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Early onset or syndromic epilepsy v1.188 PTF1A Tracy Lester reviewed gene: PTF1A: Rating: AMBER; Mode of pathogenicity: ; Publications: 28663161; Phenotypes: Pancreatic agenesis 2, 615935, Pancreatic and cerebellar agenesis, 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PSPH Tracy Lester reviewed gene: PSPH: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Phosphoserine phosphatase deficiency, 614023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PSAT1 Tracy Lester reviewed gene: PSAT1: Rating: RED; Mode of pathogenicity: ; Publications: 17436247; Phenotypes: Neu-Laxova syndrome 2, 616038 , ?Phosphoserine aminotransferase deficiency, 610992; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 POMT2 Tracy Lester reviewed gene: POMT2: Rating: RED; Mode of pathogenicity: ; Publications: 17878207; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 613150, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation) , 613156, Muscular dystrophy-dystroglycanopathy (limb-girdle), 613158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGQ Tracy Lester reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: ; Publications: 24463883; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGH Tracy Lester reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: ; Publications: 29573052; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17, 618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGC Tracy Lester reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: ; Publications: 27694521; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, 617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PEX5 Tracy Lester reviewed gene: PEX5: Rating: GREEN; Mode of pathogenicity: ; Publications: 7719337; Phenotypes: Peroxisome biogenesis disorder 2A (Zellweger), 214110 , Peroxisome biogenesis disorder 2B, 202370, Rhizomelic chondrodysplasia punctata type 5, 616716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PDSS2 Tracy Lester reviewed gene: PDSS2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Coenzyme Q10 deficiency primary 3, 614652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PCLO Tracy Lester reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Pontocerebellar hypoplasia, type 3, 608027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 OTX2 Tracy Lester reviewed gene: OTX2: Rating: AMBER; Mode of pathogenicity: ; Publications: 19965921, 15846561 ; Phenotypes: Microphthalmia syndromic 5, 610125, Pituitary hormone deficiency combined, 613986, Retinal dystrophy early-onset with or without pituitary dysfunction, 610125; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NUBPL Tracy Lester reviewed gene: NUBPL: Rating: AMBER; Mode of pathogenicity: ; Publications: 20818383; Phenotypes: Mitochondrial complex I deficiency, nuclear type 21, 618242; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NPRL2 Tracy Lester reviewed gene: NPRL2: Rating: AMBER; Mode of pathogenicity: ; Publications: 26505888; Phenotypes: Epilepsy familial focal with variable foci 2, 617116; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NEDD4L Tracy Lester reviewed gene: NEDD4L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Periventricular nodular heterotopia 7, 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NECAP1 Tracy Lester reviewed gene: NECAP1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24399846; Phenotypes: ?Epileptic encephalopathy, early infantile, 21, 615833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFS7 Tracy Lester reviewed gene: NDUFS7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3, 618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFS6 Tracy Lester reviewed gene: NDUFS6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 9, 618232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFS2 Tracy Lester reviewed gene: NDUFS2: Rating: AMBER; Mode of pathogenicity: ; Publications: 20819849; Phenotypes: Mitochondrial complex I deficiency, nuclear type 6, 618228; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFS1 Tracy Lester reviewed gene: NDUFS1: Rating: AMBER; Mode of pathogenicity: ; Publications: 11349233; Phenotypes: Mitochondrial complex I deficiency, nuclear type 5, 618226; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFAF4 Tracy Lester reviewed gene: NDUFAF4: Rating: AMBER; Mode of pathogenicity: ; Publications: 19463981, 28853723; Phenotypes: Mitochondrial complex I deficiency, nuclear type 15, 618237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFAF3 Tracy Lester reviewed gene: NDUFAF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 19463981; Phenotypes: Mitochondrial complex I deficiency nuclear type 18, 618240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFA2 Tracy Lester reviewed gene: NDUFA2: Rating: AMBER; Mode of pathogenicity: ; Publications: 18513682; Phenotypes: ?Mitochondrial complex I deficiency nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDP Tracy Lester reviewed gene: NDP: Rating: RED; Mode of pathogenicity: ; Publications: 17334993, 27217716; Phenotypes: Norrie disease, 310600; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 MED17 Tracy Lester reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: ; Publications: 20950787; Phenotypes: Microcephaly postnatal progressive with seizures and brain atrophy, 613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MAST1 Tracy Lester reviewed gene: MAST1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, 618273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MANBA Tracy Lester reviewed gene: MANBA: Rating: AMBER; Mode of pathogenicity: ; Publications: 22369051; Phenotypes: Mannosidosis, beta, 248510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 LNPK Tracy Lester reviewed gene: LNPK: Rating: AMBER; Mode of pathogenicity: ; Publications: 30032983; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, 618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 LIPT2 Tracy Lester reviewed gene: LIPT2: Rating: RED; Mode of pathogenicity: ; Publications: 28757203; Phenotypes: Encephalopathy neonatal severe with lactic acidosis and brain abnormalities, 617668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 LARGE1 Tracy Lester reviewed gene: LARGE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 613154, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation) type B, 608840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KPTN Tracy Lester reviewed gene: KPTN: Rating: AMBER; Mode of pathogenicity: ; Publications: 24239382; Phenotypes: Mental retardation 41, 615637; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KIAA1109 Tracy Lester reviewed gene: KIAA1109: Rating: GREEN; Mode of pathogenicity: ; Publications: 29290337; Phenotypes: Alkuraya-Kucinskas syndrome, 617822; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCNMA1 Tracy Lester reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Cerebellar atrophy developmental delay and seizures, 617643, Paroxysmal nonkinesigenic dyskinesia 3 with or without generalized epilepsy, 609446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ISPD Tracy Lester reviewed gene: ISPD: Rating: AMBER; Mode of pathogenicity: ; Publications: 15937479, 26195193 ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 7 614643, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 7 616052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HSPD1 Tracy Lester reviewed gene: HSPD1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Leukodystrophy hypomyelinating 4, 612233, Spastic paraplegia 13, 605280; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HPRT1 Tracy Lester reviewed gene: HPRT1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: HPRT-related gout, 300323, Lesch-Nyhan syndrome, 300322; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 HOXA1 Tracy Lester reviewed gene: HOXA1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Athabaskan brainstem dysgenesis syndrome, 601536 , Bosley-Salih-Alorainy syndrome, 601536; Mode of inheritance: Unknown
Early onset or syndromic epilepsy v1.188 HEXB Tracy Lester reviewed gene: HEXB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Sandhoff disease infantile juvenile and adult forms, 268800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HCCS Tracy Lester reviewed gene: HCCS: Rating: RED; Mode of pathogenicity: ; Publications: 17033964; Phenotypes: Linear skin defects with multiple congenital anomalies, 309801; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 GTPBP3 Tracy Lester reviewed gene: GTPBP3: Rating: GREEN; Mode of pathogenicity: ; Publications: 25434004; Phenotypes: Combined oxidative phosphorylation deficiency 23, 616198; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GLRA1 Tracy Lester reviewed gene: GLRA1: Rating: AMBER; Mode of pathogenicity: ; Publications: 20631190; Phenotypes: Hyperekplexia 1, 149400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GLI3 Tracy Lester reviewed gene: GLI3: Rating: RED; Mode of pathogenicity: ; Publications: 11484201; Phenotypes: Greig cephalopolysyndactyly syndrome, 175700, {Hypothalamic hamartomas, somatic}, 241800 , Pallister-Hall syndrome, 146510, Polydactyly postaxial types A1 and B, 174200, Polydactyly preaxial type IV, 174700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FOXRED1 Tracy Lester reviewed gene: FOXRED1: Rating: AMBER; Mode of pathogenicity: ; Publications: 20818383, 27215383; Phenotypes: Mitochondrial complex I deficiency nuclear type 19, 618241; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FKRP Tracy Lester reviewed gene: FKRP: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A 613153, Muscular dystrophy-dystroglycanopathy (congenital with or without mental retardation) type B, 606612, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 5, 607155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FASTKD2 Tracy Lester reviewed gene: FASTKD2: Rating: AMBER; Mode of pathogenicity: ; Publications: 28499982, 18771761, 25916514 ; Phenotypes: ?Mitochondrial complex IV deficiency, 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EIF2B3 Tracy Lester reviewed gene: EIF2B3: Rating: GREEN; Mode of pathogenicity: ; Publications: 21307862; Phenotypes: Leukoencephalopathy with vanishing white matter, 603896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EIF2B1 Tracy Lester reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25843247, 25761052 ; Phenotypes: Leukoencephalopathy with vanishing white matter, 603896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EFHC1 Tracy Lester reviewed gene: EFHC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19901254; Phenotypes: {Epilepsy, juvenile absence, susceptibility to, 1}, 607631 , {Myoclonic epilepsy, juvenile, susceptibility to, 1}, 254770; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DPM2 Tracy Lester reviewed gene: DPM2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23109149, 19901254 ; Phenotypes: Congenital disorder of glycosylation type Iu, 615042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DOLK Tracy Lester reviewed gene: DOLK: Rating: AMBER; Mode of pathogenicity: ; Publications: 23890587; Phenotypes: Congenital disorder of glycosylation type Im, 610768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DNAJC6 Tracy Lester reviewed gene: DNAJC6: Rating: AMBER; Mode of pathogenicity: ; Publications: 23211418; Phenotypes: Parkinson disease 19a juvenile-onset, 615528, Parkinson disease 19b early-onset, 615528; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DHCR24 Tracy Lester reviewed gene: DHCR24: Rating: AMBER; Mode of pathogenicity: ; Publications: 21559050, 21671375 ; Phenotypes: Desmosterolosis, 602398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DBT Tracy Lester reviewed gene: DBT: Rating: GREEN; Mode of pathogenicity: ; Publications: 1990841; Phenotypes: Maple syrup urine disease,type II 248600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29795476, 29630738 ; Phenotypes: Epileptic encephalopathy early infantile 67, 618141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CSNK2B Tracy Lester reviewed gene: CSNK2B: Rating: GREEN; Mode of pathogenicity: ; Publications: 28762608, 28585349 ; Phenotypes: Intellectual disability with or without myoclonic epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 COX15 Tracy Lester reviewed gene: COX15: Rating: AMBER; Mode of pathogenicity: ; Publications: 12474143; Phenotypes: Cardioencephalomyopathy fatal infantile due to cytochrome c oxidase deficiency 2 615119 , Leigh syndrome due to cytochrome c oxidase deficiency, 256000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COX10 Tracy Lester reviewed gene: COX10: Rating: AMBER; Mode of pathogenicity: ; Publications: 10767350; Phenotypes: Leigh syndrome due to mitochondrial COX4 deficiency, 256000 , Mitochondrial, Mitochondrial complex IV deficiency, 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COQ6 Tracy Lester reviewed gene: COQ6: Rating: AMBER; Mode of pathogenicity: ; Publications: 21540551; Phenotypes: Coenzyme Q10 deficiency, primary, 6, 614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COG8 Tracy Lester reviewed gene: COG8: Rating: AMBER; Mode of pathogenicity: ; Publications: 17331980, 17220172 ; Phenotypes: Congenital disorder of glycosylation, type IIh, 611182; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 COG6 Tracy Lester reviewed gene: COG6: Rating: AMBER; Mode of pathogenicity: ; Publications: 20605848; Phenotypes: Congenital disorder of glycosylation type IIl, 614576 , Shaheen syndrome, 615328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COG4 Tracy Lester reviewed gene: COG4: Rating: AMBER; Mode of pathogenicity: ; Publications: 21185756; Phenotypes: Congenital disorder of glycosylation type IIj, 613489 , Saul-Wilson syndrome, 618150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CNPY3 Tracy Lester reviewed gene: CNPY3: Rating: GREEN; Mode of pathogenicity: ; Publications: 29394991; Phenotypes: Epileptic encephalopathy, early infantile, 60, 617929; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CCND2 Tracy Lester reviewed gene: CCND2: Rating: RED; Mode of pathogenicity: ; Publications: 24705253; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CCDC88C Tracy Lester reviewed gene: CCDC88C: Rating: AMBER; Mode of pathogenicity: ; Publications: 21031079; Phenotypes: Hydrocephalus, congenital, 1, 236600 , ?Spinocerebellar ataxia 40, 616053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CCDC88A Tracy Lester reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26917597; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CACNA2D2 Tracy Lester reviewed gene: CACNA2D2: Rating: AMBER; Mode of pathogenicity: ; Publications: 24358150; Phenotypes: ? Epileptic encephalopathy ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CACNA1H Tracy Lester reviewed gene: CACNA1H: Rating: AMBER; Mode of pathogenicity: ; Publications: 15048902; Phenotypes: {Epilepsy, childhood absence, susceptibility to, 6}, 611942 , {Epilepsy, idiopathic generalized, susceptibility to, 6}, 611942 , Hyperaldosteronism, familial, type IV, 617027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ATP6AP2 Tracy Lester reviewed gene: ATP6AP2: Rating: RED; Mode of pathogenicity: ; Publications: 26467484, 23595882, 29127204; Phenotypes: ?Parkinsonism with spasticity X-linked 300911, Mental retardation X-linked syndromic Hedera type 300423; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 ATP5A1 Tracy Lester reviewed gene: ATP5A1: Rating: RED; Mode of pathogenicity: ; Publications: 23599390; Phenotypes: ?Combined oxidative phosphorylation deficiency 22 616045, ?Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ATP1A2 Tracy Lester reviewed gene: ATP1A2: Rating: AMBER; Mode of pathogenicity: ; Publications: 15159495; Phenotypes: Alternating hemiplegia of childhood 1, 104290 , Migraine familial basilar, 602481 , Migraine, familial hemiplegic, 2, 602481; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ADAT3 Tracy Lester reviewed gene: ADAT3: Rating: AMBER; Mode of pathogenicity: ; Publications: 23620220; Phenotypes: Mental retardation autosomal recessive 36, 615286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ZBTB18 Tracy Lester reviewed gene: ZBTB18: Rating: GREEN; Mode of pathogenicity: ; Publications: 27598823; Phenotypes: Mental retardation 22, 612337; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 YWHAG Tracy Lester reviewed gene: YWHAG: Rating: GREEN; Mode of pathogenicity: ; Publications: 28777935; Phenotypes: Epileptic encephalopathy early infantile 56, 605356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 WDR73 Tracy Lester reviewed gene: WDR73: Rating: GREEN; Mode of pathogenicity: ; Publications: 30315938, 20083416 ; Phenotypes: Galloway-Mowat syndrome 1, 251300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 WDR62 Tracy Lester reviewed gene: WDR62: Rating: AMBER; Mode of pathogenicity: ; Publications: 20729831; Phenotypes: Microcephaly 2 primary autosomal recessive with or without cortical malformations, 604317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 WASF1 Tracy Lester reviewed gene: WASF1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29961568; Phenotypes: intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 VARS Tracy Lester reviewed gene: VARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 26539891, 29691655 ; Phenotypes: Neurodevelopmental disorder with microcephaly seizures and cortical atrophy, 617802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 UNC80 Tracy Lester reviewed gene: UNC80: Rating: GREEN; Mode of pathogenicity: ; Publications: 26708751; Phenotypes: Hypotonia infantile with psychomotor retardation and characteristic facies 2, 616801; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 UFM1 Tracy Lester reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29868776, 28931644 ; Phenotypes: Leukodystrophy hypomyelinating 14 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 UBA5 Tracy Lester reviewed gene: UBA5: Rating: GREEN; Mode of pathogenicity: ; Publications: 27545674; Phenotypes: Epileptic encephalopathy early infantile 44, 617132; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TUBG1 Tracy Lester reviewed gene: TUBG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23603762; Phenotypes: Cortical dysplasia complex with other brain malformations 4, 615412; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TUBB4A Tracy Lester reviewed gene: TUBB4A: Rating: GREEN; Mode of pathogenicity: ; Publications: 25168210; Phenotypes: Dystonia 4 torsion autosomal dominant, 128101, Leukodystrophy hypomyelinating 6, 612438; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TUBB3 Tracy Lester reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: ; Publications: 28503613, 28378416, 26639658; Phenotypes: Cortical dysplasia complex with other brain malformations 1, 614039, Fibrosis of extraocular muscles congenital 3A, 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TUBB2B Tracy Lester reviewed gene: TUBB2B: Rating: GREEN; Mode of pathogenicity: ; Publications: 19465910; Phenotypes: Cortical dysplasia complex with other brain malformations 7, 610031; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TUBB2A Tracy Lester reviewed gene: TUBB2A: Rating: AMBER; Mode of pathogenicity: ; Publications: 24702957; Phenotypes: Cortical dysplasia complex with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TUBA1A Tracy Lester reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 17584854, 18954413 ; Phenotypes: Lissencephaly 3, 611603; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TSEN54 Tracy Lester reviewed gene: TSEN54: Rating: GREEN; Mode of pathogenicity: ; Publications: 20956791, 20952379 ; Phenotypes: ?Pontocerebellar hypoplasia type 5, 610204, Pontocerebellar hypoplasia type 2A, 277470, Pontocerebellar hypoplasia type 4, 225753; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TSEN2 Tracy Lester reviewed gene: TSEN2: Rating: AMBER; Mode of pathogenicity: ; Publications: 23562994; Phenotypes: Pontocerebellar hypoplasia type 2B, 612389; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TSC2 Tracy Lester reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28215400; Phenotypes: Tuberous sclerosis-2, 613254; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TSC1 Tracy Lester reviewed gene: TSC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28215400; Phenotypes: Tuberous sclerosis-1, 191100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TRIM8 Tracy Lester reviewed gene: TRIM8: Rating: GREEN; Mode of pathogenicity: ; Publications: 27346735, 30244534 ; Phenotypes: epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TREX1 Tracy Lester reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20876473; Phenotypes: Aicardi-Goutieres syndrome 1 dominant and recessive, 225750, Chilblain lupus, 610448, Vasculopathy retinal with cerebral leukodystrophy, 192315; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TMEM70 Tracy Lester reviewed gene: TMEM70: Rating: AMBER; Mode of pathogenicity: ; Publications: 25326274, 21147908 ; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency nuclear type 2, 614052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TBL1XR1 Tracy Lester reviewed gene: TBL1XR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25102098; Phenotypes: Mental retardation autosomal dominant 41, 616944, Pierpont syndrome, 602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TBCK Tracy Lester reviewed gene: TBCK: Rating: GREEN; Mode of pathogenicity: ; Publications: 25558065, 27275012 ; Phenotypes: Hypotonia infantile with psychomotor retardation and characteristic facies 3, 616900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TBCD Tracy Lester reviewed gene: TBCD: Rating: GREEN; Mode of pathogenicity: ; Publications: 28158450, 27666370; Phenotypes: Encephalopathy progressive early-onset with brain atrophy and thin corpus callosum, 617193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TANGO2 Tracy Lester reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26805782, 30245509 ; Phenotypes: Metabolic encephalomyopathic crises recurrent with rhabdomyolysis cardiac arrhythmias and neurodegeneration, 616878; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SYN1 Tracy Lester reviewed gene: SYN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 21441247; Phenotypes: Epilepsy X-linked with variable learning disabilities and behavior disorders, 300491; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 SURF1 Tracy Lester reviewed gene: SURF1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24027061, 23829769, 29481804 ; Phenotypes: Charcot-Marie-Tooth disease type 4K, 616684, Leigh syndrome, due to COX IV deficiency, 256000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SUCLA2 Tracy Lester reviewed gene: SUCLA2: Rating: GREEN; Mode of pathogenicity: ; Publications: 15877282, 17301081 , 23759946 ; Phenotypes: Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), 612073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 STAMBP Tracy Lester reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: ; Publications: 21271646, 23542699 ; Phenotypes: Microcephaly-capillary malformation syndrome, 614261; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 STAG1 Tracy Lester reviewed gene: STAG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28119487; Phenotypes: Mental retardation autosomal dominant, 47 617635; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ST3GAL5 Tracy Lester reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: ; Publications: 15502825, 22990144, 24026681 ; Phenotypes: Salt and pepper developmental regression syndrome, 609056; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SNORD118 Tracy Lester reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: ; Publications: 28177126; Phenotypes: Leukoencephalopathy brain calcifications and cysts, 614561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SMS Tracy Lester reviewed gene: SMS: Rating: GREEN; Mode of pathogenicity: ; Publications: 30237987; Phenotypes: Mental retardation X-linked Snyder-Robinson type, 309583; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 SMARCA2 Tracy Lester reviewed gene: SMARCA2: Rating: GREEN; Mode of pathogenicity: ; Publications: 22426308, 27665729; Phenotypes: Nicolaides-Baraitser syndrome, 601358; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SLC6A8 Tracy Lester reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: ; Publications: 11898126, 26951207; Phenotypes: Cerebral creatine deficiency syndrome 1, 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 SLC25A12 Tracy Lester reviewed gene: SLC25A12: Rating: AMBER; Mode of pathogenicity: ; Publications: 24515575, 19641205 ; Phenotypes: Epileptic encephalopathy early infantile 39, 612949; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC1A4 Tracy Lester reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: ; Publications: 26138499, 26041762 ; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SETBP1 Tracy Lester reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25217958, 28346496 ; Phenotypes: Mental retardation autosomal dominant 29,616078, Schinzel-Giedion midface retraction syndrome, 269150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SEPSECS Tracy Lester reviewed gene: SEPSECS: Rating: GREEN; Mode of pathogenicity: ; Publications: 27576344; Phenotypes: Pontocerebellar hypoplasia type 2D, 613811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SCO2 Tracy Lester reviewed gene: SCO2: Rating: AMBER; Mode of pathogenicity: ; Publications: 15210538; Phenotypes: Cardioencephalomyopathy fatal infantile due to cytochrome c oxidase deficiency, 604377, Myopia, 608908; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SCO1 Tracy Lester reviewed gene: SCO1: Rating: AMBER; Mode of pathogenicity: ; Publications: 19268667, 11013136 ; Phenotypes: Mitochondrial complex IV deficiency, 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SCN3A Tracy Lester reviewed gene: SCN3A: Rating: GREEN; Mode of pathogenicity: ; Publications: 28235671 , 29466837 ; Phenotypes: Epilepsy familial focal with variable foci, 617935 AD, Epileptic encephalopathy early infantile, 617938; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SAMHD1 Tracy Lester reviewed gene: SAMHD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29239743; Phenotypes: ?Chilblain lupus, 614415 AD, Aicardi-Goutieres syndrome, 612952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RTTN Tracy Lester reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: ; Publications: 22939636; Phenotypes: Microcephaly short stature and polymicrogyria with seizures, 614833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RTN4IP1 Tracy Lester reviewed gene: RTN4IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 26593267, 29181510; Phenotypes: Optic atrophy 10 with or without ataxia mental retardation and seizures, 616732; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RORB Tracy Lester reviewed gene: RORB: Rating: GREEN; Mode of pathogenicity: ; Publications: 27352968; Phenotypes: epilepsy absence seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 RORA Tracy Lester reviewed gene: RORA: Rating: GREEN; Mode of pathogenicity: ; Publications: 29656859; Phenotypes: Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, 618060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ROGDI Tracy Lester reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: ; Publications: 22482807; Phenotypes: Kohlschutter-Tonz syndrome, 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RNASET2 Tracy Lester reviewed gene: RNASET2: Rating: GREEN; Mode of pathogenicity: ; Publications: 19525954; Phenotypes: Leukoencephalopathy cystic without megalencephaly, 612951; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RNASEH2C Tracy Lester reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: ; Publications: 25604658; Phenotypes: Aicardi-Goutieres syndrome, 610329; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RNASEH2B Tracy Lester reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: ; Publications: 25604658; Phenotypes: Aicardi-Goutieres syndrome, 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RNASEH2A Tracy Lester reviewed gene: RNASEH2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 25604658; Phenotypes: Aicardi-Goutieres syndrome, 610333; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RMND1 Tracy Lester reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23022098, 27412952 ; Phenotypes: Combined oxidative phosphorylation deficiency, 614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RHOBTB2 Tracy Lester reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29276004; Phenotypes: Epileptic encephalopathy early infantile, 618004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 RFT1 Tracy Lester reviewed gene: RFT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19701946; Phenotypes: Congenital disorder of glycosylation type In, 612015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RELN Tracy Lester reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: ; Publications: 7682675; Phenotypes: Lissencephaly 2 (Norman-Roberts type), 257320, {Epilepsy, familial temporal lobe, 7}, 616436; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RARS2 Tracy Lester reviewed gene: RARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 20635367; Phenotypes: Pontocerebellar hypoplasia, 611523; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RALA Tracy Lester reviewed gene: RALA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: intellectual disability and developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 RAB18 Tracy Lester reviewed gene: RAB18: Rating: GREEN; Mode of pathogenicity: ; Publications: 21473985; Phenotypes: Warburg micro syndrome, 614222; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RAB11B Tracy Lester reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: ; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait absent speech and decreased cortical white matter, 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 QDPR Tracy Lester reviewed gene: QDPR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperphenylalaninemia BH4-deficient, 261630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PTS Tracy Lester reviewed gene: PTS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperphenylalaninemia BH4-deficient A, 261640; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PTPN23 Tracy Lester reviewed gene: PTPN23: Rating: GREEN; Mode of pathogenicity: ; Publications: 29090338; Phenotypes: epileptic encephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PTEN Tracy Lester reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: 11726927, 12085208, 11726926 ; Phenotypes: Cowden syndrome, 158350, Lhermitte-Duclos syndrome, 158350, Macrocephaly/autism syndrome, 605309, VATER association with macrocephaly and ventriculomegaly, 276950, {Glioma susceptibility 2}, 613028, {Meningioma}, 607174, ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PSAP Tracy Lester reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: ; Publications: 19267410; Phenotypes: Combined SAP deficiency 611721, Gaucher disease, atypical 610539, Krabbe disease, atypical 611722, Metachromatic leukodystrophy due to SAP-b deficiency 249900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PRMT7 Tracy Lester reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: ; Publications: 26437029; Phenotypes: short stature brachydactyly intellectual developmental disability and seizures 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PRICKLE1 Tracy Lester reviewed gene: PRICKLE1: Rating: GREEN; Mode of pathogenicity: ; Publications: 21276947, 21276947; Phenotypes: Epilepsy progressive myoclonic, 612437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PPT1 Tracy Lester reviewed gene: PPT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 11717424; Phenotypes: Ceroid lipofuscinosis neuronal, 256730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PPP3CA Tracy Lester reviewed gene: PPP3CA: Rating: GREEN; Mode of pathogenicity: ; Publications: 28942967; Phenotypes: Arthrogryposis cleft palate craniosynostosis and impaired intellectual development, 618265, Epileptic encephalopathyinfantile or early childhood, 617711; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 POMT1 Tracy Lester reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19299310; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), 236670, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), 613155, Muscular dystrophy-dystroglycanopathy (limb-girdle), 60930; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 POMGNT1 Tracy Lester reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15466003; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 3 253280, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation)type B, 3 613151, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 3 613157 , Retinitis pigmentosa 76 617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PMM2 Tracy Lester reviewed gene: PMM2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26453362; Phenotypes: Congenital disorder of glycosylation, 212065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PLAA Tracy Lester reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: ; Publications: 28007986, 28413018 ; Phenotypes: Neurodevelopmental disorder with progressive microcephaly spasticity and brain anomalies, 617527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIK3R2 Tracy Lester reviewed gene: PIK3R2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26860062; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PIK3CA Tracy Lester reviewed gene: PIK3CA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PIGW Tracy Lester reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: 27626616; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect, 616025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGO Tracy Lester reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: ; Publications: 22683086; Phenotypes: Hyperphosphatasia with mental retardation syndrome, 614749; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGG Tracy Lester reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: ; Publications: 26996948; Phenotypes: Mental retardation, 616917; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PHGDH Tracy Lester reviewed gene: PHGDH: Rating: GREEN; Mode of pathogenicity: ; Publications: 11751922; Phenotypes: Neu-Laxova syndrome, 256520, Phosphoglycerate dehydrogenase deficiency, 601815; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PHACTR1 Tracy Lester reviewed gene: PHACTR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30256902; Phenotypes: Epileptic encephalopathy early infantile, 618298; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PEX7 Tracy Lester reviewed gene: PEX7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX6 Tracy Lester reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX3 Tracy Lester reviewed gene: PEX3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX2 Tracy Lester reviewed gene: PEX2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX19 Tracy Lester reviewed gene: PEX19: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX13 Tracy Lester reviewed gene: PEX13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX12 Tracy Lester reviewed gene: PEX12: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 PEX10 Tracy Lester reviewed gene: PEX10: Rating: AMBER; Mode of pathogenicity: ; Publications: 28784167; Phenotypes: Peroxisome biogenesis disorder 6A (Zellweger), 614870, Peroxisome biogenesis disorder, 614871; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PEX1 Tracy Lester reviewed gene: PEX1: Rating: AMBER; Mode of pathogenicity: ; Publications: 16141001; Phenotypes: Heimler syndrome 1 234580, Peroxisome biogenesis disorder 1A (Zellweger) 214100, Peroxisome biogenesis disorder 1B (NALD/IRD) 601539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PET100 Tracy Lester reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: ; Publications: 24462369; Phenotypes: Mitochondrial complex IV deficiency,220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PDHX Tracy Lester reviewed gene: PDHX: Rating: GREEN; Mode of pathogenicity: ; Publications: 25087164; Phenotypes: Lacticacidemia due to PDX1 deficiency, 245349; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PDHA1 Tracy Lester reviewed gene: PDHA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 27896109; Phenotypes: Pyruvate dehydrogenase E1-alpha deficiency, 312170; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 PCDH12 Tracy Lester reviewed gene: PCDH12: Rating: GREEN; Mode of pathogenicity: ; Publications: 27164683; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PCCB Tracy Lester reviewed gene: PCCB: Rating: GREEN; Mode of pathogenicity: ; Publications: 7386459; Phenotypes: Propionicacidemia, 606054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PCCA Tracy Lester reviewed gene: PCCA: Rating: GREEN; Mode of pathogenicity: ; Publications: 30014764; Phenotypes: Propionicacidemia, 606054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PAH Tracy Lester reviewed gene: PAH: Rating: GREEN; Mode of pathogenicity: ; Publications: 8097262, 25014052 ; Phenotypes: Phenylketonuria 261600, [Hyperphenylalaninemia, non-PKU mild], 261600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PAFAH1B1 Tracy Lester reviewed gene: PAFAH1B1: Rating: GREEN; Mode of pathogenicity: ; Publications: 11502906, 11754098 ; Phenotypes: Lissencephaly, 607432, Subcortical laminar heterotopia, 607432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PACS2 Tracy Lester reviewed gene: PACS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 30290155; Phenotypes: Epileptic encephalopathy, early infantile, 618067; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PACS1 Tracy Lester reviewed gene: PACS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23159249; Phenotypes: Schuurs-Hoeijmakers syndrome, 615009; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 OTUD6B Tracy Lester reviewed gene: OTUD6B: Rating: GREEN; Mode of pathogenicity: ; Publications: 28343629; Phenotypes: Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 617452; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 OPHN1 Tracy Lester reviewed gene: OPHN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 18512229 , 12805098 ; Phenotypes: Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 OCLN Tracy Lester reviewed gene: OCLN: Rating: GREEN; Mode of pathogenicity: ; Publications: 28386946; Phenotypes: Pseudo-TORCH syndrome, 251290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NTRK2 Tracy Lester reviewed gene: NTRK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100083; Phenotypes: Epileptic encephalopathy, early infantile, 617830, Obesity, hyperphagia, and developmental delay 613886; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NSDHL Tracy Lester reviewed gene: NSDHL: Rating: GREEN; Mode of pathogenicity: ; Publications: 21129721; Phenotypes: CHILD syndrome, 308050, CK