHX8 Zornitza Stark Marked gene: LHX8 as ready
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Mendeliome v1.2763 LHX8 Zornitza Stark Classified gene: LHX8 as Green List (high evidence)
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Classified gene: KPNA7 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.2 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, #MIM 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2762 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2762 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2761 KIAA1683 Zornitza Stark gene: KIAA1683 was added
gene: KIAA1683 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KIAA1683 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1683 were set to 36321563; 39872118; 37140151; 37184908; 40437858
Phenotypes for gene: KIAA1683 were set to Spermatogenic failure 78, #MIM 620170
Review for gene: KIAA1683 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 36321563, 39872118, 37140151, 37184908 (>3 unrelated Chinese men with infertility due to spermatogenic failure with hom/com het variants).

New paper: i) PMID: 40437858 (2025)- novel hom p.Trp796Ter in infertile man with fertilization failure and history of two miscarriages with his partner. According to the prediction of protein conformations, it was found that the protein conformations were truncated in the mutated IQCN gene, which probably affected the function of the patient's sperm.
Sources: Expert list
Mendeliome v1.2760 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2760 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2759 KCNU1 Zornitza Stark gene: KCNU1 was added
gene: KCNU1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNU1 were set to 34980136; 35551387; 20138882; 21427226; 25271166; 35551387
Phenotypes for gene: KCNU1 were set to Spermatogenic failure 79, #MIM 620196
Review for gene: KCNU1 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 34980136, 35551387- 3 unrelated male with spermatogenic failure with different homozygous variants, supported by functional evidence; PubMed: 20138882, 21427226, 25271166- Slo3 -/- KO mice were infertile, 35551387- mice with homozygous H720R variant, corresponding to the human H715R variant recapitulated human phenotype.
Sources: Expert list
Mendeliome v1.2758 GGN Zornitza Stark Classified gene: GGN as Green List (high evidence)
Mendeliome v1.2758 GGN Zornitza Stark Gene: ggn has been classified as Green List (High Evidence).
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Changed rating: GREEN
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Added comment: PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.; Changed publications: 31985809, 33108537, 23451117; Changed phenotypes: Spermatogenic failure 69, MIM# 619826
Infertility and Recurrent Pregnancy Loss v1.2 GGN Zornitza Stark reviewed gene: GGN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2757 FOXD1 Zornitza Stark Marked gene: FOXD1 as ready
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2757 FOXD1 Zornitza Stark Classified gene: FOXD1 as Green List (high evidence)
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2756 FOXD1 Zornitza Stark gene: FOXD1 was added
gene: FOXD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FOXD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXD1 were set to 27805902; 31395028
Phenotypes for gene: FOXD1 were set to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
Review for gene: FOXD1 was set to GREEN
Added comment: i) PMID: 27805902- 18 heterozygous (only 10 were nonsynonymous) variants were identified only in recurrent spontaneous abortion (RSA) patients (total of 33 patients) not seen in ctrl group, and only 3 variants had functional assays performed- p.Ala356Gly (x1 patient),p.Ile364Met (x2 patients), and p.Ins429AlaAla (x12 patients). In vitro assays revealed they had a functional effect as they led to perturbations in FOXD1 transactivation properties on promoters of the Placental Growth Factor (PGF) and the complement component gene (C3) having key roles during implantation/placentation.

ii) PMID: 31395028- 9 heterozygous non-synonymous variants in patients affected by PE, IUGR, RPL and repeated implantation failure (RIF) , two of which (p.His267Tyr found in one RIF patient and p.Arg57del in one IUGR woman) represented novel and coherent candidates for in vitro testing. Functional experiments revealed that both led to an increased C3 (complement C3) promoter transcriptional activity. Also found increased FOXD1-p.Arg57del variant transactivation capacity on the PlGF (placental growth factor) promoter.The FOXD1 p.Ala356Gly and p.Ile364Met variants (previously found in RPL patients in PMID: 27805902) have also been identified in the present work in women with PE and IUGR and with isolated IUGR, respectively.