syndrome, 300831; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 NSD1 Tracy Lester reviewed gene: NSD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23592277; Phenotypes: Leukemia, acute myeloid, 601626, Sotos syndrome 1, 117550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NRXN1 Tracy Lester reviewed gene: NRXN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19896112, 22617343 ; Phenotypes: Pitt-Hopkins-like syndrome 2 614325, {Schizophrenia, susceptibility to, 17}, 614332; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NPRL3 Tracy Lester reviewed gene: NPRL3: Rating: GREEN; Mode of pathogenicity: ; Publications: 26505888; Phenotypes: Epilepsy, familial focal, with variable foci 3, 617118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 NHLRC1 Tracy Lester reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15781812 , 21505799; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora), 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NGLY1 Tracy Lester reviewed gene: NGLY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFV1 Tracy Lester reviewed gene: NDUFV1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFS8 Tracy Lester reviewed gene: NDUFS8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFS4 Tracy Lester reviewed gene: NDUFS4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFAF5 Tracy Lester reviewed gene: NDUFAF5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFAF2 Tracy Lester reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 18180188; Phenotypes: Mitochondrial complex I deficiency, nuclear type 10, 618233; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 NDUFA10 Tracy Lester reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: ; Publications: 21150889, 30423443; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22, 618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NDUFA1 Tracy Lester reviewed gene: NDUFA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19185523, 25356405; Phenotypes: Mitochondrial complex I deficiency, nuclear type 12, 301020; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 NDE1 Tracy Lester reviewed gene: NDE1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22523559, 30637988 ; Phenotypes: ?Microhydranencephaly, 605013, Lissencephaly 4 (with microcephaly), 614019; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NARS2 Tracy Lester reviewed gene: NARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 25385316, 25807530, 30327238 ; Phenotypes: Combined oxidative phosphorylation deficiency, 616239; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 NAGA Tracy Lester reviewed gene: NAGA: Rating: GREEN; Mode of pathogenicity: ; Publications: 11313741; Phenotypes: Kanzaki disease 609242 , Schindler disease, type I 609241 , Schindler disease, type III 609241; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MTR Tracy Lester reviewed gene: MTR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Homocystinuria-megaloblastic anemia, cblG complementation type, 250940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MTHFR Tracy Lester reviewed gene: MTHFR: Rating: GREEN; Mode of pathogenicity: ; Publications: 3580562, 29391032 ; Phenotypes: Homocystinuria due to MTHFR deficiency, 236250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MPDU1 Tracy Lester reviewed gene: MPDU1: Rating: GREEN; Mode of pathogenicity: ; Publications: 11733556; Phenotypes: Congenital disorder of glycosylation, type If, 609180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MOCS2 Tracy Lester reviewed gene: MOCS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 11746050, 16021469 ; Phenotypes: Molybdenum cofactor deficiency B, 252160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MOCS1 Tracy Lester reviewed gene: MOCS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 9921896; Phenotypes: Molybdenum cofactor deficiency A 252150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MMADHC Tracy Lester reviewed gene: MMADHC: Rating: GREEN; Mode of pathogenicity: ; Publications: 18385497; Phenotypes: Homocystinuria, cblD type, variant 1 277410, Methylmalonic aciduria and homocystinuria, cblD type, 277410, Methylmalonic aciduria, cblD type, variant 2, 277410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MMACHC Tracy Lester reviewed gene: MMACHC: Rating: GREEN; Mode of pathogenicity: ; Publications: 26283149, 29068997 , 16311595, 21748408; Phenotypes: Methylmalonic aciduria and homocystinuria, cblC type, 277400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MLC1 Tracy Lester reviewed gene: MLC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29466841; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts, 604004; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MFSD8 Tracy Lester reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: ; Publications: 19201763; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, 610951, Macular dystrophy with central cone involvement 616170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MED12 Tracy Lester reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: 17334363; Phenotypes: Lujan-Fryns syndrome 309520 XLR, Ohdo syndrome, X-linked 300895 XLR, Opitz-Kaveggia syndrome 305450 XLR; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 MAP2K2 Tracy Lester reviewed gene: MAP2K2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cardiofaciocutaneous syndrome, 615280; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MAP2K1 Tracy Lester reviewed gene: MAP2K1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cardiofaciocutaneous syndrome, 615279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MAGI2 Tracy Lester reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27932480, 18565486 ; Phenotypes: Nephrotic syndrome, type 15, 617609; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MAF Tracy Lester reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: ; Publications: 25865493; Phenotypes: Ayme-Gripp syndrome, 601088, Cataract 21, multiple types, 610202; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MACF1 Tracy Lester reviewed gene: MACF1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 30471716; Phenotypes: cortical malformation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 LYST Tracy Lester reviewed gene: LYST: Rating: AMBER; Mode of pathogenicity: ; Publications: 10648412; Phenotypes: Chediak-Higashi syndrome, 214500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 LIAS Tracy Lester reviewed gene: LIAS: Rating: GREEN; Mode of pathogenicity: ; Publications: 26108146; Phenotypes: Hyperglycinemia, lactic acidosis, and seizures, 614462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KRAS Tracy Lester reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: 21686750, 21871821 ; Phenotypes: Cardiofaciocutaneous syndrome, 615278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KIF5C Tracy Lester reviewed gene: KIF5C: Rating: GREEN; Mode of pathogenicity: ; Publications: 23603762; Phenotypes: Cortical dysplasia, complex, with other brain malformations, 615282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KIF2A Tracy Lester reviewed gene: KIF2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 23603762, 29313800; Phenotypes: Cortical dysplasia, complex, with other brain malformations, 615411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KIF1A Tracy Lester reviewed gene: KIF1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 25265257; Phenotypes: Mental retardation, 614255, Neuropathy, hereditary sensory, type IIC 614213, Spastic paraplegia 30 610357; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCTD3 Tracy Lester reviewed gene: KCTD3: Rating: GREEN; Mode of pathogenicity: ; Publications: 29406573; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCNQ5 Tracy Lester reviewed gene: KCNQ5: Rating: GREEN; Mode of pathogenicity: ; Publications: 28669405; Phenotypes: Mental retardation, 617601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNK4 Tracy Lester reviewed gene: KCNK4: Rating: GREEN; Mode of pathogenicity: ; Publications: 30290154; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNJ11 Tracy Lester reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: ; Publications: 19254908, 16670688 ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 601820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCNA1 Tracy Lester reviewed gene: KCNA1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24578548; Phenotypes: Episodic ataxia/myokymia syndrome, 160120; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KARS Tracy Lester reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 29615062; Phenotypes: ?Charcot-Marie-Tooth disease, recessive intermediate, 613641, Deafness, 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 IRF2BPL Tracy Lester reviewed gene: IRF2BPL: Rating: GREEN; Mode of pathogenicity: ; Publications: 30057031; Phenotypes: Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, 618088; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 IKBKG Tracy Lester reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: 28870493, 28870493 ; Phenotypes: Incontinentia pigmenti, 308300, Immunodeficiency , 300636; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 IFIH1 Tracy Lester reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24686847, 24995871; Phenotypes: Aicardi-Goutieres syndrome, 615846, Singleton-Merten syndrome, 182250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 HSD17B4 Tracy Lester reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: ; Publications: 25882080, 27790638 ; Phenotypes: D-bifunctional protein deficiency, 261515, Perrault syndrome, 233400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HRAS Tracy Lester reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: 16170316; Phenotypes: Congenital myopathy with excess of muscle spindles, 218040, Costello syndrome, 218040, Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic, 163200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 HLCS Tracy Lester reviewed gene: HLCS: Rating: AMBER; Mode of pathogenicity: ; Publications: 22027809, 27114915; Phenotypes: Holocarboxylase synthetase deficiency, 253270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HEXA Tracy Lester reviewed gene: HEXA: Rating: GREEN; Mode of pathogenicity: ; Publications: 21937992, 9222766 ; Phenotypes: GM2-gangliosidosis, several forms, 272800, Tay-Sachs disease, 272800, [Hex A pseudodeficiency], 272800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HEPACAM Tracy Lester reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 21419380; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925, Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, 613926; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HCN2 Tracy Lester reviewed gene: HCN2: Rating: AMBER; Mode of pathogenicity: ; Publications: 29064616; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 HCFC1 Tracy Lester reviewed gene: HCFC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24011988, 26893841; Phenotypes: Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ), 309541; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 HAX1 Tracy Lester reviewed gene: HAX1: Rating: GREEN; Mode of pathogenicity: ; Publications: 18611981, 18337561 ; Phenotypes: Neutropenia, severe congenital 3, 610738; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HACE1 Tracy Lester reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: ; Publications: 26424145, 26437029 ; Phenotypes: Spastic paraplegia and psychomotor retardation with or without seizures, 616756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GTPBP2 Tracy Lester reviewed gene: GTPBP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26675814, 29449720 ; Phenotypes: Jaberi-Elahi syndrome, 617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GRIN2D Tracy Lester reviewed gene: GRIN2D: Rating: GREEN; Mode of pathogenicity: ; Publications: 27616483, 30280376 ; Phenotypes: Epileptic encephalopathy, early infantile, 617162; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GRIA4 Tracy Lester reviewed gene: GRIA4: Rating: GREEN; Mode of pathogenicity: ; Publications: 29220673; Phenotypes: Neurodevelopmental disorder with or without seizures and gait abnormalities, 617864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GPHN Tracy Lester reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: ; Publications: 22040219, 24561070; Phenotypes: Molybdenum cofactor deficiency C, 615501; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GOSR2 Tracy Lester reviewed gene: GOSR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 21549339, 30363482 ; Phenotypes: Epilepsy, progressive myoclonic, 614018; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GNB5 Tracy Lester reviewed gene: GNB5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Intellectual developmental disorder with cardiac arrhythmia, 617173, Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GNB1 Tracy Lester reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 27108799; Phenotypes: Mental retardation , 616973; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GNAQ Tracy Lester reviewed gene: GNAQ: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 28454448; Phenotypes: Capillary malformations, congenital, 1, somatic, mosaic 163000, Sturge-Weber syndrome, somatic, mosaic 185300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GM2A Tracy Lester reviewed gene: GM2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 26203402, 28417072 ; Phenotypes: GM2-gangliosidosis, AB variant, 272750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GLUL Tracy Lester reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: ; Publications: 21353613, 16267323 ; Phenotypes: Glutamine deficiency, congenital, 610015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GLUD1 Tracy Lester reviewed gene: GLUD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19254908; Phenotypes: Hyperinsulinism-hyperammonemia syndrome, 606762; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GLDC Tracy Lester reviewed gene: GLDC: Rating: GREEN; Mode of pathogenicity: ; Publications: 10798358, 29304759, 26947380 ; Phenotypes: Glycine encephalopathy, 605899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GLB1 Tracy Lester reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29439846; Phenotypes: GM1-gangliosidosis, type I 230500 , GM1-gangliosidosis, type II 230600, GM1-gangliosidosis, type III 230650, Mucopolysaccharidosis type IVB (Morquio) 253010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GFM1 Tracy Lester reviewed gene: GFM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 21119709; Phenotypes: Combined oxidative phosphorylation deficiency, 609060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GFAP Tracy Lester reviewed gene: GFAP: Rating: GREEN; Mode of pathogenicity: ; Publications: 11587071, 22496548 ; Phenotypes: Alexander disease, 203450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GCH1 Tracy Lester reviewed gene: GCH1: Rating: AMBER; Mode of pathogenicity: ; Publications: 7730309, 29948246; Phenotypes: Dystonia, DOPA-responsive, with or without hyperphenylalaninemia 128230, Hyperphenylalaninemia, BH4-deficient, B 233910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GBA Tracy Lester reviewed gene: GBA: Rating: GREEN; Mode of pathogenicity: ; Publications: 15329082, 18338393 ; Phenotypes: Gaucher disease, perinatal lethal 608013, Gaucher disease, type I 230800, Gaucher disease, type II 230900, Gaucher disease, type III 231000, Gaucher disease, type IIIC 231005, {Lewy body dementia, susceptibility to} 127750, {Parkinson disease, late-onset, susceptibility to} 168600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GAMT Tracy Lester reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: ; Publications: 19027335; Phenotypes: Cerebral creatine deficiency syndrome, 612736; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GALC Tracy Lester reviewed gene: GALC: Rating: GREEN; Mode of pathogenicity: ; Publications: 25260228; Phenotypes: Krabbe disease, 245200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GABRB2 Tracy Lester reviewed gene: GABRB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29053855; Phenotypes: Epileptic encephalopathy, infantile or early childhood, 617829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FUT8 Tracy Lester reviewed gene: FUT8: Rating: GREEN; Mode of pathogenicity: ; Publications: 29304374; Phenotypes: Congenital disorder of glycosylation with defective fucosylation, 618005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FUCA1 Tracy Lester reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 27706744; Phenotypes: Fucosidosis, 230000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FRRS1L Tracy Lester reviewed gene: FRRS1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 27236917; Phenotypes: Epileptic encephalopathy, early infantile, 616981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FOLR1 Tracy Lester reviewed gene: FOLR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22586289; Phenotypes: Neurodegeneration due to cerebral folate transport deficiency, 613068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FLNA Tracy Lester reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: ; Publications: 20014127; Phenotypes: Heterotopia periventricular, 1 300049; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 FKTN Tracy Lester reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1X 611615, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 253800, Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 613152, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 611588, ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FH Tracy Lester reviewed gene: FH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Fumarase deficiency, 606812, Leiomyomatosis and renal cell cancer, 150800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FGFR3 Tracy Lester reviewed gene: FGFR3: Rating: AMBER; Mode of pathogenicity: ; Publications: 27485793; Phenotypes: Achondroplasia, 100800, Bladder cancer, somatic, 109800, CATSHL syndrome, 610474, Cervical cancer, somatic, 603956, Colorectal cancer, somatic, 114500, Crouzon syndrome with acanthosis nigricans, 612247, Hypochondroplasia, 146000, LADD syndrome, 149730, Muenke syndrome, 602849, Nevus, epidermal, somatic, 162900, SADDAN, 616482, Spermatocytic seminoma, somatic, 273300, Thanatophoric dysplasia, type I, 187600, Thanatophoric dysplasia, type II, 187601, ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FGF12 Tracy Lester reviewed gene: FGF12: Rating: GREEN; Mode of pathogenicity: ; Publications: 27872899, 27164707 ; Phenotypes: Epileptic encephalopathy, early infantile, 617166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FBXO11 Tracy Lester reviewed gene: FBXO11: Rating: GREEN; Mode of pathogenicity: ; Publications: 30057029; Phenotypes: Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, 618089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FBXL4 Tracy Lester reviewed gene: FBXL4: Rating: GREEN; Mode of pathogenicity: ; Publications: 23993193; Phenotypes: Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FARS2 Tracy Lester reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 24161539, 29126765; Phenotypes: Combined oxidative phosphorylation deficiency 14, 614946, Spastic paraplegia 77, 617046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 FAR1 Tracy Lester reviewed gene: FAR1: Rating: AMBER; Mode of pathogenicity: ; Publications: 25439727; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, 616154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EXOSC3 Tracy Lester reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: ; Publications: 24524299; Phenotypes: Pontocerebellar hypoplasia, type 1B, 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ETHE1 Tracy Lester reviewed gene: ETHE1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20528888; Phenotypes: Ethylmalonic encephalopathy, 602473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EMX2 Tracy Lester reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Schizencephaly, 269160; Mode of inheritance: Unknown
Early onset or syndromic epilepsy v1.188 EIF3F Tracy Lester reviewed gene: EIF3F: Rating: GREEN; Mode of pathogenicity: ; Publications: 30409806; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EIF2S3 Tracy Lester reviewed gene: EIF2S3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27333055, 28055140 ; Phenotypes: MEHMO syndrome, 300148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 EIF2B5 Tracy Lester reviewed gene: EIF2B5: Rating: GREEN; Mode of pathogenicity: ; Publications: 21484434; Phenotypes: Leukoencephalopathy with vanishing white matter, 603896, Ovarioleukodystrophy 603896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EIF2B4 Tracy Lester reviewed gene: EIF2B4: Rating: GREEN; Mode of pathogenicity: ; Publications: 26043506; Phenotypes: Leukoencephalopathy with vanishing white matter, 603896, Ovarioleukodystrophy, 603896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EIF2B2 Tracy Lester reviewed gene: EIF2B2: Rating: GREEN; Mode of pathogenicity: ; Publications: 22678813, 24891910; Phenotypes: Leukoencephalopathy with vanishing white matter, 603896, Ovarioleukodystrophy, 603896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EFTUD2 Tracy Lester reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: ; Publications: 22305528; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type, 610536; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 EEF1A2 Tracy Lester reviewed gene: EEF1A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27441201, 28378778 ; Phenotypes: Epileptic encephalopathy, early infantile, 616409, Mental retardation , 616393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 EARS2 Tracy Lester reviewed gene: EARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 22492562; Phenotypes: Combined oxidative phosphorylation deficiency, 614924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DYNC1H1 Tracy Lester reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: ; Publications: 21076407, 23603762, 27331017 ; Phenotypes: Charcot-Marie-Tooth disease,axonal type, 614228, Mental retardation autosomal dominant 614563, Spinal muscular atrophy lower extremity-predominant 1, AD 158600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DPM1 Tracy Lester reviewed gene: DPM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23856421; Phenotypes: Congenital disorder of glycosylation type Ie, 608799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DPAGT1 Tracy Lester reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22304930, 12872255, 23249953 ; Phenotypes: Congenital disorder of glycosylation type Ij, 608093, Myasthenic syndrome congenital, 13 with tubular aggregates, 614750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DNM1L Tracy Lester reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 26604000, 27145208 ; Phenotypes: Encephalopathy lethal due to defective mitochondrial peroxisomal fission, 614388, Optic atrophy, 610708; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DHX30 Tracy Lester reviewed gene: DHX30: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100085; Phenotypes: Neurodevelopmental disorder with severe motor impairment and absent language, 617804; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DHDDS Tracy Lester reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100083; Phenotypes: ?Congenital disorder of glycosylation, 613861 , Developmental delay and seizures with or without movement abnormalities, 617836, Retinitis pigmentosa, 613861; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DHCR7 Tracy Lester reviewed gene: DHCR7: Rating: AMBER; Mode of pathogenicity: ; Publications: 20052364; Phenotypes: Smith-Lemli-Opitz syndrome, 270400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DENND5A Tracy Lester reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: ; Publications: 27866705, 27431290 ; Phenotypes: pileptic encephalopathy early infantile, 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DEAF1 Tracy Lester reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: ; Publications: 26048982; Phenotypes: ?Dyskinesia, seizures, and intellectual developmental disorder 617171, Mental retardation autosomal dominant, 615828; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DDX3X Tracy Lester reviewed gene: DDX3X: Rating: GREEN; Mode of pathogenicity: ; Publications: 26235985; Phenotypes: Mental retardation, 300958; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 DCX Tracy Lester reviewed gene: DCX: Rating: GREEN; Mode of pathogenicity: ; Publications: 12034802, 19098909 ; Phenotypes: Lissencephaly, 300067, Subcortical laminal heterotopia, 300067; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 D2HGDH Tracy Lester reviewed gene: D2HGDH: Rating: GREEN; Mode of pathogenicity: ; Publications: 15609246, 26178471 ; Phenotypes: D-2-hydroxyglutaric aciduria, 600721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CTSD Tracy Lester reviewed gene: CTSD: Rating: GREEN; Mode of pathogenicity: ; Publications: 16670177; Phenotypes: Ceroid lipofuscinosis, neuronal, 610127; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CSTB Tracy Lester reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: ; Publications: 8596935, 17003839 ; Phenotypes: Epilepsy progressive myoclonic 1A (Unverricht and Lundborg), 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CREBBP Tracy Lester reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: ; Publications: 12566391, 25599811; Phenotypes: Rubinstein-Taybi syndrome, 180849; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 COQ9 Tracy Lester reviewed gene: COQ9: Rating: GREEN; Mode of pathogenicity: ; Publications: 26081641; Phenotypes: Coenzyme Q10 deficiency primary, 614654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COQ4 Tracy Lester reviewed gene: COQ4: Rating: GREEN; Mode of pathogenicity: ; Publications: 25658047; Phenotypes: Coenzyme Q10 deficiency primary, 616276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COQ2 Tracy Lester reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: 17855635; Phenotypes: Coenzyme Q10 deficiency primary, 607426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COL4A2 Tracy Lester reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 22209246; Phenotypes: Porencephaly, 614483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 COL4A1 Tracy Lester reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23225343; Phenotypes: Retinal arteries tortuosity of 180000, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, 611773, Brain small vessel disease with or without ocular anomalies, 607595, Porencephaly, 175780, Schizencephaly 269160; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 COL18A1 Tracy Lester reviewed gene: COL18A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19160445; Phenotypes: Knobloch syndrome, 267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 COG7 Tracy Lester reviewed gene: COG7: Rating: GREEN; Mode of pathogenicity: ; Publications: 17395513; Phenotypes: Congenital disorder of glycosylation, 608779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CNNM2 Tracy Lester reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: ; Publications: 24699222; Phenotypes: Hypomagnesemia renal, 613882, Hypomagnesemia, seizures, and mental retardation 616418; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CLN3 Tracy Lester reviewed gene: CLN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 7553855; Phenotypes: Ceroid lipofuscinosis neuronal, 204200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CLCN4 Tracy Lester reviewed gene: CLCN4: Rating: GREEN; Mode of pathogenicity: ; Publications: 27550844; Phenotypes: Raynaud-Claes syndrome, 300114; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 CC2D2A Tracy Lester reviewed gene: CC2D2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 22241855; Phenotypes: COACH syndrome 216360, Joubert syndrome, 612285, Meckel syndrome, 612284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CASK Tracy Lester reviewed gene: CASK: Rating: GREEN; Mode of pathogenicity: ; Publications: 21954287; Phenotypes: FG syndrome, 300422 , Mental retardation and microcephaly with pontine and cerebellar hypoplasia, 300749, Mental retardation with or without nystagmus, 300422; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 CAD Tracy Lester reviewed gene: CAD: Rating: GREEN; Mode of pathogenicity: ; Publications: 28007989; Phenotypes: Epileptic encephalopathy early infantile, 616457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CACNA1G Tracy Lester reviewed gene: CACNA1G: Rating: GREEN; Mode of pathogenicity: ; Publications: 17397049, 29878067 ; Phenotypes: Spinocerebellar ataxia, 616795, Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits, 618087; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CACNA1E Tracy Lester reviewed gene: CACNA1E: Rating: GREEN; Mode of pathogenicity: ; Publications: 30343943; Phenotypes: Epileptic encephalopathy, early infantile, 618285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CACNA1A Tracy Lester reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 11061267, 25735478; Phenotypes: Epileptic encephalopathy early infantile, 42 617106, Episodic ataxia, 108500, Migraine, familial hemiplegic, 141500, Migraine, familial hemiplegic, with progressive cerebellar ataxia 141500, Spinocerebellar ataxia,183086; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 C12orf57 Tracy Lester reviewed gene: C12orf57: Rating: GREEN; Mode of pathogenicity: ; Publications: 23453666; Phenotypes: Temtamy syndrome, 218340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BTD Tracy Lester reviewed gene: BTD: Rating: GREEN; Mode of pathogenicity: ; Publications: 24075304, 25423671 ; Phenotypes: Biotinidase deficiency, 253260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BRAF Tracy Lester reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: ; Publications: 19206169, 18042262; Phenotypes: Adenocarcinoma of lung, somatic 211980, Cardiofaciocutaneous syndrome, 115150, Colorectal cancer, somatic, LEOPARD syndrome, 613707, Melanoma, malignant, somatic, Nonsmall cell lung cancer, somatic, Noonan syndrome, 613706; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 BOLA3 Tracy Lester reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: ; Publications: 24334290; Phenotypes: Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, 614299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BCS1L Tracy Lester reviewed gene: BCS1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 11528392; Phenotypes: Bjornstad syndrome, 262000, GRACILE syndrome, 603358, Leigh syndrome, 256000, Mitochondrial complex III deficiency, 124000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BCKDHB Tracy Lester reviewed gene: BCKDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 28919799; Phenotypes: Maple syrup urine disease, 248600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BCKDHA Tracy Lester reviewed gene: BCKDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 28919799; Phenotypes: Maple syrup urine disease, 248600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ATP7A Tracy Lester reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: ; Publications: 7842019, 21924848 ; Phenotypes: Menkes disease, 309400, Occipital horn syndrome, 304150, Spinal muscular atrophy, distal, 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 ATP6V1A Tracy Lester reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 29668857; Phenotypes: Cutis laxa, type IID, 617403, Epileptic encephalopathy, infantile or early childhood, 618012; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ATP1A1 Tracy Lester reviewed gene: ATP1A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30388404; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2DD, 618036; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ASPA Tracy Lester reviewed gene: ASPA: Rating: GREEN; Mode of pathogenicity: ; Publications: 1643757; Phenotypes: Canavan disease, 271900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ARV1 Tracy Lester reviewed gene: ARV1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25558065, 27270415; Phenotypes: Epileptic encephalopathy, early infantile, 617020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ARID1B Tracy Lester reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: ; Publications: 22405089; Phenotypes: Coffin-Siris syndrome, 135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ARG1 Tracy Lester reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 2365823, 29726057 ; Phenotypes: Argininemia, 207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ARFGEF2 Tracy Lester reviewed gene: ARFGEF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 14647276; Phenotypes: Periventricular heterotopia with microcephaly, 608097; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 AP3B2 Tracy Lester reviewed gene: AP3B2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27889060; Phenotypes: Epileptic encephalopathy, early infantile, 617276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 AMT Tracy Lester reviewed gene: AMT: Rating: GREEN; Mode of pathogenicity: ; Publications: 25231368; Phenotypes: Glycine encephalopathy, 605899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 AMPD2 Tracy Lester reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28815207, 23911318 ; Phenotypes: ?Spastic paraplegia 63 615686, Pontocerebellar hypoplasia, 615809; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALPL Tracy Lester reviewed gene: ALPL: Rating: AMBER; Mode of pathogenicity: ; Publications: 3350970, 7550313 ; Phenotypes: Hypophosphatasia, adult 146300, Hypophosphatasia, childhood 241510, Hypophosphatasia, infantile 241500, Odontohypophosphatasia, 146300, ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALG9 Tracy Lester reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital disorder of glycosylation, 608776, Gillessen-Kaesbach-Nishimura syndrome, 263210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALG8 Tracy Lester reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital disorder of glycosylation, type Ih 608104, Polycystic liver disease 3 with or without kidney cysts 617874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALG6 Tracy Lester reviewed gene: ALG6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital disorder of glycosylation, 603147; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALG3 Tracy Lester reviewed gene: ALG3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital disorder of glycosylation, 601110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALG1 Tracy Lester reviewed gene: ALG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20679665; Phenotypes: Congenital disorder of glycosylation, type Ik, 608540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALDH5A1 Tracy Lester reviewed gene: ALDH5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 14635103; Phenotypes: Succinic semialdehyde dehydrogenase deficiency, 271980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 AKT3 Tracy Lester reviewed gene: AKT3: Rating: GREEN; Mode of pathogenicity: ; Publications: 21159799, 22729224 ; Phenotypes: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 615937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 AKT1 Tracy Lester reviewed gene: AKT1: Rating: RED; Mode of pathogenicity: ; Publications: 25722288; Phenotypes: Breast cancer, somatic, 114480, Colorectal cancer, somatic, 114500, Cowden syndrome, 615109, Ovarian cancer, somatic, 167000, Proteus syndrome, somatic 176920, {Schizophrenia, susceptibility to} 181500; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 AIMP1 Tracy Lester reviewed gene: AIMP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24958424, 21092922 ; Phenotypes: Leukodystrophy, hypomyelinating, 260600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ADPRHL2 Tracy Lester reviewed gene: ADPRHL2: Rating: GREEN; Mode of pathogenicity: ; Publications: 30100084; Phenotypes: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, 618170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ADGRG1 Tracy Lester reviewed gene: ADGRG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15044805, ; Phenotypes: Polymicrogyria, bilateral frontoparietal, 606854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ADAR Tracy Lester reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: ; Publications: 27937139, 24011626 ; Phenotypes: Aicardi-Goutieres syndrome, 615010, Dyschromatosis symmetrica hereditaria, 127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ACOX1 Tracy Lester reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: ; Publications: 18536048; Phenotypes: Peroxisomal acyl-CoA oxidase deficiency, 264470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ABAT Tracy Lester reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: ; Publications: 10407778, 27903293 ; Phenotypes: GABA-transaminase deficiency, 613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ZEB2 Tracy Lester reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 16532472, 23466526 ; Phenotypes: Mowat-Wilson syndrome, 235730; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 WWOX Tracy Lester reviewed gene: WWOX: Rating: GREEN; Mode of pathogenicity: ; Publications: 24369382, 24456803 ; Phenotypes: pileptic encephalopathy, early infantile, 616211, Esophageal squamous cell carcinoma, somatic 133239, Spinocerebellar ataxia 12 614322; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 WDR45B Tracy Lester reviewed gene: WDR45B: Rating: AMBER; Mode of pathogenicity: ; Publications: 28503735; Phenotypes: Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 WDR45 Tracy Lester reviewed gene: WDR45: Rating: GREEN; Mode of pathogenicity: ; Publications: 23176820; Phenotypes: Neurodegeneration with brain iron accumulation, 300894; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 UBE3A Tracy Lester reviewed gene: UBE3A: Rating: GREEN; Mode of pathogenicity: ; Publications: 28297715, 11748306 ; Phenotypes: Angelman syndrome, 105830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Early onset or syndromic epilepsy v1.188 UBE2A Tracy Lester reviewed gene: UBE2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 16909393, 24053514 ; Phenotypes: Mental retardation, X-linked syndromic, Nascimento-type, 300860; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 TRPM6 Tracy Lester reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: ; Publications: 12032568; Phenotypes: Hypomagnesemia 1, intestinal, 602014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TRAK1 Tracy Lester reviewed gene: TRAK1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28364549; Phenotypes: Epileptic encephalopathy, early infantile, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TPP1 Tracy Lester reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 17959406, 10665500, 20820830 ; Phenotypes: eroid lipofuscinosis, neuronal, 204500, Spinocerebellar ataxia, 609270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 TCF4 Tracy Lester reviewed gene: TCF4: Rating: GREEN; Mode of pathogenicity: ; Publications: 19938247; Phenotypes: Corneal dystrophy, Fuchs endothelial, 613267, Pitt-Hopkins syndrome, 610954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 TBC1D24 Tracy Lester reviewed gene: TBC1D24: Rating: GREEN; Mode of pathogenicity: ; Publications: 27281533; Phenotypes: Deafness , 614617, Deafness, 616044, DOORS syndrome 220500, Epileptic encephalopathy, early infantile, 615338, Myoclonic epilepsy, infantile, familial 605021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SZT2 Tracy Lester reviewed gene: SZT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23932106, 24324832 ; Phenotypes: Epileptic encephalopathy, early infantile, 615476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SYNJ1 Tracy Lester reviewed gene: SYNJ1: Rating: GREEN; Mode of pathogenicity: ; Publications: 27435091; Phenotypes: Epileptic encephalopathy, early infantile, 617389, Parkinson disease 20, early-onset, 615530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SYNGAP1 Tracy Lester reviewed gene: SYNGAP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23708187; Phenotypes: Mental retardation, 612621; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SUOX Tracy Lester reviewed gene: SUOX: Rating: GREEN; Mode of pathogenicity: ; Publications: 28725568; Phenotypes: Sulfite oxidase deficiency, 272300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 STXBP1 Tracy Lester reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 18469812, 19557857 ; Phenotypes: Epileptic encephalopathy, early infantile, 612164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 STX1B Tracy Lester reviewed gene: STX1B: Rating: GREEN; Mode of pathogenicity: ; Publications: 25362483; Phenotypes: Generalized epilepsy with febrile seizures plus, 616172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 STRADA Tracy Lester reviewed gene: STRADA: Rating: GREEN; Mode of pathogenicity: ; Publications: 17522105, 23616120, 27170158 ; Phenotypes: Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SPTAN1 Tracy Lester reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20493457, 22258530 ; Phenotypes: Epileptic encephalopathy, early infantile, 613477; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SLC9A6 Tracy Lester reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: ; Publications: 20395263, 24123876 ; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, 300243; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: AMBER; Mode of pathogenicity: ; Publications: 24596948 , 15592994; Phenotypes: Hartnup disorder,234500, Hyperglycinuria,138500, Iminoglycinuria, digenic,242600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC6A1 Tracy Lester reviewed gene: SLC6A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25865495; Phenotypes: Myoclonic-atonic epilepsy, 616421; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SLC35A2 Tracy Lester reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23561849, 24115232 ; Phenotypes: Congenital disorder of glycosylation, type Iim, 300896; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 SLC2A1 Tracy Lester reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20129935; Phenotypes: Dystonia 9,601042, GLUT1 deficiency syndrome 1, infantile onset, severe,606777, GLUT1 deficiency syndrome 2, childhood onset,612126, Stomatin-deficient cryohydrocytosis with neurologic defects,608885, {Epilepsy, idiopathic generalized, susceptibility to, 12},614847; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC25A22 Tracy Lester reviewed gene: SLC25A22: Rating: GREEN; Mode of pathogenicity: ; Publications: 19780765, 24596948 , 15592994; Phenotypes: Epileptic encephalopathy, early infantile, 609304; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC25A1 Tracy Lester reviewed gene: SLC25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29226520, 23561848 ; Phenotypes: ?Myasthenic syndrome, congenital, 23, presynaptic 618197, Combined D-2- and L-2-hydroxyglutaric aciduria, 615182; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC1A2 Tracy Lester reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27476654, 28777935 ; Phenotypes: Epileptic encephalopathy, early infantile, 617105; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SLC16A2 Tracy Lester reviewed gene: SLC16A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27212794; Phenotypes: Allan-Herndon-Dudley syndrome, 300523; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 SLC13A5 Tracy Lester reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: ; Publications: 24995870; Phenotypes: Epileptic encephalopathy, early infantile, 615905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SLC12A5 Tracy Lester reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: ; Publications: 26333769, 27436767 ; Phenotypes: Epileptic encephalopathy, early infantile, 616645, {Epilepsy, idiopathic generalized, susceptibility to}, 616685 ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SIK1 Tracy Lester reviewed gene: SIK1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25839329; Phenotypes: Epileptic encephalopathy, early infantile, 616341; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SETD5 Tracy Lester reviewed gene: SETD5: Rating: AMBER; Mode of pathogenicity: ; Publications: 25138099, 24680889 ; Phenotypes: Mental retardation, 615761; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SCN9A Tracy Lester reviewed gene: SCN9A: Rating: AMBER; Mode of pathogenicity: ; Publications: 19763161, 23895530 ; Phenotypes: Epilepsy, generalized, with febrile seizures plus, type 7,613863, Erythermalgia, primary,133020, Febrile seizures, familial,613863, HSAN2D,243000, Insensitivity to pain, congenital,243000, Paroxysmal extreme pain disorder,167400, Small fiber neuropathy,133020; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SCN8A Tracy Lester reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: ; Publications: 22365152, 24194747 ; Phenotypes: ?Cognitive impairment with or without cerebellar ataxia,614306, Epileptic encephalopathy, early infantile,614558, Seizures, benign familial infantile,617080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SCN2A Tracy Lester reviewed gene: SCN2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 23935176, 28256214 ; Phenotypes: Epileptic encephalopathy, early infantile,613721, Seizures, benign familial infantile,607745; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SCN1B Tracy Lester reviewed gene: SCN1B: Rating: GREEN; Mode of pathogenicity: ; Publications: 23148524, 19710327, 17020904 ; Phenotypes: Atrial fibrillation, familial,615377, Brugada syndrome,612838, Cardiac conduction defect, nonspecific,612838, Epilepsy, generalized, with febrile seizures plus, type 1,604233, Epileptic encephalopathy, early infantile, 52,617350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 SCN1A Tracy Lester reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 12821740; Phenotypes: Epilepsy, generalized, with febrile seizures plus,604403, Epileptic encephalopathy, early infantile, (Dravet syndrome),607208, Febrile seizures, familial,604403, Migraine, familial hemiplegic,609634; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 SCARB2 Tracy Lester reviewed gene: SCARB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 18308289, 22032306 ; Phenotypes: Epilepsy, progressive myoclonic 4, with or without renal failure,254900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 RANBP2 Tracy Lester reviewed gene: RANBP2: Rating: AMBER; Mode of pathogenicity: ; Publications: 19118815; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 QARS Tracy Lester reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 24656866, 25432320 ; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, 615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PURA Tracy Lester reviewed gene: PURA: Rating: GREEN; Mode of pathogenicity: ; Publications: 25439098; Phenotypes: Mental retardation, 616158; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PRRT2 Tracy Lester reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23077018, 24101679, 22832103 ; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis,602066, Episodic kinesigenic dyskinesia,128200, Seizures, benign familial infantile,605751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 PRODH Tracy Lester reviewed gene: PRODH: Rating: AMBER; Mode of pathogenicity: ; Publications: 12217952, ; Phenotypes: Hyperprolinemia, type I, 239500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 POLG Tracy Lester reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: ; Publications: 1663941, 19578034 ; Phenotypes: Mitochondrial DNA depletion syndrome 4A (Alpers type),203700, Mitochondrial DNA depletion syndrome 4B (MNGIE type),613662, Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE),607459, Progressive external ophthalmoplegia,157640, Progressive external ophthalmoplegia,258450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PNPO Tracy Lester reviewed gene: PNPO: Rating: GREEN; Mode of pathogenicity: ; Publications: 26535729, 15772097 ; Phenotypes: Pyridoxamine 5'-phosphate oxidase deficiency, 610090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PNKP Tracy Lester reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: ; Publications: 20118933; Phenotypes: Ataxia-oculomotor apraxia,616267, Microcephaly, seizures, and developmental delay,613402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PLPBP Tracy Lester reviewed gene: PLPBP: Rating: GREEN; Mode of pathogenicity: ; Publications: 27912044, 28391250 ; Phenotypes: Epilepsy, early-onset, vitamin B6-dependent, 617290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PLCB1 Tracy Lester reviewed gene: PLCB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20833646, 24684524, 26818157 ; Phenotypes: Epileptic encephalopathy, early infantile, 613722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGT Tracy Lester reviewed gene: PIGT: Rating: GREEN; Mode of pathogenicity: ; Publications: 24906948, 23636107 ; Phenotypes: ?Paroxysmal nocturnal hemoglobinuria,615399, Multiple congenital anomalies-hypotonia-seizures syndrome,615398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGN Tracy Lester reviewed gene: PIGN: Rating: GREEN; Mode of pathogenicity: ; Publications: 24253414, 21493957 ; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome, 614080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 PIGA Tracy Lester reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: ; Publications: 25885527, 29656098 ; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome,300868, Paroxysmal nocturnal hemoglobinuria, somatic,300818; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 PCDH19 Tracy Lester reviewed gene: PCDH19: Rating: GREEN; Mode of pathogenicity: ; Publications: 19752159; Phenotypes: Epileptic encephalopathy, early infantile, 300088; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 NEXMIF Tracy Lester reviewed gene: NEXMIF: Rating: GREEN; Mode of pathogenicity: ; Publications: 23615299, 27358180 ; Phenotypes: Mental retardation, X-linked, 300912; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 NACC1 Tracy Lester reviewed gene: NACC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28132692; Phenotypes: Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MTOR Tracy Lester reviewed gene: MTOR: Rating: GREEN; Mode of pathogenicity: ; Publications: 26542245, 28892148 ; Phenotypes: Focal cortical dysplasia, type II, somatic,607341, Smith-Kingsmore syndrome,616638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MOGS Tracy Lester reviewed gene: MOGS: Rating: GREEN; Mode of pathogenicity: ; Publications: 24716661, 30587846 ; Phenotypes: Congenital disorder of glycosylation, type Iib, 606056; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MFF Tracy Lester reviewed gene: MFF: Rating: GREEN; Mode of pathogenicity: ; Publications: 22499341, 26783368 ; Phenotypes: Encephalopathy due to defective mitochondrial and peroxisomal fission, 617086; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MEF2C Tracy Lester reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: ; Publications: 20513142; Phenotypes: chromosome 5q14.3 deletion syndrome,613443, Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations,613443; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 MECP2 Tracy Lester reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 30425922, 21916843, 17387578 ; Phenotypes: Encephalopathy, neonatal severe,300673, Mental retardation, X-linked syndromic, Lubs type,300260, Mental retardation, X-linked, syndromic 13,300055, Rett syndrome,312750, Rett syndrome, atypical,312750, Rett syndrome, preserved speech variant,312750, {Autism susceptibility, X-linked 3},300496; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 MDH2 Tracy Lester reviewed gene: MDH2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27989324; Phenotypes: Epileptic encephalopathy, early infantile, 617339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MBOAT7 Tracy Lester reviewed gene: MBOAT7: Rating: GREEN; Mode of pathogenicity: ; Publications: 27616480; Phenotypes: Mental retardation, 617188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 MBD5 Tracy Lester reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: ; Publications: 23422940; Phenotypes: Mental retardation, 156200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 LGI1 Tracy Lester reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: ; Publications: 11810107; Phenotypes: Epilepsy, familial temporal lobe, 600512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KIF1BP Tracy Lester reviewed gene: KIF1BP: Rating: AMBER; Mode of pathogenicity: ; Publications: 23427148; Phenotypes: Goldberg-Shprintzen megacolon syndrome, 609460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCTD7 Tracy Lester reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: ; Publications: 22693283; Phenotypes: Epilepsy, progressive myoclonic , with or without intracellular inclusions, 611726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCNT1 Tracy Lester reviewed gene: KCNT1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 23086397, 26122718; Phenotypes: Epilepsy, nocturnal frontal lobe, 615005, Epileptic encephalopathy, early infantile, 614959; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNQ3 Tracy Lester reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: ; Publications: 14534157; Phenotypes: Seizures, benign neonatal, 121201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNQ2 Tracy Lester reviewed gene: KCNQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27602407, 14534157 ; Phenotypes: Epileptic encephalopathy, early infantile, 613720, Myokymia, 121200, Seizures, benign neonatal, 121200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNJ10 Tracy Lester reviewed gene: KCNJ10: Rating: GREEN; Mode of pathogenicity: ; Publications: 19420365; Phenotypes: Enlarged vestibular aqueduct, digenic, 600791, SESAME syndrome 612780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 KCNC1 Tracy Lester reviewed gene: KCNC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25401298; Phenotypes: Epilepsy, progressive myoclonic, 616187; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNB1 Tracy Lester reviewed gene: KCNB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25164438, 29264397 ; Phenotypes: Epileptic encephalopathy, 616056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 KCNA2 Tracy Lester reviewed gene: KCNA2: Rating: GREEN; Mode of pathogenicity: ; Publications: 25751627, 28032718 ; Phenotypes: Epileptic encephalopathy,616366; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ITPA Tracy Lester reviewed gene: ITPA: Rating: GREEN; Mode of pathogenicity: ; Publications: 26224535, 27770805 ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 IQSEC2 Tracy Lester reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26793055, 23674175 ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 IER3IP1 Tracy Lester reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 21835305, 24138066 ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 IDH2 Tracy Lester reviewed gene: IDH2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HTRA2 Tracy Lester reviewed gene: HTRA2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27696117, 27208207 ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HNRNPU Tracy Lester reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: 27652284; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 HNRNPH2 Tracy Lester reviewed gene: HNRNPH2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27545675; Phenotypes: Mental retardation, X-linked, syndromic, Bain type,300986; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 HMGCL Tracy Lester reviewed gene: HMGCL: Rating: GREEN; Mode of pathogenicity: ; Publications: 28583327; Phenotypes: HMG-CoA lyase deficiency,246450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 HECW2 Tracy Lester reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27389779; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language, 617268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 HCN1 Tracy Lester reviewed gene: HCN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 24747641, 25678871; Phenotypes: Epileptic encephalopathy, early infantile, 24,615871; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GSS Tracy Lester reviewed gene: GSS: Rating: AMBER; Mode of pathogenicity: ; Publications: 26984560; Phenotypes: Glutathione synthetase deficiency,266130, Hemolytic anemia due to glutathione synthetase deficiency,231900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GRIN2B Tracy Lester reviewed gene: GRIN2B: Rating: GREEN; Mode of pathogenicity: ; Publications: 20890276; Phenotypes: Epileptic encephalopathy, early infantile, 27,616139, Mental retardation 6,613970; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GRIN2A Tracy Lester reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 20890276; Phenotypes: Epilepsy, focal, with speech disorder and with or without mental retardation,245570; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GRIN1 Tracy Lester reviewed gene: GRIN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 27164704; Phenotypes: Neurodevelopmental disorder with or without hyperkinetic movements and seizures,614254, Neurodevelopmental disorder with or without hyperkinetic movements and seizures,617820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GPAA1 Tracy Lester reviewed gene: GPAA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100095; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 15,617810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GNAO1 Tracy Lester reviewed gene: GNAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23993195, 28357411 ; Phenotypes: Epileptic encephalopathy, early infantile, 17,615473, Neurodevelopmental disorder with involuntary movements,617493; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GLYCTK Tracy Lester reviewed gene: GLYCTK: Rating: AMBER; Mode of pathogenicity: ; Publications: 30637540; Phenotypes: D-glyceric aciduria,220120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 GABRG2 Tracy Lester reviewed gene: GABRG2: Rating: GREEN; Mode of pathogenicity: ; Publications: 11748509, 27066572 ; Phenotypes: Epilepsy, generalized, with febrile seizures plus, type 3,611277, Febrile seizures, familial, 8,611277, {Epilepsy, childhood absence, susceptibility to, 2},607681; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GABRB3 Tracy Lester reviewed gene: GABRB3: Rating: GREEN; Mode of pathogenicity: ; Publications: 18514161, 27476654 ; Phenotypes: Epileptic encephalopathy, early infantile, 43,617113, {Epilepsy, childhood absence, susceptibility to, 5},612269; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GABRA1 Tracy Lester reviewed gene: GABRA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24623842, 27521439; Phenotypes: Epileptic encephalopathy, early infantile, 19,615744, {Epilepsy, childhood absence, susceptibility to, 4},611136, {Epilepsy, juvenile myoclonic, susceptibility to, 5},611136; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 GABBR2 Tracy Lester reviewed gene: GABBR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28856709, 29100083 ; Phenotypes: Epileptic encephalopathy, early infantile, 59,617904, Neurodevelopmental disorder with poor language and loss of hand skills,617903, {Nicotine dependence, protection against},188890, {Nicotine dependence, susceptibility to},188890; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 FOXG1 Tracy Lester reviewed gene: FOXG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30533527; Phenotypes: Rett syndrome, congenital variant,613454; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 EPM2A Tracy Lester reviewed gene: EPM2A: Rating: GREEN; Mode of pathogenicity: ; Publications: 11175283; Phenotypes: Epilepsy, progressive myoclonic 2A (Lafora),254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EPG5 Tracy Lester reviewed gene: EPG5: Rating: GREEN; Mode of pathogenicity: ; Publications: 25331754; Phenotypes: Vici syndrome,242840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EML1 Tracy Lester reviewed gene: EML1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24859200; Phenotypes: Band heterotopia,600348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 EHMT1 Tracy Lester reviewed gene: EHMT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 16826528, 19264732; Phenotypes: Kleefstra syndrome 1,610253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DYRK1A Tracy Lester reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 23099646, 21294719 ; Phenotypes: Mental retardation 7,614104; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DPYD Tracy Lester reviewed gene: DPYD: Rating: GREEN; Mode of pathogenicity: ; Publications: 28275972, 19296131 ; Phenotypes: 5-fluorouracil toxicity,274270, Dihydropyrimidine dehydrogenase deficiency,274270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DOCK7 Tracy Lester reviewed gene: DOCK7: Rating: GREEN; Mode of pathogenicity: ; Publications: 24814191, ; Phenotypes: Epileptic encephalopathy, early infantile, 23,615859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DNM1 Tracy Lester reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25262651, 27066543 ; Phenotypes: Epileptic encephalopathy, early infantile, 31,616346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 DIAPH1 Tracy Lester reviewed gene: DIAPH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 26463574, 24781755 ; Phenotypes: Deafness 1,124900, Seizures, cortical blindness, microcephaly syndrome,616632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 DEPDC5 Tracy Lester reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: ; Publications: 9851433, 23542697 ; Phenotypes: Epilepsy, familial focal, with variable foci 1,604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CYFIP2 Tracy Lester reviewed gene: CYFIP2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 29534297, ; Phenotypes: Epileptic encephalopathy, early infantile, 65,618008; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CPA6 Tracy Lester reviewed gene: CPA6: Rating: GREEN; Mode of pathogenicity: ; Publications: 23105115, 21922598 ; Phenotypes: Epilepsy, familial temporal lobe, 5,614417, Febrile seizures, familial, 11,614418; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CNTNAP2 Tracy Lester reviewed gene: CNTNAP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 16571880, 18179893, 27439707 ; Phenotypes: Cortical dysplasia-focal epilepsy syndrome,610042, Pitt-Hopkins like syndrome 1,610042, {Autism susceptibility 15},612100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CNKSR2 Tracy Lester reviewed gene: CNKSR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28098945, 25223753 ; Phenotypes: Mental retardation, X-linked, syndromic, Houge type,301008; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 CLTC Tracy Lester reviewed gene: CLTC: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100083, 26822784 ; Phenotypes: Mental retardation 56,617854; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CLN8 Tracy Lester reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: ; Publications: 10508524, ; Phenotypes: Ceroid lipofuscinosis, neuronal, 8,600143, Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant,610003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 CIC Tracy Lester reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: ; Publications: 28288114; Phenotypes: Mental retardation 45,617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CHRNB2 Tracy Lester reviewed gene: CHRNB2: Rating: GREEN; Mode of pathogenicity: loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 11104662, 25717303 ; Phenotypes: Epilepsy, nocturnal frontal lobe, 3,605375; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CHRNA4 Tracy Lester reviewed gene: CHRNA4: Rating: GREEN; Mode of pathogenicity: loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 29454195, 21753767 ; Phenotypes: Epilepsy, nocturnal frontal lobe, 1,600513, {Nicotine addiction, susceptibility to},188890; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CHRNA2 Tracy Lester reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 16826524 , 25770198 ; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4,610353; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CHD2 Tracy Lester reviewed gene: CHD2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23020937, 23708187 ; Phenotypes: Epileptic encephalopathy, childhood-onset,615369; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 CDKL5 Tracy Lester reviewed gene: CDKL5: Rating: GREEN; Mode of pathogenicity: ; Publications: 15492925, 17993579 ; Phenotypes: Epileptic encephalopathy, early infantile, 2,300672; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 CACNA1D Tracy Lester reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 23913001 , 28472301 ; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities,615474, Sinoatrial node dysfunction and deafness,614896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 BSCL2 Tracy Lester reviewed gene: BSCL2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23564749, ; Phenotypes: Lipodystrophy, congenital generalized, type 2,269700, Neuropathy, distal hereditary motor, type VA,600794, Silver spastic paraplegia syndrome,270685, Encephalopathy, progressive, with or without lipodystrophy,615924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 BRAT1 Tracy Lester reviewed gene: BRAT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 26483087, 27282546 ; Phenotypes: Rigidity and multifocal seizure syndrome, lethal neonatal, 614498, Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, 618056; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ATRX Tracy Lester reviewed gene: ATRX: Rating: GREEN; Mode of pathogenicity: ; Publications: 16722615; Phenotypes: Alpha-thalassemia myelodysplasia syndrome, somatic, 300448, Alpha-thalassemia/mental retardation syndrome, 301040, Mental retardation-hypotonic facies syndrome, X-linked,309580; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 ATP6V0A2 Tracy Lester reviewed gene: ATP6V0A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 18157129, 22773132 ; Phenotypes: Cutis laxa, type IIA,219200, Wrinkly skin syndrome,278250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ATP1A3 Tracy Lester reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 25656163, 24739246, 29291920, 30392841 ; Phenotypes: Alternating hemiplegia of childhood 2, 614820, CAPOS syndrome,601338, Dystonia-12, 128235; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.188 ARX Tracy Lester reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: ; Publications: 17490853, 17668384, 18462864 ; Phenotypes: Epileptic encephalopathy, early infantile, 1, 308350, Hydranencephaly with abnormal genitalia,300215 , Lissencephaly, X-linked 2, 300215, Mental retardation, X-linked 29, 300419, Partington syndrome,309510, Proud syndrome, 300004; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 ARHGEF9 Tracy Lester reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: ; Publications: 21633362, 15215304 ; Phenotypes: Epileptic encephalopathy, early infantile, 8, 300607; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 ALG13 Tracy Lester reviewed gene: ALG13: Rating: GREEN; Mode of pathogenicity: ; Publications: 23033978, 24501762; Phenotypes: Epileptic encephalopathy, early infantile, 36, 300884, ?Congenital disorder of glycosylation, type Is, 300884; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.188 ALG11 Tracy Lester reviewed gene: ALG11: Rating: GREEN; Mode of pathogenicity: ; Publications: 20080937, 22213132 ; Phenotypes: Congenital disorder of glycosylation, type Ip, 613661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ALDH7A1 Tracy Lester reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 17068770, 17721876; Phenotypes: Epilepsy, pyridoxine-dependent, 266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 ADSL Tracy Lester reviewed gene: ADSL: Rating: GREEN; Mode of pathogenicity: ; Publications: 10090474, 12016589; Phenotypes: Adenylosuccinase deficiency, 103050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 AARS Tracy Lester reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 25817015, 28493438 ; Phenotypes: Charcot-Marie-Tooth disease, 613287, Early Infantile Epileptic encephalopathy, 601065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.187 ZIC2 Rebecca Foulger gene: ZIC2 was added
gene: ZIC2 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: ZIC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ZIC2 were set to Holoprosencephaly 5, 609637
Early onset or syndromic epilepsy v1.187 TGIF1 Rebecca Foulger gene: TGIF1 was added
gene: TGIF1 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: TGIF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TGIF1 were set to Holoprosencephaly 4, 142946
Early onset or syndromic epilepsy v1.187 STIL Rebecca Foulger gene: STIL was added
gene: STIL was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: STIL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STIL were set to Microcephaly 7, primary, 612703
Early onset or syndromic epilepsy v1.187 SLC25A19 Rebecca Foulger gene: SLC25A19 was added
gene: SLC25A19 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: SLC25A19 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC25A19 were set to Microcephaly, Amish type, 607196; Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type), 613710
Early onset or syndromic epilepsy v1.187 PTCH1 Rebecca Foulger gene: PTCH1 was added
gene: PTCH1 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTCH1 were set to Basal cell nevus syndrome, 109400; Holoprosencephaly 7, 610828; Basal cell carcinoma, somatic, 605462
Early onset or syndromic epilepsy v1.187 PRDM8 Rebecca Foulger gene: PRDM8 was added
gene: PRDM8 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: PRDM8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM8 were set to 22961547
Phenotypes for gene: PRDM8 were set to ?Epilepsy, progressive myoclonic, 10, 616640
Early onset or syndromic epilepsy v1.187 LMNB2 Rebecca Foulger gene: LMNB2 was added
gene: LMNB2 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,Expert Review Red,NHS GMS
Mode of inheritance for gene: LMNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMNB2 were set to 16826530
Phenotypes for gene: LMNB2 were set to {Lipodystrophy, partial, acquired, susceptibility to}, 608709; ?Epilepsy, progressive myoclonic, 9, 616540
Early onset or syndromic epilepsy v1.187 GUF1 Rebecca Foulger gene: GUF1 was added
gene: GUF1 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,NHS GMS,Expert Review Amber
Mode of inheritance for gene: GUF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUF1 were set to 26486472
Phenotypes for gene: GUF1 were set to ?Epileptic encephalopathy, early infantile, 40, 617065
Early onset or syndromic epilepsy v1.187 GABRB1 Rebecca Foulger gene: GABRB1 was added
gene: GABRB1 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,NHS GMS,Expert Review Amber
Mode of inheritance for gene: GABRB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRB1 were set to 26950270; 27273810
Phenotypes for gene: GABRB1 were set to Epileptic encephalopathy, early infantile, 45, 617153
Early onset or syndromic epilepsy v1.187 CTSF Rebecca Foulger gene: CTSF was added
gene: CTSF was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,NHS GMS,Expert Review Amber
Mode of inheritance for gene: CTSF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTSF were set to 16508006
Phenotypes for gene: CTSF were set to Ceroid lipofuscinosis, neuronal, 13, Kufs type, 615362
Early onset or syndromic epilepsy v1.187 CERS1 Rebecca Foulger gene: CERS1 was added
gene: CERS1 was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,NHS GMS,Expert Review Amber
Mode of inheritance for gene: CERS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CERS1 were set to 19243074
Phenotypes for gene: CERS1 were set to ?Epilepsy, progressive myoclonic, 8, 616230
Early onset or syndromic epilepsy v1.187 ADRA2B Rebecca Foulger gene: ADRA2B was added
gene: ADRA2B was added to Genetic epilepsy syndromes. Sources: Wessex and West Midlands GLH,NHS GMS,Expert Review Amber
Mode of inheritance for gene: ADRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADRA2B were set to 11701600
Phenotypes for gene: ADRA2B were set to Epilepsy, myoclonic, familial adult, 2, 607876
Early onset or syndromic epilepsy v1.186 PIGB Catherine Snow commented on gene: PIGB
Early onset or syndromic epilepsy v1.186 PIGB Catherine Snow Classified gene: PIGB as Green List (high evidence)
Early onset or syndromic epilepsy v1.186 PIGB Catherine Snow Gene: pigb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.185 CUL4B Rebecca Foulger changed review comment from: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures are reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).; to: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures are reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizures in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Early onset or syndromic epilepsy v1.185 CUL4B Rebecca Foulger changed review comment from: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures is reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).; to: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures are reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Early onset or syndromic epilepsy v1.185 HEXB Rebecca Foulger Classified gene: HEXB as Green List (high evidence)
Early onset or syndromic epilepsy v1.185 HEXB Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Sufficient cases of Sandhoff disease with seizures (PMID:28553389, PMID:7626071, PMID: 30075786) for inclusion on panel.
Early onset or syndromic epilepsy v1.185 HEXB Rebecca Foulger Gene: hexb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.184 AP2M1 Catherine Snow Tag missense tag was added to gene: AP2M1.
Early onset or syndromic epilepsy v1.184 DHCR7 Rebecca Foulger Publications for gene: DHCR7 were set to
Early onset or syndromic epilepsy v1.183 DHCR7 Rebecca Foulger Phenotypes for gene: DHCR7 were changed from Smith-Lemli-Opitz syndrome 270400 to Smith-Lemli-Opitz syndrome, 270400
Early onset or syndromic epilepsy v1.182 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.182 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Demoted rating from Green to Amber following agreement from Helen Brittain (Genomics England clinical team). DHCR7 is currently Green based on its association with Smith-Lemli-Opitz syndrome (SLOS). Seizures are uncommon (1/23 in PMID:24920862 and 1/3 in PMID:29226552). A 2002 paper (PMID:10807690) also suggests seizures are no more common than in general population. Therefore further evidence is required for a clear link between DHCR7 and seizure phenotype. Note that DHCR7 has been promoted to Green on the metabolism panels so will be Green on the GMS epilepsy superpanel through the metabolic phenotype.
Early onset or syndromic epilepsy v1.182 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.181 RANBP2 Rebecca Foulger changed review comment from: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information is required for a clear gene:disease association.; to: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information (e.g. on penetrance) is required for a clear gene:disease association.
Early onset or syndromic epilepsy v1.181 RANBP2 Rebecca Foulger Classified gene: RANBP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.181 RANBP2 Rebecca Foulger Added comment: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information is required for a clear gene:disease association.
Early onset or syndromic epilepsy v1.181 RANBP2 Rebecca Foulger Gene: ranbp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.180 DEGS1 Rebecca Foulger Classified gene: DEGS1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.180 DEGS1 Rebecca Foulger Added comment: Comment on list classification: DEGS1 was added to the panel and rated Green by Konstantinos Varvagiannis. Seizures are a common part of the Leukodystrophy phenotype, as reported in unrelated individuals from multiple papers (PMIDs 30620338,30620337,31186544). Therefore sufficient evidence to rate Green.
Early onset or syndromic epilepsy v1.180 DEGS1 Rebecca Foulger Gene: degs1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.179 DEGS1 Rebecca Foulger Phenotypes for gene: DEGS1 were changed from Leukodystrophy hypomyelinating 18, 618404 to Leukodystrophy hypomyelinating 18, 618404; seizures
Early onset or syndromic epilepsy v1.178 DEGS1 Rebecca Foulger changed review comment from: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S); to: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S).
Early onset or syndromic epilepsy v1.178 DEGS1 Rebecca Foulger commented on gene: DEGS1: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S)
Early onset or syndromic epilepsy v1.178 DEGS1 Rebecca Foulger commented on gene: DEGS1: PMID:30620337: Pant et al., 2019 report DEGS1 variants as the cause of ypomyelinating leukodystrophy in 19 patients from 13 unrelated families. Of the 19 affected patients, seizures were frequently observed (80%) and include clonic tonic, status epilepticus and partial (plus one febrile case in family 12).
Early onset or syndromic epilepsy v1.178 DEGS1 Rebecca Foulger commented on gene: DEGS1
Early onset or syndromic epilepsy v1.178 SLC25A12 Rebecca Foulger commented on gene: SLC25A12
Early onset or syndromic epilepsy v1.178 ALKBH8 Catherine Snow edited their review of gene: ALKBH8: Changed rating: GREEN
Early onset or syndromic epilepsy v1.178 ALKBH8 Catherine Snow changed review comment from: Expert review by Konstantinos Varvagiannis on ALKBH8. Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other phenotype features were noted in few.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.