Documented in FeRGI database- limited evidence for repeated implantation failure.
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.2 FOXD1 Zornitza Stark Phenotypes for gene: FOXD1 were changed from Recurrent pregnancy loss and repeated implantation failure susceptibility to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
Mendeliome v1.2755 FBXO43 Zornitza Stark Marked gene: FBXO43 as ready
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2755 FBXO43 Zornitza Stark Classified gene: FBXO43 as Green List (high evidence)
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2754 FBXO43 Zornitza Stark gene: FBXO43 was added
gene: FBXO43 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBXO43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO43 were set to 34052850; 30878252; 34595750
Phenotypes for gene: FBXO43 were set to Oocyte/zygote/embryo maturation arrest 12, MIM# 619697; Spermatogenic failure 64, MIM# 619696
Review for gene: FBXO43 was set to GREEN
Added comment: Literature in OMIM: PMID: 34052850 (three different homozygous variants in 3 unrelated women; 30878252, 34595750 (two different families with different homozygous variants)
Sources: Expert list
Mendeliome v1.2753 ELL3 Zornitza Stark Marked gene: ELL3 as ready
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Mendeliome v1.2753 ELL3 Zornitza Stark Classified gene: ELL3 as Green List (high evidence)
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.1 ELL3 Zornitza Stark reviewed gene: ELL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2752 ELL3 Zornitza Stark gene: ELL3 was added
gene: ELL3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ELL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELL3 were set to 39820605
Phenotypes for gene: ELL3 were set to Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related
Review for gene: ELL3 was set to GREEN
Added comment: PMID:39820605- 8 different heterozygous variants (5 missense, 3 splicing) in 8 unrelated couples who experienced consecutive early miscarriages due to embryonic aneuploidy. For the three splice variants, mini-gene splicing assays revealed that all led to abnormal splicing, and consequently premature termination of translation or exon skipping, consistent with LOF effect. Findings from functional analysis on human oocytes and knockout mouse oocytes overall supporting that ELL3 depletion increases the incidence of meiotic spindle abnormality and oocyte aneuploidy.
Sources: Expert list
Mendeliome v1.2751 CHEK1 Zornitza Stark Marked gene: CHEK1 as ready
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2751 CHEK1 Zornitza Stark Classified gene: CHEK1 as Green List (high evidence)
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2750 CHEK1 Zornitza Stark gene: CHEK1 was added
gene: CHEK1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CHEK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK1 were set to 33953335; 33948904
Phenotypes for gene: CHEK1 were set to Oocyte/zygote/embryo maturation arrest 21, MIM# 620610
Review for gene: CHEK1 was set to GREEN
Added comment: Literature in OMIM- PMID: 33953335; 33948904
- >3 unrelated with infertility due to zygote/embryo cleavage arrest with three different missense variants and 1 1bp deletion. Functional studies using transfection studies showed that all mutant increased cytoplasmic localization significantly greater kinase activity. Injection of all mutant cRNA into mouse zygotes with 2 distinct pronuclei also resulted in significantly decreased cleavage rates compared to wildtype.
Sources: Expert list
Mendeliome v1.2749 CDC25A Zornitza Stark Marked gene: CDC25A as ready
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2749 CDC25A Zornitza Stark Classified gene: CDC25A as Green List (high evidence)
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2748 CDC25A Zornitza Stark gene: CDC25A was added
gene: CDC25A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC25A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC25A were set to 40342881; 30009144; 16720623
Phenotypes for gene: CDC25A were set to Spermatogenic failure, MONDO:0004983, CDC25A-related
Review for gene: CDC25A was set to GREEN
Added comment: i) PMID: 40342881- Five novel heterozygous variants (Lys500Asn in 8 cases, His459Leu in 12 cases, Ser485Asp, Thr503Ser, c.1434 + 5G>C) and one previously identified SNP (in 7 cases) in azoospermic males from the Bengali-speaking Indian population. qPCR analysis indicated downregulation of CDC25A mRNA expression in azoospermic patients relative to fertile controls. Relative expression levels of CDC25A were about 2.5-fold lower in azoospermic testicular tissue and semen samples, reflecting diminished transcriptional activity in affected patients. This reduction in gene expression may reflect a potential functional deficiency of CDC25A, contributing to spermatogenic arrest. The decreased level of CDC25A mRNA levels corresponds with the findings of pathogenic variants identified in azoospermic patients, thus solidifying the evidence of CDC25A mutations contributing to male infertility.