ALKBH8 can be included in the epilepsy panel as Amber awaiting further evidence and tagged on the watchlist.; to: ALKBH8 had been identified by Genomic England curator when article was in press. Requested clinical team for support on rating on ID panel, clinical team advised "there are 7 affected individuals from two families with different LOF variants. They all have ID / GDD. There has been some functional work to indicate a lack of gene function in support. On balance I think this just meets our criteria for a green rating. 6/7 had seizures too so probably worth adding there too."
Early onset or syndromic epilepsy v1.177 KCNH5 Catherine Snow Source Expert Review Red was added to KCNH5.
Mode of inheritance for gene KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes epilepsy for gene: KCNH5
Rating Changed from No List (delete) to Red List (low evidence)
Early onset or syndromic epilepsy v1.177 KCND2 Catherine Snow Source Expert Review Red was added to KCND2.
Mode of inheritance for gene KCND2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mode of pathogenicity for gene KCND2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added phenotypes epilepsy; autism for gene: KCND2
Rating Changed from No List (delete) to Red List (low evidence)
Early onset or syndromic epilepsy v1.177 ZNF142 Catherine Snow Source Expert Review was added to ZNF142.
Source Expert Review Amber was added to ZNF142.
Added phenotypes Neurodevelopmental disorder with impaired speech and hyperkinetic movements, 618425 for gene: ZNF142
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 ZMIZ1 Catherine Snow Source Expert Review was added to ZMIZ1.
Source Expert Review Amber was added to ZMIZ1.
Publications for gene ZMIZ1 were changed from 29754769; 18053775; 17967885; 26163108; 27479843 to 18053775; 27479843; 29754769; 17967885; 26163108
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 TRRAP Catherine Snow Source Expert Review was added to TRRAP.
Source Expert Review Amber was added to TRRAP.
Added phenotypes Developmental delay with or without dysmorphic facies and autism, 603015 for gene: TRRAP
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 RNF13 Catherine Snow Source Expert Review was added to RNF13.
Source Expert Review Amber was added to RNF13.
Added phenotypes Epileptic encephalopathy, early infantile, 73 for gene: RNF13
Publications for gene RNF13 were changed from to 30595371
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 LSS Catherine Snow Source Expert Review was added to LSS.
Source Expert Review Amber was added to LSS.
Added phenotypes Cataract 44, 616509, Hypotrichosis 14, 618275 for gene: LSS
Publications for gene LSS were changed from 30723320 to 30723320; 26200341; 30401459; 29016354
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 FUK Catherine Snow Source Expert Review was added to FUK.
Source Expert Review Amber was added to FUK.
Added phenotypes Congenital disorder of glycosylation with defective fucosylation 2, 618324 for gene: FUK
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.177 ZDHHC9 Catherine Snow Source Expert Review Green was added to ZDHHC9.
Source Expert Review was added to ZDHHC9.
Added phenotypes Mental retardation, X-linked syndromic, Raymond type, 300799 for gene: ZDHHC9
Publications for gene ZDHHC9 were changed from 26000327 to 24357419; 26000327; 29681091
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 WARS2 Catherine Snow Source Expert Review Green was added to WARS2.
Source Expert Review was added to WARS2.
Added phenotypes Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710 for gene: WARS2
Publications for gene WARS2 were changed from 28236339; 28650581; 28905505; 29783990; 29120065 to 29783990; 28236339; 29120065; 28650581; 28905505
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 VPS11 Catherine Snow Source Expert Review Green was added to VPS11.
Source Expert Review was added to VPS11.
Added phenotypes Leukodystrophy, hypomyelinating, 12 for gene: VPS11
Publications for gene VPS11 were changed from 27120463; 26307567; 27473128 to 27473128; 26307567; 27120463
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 VAMP2 Catherine Snow Source Expert Review Green was added to VAMP2.
Source Expert Review was added to VAMP2.
Added phenotypes Generalized hypotonia, Global developmental delay, Intellectual disability, Autistic behavior, Stereotypic behavior, Seizures, Abnormality of movement, Cortical visual impairment for gene: VAMP2
Publications for gene VAMP2 were changed from 30929742 to 27458546; 22183055; 30929742
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 SNAP25 Catherine Snow Source Expert Review Green was added to SNAP25.
Source Expert Review was added to SNAP25.
Added phenotypes ?Myasthenic syndrome, congenital, 18 for gene: SNAP25
Publications for gene SNAP25 were changed from 29491473; 28135719; 29100083; 25381298; 25003006 to 29100083; 28135719; 25003006; 29491473; 25381298; 30914295
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 PPP2CA Catherine Snow Source Expert Review Green was added to PPP2CA.
Source Expert Review was added to PPP2CA.
Added phenotypes Neurodevelopmental disorder and language delay with or without structural brain abnormalities, 618354 for gene: PPP2CA
Publications for gene PPP2CA were changed from 29274472; 30030003 to 29274472; 30030003; 30595372
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 P4HTM Catherine Snow Source Expert Review Green was added to P4HTM.
Source Expert Review was added to P4HTM.
Added phenotypes Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay for gene: P4HTM
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 KCNT2 Catherine Snow Source Expert Review Green was added to KCNT2.
Source Expert Review was added to KCNT2.
Mode of inheritance for gene KCNT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes ?Epileptic encephalopathy, early infantile, 57 for gene: KCNT2
Publications for gene KCNT2 were changed from 29740868; 29069600 to 29069600; 29740868
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 DHPS Catherine Snow Source Expert Review Green was added to DHPS.
Source Expert Review was added to DHPS.
Added phenotypes Abnormality of head or neck; Seizures; EEG abnormality; Behavioral abnormality; Abnormal muscle tone; Intellectual disability; Global developmental delay for gene: DHPS
Publications for gene DHPS were changed from 21389784; 21850436 to 21389784; 30661771; 21850436
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 ATN1 Catherine Snow Source Expert Review Green was added to ATN1.
Source Expert Review was added to ATN1.
Added phenotypes Hypotonia; Epilepsy; Digit Abnormalities; Developmental Delay for gene: ATN1
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 AP2M1 Catherine Snow Source Expert Review Green was added to AP2M1.
Source Expert Review was added to AP2M1.
Mode of pathogenicity for gene AP2M1 was changed from None to Other
Added phenotypes Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior for gene: AP2M1
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.177 ALKBH8 Catherine Snow Source Expert Review Green was added to ALKBH8.
Source Expert Review was added to ALKBH8.
Added phenotypes Seizures; Developmental Delay; Intellectual Disability for gene: ALKBH8
Publications for gene ALKBH8 were changed from 31079898 to 31130284; 31079898
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.176 KIF1BP Rebecca Foulger commented on gene: KIF1BP
Early onset or syndromic epilepsy v1.176 FLNA Rebecca Foulger Publications for gene: FLNA were set to 15668422; 20014127; 25755106
Early onset or syndromic epilepsy v1.175 FLNA Rebecca Foulger Publications for gene: FLNA were set to
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA: PMID:25755106. In a woman and her 3 daughters with a complex phenotype comprising both periventricular nodular heterotopia and Melnick-Needles syndrome, Parrini et al. (2015) identified a c.622G-C transversion in exon 3 of the FLNA gene (G208R). The 3 daughters had onset of seizures in the first decade.
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA: PMID:20014127. In an 18-month-old girl with periventricular nodular heterotopia and seizures, Jefferies et al. (2010) identified a heterozygous 7896G-A transition in the FLNA gene (W2632X).
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA
Early onset or syndromic epilepsy v1.174 FGFR3 Rebecca Foulger Publications for gene: FGFR3 were set to 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976; http://doi.org/10.15844/pedneurbriefs-26-12-6; http://www.ashg.org/genetics/ashg07s/f20570.htm; https://jicna.org/index.php/journal/article/view/100
Early onset or syndromic epilepsy v1.173 FGFR3 Rebecca Foulger commented on gene: FGFR3
Early onset or syndromic epilepsy v1.173 EMX2 Rebecca Foulger changed review comment from: Faiella et al., 1997 (PMID:9359037) summarise 10 patients with Schizencephaly. 6 patients were heterozygous for de novo variants in EMX2 (including 2 brothers). 3 of these unrelated patients have EMX2 variants (patients VF, MB and PB).; to: Faiella et al., 1997 (PMID:9359037) summarise 10 patients with Schizencephaly. 6 patients were heterozygous for de novo variants in EMX2 (including 2 brothers). 3 of these unrelated patients have partial epilepsy (patients VF, MB and PB).
Early onset or syndromic epilepsy v1.173 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:29226552: Dang Do et al., 2018 report 3 individuals with SLOS- seizures seen in 1 of 3 patients.
Early onset or syndromic epilepsy v1.173 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:10807690: Kelley et al., 2000 report that seizures are uncommon in biochemically-proven cases of Smith-Lemli-Poitz syndrome (SLOS), and may not be substantially more frequent than in children without SLOS.
Early onset or syndromic epilepsy v1.173 DHCR7 Rebecca Foulger commented on gene: DHCR7
Early onset or syndromic epilepsy v1.173 ALPL Rebecca Foulger Publications for gene: ALPL were set to 11999978; 28802630; 23479201; 27086862; 30655187; 30083035
Early onset or syndromic epilepsy v1.172 ALPL Rebecca Foulger commented on gene: ALPL: PMID:30979546: Whyte et al., 2019 report Vitamin B6-dependent seizures in 10/38 (26%) of patients: 7 patients had documented seizures and 3 patients had a family hisotry of seizures based upon medical records.
Early onset or syndromic epilepsy v1.172 ALPL Rebecca Foulger commented on gene: ALPL: PMID:30083035: Oyachi et al., 2018 report a newborn girl with compound het variants in ALPL (c.1559delT/p.Ser188Pro). The patient had seizures on days 2-4, treated with pyridoxine.
Early onset or syndromic epilepsy v1.172 ALPL Rebecca Foulger commented on gene: ALPL: PMID:27086862 (2018) report a female infantile hypophosphatasia patient who presented with pyridoxine-responsive myoclonic seizures and a novel homozygous mutation in the ALPL gene(c.799_804delCACTTC). Parents were heterozygous for the variant.
Early onset or syndromic epilepsy v1.172 ALPL Rebecca Foulger Publications for gene: ALPL were set to 11999978; 28802630; 23479201
Early onset or syndromic epilepsy v1.171 ATRX Rebecca Foulger commented on gene: ATRX: PMID:16955409: Badens et al. 2006 report a 4 year old female with a heterozygous R246C variant in ATRX and a skewed pattern of X-inactivation where her maternally-inherited X chromosome that carried the de novo variant remained active. Clinical features included severed DD. Epilepsy/seizures were not reported amongst her phenotypes.
Early onset or syndromic epilepsy v1.171 ATRX Rebecca Foulger Publications for gene: ATRX were set to 25606380: 11449489; 7697714; 11050622
Early onset or syndromic epilepsy v1.170 ATRX Rebecca Foulger Publications for gene: ATRX were set to Gibbons et al (1995) Cell 80: 837-845; Stevenson et al (2000) Am J Med Genet 94: 383-385
Early onset or syndromic epilepsy v1.169 ATRX Rebecca Foulger commented on gene: ATRX
Early onset or syndromic epilepsy v1.169 SLC9A6 Rebecca Foulger Phenotypes for gene: SLC9A6 were changed from Mental retardation, X-linked syndromic, Christianson type to Mental retardation, X-linked syndromic, Christianson type, 300243
Early onset or syndromic epilepsy v1.168 SLC9A6 Rebecca Foulger Added comment: Comment on mode of inheritance: Comment on mode of inheritance: Changed the MOI from XLR to XLD based on Pescosolido et al., 2014 (PMID:25044251) who report some symptoms (mild to moderate ID) in heterozygous female carriers. Note that NHE6 is an alias for SLC9A6. Although Gene2Phenotype list a hemizygous inheritance for 'MENTAL RETARDATION SYNDROMIC X-LINKED CHRISTIANSON TYPE' OMIM record an XLD inheritance for MIM:300243.
Early onset or syndromic epilepsy v1.168 SLC9A6 Rebecca Foulger Mode of inheritance for gene: SLC9A6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.167 DEGS1 Konstantinos Varvagiannis gene: DEGS1 was added
gene: DEGS1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544
Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, 618404
Penetrance for gene: DEGS1 were set to Complete
Review for gene: DEGS1 was set to GREEN
Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies :
[1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families
[2] Karsai et al. 2019 (PMID: 30620338) : 1 individual
[3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred

As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al.

DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation.

Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1.

Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain.

Extensive studies have been carried out and demonstrated:
- impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc).
- increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer),
- high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development.
- decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot)
- In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts.

Previous animal models:
Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162).
----
The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P.
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As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc).
Sources: Literature
Early onset or syndromic epilepsy v1.167 PIGB Konstantinos Varvagiannis gene: PIGB was added
gene: PIGB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
Added comment: Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants.

Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s.

PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein.

Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9).

8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD.

Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln].

Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible.

The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced.

PIGB is not associated with any phenotype in OMIM/G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID and epilepsy panels probably as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.167 TRAK1 Sarah Leigh Phenotypes for gene: TRAK1 were changed from Fatal encephalopathy to Epileptic encephalopathy, early infantile, 68 618201
Early onset or syndromic epilepsy v1.166 SLC9A6 Rebecca Foulger Publications for gene: SLC9A6 were set to Gilfillan et al (2008) Am J Hum Genet 82: 1003_1010
Early onset or syndromic epilepsy v1.165 KCNJ11 Rebecca Foulger Publications for gene: KCNJ11 were set to 25678012; 16670688; 16609879; 27681997; 17065345
Early onset or syndromic epilepsy v1.164 DEAF1 Rebecca Foulger Publications for gene: DEAF1 were set to 26048982; 28940898; 26834045; 30109124
Early onset or syndromic epilepsy v1.163 DEAF1 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:30923367 supports the 'BOTH monoallelic and biallelic' MOI:. Nabais et al., 2019 investigated AD and AR DEAF1 variants in a cohort of 23 patients. With the exception of microcephaly, most phenotypes (including ID, DD and seizures) were reported in patients with biallelic and pathogenic de novo DEAF1 variants.
Early onset or syndromic epilepsy v1.163 DEAF1 Rebecca Foulger Mode of inheritance for gene: DEAF1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.162 CNKSR2 Rebecca Foulger Mode of inheritance for gene: CNKSR2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.161 CNKSR2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated mode of inheritance from XLR to XLD based on PMID:28098945, so that affected females are detected. Damiano et al., 2017 report the first female with a CNKSR2 variant and childhood epilepsy- the sister had a less severe phenotype than her two brothers, which could be subject to X-inactivation (not directly measured). The mother, who also carries the point mutation, had only febrile seizures.
Early onset or syndromic epilepsy v1.161 CNKSR2 Rebecca Foulger Mode of inheritance for gene: CNKSR2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.160 CNKSR2 Rebecca Foulger Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892
Early onset or syndromic epilepsy v1.159 CACNA1D Rebecca Foulger Mode of pathogenicity for gene: CACNA1D was changed from None to Other
Early onset or syndromic epilepsy v1.158 CACNA1D Rebecca Foulger Publications for gene: CACNA1D were set to 28472301; 23913001; 30698561
Early onset or syndromic epilepsy v1.157 CACNA1D Rebecca Foulger Added comment: Comment on mode of inheritance: Primary aldosteronism, seizures, and neurologic abnormalities (MIM: 615474) has AD inheritance. Seizures are not generally reported for the biallelic disorder Sinoatrial node dysfunction and deafness (MIM:614896). However, PMID:30054272 report an Arabic individual from consanguineous parents with moderate hearing impairment, ID, DD and epilepsy and a homozygous missense variant in CACNA1D (Gln567His). Seizures began age 4 months. The individual also had a homozygous OTOG variant, but this was present in a heterozygous state in the gnomAD browser. Both parents were heterozygous for the OTOG and CACNA1D variants.
Early onset or syndromic epilepsy v1.157 CACNA1D Rebecca Foulger Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.156 CACNA1D Rebecca Foulger Publications for gene: CACNA1D were set to 28472301; 23913001
Early onset or syndromic epilepsy v1.155 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077
Early onset or syndromic epilepsy v1.154 HCN2 Rebecca Foulger changed review comment from: Comment on mode of inheritance: PMID:29064616: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.; to: Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.
Early onset or syndromic epilepsy v1.154 HCN2 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:29064616: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.
Early onset or syndromic epilepsy v1.154 HCN2 Rebecca Foulger Mode of inheritance for gene: HCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.153 RELN Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from monoallelic to 'BOTH monoallelic and biallelic' based on papers reporting seizures as part of AR lissencephaly phenotype: PMID:17431900 (Zaki et al 2007) and PMID:10973257 (Hong et al, 2000).
Early onset or syndromic epilepsy v1.153 RELN Rebecca Foulger Mode of inheritance for gene: RELN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.152 PRICKLE1 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from biallelic to BOTH monoallelic and biallelic based on PMID:21276947. Tao et al. 2011 sequenced PRICKLE1 (and PRICKLE2) in 88 unrelated patients with myoclonus epilepsy and found two patients with heterozygous missense mutations in PRICKLE1: p.Arg144His and p.Tyr472His. The variants were not found in control data sets. The authors therefore suggest that the heterozygous PRICKLE1 variants are also associated with myoclonus epilepsy.
Early onset or syndromic epilepsy v1.152 PRICKLE1 Rebecca Foulger Mode of inheritance for gene: PRICKLE1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.151 NEXMIF Rebecca Foulger Publications for gene: NEXMIF were set to PMID:23615299
Early onset or syndromic epilepsy v1.150 NEXMIF Rebecca Foulger Phenotypes for gene: NEXMIF were changed from Mental retardation, X-linked 98 to Mental retardation, X-linked 98, 300912
Early onset or syndromic epilepsy v1.149 NEXMIF Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLR to XLD to match the XLD recorded for 'Mental retardation, X-linked 98' in OMIM (MIM:300912) and Gene2Phenotype, which records X-linked dominant inheritance for 'Intellectual disability and epilepsy' in addition to hemizgyous inheritance for 'KIAA2022'. An XLD inheritance is supported by PMID:27358180 which reports 14 female patients who carry a heterozygous de novo KIAA2022 variant and share a phenotype characterised by intellectual disability and epilepsy.
Early onset or syndromic epilepsy v1.149 NEXMIF Rebecca Foulger Mode of inheritance for gene: NEXMIF was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.148 CLCN4 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLR to XLD to match XLD MOI for 'Raynaud-Claes syndrome' (MIM:300114) in OMIM.
Early onset or syndromic epilepsy v1.148 CLCN4 Rebecca Foulger Mode of inheritance for gene: CLCN4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.147 ALPL Rebecca Foulger Added comment: Comment on publications: ALPL is called by its alias TNSALP in many publications.
Early onset or syndromic epilepsy v1.147 ALPL Rebecca Foulger Publications for gene: ALPL were set to
Early onset or syndromic epilepsy v1.146 WDR62 Rebecca Foulger Publications for gene: WDR62 were set to 21834044; 20890278; 20729831
Early onset or syndromic epilepsy v1.145 WDR45B Rebecca Foulger Added comment: Comment on phenotypes: Now (July 9th 2019) associated with a disorder in OMIM (617977).
Early onset or syndromic epilepsy v1.145 WDR45B Rebecca Foulger Phenotypes for gene: WDR45B were changed from profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977; profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations
Early onset or syndromic epilepsy v1.144 TRPM3 Rebecca Foulger Classified gene: TRPM3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.144 TRPM3 Rebecca Foulger Added comment: Comment on list classification: TRPM3 was added to the panel and rated Green by Konstantinos Varvagiannis based on PMID:31278393 (Dyment et al 2019). Although 8 probands were reported, 1 proband carries a VUS and an additional splice variant in DDB1. Therefore only variant is pathogenic, and this is missense, and de novo in all cases. The authors also note that heterozygous LOF variants in TRPM3 are observed in the general population. Not yet associated with a disorder in Gene2Phenotype or OMIM. Therefore have rated Amber and added 'watchlist' tag awaiting further cases or additional functional studies.
Early onset or syndromic epilepsy v1.144 TRPM3 Rebecca Foulger Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.143 TRPM3 Rebecca Foulger commented on gene: TRPM3
Early onset or syndromic epilepsy v1.143 TRPM3 Rebecca Foulger Tag watchlist tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v1.143 TRPM3 Rebecca Foulger Tag missense tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v1.143 TRPM3 Rebecca Foulger Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
Early onset or syndromic epilepsy v1.142 CLCN6 Sarah Leigh Added comment: Comment on publications: PMID 29667327 - one case with seizures, no other work up

PMID 26658788 - reference to rare traits and BP control

PMID 25794116 - three families with variants and a history of seizures. However one person with a reported phenotype of seizures was variant negative and the functional work does not look compelling
Early onset or syndromic epilepsy v1.142 CLCN6 Sarah Leigh Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116
Early onset or syndromic epilepsy v1.141 CLCN6 Sarah Leigh Classified gene: CLCN6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.141 CLCN6 Sarah Leigh Gene: clcn6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.140 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CLCN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116
Review for gene: CLCN6 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v1.139 NPRL2 Rebecca Foulger commented on gene: NPRL2
Early onset or syndromic epilepsy v1.139 NPRL2 Rebecca Foulger Phenotypes for gene: NPRL2 were changed from Epilepsy, familial focal, with variable foci 2 617116 to Epilepsy, familial focal, with variable foci 2, 617116
Early onset or syndromic epilepsy v1.138 NPRL2 Rebecca Foulger Publications for gene: NPRL2 were set to 26505888; 27173016
Early onset or syndromic epilepsy v1.137 KPTN Rebecca Foulger Phenotypes for gene: KPTN were changed from Mental retardation, autosomal recessive 41615637 to Mental retardation, autosomal recessive 4,1615637; seizures
Early onset or syndromic epilepsy v1.136 KPTN Rebecca Foulger Classified gene: KPTN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.136 KPTN Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber following evaluation of Green review by Zornitza. No further cases of KPTN variants associated with epilepsy/seizures are reported in the literature since PMID:24239382 (Baple et al., 2014: Founder effect in Amish community) and PMID:25847626 (Pajualu et al. 2015, 2 Estonian siblings with seizures in the brother). Although the association with ID is clearer, more epilepsy cases are required for a diagnostic-grade rating.
Early onset or syndromic epilepsy v1.136 KPTN Rebecca Foulger Gene: kptn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.135 CYP27A1 Rebecca Foulger Phenotypes for gene: CYP27A1 were changed from Cerebrotendinous xanthomatosis 213700 to Cerebrotendinous xanthomatosis, 213700; seizures; photosensitive epilepsy
Early onset or syndromic epilepsy v1.134 CYP27A1 Rebecca Foulger Publications for gene: CYP27A1 were set to 18227423
Early onset or syndromic epilepsy v1.133 CYP27A1 Rebecca Foulger Classified gene: CYP27A1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.133 CYP27A1 Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Red to Green based on external review by Philip Dawson. Although seizures are not a consistent feature of CTX patients, there are plenty of cases in the literature of seizures reported in CTX cohorts and individual cases (e.g. PMIDs 29484516 and 22336472) to support inclusion on this panel.
Early onset or syndromic epilepsy v1.133 CYP27A1 Rebecca Foulger Gene: cyp27a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.132 CYP27A1 Rebecca Foulger changed review comment from: PMID:29484516. Wong et al 2018 evaluated 5 cases of cerebrotendinous xanthomatosis (CTX) patients.
CTX is an autosomal recessive condition caused by variants in CYP27A1. Seizures reported in 1/5 cases at 24 years old.; to: PMID:29484516. Wong et al 2018 evaluated 5 cases of cerebrotendinous xanthomatosis (CTX) patients. CTX is an autosomal recessive condition caused by variants in CYP27A1. Seizures reported in 1/5 cases at 24 years old. They also analysed 194 cases from the literature and reported seizures in 37/194 cases (19%).
Early onset or syndromic epilepsy v1.132 CYP27A1 Rebecca Foulger commented on gene: CYP27A1: PMID:22336472. Koyama et al. 2012. An 18 year old Japanese female with a history of epileptic seizures amongst her phenotypes. She had compound heterozygous variants in CYP27A1: maternally-inherited V413D and paternally-inherited R474W. The variants were not present in Japanese controls.
Early onset or syndromic epilepsy v1.132 CYP27A1 Rebecca Foulger commented on gene: CYP27A1: PMID:24442603. Mignarri et al 2014. In their CTX cohort of 55 patients, 18 were reported with epilepsy (33%). They report 14/54 (26%) and 8/25 (32%) of epilepsy cases in previous cohorts.
Early onset or syndromic epilepsy v1.132 CYP27A1 Rebecca Foulger commented on gene: CYP27A1: PMID:29484516. Wong et al 2018 evaluated 5 cases of cerebrotendinous xanthomatosis (CTX) patients.
CTX is an autosomal recessive condition caused by variants in CYP27A1. Seizures reported in 1/5 cases at 24 years old.
Early onset or syndromic epilepsy v1.132 CYP27A1 Rebecca Foulger commented on gene: CYP27A1
Early onset or syndromic epilepsy v1.132 KCNMA1 Rebecca Foulger Added comment: Comment on phenotypes: MIM:617643 has AR inheritance in OMIM. MIM:609446 has monoallelic inheritance in OMIM.
Early onset or syndromic epilepsy v1.132 KCNMA1 Rebecca Foulger Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures 617643 AR; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy 609446 AD to ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446
Early onset or syndromic epilepsy v1.131 KCNMA1 Rebecca Foulger Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911
Early onset or syndromic epilepsy v1.130 KCNMA1 Rebecca Foulger commented on gene: KCNMA1: PMID:29545233. Yesil et al., 2018 report a patient with a novel homozygous truncating variant in KCNMA1 (p.Arg458Ter) presentint with paroxysmal dyskinesia, epileptic seizures, ID, and corticospinal–cerebellar tract atrophy.
Early onset or syndromic epilepsy v1.130 KCNMA1 Rebecca Foulger commented on gene: KCNMA1: PMID:15937479. Du et al., 2005 studied a large family with generalized epilepsy and paroxysmal dyskinesia (GEPD). 5/16 had seizures + paroxysmal dyskinesia (PNKD), and a further 4/16 had seizures only. c.1301A>G (Asp434Gly). They identified a heterozygous c.1301A>G (Asp434Gly) in KCNMA1 in the proband (IV-8) of the family and in all 13 affected individuals that were genotyped. The variant was absent in 5 unaffected individuals.
Early onset or syndromic epilepsy v1.130 KCNMA1 Rebecca Foulger commented on gene: KCNMA1: PMID:26195193. Zhang et al 2015 describe 2 unrelated children with early-onset PNKD and developmental delay carrying de novo mutations in KCNMA1. Seizures were not reported until age 2 and 7. Two de novo heterozygous missense mutations in KCNMA1 were identified in these cases: c.2650G>A (p.Glu884Lys) and c.3158A>G (p.Asn1053Ser).
Early onset or syndromic epilepsy v1.130 KCNMA1 Rebecca Foulger commented on gene: KCNMA1
Early onset or syndromic epilepsy v1.130 DOLK Rebecca Foulger Classified gene: DOLK as Green List (high evidence)
Early onset or syndromic epilepsy v1.130 DOLK Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on external review by Konstantinos Varvagiannis, the third case of seizures reported in PMID:24144945, and the review of seizure phenotypes also reported by PMID:24144945. Although seizures are not reported in all patients, the association of CDG is confirmed in DDG2P, seizures can be severe, and there are sufficient cases for inclusion on panel.
Early onset or syndromic epilepsy v1.130 DOLK Rebecca Foulger Gene: dolk has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.129 DOLK Rebecca Foulger Publications for gene: DOLK were set to 23890587; 17273964
Early onset or syndromic epilepsy v1.128 DOLK Rebecca Foulger commented on gene: DOLK: PMID:28816422 (Rush et al., 2017) report 2 sisters with novel compound het DOLK variants: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Patient 2 had one seizure at 53 days old- the seizures did not recur and the patient died age 64 days. Seizures were not noted for her sister (Patient 1), although she died at just over a week old.
Early onset or syndromic epilepsy v1.128 DOLK Rebecca Foulger commented on gene: DOLK: PMID:24144945 (Lieu et al., 2013) report a male neonate born to non-consanguineous Palestinian origin parents, with phenotypes including dysmorphic features, genital abnormalities, talipes equinovarus, and severe refractory generalized seizures. He harboured a homozygous p.Q483K DOLK variant- in patient fibroblasts this missense variant severely reduced substrate binding and cataytic activity. They also summarise clinical data of previous DOLK-CDG patients, and report seizures in 7/18 patients (Table 1 and article text).
Early onset or syndromic epilepsy v1.128 TRPM3 Konstantinos Varvagiannis changed review comment from: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature; to: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Early onset or syndromic epilepsy v1.128 TRPM3 Konstantinos Varvagiannis gene: TRPM3 was added
gene: TRPM3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior
Penetrance for gene: TRPM3 were set to unknown
Mode of pathogenicity for gene: TRPM3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TRPM3 was set to GREEN
Added comment: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Early onset or syndromic epilepsy v1.128 FUT8 Louise Daugherty Phenotypes for gene: FUT8 were changed from Congenital disorder of glycosylation with defective fucosylation, 618005; Intellectual disability to Congenital disorder of glycosylation with defective fucosylation, 618005; seizures
Early onset or syndromic epilepsy v1.127 FUT8 Louise Daugherty Deleted their comment
Early onset or syndromic epilepsy v1.127 PEX5 Rebecca Foulger commented on gene: PEX5
Early onset or syndromic epilepsy v1.127 HEXB Rebecca Foulger Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; seizures to Sandhoff disease, infantile, juvenile, and adult forms, 268800; seizures; myoclonic epilepsy
Early onset or syndromic epilepsy v1.126 HEXB Rebecca Foulger Publications for gene: HEXB were set to 2967418; 21153386; 22848519; 30075786
Early onset or syndromic epilepsy v1.125 HEXB Rebecca Foulger commented on gene: HEXB: PMID:28553389: Gowda et al., 2017 report a 1 year old boy with Sanhoff disease without hepatosplenomegaly, and a homozygous missense variant in HEXB (p.Cys534Tyr). The boy suffered from focal seizures from 11 months. A sibling died age 18 months with 'similar complaints'. Further controls or segregation analysis was not performed. The authors say the same variant was reported previously in a Japanese case which showed myoclonic epilepsy and hepatosplenomegaly (PMID:7626071).
Early onset or syndromic epilepsy v1.125 HEXB Rebecca Foulger Publications for gene: HEXB were set to 2967418; 21153386; 22848519
Early onset or syndromic epilepsy v1.124 HEXB Rebecca Foulger commented on gene: HEXB: PMID: 30075786: Tavasoli et al., 2018 studied 25 Iranian patients with Sandhoff disease. 8/25 patients had seizures (Table 2) with a mean age at presentation 5.6 months. HEXB gene mutation studies were performed in 8 patients, including 2 patients with seizures (novel HEXB variants were identified in patients 4 and 13).
Early onset or syndromic epilepsy v1.124 HEXB Rebecca Foulger commented on gene: HEXB
Early onset or syndromic epilepsy v1.124 HEXB Rebecca Foulger Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, 268800; seizures
Early onset or syndromic epilepsy v1.123 HEXB Rebecca Foulger Publications for gene: HEXB were set to 2967418; 21153386
Early onset or syndromic epilepsy v1.122 DPM2 Rebecca Foulger Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu 615042; seizures
Early onset or syndromic epilepsy v1.121 DPM2 Rebecca Foulger Publications for gene: DPM2 were set to 23109149
Early onset or syndromic epilepsy v1.120 DPM2 Rebecca Foulger Classified gene: DPM2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.120 DPM2 Rebecca Foulger Added comment: Comment on list classification: Reassessing rating of DPM2 during curation of GMS panel: Evidence remains insufficient for a diagnostic-rating (3 patients from 2 families in the literature: PMIDs 23109149 and 26453362).
Early onset or syndromic epilepsy v1.120 DPM2 Rebecca Foulger Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.119 DPM2 Rebecca Foulger commented on gene: DPM2: PMID:26453362: Fiumara et al. 2016 report a patient (patient 2) with Early-onset epileptic encephalopathy (seizure onset in first week). This girl has been previously reported in PMID:23109149 (patient 1 in Barone et al., 2012).
Early onset or syndromic epilepsy v1.119 DPM2 Rebecca Foulger commented on gene: DPM2
Early onset or syndromic epilepsy v1.119 BCKDHA Rebecca Foulger Publications for gene: BCKDHA were set to 2703538; 8037208; 9582350; 31119508
Early onset or syndromic epilepsy v1.118 BCKDHB Rebecca Foulger Publications for gene: BCKDHB were set to 31119508
Early onset or syndromic epilepsy v1.117 BCKDHB Rebecca Foulger Publications for gene: BCKDHB were set to
Early onset or syndromic epilepsy v1.116 BCKDHA Rebecca Foulger Publications for gene: BCKDHA were set to 2703538; 8037208; 9582350
Early onset or syndromic epilepsy v1.115 DBT Rebecca Foulger Tag watchlist was removed from gene: DBT.
Early onset or syndromic epilepsy v1.115 DBT Rebecca Foulger Phenotypes for gene: DBT were changed from Maple syrup urine disease, type II, 248600 to Maple syrup urine disease, type II, 248600; seizures; convulsions
Early onset or syndromic epilepsy v1.114 DBT Rebecca Foulger Publications for gene: DBT were set to
Early onset or syndromic epilepsy v1.113 DBT Rebecca Foulger Classified gene: DBT as Green List (high evidence)
Early onset or syndromic epilepsy v1.113 DBT Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following publication of two 2019 papers (PMID:31112740 and PMID:31119508) who report MSUD patients with seizures and biallelic variants in DBT. Each paper reports individuals from a different ethnic group. Sufficient unrelated cases for a diagnostic-green rating.
Early onset or syndromic epilepsy v1.113 DBT Rebecca Foulger Gene: dbt has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.112 DBT Rebecca Foulger commented on gene: DBT: PMID:31112740. Yang et al 2019 identify a Chinese patient with MSUD (Patient 2) with compound het DBT variants: missense p.Leu69Arg and nonsense R291*. Patient 2 was recorded with Convulsions (Table 1). Leu69 is located in the LBD of the encoded BCKD protein, and therefore likely to affect the function of the protein. Segregation analysis was not performed. The 1000 Genome Project data was used to filter the data, and variants were validated by Sanger sequencing.
Early onset or syndromic epilepsy v1.112 PARS2 Eleanor Williams Classified gene: PARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.112 PARS2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green as found in more than 3 cases and variants segregate with the condition in all families.
Early onset or syndromic epilepsy v1.112 PARS2 Eleanor Williams Gene: pars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.111 PARS2 Eleanor Williams gene: PARS2 was added
gene: PARS2 was added to Genetic epilepsy syndromes. Sources: Other
Mode of inheritance for gene: PARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PARS2 were set to 22237560; 25629079; 27290639; 29410512; 29410512; 29915213
Phenotypes for gene: PARS2 were set to Epileptic encephalopathy, early infantile, 75, 618437
Review for gene: PARS2 was set to GREEN
Added comment: An association of this gene with Epileptic encephalopathy, early infantile, 75 (#618437) has recently been added to OMIM (May 2019). The gene is predicted to encode for prolyl-tRNA synthetase.

Compound heterozygous mutations in PARS2 have been reported in individuals from 4 unrelated families (Swedish (PMID: 22237560, 25629079), Polish (PMID: 27290639, 29410512), Japanese (PMID: 28077841), Chinese (PMID: 29915213). In all cases the children presented with seizures/epilepsy under the age of 1 year. Other clinical features included developmental delay in all and dilated cardiomyopathy in 2 patients.

Of the seven variants reported six are missense and one is a 1 bp duplication resulting in a frameshift. In the publication about the Chinese family (PMID: 29915213) OMIM report that the missense variants were assessed as being pathogenic according to ACMG guidelines.

In all families the variants segregated with the disorder.