ii) PMID: 30009144,16720623- decreased expression of CDC25A observed in testicular biopsies from azoospermic men, suggesting association with meiotic arrest as the etiology of spermatogenic failure.
Sources: Literature
Mendeliome v1.2747 CAPS Zornitza Stark Marked gene: CAPS as ready
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2747 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2746 CAPS Zornitza Stark gene: CAPS was added
gene: CAPS was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CAPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPS were set to 30339840
Phenotypes for gene: CAPS were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Review for gene: CAPS was set to AMBER
Added comment: PMID: 30339840- Homozygous p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Expert list
Mendeliome v1.2745 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2745 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2744 C4BPA Zornitza Stark gene: C4BPA was added
gene: C4BPA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C4BPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C4BPA were set to 23508668
Phenotypes for gene: C4BPA were set to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Review for gene: C4BPA was set to AMBER
Added comment: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q).
- The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution.
R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls.
- Homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Expert list
Mendeliome v1.2743 C11orf80 Zornitza Stark Marked gene: C11orf80 as ready
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2743 C11orf80 Zornitza Stark Classified gene: C11orf80 as Amber List (moderate evidence)
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2742 C11orf80 Zornitza Stark Tag new gene name tag was added to gene: C11orf80.
Mendeliome v1.2742 C11orf80 Zornitza Stark gene: C11orf80 was added
gene: C11orf80 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C11orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C11orf80 were set to 30388401; 36732965
Phenotypes for gene: C11orf80 were set to Recurrent hydatidiform mole 4, MIM # 618432
Review for gene: C11orf80 was set to AMBER
Added comment: Note: HGNC Approved Gene Symbol- TOP6BL

Literature in OMIM- PubMed: 30388401- Two unrelated females with RHMs carrying a homozygous p.Glu262∗ and p.Ser501Pro, respectively.

New paper (biallelic variants for OZEMA/NOA)
i) PMID: 36732965- A homozygous LOF p.E162* in four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility. Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient.
Sources: Expert list
Mendeliome v1.2741 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Shukla-Vernon syndrome, MIM#301029 to Shukla-Vernon syndrome, MIM#301029; Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2740 BCORL1 Zornitza Stark Publications for gene: BCORL1 were set to 24123876; 30941876
Mendeliome v1.2739 BCORL1 Zornitza Stark Mode of inheritance for gene: BCORL1 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
Mendeliome v1.2738 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Mendeliome v1.2738 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Mendeliome v1.2737 BCORL1 Zornitza Stark edited their review of gene: BCORL1: Added comment: Association with spermatogenic failure:

i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.; Changed rating: GREEN; Changed publications: 24123876, 30941876, 38342987, 32376790, 39267058, 39189935; Changed phenotypes: Shukla-Vernon syndrome, MIM#301029, Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2737 BCORL1 Zornitza Stark changed review comment from: Classified as LIMITED by ClinGen.; to: Classified as LIMITED by ClinGen, Shukla-Vernon syndrome, MIM#301029
Mendeliome v1.2737 ASTL Zornitza Stark Publications for gene: ASTL were set to 34704130
Mendeliome v1.2736 ASTL Zornitza Stark Classified gene: ASTL as Green List (high evidence)
Mendeliome v1.2736 ASTL Zornitza Stark Gene: astl has been classified as Green List (High Evidence).
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Changed rating: GREEN
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Added comment: New papers (biallelic variants)
i) PMID: 37640117 - Novel compound heterozygous missense variants (p.Arg117Cys and p.Arg274Trp) in a Chinese woman with primary infertility and polyspermy in IVF. Moreover, transfection studies using CHO-K1 cells indicated that mutant cells showed abnormal ovastacin zymogen activation or decreased enzyme stability.

ii) PMID: 37133443- Biallelic variants in four independent affected individuals with primary infertility. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential.; Changed publications: 34704130, 37640117, 37133443; Changed phenotypes: Oocyte maturation defect 11, MIM# 619643
Mendeliome v1.2735 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2735 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2734 ACTL7A Zornitza Stark gene: ACTL7A was added
gene: ACTL7A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ACTL7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL7A were set to 32923619; 34727571; 36593593; 37004249; 37991128; 36574082; 35921706
Phenotypes for gene: ACTL7A were set to Spermatogenic failure 86, #MIM 620499
Review for gene: ACTL7A was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i) PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic.The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting.

ii)PMID: 36574082 (2023)- Two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Expert list
Leukodystrophy - adult onset v0.149 C1R Leah Frajman reviewed gene: C1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 37323685; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 1 MIM#130080, leukoencephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v1.1 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Genetic Epilepsy v1.169 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Genetic Epilepsy v1.168 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2733 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Mendeliome v1.2732 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autism v0.210 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Autism v0.209 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.200 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Intellectual disability syndromic and non-syndromic v1.199 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: ICoNS v0.4 TCN2 David Eckstein gene: TCN2 was added
gene: TCN2 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: TCN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TCN2 were set to PMID: 24305960
Phenotypes for gene: TCN2 were set to Transcobalamin II deficiency, MIM#275350
Penetrance for gene: TCN2 were set to Complete
Review for gene: TCN2 was set to GREEN
Added comment: Well established gene-disease association https://medlineplus.gov/genetics/condition/transcobalamin-deficiency/

Haploinsufficiency Score = 30 https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11653

Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities or death (1).

Diagnosis: Diagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid. (Orphanet https://www.orpha.net/en/disease/detail/859#)

Treatment: Multiple case reports indicate good therapeutic effects from Vitamin B12 administration (2, 3). The BNF recommends hydroxocobalamin vs cyanocobalamin for this lifelong treatment*. Orphanet indicates that (t)reatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended. (Orphanet https://www.orpha.net/en/disease/detail/859#)

* this was cited in a BMJ article https://www.bmj.com/content/349/bmj.g5389.full but I can’t access the BNF to provide a direct citation.

Included in BabyScreen+, BeginNGS, Guardian, Generation, EarlyCheck

Panels with this gene
• Bone Marrow Failure
• Mendeliome
• Combined Immunodeficiency
• Intellectual disability syndromic and non-syndromic
• Mackenzie's Mission_Reproductive Carrier Screening
• Red cell disorders
• Fetal anomalies
• Prepair 1000+
• Genomic newborn screening: BabyScreen+
• Prepair 500+
• Vitamin metabolism disorders
• Genomic newborn screening: ICoNS

Full citations
1. https://www.omim.org/entry/275350?search=%22transcobalamin%20ii%20deficiency%22&highlight=%22transcobalamin%20ii%20deficiency%22#8

2. Martino, F., Magenta, A., Troccoli, M.L. et al. Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report. Ital J Pediatr 47, 54 (2021). https://doi.org/10.1186/s13052-021-01007-6