Functional studies were only carried out in one case (PMID: 25629079). In this case the levels of prolyl-tRNA synthetase in the patient did not differ significantly from control levels when normalized to GAPDH.
Sources: Other
Early onset or syndromic epilepsy v1.110 DBT Rebecca Foulger commented on gene: DBT: PMID:31119508. Abiri et al. 2019 investigated the mutation spectrum of MSUD patients in 40 unrelated Iranian families. 5 patients (P36-P40) had homozygous or compound het variants in DBT. 4/5 of these patients had seizures reported. Four of the DBT variants were novel. None of the variants are present in controls including ExAC and the Iranome. Different variants reported in each of the 5 patients suggesting the patients are unrelated.
Early onset or syndromic epilepsy v1.110 GNB5 Rebecca Foulger Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182 to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; early infantile epileptic encephalopathy (EIEE)
Early onset or syndromic epilepsy v1.109 TRAPPC6B Rebecca Foulger changed review comment from: In 2 patients from a consanguineous family, PMID:28397838 (Harripaul et al. 2018) identified a homozygous truncating variant in TRAPPC6N. The patients were selected for non-syndromic ID, which often presents with epilepsy but seizures were not discussed in the patients.; to: In 2 patients from a consanguineous family, PMID:28397838 (Harripaul et al. 2018) identified a homozygous truncating variant in TRAPPC6N. The patients were selected for non-syndromic ID, which often presents with epilepsy .
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: Comment on list classification: Kept rating as Amber: 2 literature cases only in PMID:28777934. Seizures are a phenotype of both cases but further cases required for a diagnostic rating.; to: Comment on list classification: Kept rating as Amber: 2 families only in PMID:28777934. Seizures are a phenotype in 2/3 of the patients (one patient from each family).
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports epilepsy in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).; to: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. Epilepsy is reported in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).
Early onset or syndromic epilepsy v1.109 TRAPPC12 Rebecca Foulger changed review comment from: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports seizures in all 3 patients.; to: In 3 patients from 2 unrelated families with early-onset progressive encephalopathy with brain atrophy and spasticity (MIM:617669), Milev et al. (2017, PMID:28777934) identified homozygous or compound heterozygous mutations in the TRAPPC12 gene. The article text reports epilepsy in 2/3 patients (the patient from family I, and one of the sisters from family II; the other sister showed monoclonic jerks only).
Early onset or syndromic epilepsy v1.109 TRAF7 Rebecca Foulger Tag watchlist tag was added to gene: TRAF7.
Early onset or syndromic epilepsy v1.109 TRAF7 Rebecca Foulger Classified gene: TRAF7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.109 TRAF7 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber following external review by Konstantinos Varvagiannis: currently seizures are not a consistent phenotype (2/7 patients in PMID:29961569). Disease confidence rating in Gene2Phenotype is 'probable' for the disorder: Developmental Delay Congenital Anomalies and Dysmorphic Features. Added watchlist tag as further cases of seizures/epilepsy are required for a Green rating.
Early onset or syndromic epilepsy v1.109 TRAF7 Rebecca Foulger Gene: traf7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.108 TRAF7 Rebecca Foulger commented on gene: TRAF7: PMID 29961569: Tokita et al, 2018 report TRAF7 missense variants in seven unrelated individuals. Seizures reported in two patients, plus 'possible absence seizures' reported in patient 6.
Early onset or syndromic epilepsy v1.108 SMC1A Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to X-linked dominant to match Gene2Phenotype and the MOI for SMC1A on the Intellectual disability panel. So far, mostly females have gross gene alterations of SMC1A, which are likely not tolerated in males (PMID:19842212).
Early onset or syndromic epilepsy v1.108 SMC1A Rebecca Foulger Mode of inheritance for gene: SMC1A 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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.107 SMC1A Rebecca Foulger Classified gene: SMC1A as Green List (high evidence)
Early onset or syndromic epilepsy v1.107 SMC1A Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on external review by Deb Pal, and a literature review. Plenty of recent papers reporting SMC1A variants causing epilepsy in female patients (e.g. PMIDs:31098032, 28677859, 28166369, 26752331,26386245,26358754). SMC1A variants can cause Cornelia de Lange syndrome (CdLS) but can also cause ID and epilepsy in the absence of CdLS features (PMID:31185419). Plus 'confirmed' rating in Gene2Phenotype for EPILEPTIC ENCEPHALOPATHY.
Early onset or syndromic epilepsy v1.107 SMC1A Rebecca Foulger Gene: smc1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.106 SMC1A Rebecca Foulger Publications for gene: SMC1A were set to 16604071; 17273969; 31185419; 31098032
Early onset or syndromic epilepsy v1.105 SMC1A Rebecca Foulger Publications for gene: SMC1A were set to 16604071; 17273969; 31185419
Early onset or syndromic epilepsy v1.104 SMC1A Rebecca Foulger Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY to Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY; Rett-like phenotype
Early onset or syndromic epilepsy v1.103 SMC1A Rebecca Foulger Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2 300590 to Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY
Early onset or syndromic epilepsy v1.102 SMC1A Rebecca Foulger Publications for gene: SMC1A were set to 16604071; 17273969
Early onset or syndromic epilepsy v1.101 SMC1A Rebecca Foulger changed review comment from: PMID:31185419: Oguni et al 2019 report a missense variant (c.2683C>G:pArg895Gly) of SMC1A affecting a daughter (proband) and her mother. The daughter began having epileptic seizures age 2 years 1 month, progressing into cluster seizures. The mother began to have cluter seizures age 12 and had moderate ID. Neither individual had typical CdLS morphological features. Sequencing confirmed the variant was present in daughter and mother, but not other maternal family members. Blood samples from the paternal side were unavailable.; to: PMID:31185419: Oguni et al 2019 report a missense variant (c.2683C>G:pArg895Gly) of SMC1A affecting a daughter (proband) and her mother. The daughter began having epileptic seizures age 2 years 1 month, progressing into cluster seizures. The mother began to have cluster seizures age 12 and had moderate ID. Neither individual had typical CdLS morphological features. Sequencing confirmed the variant was present in daughter and mother, but not other maternal family members. Blood samples from the paternal side were unavailable.
Early onset or syndromic epilepsy v1.101 SMC1A Rebecca Foulger commented on gene: SMC1A
Early onset or syndromic epilepsy v1.101 USP7 Rebecca Foulger Classified gene: USP7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.101 USP7 Rebecca Foulger Added comment: Comment on list classification: USP7 was added to the panel and rated Green by Konstantinos Varvagiannis. Not currently associated with a disorder in OMIM, but has a 'possible' Disease confidence in Gene2Phenotype for the disorder: Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism (based on PMID:26365382). There is now a 2019 paper in addition to PMID:26365382 (PMID:30679821). In total, nearly half (10/22) individuals have a seizure phenotype. However, the Tyr143Ter variant described by both PMID:26365382 and PMID:30679821 is a VUS, and the microdeletions in other patients cover additional genes (PMID:26365382 Figure 5). Plus three patients in PMID:30679821 harbour variants in additional genes. Rated Amber until there is more evidence that USP7 variants are causative for the seizure phenotype.
Early onset or syndromic epilepsy v1.101 USP7 Rebecca Foulger Gene: usp7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.100 USP7 Rebecca Foulger commented on gene: USP7: PMID:30679821: Fountain et al., 2019 report on the clinical and genetic spectrum of 16 new and 7 previously reported (by PMID:26365382) individuals with USP7 heterozygous de novo variants. The variants include 2 deletions, 3 nonsense, 3 splice site variants and 8 missense variants. Seizures are recorded in 10/22 patients. Note that Patients 18 and 20 harbor additional variants in TMEM106B and SLC2A1, Patient 19 also has a de novo heterozygous 102.5-kb mosaic loss of uncertain significance at 10q21.1.
Early onset or syndromic epilepsy v1.100 USP7 Rebecca Foulger commented on gene: USP7
Early onset or syndromic epilepsy v1.100 USP7 Rebecca Foulger Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism
Early onset or syndromic epilepsy v1.100 USP7 Rebecca Foulger Phenotypes for gene: USP7 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Seizures; Abnormality of brain morphology; Hypogonadism to Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism
Early onset or syndromic epilepsy v1.99 PIGH Rebecca Foulger Classified gene: PIGH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.99 PIGH Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber following review of Literature evidence. Although Zornitza rates as Green, PIGH is not yet associated with a disorder in Gene2Phenotype. There are only two relevant papers in the literature: PMID:29573052 report two siblings, and the individual in PMID:29603516 had only febrile seizures (no epilepsy).
Early onset or syndromic epilepsy v1.99 PIGH Rebecca Foulger Gene: pigh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.98 PIGH Rebecca Foulger changed review comment from: PMID:29603516: Nguyen et al., 2018 identified an individual with a missense variant (p.Ser103Pro) in gene PIGH. The affected individual had hypotonia, moderate developmental delay, and autism. The proband did not have epilepsy; however, he did have two episodes of febrile seizures.; to: PMID:29603516: Nguyen et al., 2018 identified an individual with a missense variant (p.Ser103Pro) in gene PIGH. The affected individual who was born of consanguineous Indian parents had hypotonia, moderate developmental delay, and autism. The proband did not have epilepsy; however, he did have two episodes of febrile seizures.
Early onset or syndromic epilepsy v1.98 PIGH Rebecca Foulger Added comment: Comment on publications: PMID:29603510 isn't relevant to epilepsy so haven't included in the Publication field. Zornitza probably meant PMID:29603516.
Early onset or syndromic epilepsy v1.98 PIGH Rebecca Foulger Publications for gene: PIGH were set to 29603516; 29573052
Early onset or syndromic epilepsy v1.97 PIGH Rebecca Foulger commented on gene: PIGH: PMID:29603516: Nguyen et al., 2018 identified an individual with a missense variant (p.Ser103Pro) in gene PIGH. The affected individual had hypotonia, moderate developmental delay, and autism. The proband did not have epilepsy; however, he did have two episodes of febrile seizures.
Early onset or syndromic epilepsy v1.97 PIGH Rebecca Foulger commented on gene: PIGH
Early onset or syndromic epilepsy v1.97 PIGH Rebecca Foulger Phenotypes for gene: PIGH were changed from Glycosylphosphatidylinositol biosynthesis defect 17 618010 to Glycosylphosphatidylinositol biosynthesis defect 17, 618010; epilepsy; febrile seizures
Early onset or syndromic epilepsy v1.96 CACNA1B Louise Daugherty Classified gene: CACNA1B as Green List (high evidence)
Early onset or syndromic epilepsy v1.96 CACNA1B Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Early onset or syndromic epilepsy v1.96 CACNA1B Louise Daugherty Gene: cacna1b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.95 PIGC Rebecca Foulger Classified gene: PIGC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.95 PIGC Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber following external review by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype, and currently only 2 families from one paper identified in the literature (PMID:27694521) for PIGC.
Early onset or syndromic epilepsy v1.95 PIGC Rebecca Foulger Gene: pigc has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.94 CACNA1B Louise Daugherty Added comment: Comment on phenotypes: added Progressive Epilepsy-Dyskinesia from PMID:30982612. gene-phenotype currently not listed in OMIM
Early onset or syndromic epilepsy v1.94 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia
Early onset or syndromic epilepsy v1.93 PIGC Rebecca Foulger Phenotypes for gene: PIGC were changed from to Glycosylphosphatidylinositol biosynthesis defect 16, 617816
Early onset or syndromic epilepsy v1.92 PIGC Rebecca Foulger Mode of inheritance for gene: PIGC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.91 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia
Early onset or syndromic epilepsy v1.90 CACNA1B Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Early onset or syndromic epilepsy v1.90 CACNA1B Louise Daugherty Publications for gene: CACNA1B were set to
Early onset or syndromic epilepsy v1.89 PIGC Rebecca Foulger changed review comment from: PMID:27694521: Edvardson et al. 2017 studied 2 unrelated families (two siblings from a consanguineous Moslem-Arab parents, and a son of unrelated Sephardic-Jewish parents) who suffered from global DD, ID and seizures. PIGC variants were found: homozygous p.L189W in one family, and compound het variant (L212P/R21X) in another.; to: PMID:27694521: Edvardson et al. 2017 studied 2 unrelated families (two siblings from consanguineous Moslem-Arab parents, and a son of unrelated Sephardic-Jewish parents) who suffered from global DD, ID and seizures. PIGC variants were found: homozygous p.L189W in one family, and compound het variant (L212P/R21X) in another.
Early onset or syndromic epilepsy v1.89 PIGC Rebecca Foulger changed review comment from: PMID:27694521: Edvardson et al. 201x studied 2 unrelated families (two siblings from a consanguineous Moslem-Arab parents, and a son of unrelated Sephardic-Jewish parents) who suffered from global DD, ID and seizures. PIGC variants were found: homozygous p.L189W in one family, and compound het variant (L212P/R21X) in another.; to: PMID:27694521: Edvardson et al. 2017 studied 2 unrelated families (two siblings from a consanguineous Moslem-Arab parents, and a son of unrelated Sephardic-Jewish parents) who suffered from global DD, ID and seizures. PIGC variants were found: homozygous p.L189W in one family, and compound het variant (L212P/R21X) in another.
Early onset or syndromic epilepsy v1.89 PIGC Rebecca Foulger commented on gene: PIGC
Early onset or syndromic epilepsy v1.89 KIAA1109 Rebecca Foulger changed review comment from: Comment on list classification: Re-assessed gene:disease evidence based on 2019 paper (PMID:30906834). Kept rating as Amber awaiting further information: seizures present in 2 Lithuanian siblings (PMID:29290337) plus two African-American siblings (PMID:30906834). Plus Drosophila model. There is limited patient information because severe LOF alleles are incompatible with life.; to: Comment on list classification: Re-assessed gene:disease evidence based on 2019 paper (PMID:30906834). Kept rating as Amber awaiting further information: seizures present in 2 Lithuanian siblings (PMID:29290337) plus two African-American siblings (PMID:30906834). Plus Drosophila model (PMID:19640479). There is limited patient information because severe LOF alleles are incompatible with life.
Early onset or syndromic epilepsy v1.89 KIAA1109 Rebecca Foulger Classified gene: KIAA1109 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.89 KIAA1109 Rebecca Foulger Added comment: Comment on list classification: Re-assessed gene:disease evidence based on 2019 paper (PMID:30906834). Kept rating as Amber awaiting further information: seizures present in 2 Lithuanian siblings (PMID:29290337) plus two African-American siblings (PMID:30906834). Plus Drosophila model. There is limited patient information because severe LOF alleles are incompatible with life.
Early onset or syndromic epilepsy v1.89 KIAA1109 Rebecca Foulger Gene: kiaa1109 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.88 KIAA1109 Rebecca Foulger Phenotypes for gene: KIAA1109 were changed from Alkuraya-Kucinskas syndrome 617822 to Alkuraya-Kucinskas syndrome 617822; seizures
Early onset or syndromic epilepsy v1.87 KIAA1109 Rebecca Foulger Publications for gene: KIAA1109 were set to 29290337; 19640479
Early onset or syndromic epilepsy v1.86 KIAA1109 Rebecca Foulger commented on gene: KIAA1109
Early onset or syndromic epilepsy v1.86 EFHC1 Rebecca Foulger Publications for gene: EFHC1 were set to 17159113; 18505993; 15258581; 19147686; 28370826
Early onset or syndromic epilepsy v1.85 EFHC1 Rebecca Foulger commented on gene: EFHC1: PMID:29750216: Thounaojam et al., 2017 studied 63 Indian patients from 63 independent families with Juvenile myoclonic epilepsy (JME) and found 4 heterozygous coding variants (R221C, R260Q, R294H and R244STOP) and 1 homozygous and one heterozygous coding variant (R159W, which is considered a polymorphism). Lack of family samples meant the mode of inheritance couldn't be followed up.
Early onset or syndromic epilepsy v1.85 EFHC1 Rebecca Foulger commented on gene: EFHC1: PMID:31056551: Heyne et al., 2019 performed a large-scale analysis of previously-sequenced variants in individuals with a 'neurodevelopmental disorder with epilepsy. They show that EFHC1 showed equal frequencies of ultra-rare variants in cases and controls supporting the existing evidence that EFHC1 may not be truly associated with epilepsy.
Early onset or syndromic epilepsy v1.85 EFHC1 Rebecca Foulger changed review comment from: PMID:28370826. Raju et al., 2017 examine 480 Juvenile myoclonic epilepsy patients from India, and identified 13 variants (11 of which were novel, 10 of which are predicted to be pathogenic) in 28 JME patients. They were absent or uncommon among controls. Patients with family histories of progressive myoclonic epilepsy (PME) were not included in the study. The authors submitted their variants to LOVD, including 14 polymorphisms that were common in controls and databases (https://databases.lovd.nl/shared/variants/EFHC1/unique).; to: PMID:28370826. Raju et al., 2017 examine 480 Juvenile myoclonic epilepsy patients from India, and identified 13 variants (11 of which were novel, 10 of which are predicted to be pathogenic) in 28 JME patients. They were absent or uncommon among controls. All variants were missense. Patients with family histories of progressive myoclonic epilepsy (PME) were not included in the study. The authors submitted their variants to LOVD, including 14 polymorphisms that were common in controls and databases (https://databases.lovd.nl/shared/variants/EFHC1/unique).
Early onset or syndromic epilepsy v1.85 EFHC1 Rebecca Foulger commented on gene: EFHC1
Early onset or syndromic epilepsy v1.85 EFHC1 Rebecca Foulger Publications for gene: EFHC1 were set to 17159113; 18505993; 15258581; 19147686
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Classified gene: CUL4B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Added comment: Comment on list classification: Added CUL4B to the panel and rated Amber awaiting further clinical review. Seizures are noted in the literature in >30% of patients- although there are sufficient unrelated cases, the seizure phenotype is not consistent. Plus some of the cases recorded as seizures refer to febrile seizures, which are out of scope of this panel (e.g. PMID:17236139), and detailed information on seizures is not provided in most papers.
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Gene: cul4b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:20014135: Isifor et al., 2010 report a de novo deletion of CUL4B in a boy with syndromic ID. Seizures were not reported.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:20002452: Badura-Stronka et al., 2010 report a CUL4B nonsense variant in 3 brothers with X-linked ID.
2 brothers had a single seizure, in the setting of infection. Therefore not appropriate in the context of this epilepsy panel.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger changed review comment from: PMID:17273978: Zou et al., 2007 analyse a previously reported (PMID:8135271) family (5 individuals) with X-linked ID and implicate p.R388X nonsense variant in CUL4B as the cause. 4/5 patients had seizures according to the summaries in PMID:20014135 and PMID:22182342; to: PMID:17273978: Zou et al., 2007 analyse a previously reported (PMID:8135271) family (5 individuals) with X-linked ID and implicate p.R388X nonsense variant in CUL4B as the cause. 4/5 patients had seizures according to the summaries in PMID:20014135 and PMID:22182342.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:17273978: Zou et al., 2007 analyse a previously reported (PMID:8135271) family (5 individuals) with X-linked ID and implicate p.R388X nonsense variant in CUL4B as the cause. 4/5 patients had seizures according to the summaries in PMID:20014135 and PMID:22182342
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures is reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:17236139: Tarpet et al., 2007 report CUL4B variants in 8/250 families with X-linked mental retardation. Segregation analysis is performed for all 8 families. Seizures (before age 2) reported in 8/11 affected males (Table 2). However the seizures are reported to be usually single febrile fits. The authors also note that further evidence is required to confirm that the missense variants are disease causing (e.g. in Family 432 it is possible that C638C>T (T213I) is a rare variant because ethically-matched controls were unavailable).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:25385192: Vulto-van Silfhout et al, 2015 identified CUL4B variants in 8/407 families with X-linked mental retardation. Plus CUL4B variants in an additional 3 patients (2 families) with malformations of cortical development. Ten different variants were identified in the 10 families (5 truncating, 2 splice, 1 in-frame deletion, 1 in-frame duplication, 1 missense). Across the 10 families with CUL4B variants, 7/22 (32%) of the individuals had seizures, though the phenotype was not always consistent between family members: In both family 1 (N151) and family 5 (D173), 1 of 3 individuals had seizures. The authors note that previously 17/30 (57%) of individuals with CUL4B variants were reported to have seizures.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: Seizures listed amongst the phenotypes of MENTAL RETARDATION SYNDROMIC X-LINKED CABEZAS TYPE in Gene2Phenotype. Seizures (onset <2 years) listed amongst the phenotypes in OMIM for Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM:300354.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger Publications for gene: CUL4B were set to 25385192; 17236139
Early onset or syndromic epilepsy v1.82 CUL4B Rebecca Foulger gene: CUL4B was added
gene: CUL4B was added to Genetic epilepsy syndromes. Sources: NHS GMS,Literature
Mode of inheritance for gene: CUL4B was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CUL4B were set to 25385192; 17236139
Phenotypes for gene: CUL4B were set to Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354; seizures
Added comment: Added to Genetic epilepsy syndromes panel based on gene list submitted by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.
Sources: NHS GMS, Literature
Early onset or syndromic epilepsy v1.81 CSNK2A1 Rebecca Foulger Classified gene: CSNK2A1 as Red List (low evidence)
Early onset or syndromic epilepsy v1.81 CSNK2A1 Rebecca Foulger Added comment: Comment on list classification: Rated CSNK2A1 as Red based on 1 paper (PMID:30655572) with 2 unrelated Japanese patients and de novo variants. Functional studies were not performed, and the seizures (and other features) were variable between the patients.
Early onset or syndromic epilepsy v1.81 CSNK2A1 Rebecca Foulger Gene: csnk2a1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.80 CSNK2A1 Rebecca Foulger gene: CSNK2A1 was added
gene: CSNK2A1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSNK2A1 were set to 30655572
Phenotypes for gene: CSNK2A1 were set to seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome
Review for gene: CSNK2A1 was set to AMBER
Added comment: Added CSNK2A1 to the epilepsy panel based on PMID:30655572. Nakashima et al, 2019 describe 4 patients with DD and seizures. Two of the patients (both Japanese) had de novo variants in CSNK2A1: c.593A>G, p.Lys198Arg in Patient 1, c.571C>T, p.Arg191* in Patient 2. Although both shared global DD and seizures, patient 1 showed later onset (4 yrs old) seizures which were less frequent. Additional features in Patient 1 include facial dysmorphisms, short stature and muscle weakness. Patient 2 had a more severe phenotype with seizures starting in the early infantile stage (5 months) with acute encephalopathy and death age 1 yr, 7 months. Note that Patient 1 had 3 candidate de novo deleterious variants (ATAD2B, TOPORS, CSNK2A1): ACMG variant guidelines were used to evaluate the pathogenicity of the variants. ATAD2B and TOPORS variants were likely pathogenic, and CSNK2A1 variant was pathogenic. In Patient 2, no further likely de novo variants were found.
Sources: Literature
Early onset or syndromic epilepsy v1.79 CSNK2B Rebecca Foulger Classified gene: CSNK2B as Green List (high evidence)
Early onset or syndromic epilepsy v1.79 CSNK2B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on recent 2019 paper, PMID:30655572, which reports two further unrelated cases (Japanese and Malaysian) of de novo CSNK2B variants in patients with epilepsy. Although CSNK2B is still not associated with a disorder in OMIM or Gene2Phenotype, this takes the count from two to four cases (from 3 different papers) and is therefore sufficient for a Green rating on this panel.
Early onset or syndromic epilepsy v1.79 CSNK2B Rebecca Foulger Gene: csnk2b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.78 CSNK2B Rebecca Foulger commented on gene: CSNK2B: PMID:30655572: Nakashima et al, 2019 describe 4 patients with ID, DD and seizures. Two of the patients had variants in CSNK2B: c.533_534insGT, p.(Pro179Tyrfs*49) in Malaysian Patient 3, and c.494A>G, p.(His165Arg) in Japanese Patient 4. Both had seizures within 2 months of age. Both variants occurred de novo. In each patient, only 1 likely candidate variant was proposed. Functional assays suggested that Pro179Tyrfs*49 mutant protein was produced but showed disrupted interaction with CSNK2A1.
Early onset or syndromic epilepsy v1.78 CSNK2B Rebecca Foulger Publications for gene: CSNK2B were set to 28762608; 28585349; 27094248
Early onset or syndromic epilepsy v1.77 CNPY3 Rebecca Foulger Classified gene: CNPY3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.77 CNPY3 Rebecca Foulger Added comment: Comment on list classification: Re-reviewed gene:disease association for CNPY3 during curation of GMS panel. Amber rating is still appropriate: Probable Disease confidence rating in DD-G2P for EARLY ONSET EPILEPTIC ENCEPHALOPATHY, and literature evidence remains at 3 patients from 2 unrelated families from one paper (PMID:29394991) with limited segregation data from one of the families.
Early onset or syndromic epilepsy v1.77 CNPY3 Rebecca Foulger Gene: cnpy3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.76 CNPY3 Rebecca Foulger commented on gene: CNPY3
Early onset or syndromic epilepsy v1.76 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096; 30291339; 27026573
Early onset or syndromic epilepsy v1.75 ASAH1 Rebecca Foulger Classified gene: ASAH1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.75 ASAH1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green. Confirmed Disease confidence rating in Gene2Phenotype for SPINAL MUSCULAR ATROPHY ASSOCIATED WITH PROGRESSIVE MYOCLONIC EPILEPSY. Relevant disorder in OMIM (Spinal muscular atrophy with progressive myoclonic epilepsy, 159950). Although the three families reported in PMID:22703880 share a haplotype suggesting Founder effect, there are sufficient additional papers reporting cases with additional variants. Note that although most individuals report muscle weakness followed by seizures, PMIDs 27026573 and 30291339 report muscle weakness WITHOUT epilepsy, and PMID:24164096 also report a case with seizures without muscle weakness- there is therefore some heterogeneity in the phenotype. On balance there are plenty of literature reports of seizures in patients with biallelic ASAH1 variants for inclusion on this panel.
Early onset or syndromic epilepsy v1.75 ASAH1 Rebecca Foulger Gene: asah1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.74 ASAH1 Rebecca Foulger commented on gene: ASAH1: Additional cases of seizures associated with SMA were reported in papers including PMIDs 27723502, 26526000, 25847462, 25578555, 31216804.
Early onset or syndromic epilepsy v1.74 ASAH1 Rebecca Foulger commented on gene: ASAH1: PMID:27723502 (Oguz et al, 2016) report eyelid myoclonic status epilepticus as an unusual manifestation of SMA-PME in a Turkish girl of consanguineous parents. Ambulatory problems were noted age 4. Generalized seizures developed later.
Early onset or syndromic epilepsy v1.74 ASAH1 Rebecca Foulger commented on gene: ASAH1: PMID:29169047: Yidiz et al (2018) report a 13.5 yr old girl with SMA-PME. She was the 8th child born of consanguineous parents. She presented with progressive muscle weakiness age 10, tremor, seizure (generalized epilepsy) and decreased cognitive functions. Screening revelead homozygous missense variant c.173C>T (T58M). The parents or siblings were not tested.
Early onset or syndromic epilepsy v1.74 ASAH1 Rebecca Foulger changed review comment from: PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. Ambulatory problems of the 24 year old female began around age 8 years.; to: PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. She carried two novel ASAH1 variants (Pro26Arg and c.125+1G>A splice variant leading to an unstable transcript lacking exon 2. Segregation analysis confirmed the parental inheritance and acid ceramidase activity was deficient in functional tests.
Early onset or syndromic epilepsy v1.74 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096
Early onset or syndromic epilepsy v1.73 ASAH1 Rebecca Foulger commented on gene: ASAH1: PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. Ambulatory problems of the 24 year old female began around age 8 years.
Early onset or syndromic epilepsy v1.73 ASAH1 Rebecca Foulger commented on gene: ASAH1: PMID:27026573: Filosto et al., 2016 studied 2 subjects: a 30yr old pregnant woman and her 17 year old sister affected with slowly progressive SMA since childhood but in the ABSENCE of siezures. Both subjects had a homozygous c.124A>G (T42A) variant in ASAH1.
Early onset or syndromic epilepsy v1.73 ASAH1 Rebecca Foulger commented on gene: ASAH1: PMID:24164096: In a girl who presented with absence and atonic seizures age 10, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene: c.850G>T (G284X) and c.456A>C. Each parent was found to carry one of the variants. Although c.456A>C is predicted to encode a Lys152Asn substitution, it is 2bp away from a splice donor site and fibroblast assays showed an absence of exon 6, suggesting abberant splicing. Note that the patient harboured several hundred rare variants with at least two rare non-synonymous variants within the coding sequence of 4 genes (ASAH1, OC90, CACNA1C and LAMA5) though CACNA1C and OC90 were ruled out because the variants were found to be inherited from a single parent. Unlike the cases from PMID:22703880, this patient presented with seizures as the first symptom, and displayed no significant muscle weakness.
Early onset or syndromic epilepsy v1.73 ASAH1 Rebecca Foulger commented on gene: ASAH1
Early onset or syndromic epilepsy v1.73 ASAH1 Rebecca Foulger Mode of inheritance for gene: ASAH1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.72 ASAH1 Rebecca Foulger Phenotypes for gene: ASAH1 were changed from to Spinal muscular atrophy with progressive myoclonic epilepsy, 159950
Early onset or syndromic epilepsy v1.71 RRM2B Rebecca Foulger Classified gene: RRM2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.71 RRM2B Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber after reviewing the literature evidence. The main phenotype manifests as hypotonia with lactic acidosis. Although seizures have been reported, they are variable and not common (PMID:29241262 summary records seizures in 6/78 patients, PMID:18504129 don't report seizures in any of their three patients).
Early onset or syndromic epilepsy v1.71 RRM2B Rebecca Foulger Gene: rrm2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.70 RRM2B Rebecca Foulger Publications for gene: RRM2B were set to
Early onset or syndromic epilepsy v1.69 RRM2B Rebecca Foulger Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures; status epilepticus
Early onset or syndromic epilepsy v1.68 RRM2B Rebecca Foulger commented on gene: RRM2B: Bourdon et al., 2007 (PMID:17486094) studied 7 cases of mitochondrial depletion in 4 unrelated families with RRM2B variants. Seizures were reported in Family 2: Subject 4 showed trunk hypotonia and tubulopathy shortly after birth. At 20 days of life he developed seizures, and died at 2 months after status epilepticus. His sister (Subject 5) had a similar clinical course (the authors don't explicitly state whether she had seizures).
Early onset or syndromic epilepsy v1.68 RRM2B Rebecca Foulger changed review comment from: PMID:19138848 report two Sudanese brothers with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene. Both brothers had seizures amongst their phenotypes.; to: PMID:19138848 (Kollberg et al., 2009) report two Sudanese brothers with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene. Both brothers had seizures amongst their phenotypes.
Early onset or syndromic epilepsy v1.68 RRM2B Rebecca Foulger Phenotypes for gene: RRM2B were changed from to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures
Early onset or syndromic epilepsy v1.67 RRM2B Rebecca Foulger Mode of inheritance for gene: RRM2B was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.66 RRM2B Rebecca Foulger commented on gene: RRM2B: Bornstein et al., 2008 (PMID:18504129) sequenced the RRM2B gene in 3 unrelated cases- The common clinical feature was myopathy with lactic acidosis, and none had overt seizures.
Early onset or syndromic epilepsy v1.66 RRM2B Rebecca Foulger commented on gene: RRM2B: PMID:19138848 report two Sudanese brothers with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene. Both brothers had seizures amongst their phenotypes.
Early onset or syndromic epilepsy v1.66 CUX2 Rebecca Foulger Phenotypes for gene: CUX2 were changed from Seizures; Intellectual disability; Autistic behavior; Developmental epileptic encephalopathy to Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Classified gene: CUX2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following discussion with Sarah Leigh. A personal communication from the authors of PMID:29630738 confirm that the variants seen in 9 patients were de novo and therefore not Founder effect. Although there is no functional data and there is limited information about the patients in PMIDs:29630738, 23020937 and 23934111, overall there are sufficient cases (10 individuals from 4 papers including 2 large-scale studies) and 2 Green reviews to support inclusion on the panel as a Green gene. Plus CUX2 is now associated with an EIEE disorder in OMIM.
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Gene: cux2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2: A summary of evidence: ONE variant (Glu590Lys) reported from 9 patients in Chatron et al., 2018 (PMID:29630738) and 1 patient in Barington et al., 2018 (PMID:29795476). Barington et al claim their Danish patient is a third case as there are additionally two large scale reports from Rauch et al., 2012 (PMID:23020937) and the Epi4K Consortium (Allen et al., 2013, PMID:23934111)- there is sparse information about the patients in the large-scale papers, although the Epi4K patient is a German male. Two of the 9 patients in Chatron et al came from these large-scale studies. None of the papers perform functional studies. CUX2 was previously rated Amber as there was a question mark over the relatedness of patients in Chatron et al (this has been addressed by a pers.comm from Gemma Carvill).
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2: Re-assessing the rating of CUX2 following a new Green review by Deb Pals (the new review contains the same paper (PMID:29630738) as described by Konstantinos Varvagiannis). CUX2 is now associated with an OMIM disorder: Epileptic encephalopathy, early infantile, 67, 618141. The DD-Gene2Phenotype rating is still probable.
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2
Early onset or syndromic epilepsy v1.64 RRM2B Rebecca Foulger commented on gene: RRM2B
Early onset or syndromic epilepsy v1.62 ALKBH8 Catherine Snow commented on gene: ALKBH8: Expert review by Konstantinos Varvagiannis on ALKBH8. Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other phenotype features were noted in few.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.