3. Trakadis YJ, Alfares A, Bodamer OA, Buyukavci M, Christodoulou J, Connor P, Glamuzina E, Gonzalez-Fernandez F, Bibi H, Echenne B, Manoli I, Mitchell J, Nordwall M, Prasad C, Scaglia F, Schiff M, Schrewe B, Touati G, Tchan MC, Varet B, Venditti CP, Zafeiriou D, Rupar CA, Rosenblatt DS, Watkins D, Braverman N. Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis. 2014 May;37(3):461-73. doi: https://doi.org/10.1007/s10545-013-9664-5. Epub 2013 Dec 5. PMID: 24305960.
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew edited their review of gene: ZNF597: Changed publications: 19968752, 28157578, 32576657
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew gene: ZNF597 was added
gene: ZNF597 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature,Research
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 28157578; 28157578; 2576657
Mode of pathogenicity for gene: ZNF597 was set to Other
Review for gene: ZNF597 was set to RED
Added comment: ZNF597 is an imprinted gene- maternally expressed and paternally imprinted.
- ZNF597 is highly expressed in the placenta and proposed to have an important role in placental development.
- Knockout ZNF597 mice (homozygous -/-) is embryonic lethal due to failed embryonic organization before cardiogenesis at embryonic day 7.5. This period is equivalent to human Carnegie Stage 9 that occurs during week 3 between 19 to 21 days (5 weeks' gestation).
- Literature associated with ZNF597 including maternal uniparental disomy of chromosome 16 (UPD(16)mat) or loss of paternal imprinting of ZNF59, resulting in an overexpression of ZNF597.
- Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy loss at 5-8 weeks' gestation.
Sources: Literature, Research
Infertility and Recurrent Pregnancy Loss v1.0 Zornitza Stark promoted panel to version 1.0
Infertility and Recurrent Pregnancy Loss v0.232 Zornitza Stark Panel name changed from Infertility and Pregnancy Loss to Infertility and Recurrent Pregnancy Loss
Panel status changed from internal to public
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Phenotypes for gene: NLRP14 were changed from Oocyte maturation defect and early embryo arrest to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Marked gene: GALT as ready
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Phenotypes for gene: GALT were changed from Premature ovarian failure to Galactosaemia, MIM# 230400; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Classified gene: POLR3B as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Marked gene: POLG as ready
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Phenotypes for gene: POLG were changed from Premature ovarian failure to POLG-related disorders; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Classified gene: POLG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Marked gene: MTHFR as ready
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Phenotypes for gene: MTHFR were changed from Recurrent pregnancy loss susceptibility to Homocystinuria due to MTHFR deficiency MIM#236250; Recurrent pregnancy loss susceptibility
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Classified gene: MTHFR as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Marked gene: LMNA as ready
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Female infertility, premature ovarian insufficiency to Laminopathy; Female infertility, premature ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Classified gene: LMNA as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Marked gene: IKBKG as ready
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Classified gene: IKBKG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 IKBKG Zornitza Stark Tag technically challenging tag was added to gene: IKBKG.
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Marked gene: CYP19A1 as ready
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Classified gene: CYP19A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Marked gene: CYP17A1 as ready
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Classified gene: CYP17A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Marked gene: ANKRD31 as ready
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Classified gene: ANKRD31 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.218 ANKRD31 Zornitza Stark Phenotypes for gene: ANKRD31 were changed from Premature ovarian failure to Premature ovarian failure, MONDO:0019852, ANKRD31-related
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Marked gene: BCORL1 as ready
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Spermatogenic failure to Spermatogenic failure, MONDO:0004983, BCORL1-related
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Marked gene: ANOS1 as ready
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Publications for gene: ANOS1 were set to
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Classified gene: ANOS1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Marked gene: ACTL9 as ready
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Classified gene: ACTL9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Marked gene: CHRNA1 as ready
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Classified gene: CHRNA1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 CHRNA1 Zornitza Stark reviewed gene: CHRNA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Phenotypes for gene: C4BPA were changed from recurrent pregnancy loss susceptibility to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Marked gene: C14orf39 as ready
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Classified gene: C14orf39 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Marked gene: C17orf53 as ready
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Publications for gene: C17orf53 were set to 34707299, 38105698,36099812; 31467087
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 C17orf53 Zornitza Stark Tag new gene name tag was added to gene: C17orf53.
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Marked gene: CLPP as ready
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Classified gene: CLPP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Marked gene: CLPB as ready
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Classified gene: CLPB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.203 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from Primary ovarian insufficiency to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Primary ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Marked gene: CAPS as ready
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Phenotypes for gene: CAPS were changed from Recurrent pregnancy loss to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Marked gene: FKBP4 as ready
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Phenotypes for gene: FKBP4 were changed from Recurrent pregnancy loss susceptibility to Recurrent pregnancy loss susceptibility, MONDO:0000144, FKBP4-related
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Classified gene: FKBP4 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Classified gene: NOTCH2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Gene: notch2 has been removed from the panel.
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Phenotypes for gene: NOTCH2 were changed from Primary ovarian insufficiency to Inherited primary ovarian failure, MONDO:0019852, NOTCH2-related
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Classified gene: BRCA2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 BRCA2 Zornitza Stark reviewed gene: BRCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Marked gene: FANCM as ready
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Classified gene: FANCM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Marked gene: BNC1 as ready
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Classified gene: BNC1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Marked gene: BLM as ready
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Classified gene: BLM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Phenotypes for gene: DCAF17 were changed from Hypergonadotropic/ Hypogonadotropic Hypogonadism to Woodhouse-Sakati syndrome, MIM# 241080; Hypergonadotropic/ Hypogonadotropic Hypogonadism
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Classified gene: DCAF17 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Marked gene: HSF2BP as ready
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Classified gene: HSF2BP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Publications for gene: KCNU1 were set to 34980136, 35551387; 20138882; 21427226; 25271166; 35551387
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Marked gene: MSH5 as ready
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Classified gene: MSH5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Marked gene: PIEZO1 as ready
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Classified gene: PIEZO1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 PIEZO1 Zornitza Stark reviewed gene: PIEZO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Meckel syndrome 12, MIM# 616258
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Classified gene: KIF14 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Marked gene: WT1 as ready
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Phenotypes for gene: WT1 were changed from Primary ovarian failure, MONDO:0005387 to Primary ovarian failure, MONDO:0005387, WT1-related
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Classified gene: WT1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Primary ovarian failure to Congenital disorder of glycosylation, type Ia, MIM #212065; Primary ovarian failure
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Classified gene: PMM2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Marked gene: POR as ready
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Classified gene: POR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Marked gene: RNF212B as ready
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Phenotypes for gene: RNF212B were changed from Female and male infertility with recurrent medically assisted reproduction (MAR) failures. to Infertility disorder, MONDO:0005047, RNF212B-related; Female and male infertility with recurrent medically assisted reproduction (MAR) failures.
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Classified gene: RNF212B as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Marked gene: SCN5A as ready
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Classified gene: SCN5A as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SCN5A Zornitza Stark reviewed gene: SCN5A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Classified gene: SEMA3A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Marked gene: SYCP2L as ready
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Classified gene: SYCP2L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Marked gene: SYCE1 as ready
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Classified gene: SYCE1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Classified gene: TAC3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Marked gene: TP63 as ready
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Classified gene: TP63 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Marked gene: SYCP2 as ready
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Classified gene: SYCP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Marked gene: TLE6 as ready
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Classified gene: TLE6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Phenotypes for gene: TIMP2 were changed from Recurrent pregnancy loss susceptibility, MONDO:0000144 to Recurrent pregnancy loss susceptibility, MONDO:0000144, TIMP2-related
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Marked gene: REC114 as ready
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Classified gene: REC114 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Marked gene: SYCP3 as ready
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Classified gene: SYCP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Marked gene: TACR3 as ready
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Classified gene: TACR3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Phenotypes for gene: TBPL2 were changed from Oocyte maturation arrest to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Marked gene: LHB as ready
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Classified gene: LHB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Marked gene: GNRH1 as ready
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Classified gene: GNRH1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Marked gene: TRIP13 as ready
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Classified gene: TRIP13 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Marked gene: TTN as ready
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Classified gene: TTN as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 TTN Zornitza Stark reviewed gene: TTN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lethal congenital contracture syndrome, MONDO:0017436; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Marked gene: WDR11 as ready
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Classified gene: WDR11 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Marked gene: WEE2 as ready
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Classified gene: WEE2 as Green List (high evidence)