ALKBH8 can be included in the epilepsy panel as Amber awaiting further evidence and tagged on the watchlist.
Early onset or syndromic epilepsy v1.62 ALKBH8 Catherine Snow reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31079898; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.62 SLC35A2 Eleanor Williams Phenotypes for gene: SLC35A2 were changed from Congenital disorder of glycosylation, type IIm, 300896 (includes Epileptic encephalopathy); Epileptic encephalopathy, early infantile, 22 (EIEE22); early-onset epileptic encephalopathy to Congenital disorder of glycosylation, type IIm, 300896 (includes Epileptic encephalopathy); Epileptic encephalopathy, early infantile, 22 (EIEE22); early-onset epileptic encephalopathy; epilepsy
Early onset or syndromic epilepsy v1.61 SLC35A2 Eleanor Williams Publications for gene: SLC35A2 were set to 24115232; 27743886
Early onset or syndromic epilepsy v1.60 PIGQ Eleanor Williams Phenotypes for gene: PIGQ were changed from Intractable seizures; developmental delay; optic atrophy to Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome
Early onset or syndromic epilepsy v1.59 PIGQ Eleanor Williams Publications for gene: PIGQ were set to 24463883; 25558065
Early onset or syndromic epilepsy v1.58 PIGQ Eleanor Williams Classified gene: PIGQ as Green List (high evidence)
Early onset or syndromic epilepsy v1.58 PIGQ Eleanor Williams Added comment: Comment on list classification: 3 cases plus some functional data.
Early onset or syndromic epilepsy v1.58 PIGQ Eleanor Williams Gene: pigq has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.57 PIGQ Eleanor Williams commented on gene: PIGQ
Early onset or syndromic epilepsy v1.57 KMT5B Eleanor Williams gene: KMT5B was added
gene: KMT5B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT5B were set to 29276005
Phenotypes for gene: KMT5B were set to Mental retardation, autosomal dominant 51, 617788
Review for gene: KMT5B was set to RED
Added comment: KMT5B is associated with Mental retardation, autosomal dominant 51 (#617788) in OMIM and KMT5B syndrome on Gene2phenotype. This syndrome has intellectual disability and overgrowth listed as phenotypes.

PMID: 29276005 - Faundes et al 2018 - looked at patients from the Deciphering Developmental Disorders (DDD) study that high-quality-call genetic variants in methyltransferases (KMTs) and demethylases (KDMs) not yet firmly associated with DDs. 4 patients identified with either variants or deletions in KMT5B. 2 had nonsense variants, 2 had deletions encompassing KMT5B (399 kb and 839 kb). All had mild to severe intellectual disability. 2 (1 with nonsense variant, 1 with a deletion) also had seizures.
Sources: Literature
Early onset or syndromic epilepsy v1.57 KMT5B Eleanor Williams gene: KMT5B was added
gene: KMT5B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT5B were set to 29276005
Phenotypes for gene: KMT5B were set to Mental retardation, autosomal dominant 51, 617788
Review for gene: KMT5B was set to RED
Added comment: KMT5B is associated with Mental retardation, autosomal dominant 51 (#617788) in OMIM and KMT5B syndrome on Gene2phenotype. This syndrome has intellectual disability and overgrowth listed as phenotypes.

PMID: 29276005 - Faundes et al 2018 - looked at patients from the Deciphering Developmental Disorders (DDD) study that high-quality-call genetic variants in methyltransferases (KMTs) and demethylases (KDMs) not yet firmly associated with DDs. 4 patients identified with either variants or deletions in KMT5B. 2 had nonsense variants, 2 had deletions encompassing KMT5B (399 kb and 839 kb). All had mild to severe intellectual disability. 2 (1 with nonsense variant, 1 with a deletion) also had seizures.
Sources: Literature
Early onset or syndromic epilepsy v1.56 KMT2E Eleanor Williams Classified gene: KMT2E as Green List (high evidence)
Early onset or syndromic epilepsy v1.56 KMT2E Eleanor Williams Added comment: Comment on list classification: Sufficient cases to rate green.
Early onset or syndromic epilepsy v1.56 KMT2E Eleanor Williams Gene: kmt2e has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.55 KMT2E Eleanor Williams commented on gene: KMT2E: Not associated with any phenotype in OMIM. Confirmed association with Intellectual disability in Gene2Phenotype (monoallelic)

PMID: 31079897 O'Donnell-Luria et al 2019 - report on additional 35 individuals with heterozygous variants in KMT2E and 3 previously reported males. New cases were ascertained from GeneMatcher through the Matchmaker Exchange Network and MyGene2. 34 individuals from 32 families were found to have single-nucleotide or indel variants in KMT2E, and four additional individuals had copy-number variants encompassing KMT2E. 11 unrelated individuals had epilepsy - 3 had microdeletions, 4 missense variants, 2 frameshift, 1 nonsense and 1 a variant affecting a splice site.

Sufficient cases with likely disease-causing variants to rate as green.
Early onset or syndromic epilepsy v1.55 KMT2E Eleanor Williams Added comment: Comment on publications: URL was to the paper in Bioxriv. Paper is now in Am J Hum Genet
Early onset or syndromic epilepsy v1.55 KMT2E Eleanor Williams Publications for gene: KMT2E were set to https://doi.org/10.1101/566091
Early onset or syndromic epilepsy v1.54 Ellen McDonagh Panel status changed from internal to public
Early onset or syndromic epilepsy v1.53 BCORL1 Rebecca Foulger gene: BCORL1 was added
gene: BCORL1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BCORL1 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: BCORL1 were set to 30941876
Phenotypes for gene: BCORL1 were set to Intellectual disability and seizures
Added comment: Added BCORL1 to the Genetic epilepsy syndromes panel as a Red gene based on a 2019 paper by Shukla et al (PMID:30941876) who report 5 males from 3 families with ASD, ID/DD and dysmorphic features. Three siblings (patients 3, 4 and 5) had Seizures (at 1 year, 2 year and 6 months of age, respectively). Patients 1 and 2 did not have seizures but their ID/DD phenotype was less severe than those of the three brothers. Therefore currently only one family and a Red rating.
Sources: Literature
Early onset or syndromic epilepsy v1.52 ALKBH8 Konstantinos Varvagiannis gene: ALKBH8 was added
gene: ALKBH8 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ALKBH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALKBH8 were set to 31079898
Phenotypes for gene: ALKBH8 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: ALKBH8 were set to Complete
Review for gene: ALKBH8 was set to AMBER
Added comment: Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saoudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

All presented with DD and ID (Fam1 : moderate in the proband, degree not commented on for his 3 sibs / Fam2 : mild in the proband, severe in all his 3 sibs). Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other features were noted in few.

Affected subjects from the first family were homozygous for a stopgain variant (NM_001301010.1:c.1660C>T or p.Arg554Ter) while individuals from the second family were homozygous for a frameshift one (c.1794delC or p.Trp599Glyfs*19). The variants affected in both cases the last exon of ALKBH8 and RT-PCR confirmed that they escape NMD.

Alternative causes were ruled out, at least for the proband from the second family (chromosomal analysis, SNP-array, metabolic investigations).

Linkage analysis of both families confirmed linkage to the same autozygous interval of chr11q22.3 with a LOD score of 6.

Segregation analyses in both families, confirmed homozygosity for the truncating variants in affected members and heterozygosity in their parents (or several unaffected sibs, none of those studied was homozygous for the ref. allele).

In mouse or human cells, ALKBH8 has previously been shown to be involved in tRNA modifications of the wobble uridines of specific tRNAs (PMIDs cited: 20308323, 20583019, 21653555).

LC-MS/MS analyses of tRNA extracted from LCLs derived from affected individuals, unaffected relatives (UR) and independent controls (IC) revealed that wobble nucleotide modifications were completely absent (or dramatically decreased in the case of mcm5U) in affected individuals but readily detected in UR/IC. As specific modifications were absent, substantial amounts of precursors (eg. cm5U - the precursor of mcm5U) were detected in affected individuals but not in unaffected ones.

Absence of wobble modifications (eg. mchm5U) has equally been observed in Alkbh8 knockout mice. Alkbh8-deficient mice show similar increases in precursors. Alkbh8 KO mice are however phenotypically normal (the authors comment that eventual cognitive defects were not formally evaluated and might have been missed - PMIDs cited: 20123966, 21285950).

As a result, the studies carried out confirmed the loss-of-function effect and were in line with previous functional studies in animal models, although the pathogenesis of ID remains unclear.

The expression profile of ALKBH8 is also unclear (wide profile of expression suggested developmentally, the authors studied LCLs, other studies suggest that embryonic expression is broad but becomes progressively more restricted to specific neuronal cells).

Mutations in other genes involved in tRNA modification (eg. ADAT3, PUS3, PUS7) have been shown underlie disorders affecting the CNS, with ID as a feature.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the ID/epilepsy panels as amber pending further evidence.
Sources: Literature
Early onset or syndromic epilepsy v1.52 AP2M1 Konstantinos Varvagiannis gene: AP2M1 was added
gene: AP2M1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP2M1 were set to 31104773
Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior
Penetrance for gene: AP2M1 were set to Complete
Review for gene: AP2M1 was set to GREEN
Added comment: Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4).

AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.).

The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice.

Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency.

AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively.

As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited)

AP2M1 is currently not associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green).
Sources: Literature
Early onset or syndromic epilepsy v1.52 RALA Eleanor Williams Added comment: Comment on publications: 10.1371/journal.pgen.1007671 is PMID: 30500825
Early onset or syndromic epilepsy v1.52 RALA Eleanor Williams Publications for gene: RALA were set to doi.org/10.1371/journal.pgen.1007671
Early onset or syndromic epilepsy v1.51 NECAP1 Rebecca Foulger Phenotypes for gene: NECAP1 were changed from ?Epileptic encephalopathy, early infantile,21 to Epileptic encephalopathy, early infantile, 21, 615833; Early onset epileptic encephalopathy (EOEE)
Early onset or syndromic epilepsy v1.50 NECAP1 Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to BIALLELIC to match reviews by Konstantinos and Zornitza, recent papers and OMIM.
Early onset or syndromic epilepsy v1.50 NECAP1 Rebecca Foulger Mode of inheritance for gene: NECAP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.49 NECAP1 Rebecca Foulger Publications for gene: NECAP1 were set to
Early onset or syndromic epilepsy v1.48 NECAP1 Rebecca Foulger commented on gene: NECAP1: PMID:30626896 (Mizuguchi et al. 2019) report a 16-month-old Malaysian boy who developed infantile-onset tonic-clonic and tonic seizures age 3 months, then spasms in clusters. WES identified the splice site variant c.301+1G>A in NECAP1.
Early onset or syndromic epilepsy v1.48 NECAP1 Rebecca Foulger commented on gene: NECAP1
Early onset or syndromic epilepsy v1.48 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.48 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green after discussion with Sarah Leigh; Sufficient cases from PMIDs:28058944, 18028407 and 12953268 of patients with familial hemiplegic migraine (FHM) also exhibiting seizures; PMID:28058944 (Prontera et al., 2018) calculate a co-occurrence of ~30%.
Early onset or syndromic epilepsy v1.48 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.47 CACNA1A Rebecca Foulger Classified gene: CACNA1A as Green List (high evidence)
Early onset or syndromic epilepsy v1.47 CACNA1A Rebecca Foulger Added comment: Comment on list classification: The Green review by Professor Deb Pal (KCL) supports the current Green rating of CACNA1A on this epilepsy panel.
Early onset or syndromic epilepsy v1.47 CACNA1A Rebecca Foulger Gene: cacna1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.46 CACNA1A Rebecca Foulger Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106 to Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM)
Early onset or syndromic epilepsy v1.45 CACNA1A Rebecca Foulger Added comment: Comment on publications: CACNA1A is called CACNL1A4 (the previous gene symbol) in PMID:8898206 (Ophoff et al., 1996).
Early onset or syndromic epilepsy v1.45 CACNA1A Rebecca Foulger Publications for gene: CACNA1A were set to 29056246; 27476654
Early onset or syndromic epilepsy v1.44 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: PMID:28058944 (Prontera et al., 2018) performed a review of the comorbidities of familial/sporadic hemiplegic migraine with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations. For patients carrying ATP1A2 variants, 30.9% of migraine patients also had seizures. Of 180 patients (27 families): 62 patients had epilepsy.
Early onset or syndromic epilepsy v1.44 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: Vanmolkot et al., 2003 (PMID:12953268) describe novel variants in ATP1A2 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q variant was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate; all available affected family members with FHM, benign familial infantile convulsions, or both, carried the ATP1A2 mutation.
Early onset or syndromic epilepsy v1.44 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: PMID:18028407 (Deprez et al., 2008) found ATP1A2 variants in 2/20 families (p.Gly900Arg and p.Cys702Tyr). In the two families, 6 variant carriers had the combination of epilepsy and migraine, 2 had only epilepsy, and 6 six had only migraine.
Early onset or syndromic epilepsy v1.44 ATP1A2 Rebecca Foulger Added comment: Comment on phenotypes: OMIM reports Generalized tonic-clonic seizures in 50% patients with 'Alternating hemiplegia of childhood 1' (MIM:104290) but says seizures are less common in Migraine, familial basilar/Migraine, familial hemiplegic, 2 (OMIM:602481).
Early onset or syndromic epilepsy v1.44 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome
Early onset or syndromic epilepsy v1.43 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: PMID:29610157 (Ueda et al., 2018) report a 12 year old boy with a history of complex partial seizures, ADHD and fine motor difficulty. WES revealed a de novo missense variant in ATP1A2, and a maternally inherited POLG VUS. The authors hypothesize that the ATP1A2 variant contributed to the patient's phenotype.
Early onset or syndromic epilepsy v1.43 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1 104290; Migraine, familial basilar 602481; Migraine, familial hemiplegic, 2 602481 to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome
Early onset or syndromic epilepsy v1.42 ATP1A2 Rebecca Foulger Added comment: Comment on publications: PMID:9579893 (Terwindt et al., 1997) studied a large Dutch-Canadian family in which familial hemiplegic migraine (FHM) and a benign familial infantile epileptic syndrome concur and partially cosegregate. The genetic basis of the conditions was not finalised. Note that ATP1A2 is on chromosome 1q23.2.
Early onset or syndromic epilepsy v1.42 ATP1A2 Rebecca Foulger Publications for gene: ATP1A2 were set to 15159495; 29610157
Early onset or syndromic epilepsy v1.41 ACTL6B Rebecca Foulger Classified gene: ACTL6B as Green List (high evidence)
Early onset or syndromic epilepsy v1.41 ACTL6B Rebecca Foulger Added comment: Comment on list classification: ACTL6B was added to the panel and rated Green by Konstantinos Varvagiannis. Updated rating from Grey to Green based on literature evidence provided by Konstantinos; although epilepsy is not the primary phenotype, there are sufficient unrelated cases of seizures in patients with biallelic ACTL6B variant for inclusion on the panel (PMIDs:31031012,30656450,26539891 and 30237576).
Early onset or syndromic epilepsy v1.41 ACTL6B Rebecca Foulger Gene: actl6b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.40 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the homozygous ACTL6B variant NM_016188.4:c.999T>A:p.(Cys333*) in 13 year old girl (individual 17-1447) with phenotype global developmental delay, epilepsy vs hyperekplexia, and basal ganglia abnormalities.
Early onset or syndromic epilepsy v1.40 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Karaca et al, 2015 (PMID:26539891) report a homozygous variant (NM_016188: c.G893A; p.R298Q) in two siblings BAB6569 and BAB6570 with severe ID, microcephaly, seizures and some autistic behavioral pattern (BAB6570 appears in the text but not table 1).
Early onset or syndromic epilepsy v1.40 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Fichera et al. (2019, PMID:30656450) report three individuals from 2 families with affected members characterised by early onset drug-resistant epilepsy, severe psychomotor delay, spastic tetraplegia, microcephaly, diffuse cerebral hypomyelination, and brain or cerebellar atrophy. Individuals had distinct homozygous variants in ACTL6B: NM_016188:c.820C>T;p.Gln274* and NM_016188:c.1045G>A;p.Gly349Ser.
Early onset or syndromic epilepsy v1.40 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity to Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy
Early onset or syndromic epilepsy v1.39 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. Seizure types include myoclonias, tonic and myoclonic, focal onset progressing to infantile spasms, and Epilepsy was a feature of all 11 patients (Table 1).
Early onset or syndromic epilepsy v1.39 ACTL6B Rebecca Foulger Added comment: Comment on mode of inheritance: Bell et al., 2019 (PMID:31031012) report biallelic and heterozygous variants in ACTL6B with ID/developmental delay. Seizures were reported in all the biallelic patients but infantile spasms and GTCS (generalized tonic-clonic seizure) was reported in only one heterozygous individual (D7). Therefore kept MOI as biallelic.
Early onset or syndromic epilepsy v1.39 ACTL6B Rebecca Foulger Mode of inheritance for gene: ACTL6B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.38 TSEN15 Rebecca Foulger Classified gene: TSEN15 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.38 TSEN15 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: Although Zornitza correctly notes that seizures are amongst the phenotypes of MIM:617026, there are insufficient cases to support a Green rating: PMID:27392077 (Breuss et al., 2016) report three homozygous TSEN15 variants in four individuals from three families with ID and progressive microcephaly. Epilepsy is reported in 2 of the 4 cases (families I and II) only. Added 'watchlist' tag.
Early onset or syndromic epilepsy v1.38 TSEN15 Rebecca Foulger Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.37 TSEN15 Rebecca Foulger Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F 617026 to Pontocerebellar hypoplasia, type 2F, 617026; seizures
Early onset or syndromic epilepsy v1.36 TRAF7 Rebecca Foulger Added comment: Comment on phenotypes: Updated phenotypes to include new OMIM disorder: MIM:618164 (Cardiac, facial, and digital anomalies with developmental delay).
Early onset or syndromic epilepsy v1.36 TRAF7 Rebecca Foulger Phenotypes for gene: TRAF7 were changed from Global developmental delay; Abnormal heart morphology; Abnormality of digit; Abnormality of limbs to Cardiac, facial, and digital anomalies with developmental delay, 618164; Global developmental delay; Abnormal heart morphology; Abnormality of digit; Abnormality of limbs
Early onset or syndromic epilepsy v1.35 ATP5A1 Louise Daugherty Tag new-gene-name tag was added to gene: ATP5A1.
Early onset or syndromic epilepsy v1.35 ATP5A1 Louise Daugherty commented on gene: ATP5A1
Early onset or syndromic epilepsy v1.35 ZNF142 Konstantinos Varvagiannis gene: ZNF142 was added
gene: ZNF142 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF142 were set to 31036918
Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia
Penetrance for gene: ZNF142 were set to Incomplete
Review for gene: ZNF142 was set to AMBER
Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants.

Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs.

Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects.

6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out.

ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1).

As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)].

ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P.

As a result, this gene can be considered for inclusion in the current panel as probably as amber (seizures in 5/7 individuals, though many had a single occurrence) or green.
Sources: Literature
Early onset or syndromic epilepsy v1.35 ACTL6B Konstantinos Varvagiannis gene: ACTL6B was added
gene: ACTL6B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ACTL6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL6B were set to 31031012; 30656450; 26539891; 27171548; 30237576
Phenotypes for gene: ACTL6B were set to Global developmental delay; Intellectual disability; Seizures; Spasticity
Penetrance for gene: ACTL6B were set to Complete
Review for gene: ACTL6B was set to GREEN
Added comment: Epilepsy is a typical feature in individuals with biallelic pathogenic ACTL6B variants, though it is uncommon for the dominant phenotype (only a single individual with seizures probably reported).
Intellectual disability is a prominent feature of the ACTL6B-related disorder, whether this is secondary to biallelic mutations (leading to loss-of-function) or monoallelic ones (probably by a gain-of-function mechanism).

Biallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 11 individuals from 10 families with biallelic variants, adding to 3 individuals from 2 families, recently reported in detail by Fichera et al. (2019 - PMID: 30656450). Previous reports by Karaca et al. (1 individual - 2015 - PMID: 26539891), Sajan et al. (1 individual - 2017 - PMID: 27171548), Maddirevula et al. (2019 - PMID: 30237576) are summarized by Fichera et al. Overlapping features include global DD/ID, epileptic encephalopathy and spasticity.

Monoallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 10 individuals with de novo pathogenic variant, namely a recurrent missense one (9/10 - NM_016188.4:c.1027G>A or p.Gly343Arg) as well as a further missense SNV (c.230A>G or p.Asp77Gly) on one occasion. Features included hypotonia, DD and ID, stereotypic movements, and some possibly suggestive features (wide mouth, diastema, bulbous nose).

ACTL6B (also known as BAF53B) encodes a subunit of the neuron-specific chromatin remodeling complex nBAF.

Some ACTL6B-related phenotypic features were somewhat overlapping to those of other "BAFopathies" (notably Nicolaides-Baraitser and Cofin Siris syndrome - eg. DD/ID, seizures in the recessive type, short phalanges in the dominant one) though others (eg. hair or digital abnormalities) were not observed.

Actl6b knock-out mouse neurons show deficits in dendrite development (cited: Wu et al. 2007 - PMID: 17920018). Additional previous studies have shown deficit in dendritic spine and synapse function in Actl6b KO mice, associated with impaired long-term memory and poor survival (cited: Vogel-Ciernia et al. 2013 - PMID: 23525042).

Bell et al. provide evidence for profound deficits in dendrite develpment in engineered knock-out of ACTL6B in wt human neurons, similar to what was observed in 2 individuals with biallelic mutation. The deficits were reversed upon bi-allelic repair to wild-type or exogenous ACTL6B expression. Additional studies suggested alteration of genomic binding of the BAF complex and transcriptional dysregulation of genes, among other involved in dendrite development.

Loss of ACTL6B function probably explains the recessive phenotype, while a gain-of-function effect is presumed for the dominant one (though the exact mechanism is not known).
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ACTL6B is included in gene panels for ID offered by some diagnostic laboratories.
It is part of the DD panel of G2P, associated with "Unspecified Neurodevelopmental Disorder" (monoallelic variants - disease confidence : probable).
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As a result ACTL6B can be considered for inclusion in the current panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.35 SNAP25 Konstantinos Varvagiannis gene: SNAP25 was added
gene: SNAP25 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006
Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330
Penetrance for gene: SNAP25 were set to Complete
Review for gene: SNAP25 was set to GREEN
Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below):
- Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent.
- DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants.
- Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant
- Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant
- Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant
- Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported).

Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified).

SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID.

SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.).

Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988].

Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants.

Animal models discussed:
- Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238).
- In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548).
- Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108).
- Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335).

In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable).

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

As a result SNAP25 can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.35 CYP27A1 Philip Dawson reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24442603, 29484516; Phenotypes: Cerebrotendinous xanthomatosis, 213700, Epilepsy, including childhood onset.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.35 CACNA1B Konstantinos Varvagiannis gene: CACNA1B was added
gene: CACNA1B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CACNA1B were set to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement
Penetrance for gene: CACNA1B were set to Complete
Review for gene: CACNA1B was set to GREEN
Added comment: Gorman et al. (2019 - doi.org/10.1016/j.ajhg.2019.03.005) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants. The phenotype corresponds to a developmental epilepic encephalopathy with hyperkinetic movement disorder (ID was a universal feature, DD and/or regression occurred prior to the onset of seizures in several individuals) .

CACNA1B encodes calcium channel, voltage-dependent N type, α-1B subunit (Ca v2.2). As commented by the authors, Ca v2.1 and v2.2 are important for SNARE-mediated release of neurotransmitters through modulation of Ca+2 levels. In addition, Ca v2.2 has been postulated to have a role in synaptic plasticity, synaptogenesis, migration of immature neurons, etc. It is thought to have a crucial role in neurotransmission in the early postnatal period (Ca v2.2 channels are subsequently replaced by Ca v2.1 in mature synapses within the thalamus, cerebellum and auditory brainstem). Knockout mice display neurodevelopmental abnormalities including impaired locomotor activity and memory impairment (all ref. cited within the article).

3 sibs, born to 1st cousin parents, harbored p.Leu1222Argfs*29 (NM_000718.4:c.3665del) in the homozygous state. One additional individual was homozygous for p.Arg383*. Compound heterozygosity for a frameshift and a splicing variant (p,Gly1192Cysfs* and c.4857+1G>C) was identified in 2 sibs from a 3rd family.

Expression/functional studies have not been performed for any of the variants reported.

In OMIM, monoallelic CACNA1B are associated with ?Dystonia 23 (MIM 614860) based on the identification of a heterozygous missense (R1389H) mutation in members of a Dutch with myoclonus-dystonia syndrome (Groen et al. 2015 - PMID: 25296916).

As a result, this gene can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.35 P4HTM Konstantinos Varvagiannis gene: P4HTM was added
gene: P4HTM was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: P4HTM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HTM were set to 30940925
Phenotypes for gene: P4HTM were set to Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia
Penetrance for gene: P4HTM were set to Complete
Review for gene: P4HTM was set to GREEN
Added comment: Gene added in the ID panel. Epilepsy is a feature of the disorder.
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Rahikkala et al. (2019 - PMID: 30940925) report on 13 individuals from 5 families with biallelic pathogenic P4HTM variants. 6 of these individuals from a large consanguineous family from Finland were previously reported by the same group, although studies at the time had revealed a 11.5 Mb region of homozygosity with 3 genes within this interval considered to be candidate for the patients' phenotype (P4HTM, TKT, USP4) [Kaasinen et al. - PMID: 25078763].

Common features included Hypotonia (13/13), DD and ID (the latter present in 12/13 individuals with appropriate age for evaluation) and Eye Abnormalities, reason why the acronym HIDEA is suggested for the disorder. Epilepsy was observed in 10 individuals (10/13). Hypoventilation, sleep apnea and dysautonomia were additional features reported.

Muscle biopsies from 4 individuals had variable findings suggestive of disruption of normal mitochondrial function.

Finnish patients were homozygous for a SNV - possibly a founder variant in this population - predicted to lead to a missense change in the canonical transcript (NM_177938.2:c.1073G>A) but causing an in-frame loss of the complete exon 6 of another transcript (NM_177939.2).

The latter transcript (encoding a 502 aa protein) is the prevalent one in fibroblasts/myoblasts instead of the canonical one (563 aa). It is not known whether the canonical transcript is the prevalent in brain tissue although northern blot analysis in a previous study suggested presence of a 2.3 kb mRNA in brain instead of a 1.8 kb observed in other tissues, a finding which may be suggestive of expression of the canonical transcript. [Reviewer's note: In gnomAD based on the pext values from the GTEx, the noncanonical transcript appears to be prevalent in brain regions - https://gnomad.broadinstitute.org/gene/ENSG00000178467]

All variants reported affected both transcripts. All 5 variants have been submitted to LOVD ( https://databases.lovd.nl/shared/variants/P4HTM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 - first author appearing as the submitter).

Overexpression of wt and 3 mutants (His161Pro, Gln352*and Exon6del) in insect cells followed by analysis with SDS-PAGE and western blot revealed severly reduced/abolished fraction of soluble protein for the 3 studied variants suggesting improper protein folding.

Knockout of the gene in mice leads to retinal defects and/or visual impairment in line with eye abnormalites (nystagmus, strabismus, achromic retinal fundi or cortical blindness) being a prominent feature in affected individuals. Mouse studies suggest that this gene is also important for renal function, although kidney problems were not reported in any affected individual.

Overall loss-of-function is suggested to be the underlying mechanism.

P4HTM is not associated with any phenotype in OMIM, nor in G2P. This gene is not (at least commonly) included in gene panels for ID offered by diagnostic laboratories.

As a result P4HTM can be considered for inclusion in the ID and epilepsy panels probably as green (several affected individuals) or amber.
Sources: Literature
Early onset or syndromic epilepsy v1.35 VAMP2 Konstantinos Varvagiannis gene: VAMP2 was added
gene: VAMP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VAMP2 were set to 30929742
Phenotypes for gene: VAMP2 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Autistic behavior; Stereotypic behavior; Seizures; Abnormality of movement; Cortical visual impairment
Penetrance for gene: VAMP2 were set to unknown
Review for gene: VAMP2 was set to GREEN
Added comment: Gene added in the ID panel (comments below). Epilepsy is a feature of this disorder (observed in 3 unrelated individuals, each with different VAMP2 variant).
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Salpietro et al. (2019 - PMID: 30929742 - DDD study among the co-authors) report on 5 individuals each with private heterozygous de novo variants in VAMP2.

The overlapping phenotype consisted among others of hypotonia with DD, moderate/severe ID and ASD (all in 5/5). Other features included the presence of clinical seizures (3/5 - EEG anomalies observed in all individuals), variable Rett-like stereotypies, hyperkinetic movements, central visual impairment. OFC was normal in all subjects.

VAMP2 encodes the vesicular SNARE protein synaptobrevin-2 which - along with its partners (syntaxin-1A and synaptosomal-associated protein 25) - mediates fusion of synaptic vesicles for the release of neurotransmitters. A number of synaptic proteins involved in Ca+2-regulated neurotransmitter release (eg. Munc18 encoded by STXBP1) regulate the fusion of synaptic vesicles, although SNAREs alone are sufficient for this process.

All variants localized in the v-SNARE domain (aa 31-91 - of 116 total residues - NP_0055047.2) with some phenotypic differences between variants localizing in the C-terminal end of the v-SNARE domain compared to those localizing in its proximal part. The following 3 missense variants and 2 in-frame deletions were reported (using NM_014232 as reference): c.223T>C or p.Ser75Pro - c.233A>C or p.Glu78Ala - c.230T>C or p.Phe77Ser - c.128_130delTGG or p.Val43del and c.135_137delCAT or p.Ile45del.

Functional studies were performed for 2 missense variants and were suggestive of impairment in vesicle fusion for the Ser75Pro variant. The fusion profile for Glu78Ala was however similar to wt. Upon Munc18-activated conditions, wt vesicle fusion was 2-fold increased, in contrast to a >90% loss-of-function effect which was observed for the Ser75Pro variant. Munc18 was however able to activate vesicle fusion mediated by the Glu78Ala variant. When using mixed v-liposomes (50:50 Wildtype:Ser75Pro mutant) the fusion profile was identical to the profile of homogeneous samples containing only the mutant protein which was suggestive of dominant interference of the mutant with wildtype.

In gnomAD, VAMP2 has a (low) Z-score and pLI of 1.41 and 0.89 respectively.

The authors comment that mutations in other genes encoding presynaptic proteins involved in Ca+2-regulated neurotransmitter release (eg SNAP25, STXBP1, etc) have been identified in other neurological disorders (with ID as a feature).

VAMP2 is not associated with any phenotype in OMIM or G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories.

As a result, VAMP2 can be considered for inclusion in the ID panel probably as green (5 individuals, degree of ID relevant) or amber.
Sources: Literature
Early onset or syndromic epilepsy v1.35 ASAH1 Sarah Leigh Publications for gene: ASAH1 were set to
Early onset or syndromic epilepsy v1.34 PROSC Chris Buxton commented on gene: PROSC
Early onset or syndromic epilepsy v1.34 NBEA Ivone Leong Classified gene: NBEA as Green List (high evidence)
Early onset or syndromic epilepsy v1.34 NBEA Ivone Leong Gene: nbea has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.33 NBEA Ivone Leong gene: NBEA was added
gene: NBEA was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NBEA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NBEA were set to 30269351; 28554332; 12746398; 12826745; 11450821; 3377648; 23277425; 22109531; 23153818
Phenotypes for gene: NBEA were set to Global developmental delay; Intellectual disability; Seizures; No OMIM number
Review for gene: NBEA was set to GREEN
Added comment: NBEA is not associated with any phenotypes in OMIM or Gene2Phenotype. However, there is sufficient evidence provided by Konstantinos Varvagiannis for this gene to be rated green.

Expert review from Konstantinos Varvagiannis: "PMID: 30269351 is a collaborative study reporting on 24 individuals with pathogenic de novo variants affecting NBEA. All subjects presented with neurodevelopmental disorder including developmental delay or intellectual disability. Half of the patients (12/24) had autistic features or autism. Epilepsy was a feature in 15/24 (62.5%) of patients with onset before the age of 4 years in the majority (approx. 85%). Of the 15 patients with seizures, 80% presented with generalized seizures of variable type (myoclonic, atonic and/or myoclonic-atonic, absence, tonic, clonic or tonic-clonic), 6.67% with focal seizures only and 13.33% with unclassified seizure type. Other features included developmental microcephaly (or borderilne microcephaly) in 3/24 individuals or developmental regression in 2/24. Among the variants identified: 8/24 were stopgain SNVs 5/24 were frameshift 4/24 were missense SNVs 1/24 was a splice site SNV 5/24 concerned an intragenic NBEA deletion 1/24 concerned a 2.87 Mb deletion spanning NBEA as well as additional genes (none of latter associated with disease in OMIM). Two of these individuals were reported in a previously published study of children with DD/ID (PMID: 28554332). Individuals with developmental disorders and de novo coding mutations in NBEA have been reported in further publications including the DDD study (PMID: 28135719 - subject DDD4K.01714), most summarized in the denovo-db (http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=NBEA). As also commented in the article, a patient with autism and a de novo balanced translocation disrupting NBEA has been reported (PMID: 12746398) as has also been the case with other deletions spanning NBEA (PMIDs: 12826745, 11450821, 3377648). Previous studies have suggested a role for NBEA in regulation of synaptic structure and function (PMID: 23277425,22109531) as well as a role of neurobeachin in autism-like behaviors in mice (PMID: 23153818). NBEA is intolerant to loss-of-function mutations (pLI=1 in ExAC). Most variants in the study predict loss-of-function. As a result happloinsufficiency seems to be the underlying mechanism. As the authors propose, loss-of-function variants might be associated with more specific (eg. microcephaly or myoclonic-atonic seizures) or severe phenotypic presentations, although the size of the cohort did not not allow safe conclusions. // NBEA is included in DD/ID (but not epilepsy) gene panels offered by different diagnostic labs. // As a result this gene can be considered for inclusion as green in the intellectual disability and epilepsy panels."
Sources: Expert list
Early onset or syndromic epilepsy v1.32 MPDU1 Rebecca Foulger Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If, 609180 to Congenital disorder of glycosylation, type If, 609180; seizures
Early onset or syndromic epilepsy v1.31 KMT2E Konstantinos Varvagiannis gene: KMT2E was added
gene: KMT2E was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KMT2E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT2E were set to https://doi.org/10.1101/566091
Phenotypes for gene: KMT2E were set to Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size
Penetrance for gene: KMT2E were set to unknown
Review for gene: KMT2E was set to GREEN
Added comment: Gene added in the ID panel (comments below). Epilepsy was a feature in - at least - 11 individuals (with all categories of variants : 4 with truncating, 3 with CNVs, 4 with missense SNVs). As a result this gene can be considered for inclusion in the current panel as green (or amber).

From the ID panel :

In a collaborative study, O'Donnell-Luria et al. (2019 - https://doi.org/10.1101/566091 - DDD study among the co-authors) report on 38 individuals from 36 families with heterozygous KMT2E variants. Some of these individuals were previously included in previous publications.

Developmental delay, intellectual disability, epilepsy and ASD were among the features reported, albeit of variable degree and not universal.

34 of 38 individuals had SNVs or indel variants in KMT2E and 4 individuals had CNVs spanning KMT2E (in one case intragenic, in 3 further as a contiguous gene deletion).

For 26 (of 38 individuals) the variant had arisen as a de novo event while in some cases parental sample(s) was/were unavailable to confirm the de novo occurrence or origin (from a reportedly affected parent). The variant in one family was inherited from a parent for whom information on affected/unaffected status was unavailable.

As for the variants reported: 30 were protein-truncating (of which 23 predicted to produce transcripts subject to NMD). 4 were missense. 4 were CNVs (de novo deletions, of which 1 intragenic).

Truncating variants and deletions of KMT2E suggest haploinsufficiency as the underlying mechanism for this category of variants (KMT2E has a pLI of 1 in gnomAD).

However, the somewhat different phenotype related to missense variants (degree of ID, epilepsy in all, microcephaly in some versus macrocephaly in subjects with truncating variants) may suggest a different mechanism for these variants eg. gain of function or dominant negative effect. There was no clustering observed for the missense variants reported.

Expressivity of certain features may be variable between males and females.

As the authors note : KMT2E encodes a member of the lysine N-methyltransferase 2 family, a family of enzymes with critical role in H3K4 methylation. It is highly expressed in brain, particularly during fetal development. Several monogenic neurodevelopmental disorders due to impaired regulation of H3K4 methylation are known (eg. due to KMT2D/C/B/A mutations, etc). Studies suggest that KMT2E may lack intrinsic methyltransferase activity although it may have an indirect effect on H3K4 methylation. In contrast to other members of the KMT2 family functioning as global activators of open chromatin, KMT2E is believed to be a repressor (although it's function in gene transcription regulation needs to be clarified).

A neurological phenotype of Kmt2e (Mll5) deficiency mouse models has not been reported (features included growth restriction, impaired hematopoiesis, etc).

KMT2E is not associated with any phenotype in OMIM. The gene is included in the DD panel of G2P, associated with Intellectual disability (disease confidence: confirmed / mutation consequence registered in the db : LoF).
KMT2E is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study).

As a result, this gene can be considered for upgrade to green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.31 MACF1 Rebecca Foulger Phenotypes for gene: MACF1 were changed from Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia; Lissencephaly 9 with complex brainstem malformation, 618325
Early onset or syndromic epilepsy v1.30 ATN1 Konstantinos Varvagiannis gene: ATN1 was added
gene: ATN1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATN1 were set to 30827498
Phenotypes for gene: ATN1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney
Penetrance for gene: ATN1 were set to unknown
Mode of pathogenicity for gene: ATN1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: ATN1 was set to GREEN
Added comment: Apart from CAG repeat expansions (green in the present panel) seizures have been reported in individuals with mutations in the HX repeat motif (5 unrelated individuals, each with a private variant).

As a result, ATN1 can be considered for inclusion in the Epilepsy panel as green (or amber).

Copied from the ID panel :

Palmer et al. (2019 - PMID: 30827498) report on 8 individuals all harboring de novo missense or insertion variants within a 16-amino-acid HX repeat motif (aa 1150-1065 / 8 HX repeats, where H is histidine and X any amino acid) in exon 7 of ATN1. The specific motif is distal to the Gln-rich region involved in Dentatorubro-pallidoluysian atrophy (caused by polyglutamine expansion in exon 5, due to a probable toxic GoF effect - MIM #125370). None of the subjects reported presented features of the latter disorder.

Common features included hypotonia (8/8) , DD and/or ID (8/8). Other frequent features included visual or hearing impairment, seizures (5/8 - in most presenting as neonatal/infantile onset dev. encephalopathy), feeding difficulties/functional GI disorders. Some individuals presented with congenital anomalies eg. cardiac, cleft palate, renal anomalies, anteriorly placed anus. Some facial (eg. presence of tall forehead, bitemporal narrowing, deep set eyes, sparse lateral hair, bulbous nose, open mouth appearance ,etc) or features of the extremities (overlapping fingers/toes) were also common.

Converging evidence from the literature suggests that ATN1 is a nuclear transcriptional regulator important in the control of brain and other organ development (PMIDs cited: 17150957, 25519973, 10973986). The gene is widely expressed in various tissues incl. brain, heart, lung, kidney, skeletal muscle. Expression is higher in fetal tissues particularly in brain while the gene is broadly expressed in multiple regions of the adult human brain (PMID: 7485154).

All 8 variants were missense SNVs or insertions within the HX repeat motif (aa 1150-1065) and had occurred as de novo events: c.3160C>A or p.His1054Asn, c.3172C>T or p.His1058Tyr, c.3177_3178insAACCTG or p.Ser1059_His1060insAsnLeu, c.3177_3178insGACCTG or p.Ser1059_His1060insAspLeu, c.3178C>T or p.His1060Tyr, c.3184C>G or p.His1062Asp, c.3188T>G or p.Leu1063Arg, c.3185A>G or p.His1062Arg [NM_001007026.1].

NMR studies of 2 commercialy synthesized polypeptides containing residues 1046-1067 of ATN1 and the HX motif suggested disruption in the case of His1060Tyr of the spatial and dynamical synchronization of histidines which is favored by the regularly spaced occurrence of histidines in the wild-type sequence. Under specific conditions introduction of His1060Tyr allowed zinc binding, which was not the case for the wild-type peptide, thus conferring the peptide a novel property (the consequences of which are though unknown). Clustering of the variants and presence of LoF in healthy individuals (eg. in gnomAD db) suggests that haploinsufficiency is unlikely.

Similar (HX)n repeat motifs exist in other proteins, among others RERE or AUTS2 which are associated with neurodevelopmental disorders. The authors comment that disruption of the HX motif in RERE has been reported in affected individuals and that mutations occurring in this motif are more likely to be associated with congenital anomalies, compared to mutations in the rest of the protein.

As for animal models, Atn1 -/- mice are neurologically normal. Knockdown of the gene in rat neuronal progenitor cells led to anomalies in brain development, though these could be rescued by co-transfection with human ATN1 construct (PMIDs cited: 17150957, 25519973).
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In OMIM, heterozygous pathogenic CAG trinucleotide expansions in ATN1 are associated with DRPLA (MIM #125370). The gene is not associated with any phenotype in G2P.
Sources: Literature
Early onset or syndromic epilepsy v1.30 TRRAP Konstantinos Varvagiannis gene: TRRAP was added
gene: TRRAP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures
Penetrance for gene: TRRAP were set to unknown
Mode of pathogenicity for gene: TRRAP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TRRAP was set to AMBER
Added comment: Cogné et al. (DDD study among the co-authors - PMID: 30827496) report on 24 individuals with pathogenic TRRAP variants.

17 different variants were reported. All variants were missense SNVs and on most occasions had occurred as de novo or apparently de novo events (paternity and maternity not checked). On one occasion, a parent was not unavailable although the respective grand-parents were not found to harbor the variant. Parental germline mosaicism explained the occurence of a variant in 2 sibs.

The authors suggest a strong genotype-phenotype correlation. Individuals whose variant localized within the residues 1031-1159 (NM_001244580.1) presented with a syndromic form of ID with additional malformations. ID was a universal feature in this group (for those subjects evaluated). For variants outside this cluster of residues the phenotype was rather that of ASD without ID or isolated ID with or without ASD, albeit with some exceptions (eg. F860L also associated with a syndromic presentation). ID was a feature in the majority of individuals belonging to the latter group (67% - all with DD) or overall irrespective of the variant localization (85% for those evaluated - all with DD).

** Epilepsy was a feature in 4 individuals (4/24) belonging to either group. **

All 17 variants were absent from gnomAD with CADD scores supporting a deleterious effect (SIFT/PolyPhen2 (both) predicted a tolerated/benign effect for some eg. Ala1043Thr). A few variants were recurrent, namely Ala1043Thr (5 individuals), Glu1106Lys (2), Gly1883Arg (2), Pro1932Leu (in 2 sibs).

6 further subjects (individuals 25-30, reported separately in the supplement) harbored 6 additional variants with lesser evidence for pathogenicity.

TRRAP is among the 5 most intolerant genes to missense mutations (z-score of 10.1 in ExAC) while it is also intolerant to LoF variants (pLI of 1). No deletions have been reported in DECIPHER and no LoF were identified in the study. Given type of variants and their clustering rather a gain-of-function effect or dominant-negative effect is suggested. As the authors note a LoF effect of non-clustering variants, associated with a milder phenotype cannot excluded. [Mode of pathogenicity to change if thought to be useful].

TRRAP encodes a protein involved in the recruitment to chromatin of histone acetyltransferases. The latter control the process of acetylation of lysine residues in histones and other DNA-binding proteins thus playing a major role in regulation of gene expression. In line with this, RNA sequencing analysis in skin fibroblasts from affected subjects demonstrated dysregulation of expression for several genes implicated in neuronal function and ion transport.

As summarized by the authors: In mice, Trapp knockout is embryonically lethal. Brain-specific knockout leads to premature differentiation of neural progenitors and abnormal brain development. Brain atrophy and microcephaly are observed (microcephaly was a feature in some affected individuals as well, primarily those with variants affecting residues 1031-1159). [PMIDs cited: 11544477, 24792116].

De novo TRRAP variants have been reported also in individuals with neuropsychiatric disorders (PMIDs: 21822266, 23042115, 28392909, 30424743) while TRRAP has been classified among the prenatally-biased genes relevant to its brain expression (PMID:23042115).

A de novo missense variant (c.11270G>A or p.R3757Q) was also previously reported in a study of 264 individuals with epileptic encephalopathy (Epi4K Consortium - PMID: 23934111 - indiv. ND29352).
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TRRAP is not associated with any phenotype in OMIM, nor in G2P.
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As a result, this gene can be considered for inclusion in the epilepsy panel as amber or green.
Sources: Literature
Early onset or syndromic epilepsy v1.30 FUK Louise Daugherty commented on gene: FUK
Early onset or syndromic epilepsy v1.30 FUK Louise Daugherty Tag new-gene-name tag was added to gene: FUK.
Early onset or syndromic epilepsy v1.30 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.30 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.29 NUS1 Eleanor Williams Added comment: Comment on mode of inheritance: A single family with a biallelic pattern is also reported. Further cases advised to confirm MOI.
Early onset or syndromic epilepsy v1.29 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.28 NUS1 Eleanor Williams commented on gene: NUS1: Following review by the Genomics England clinical team it was decided to rate this gene amber on the Genetic epilepsy syndromes panel at this time. Evidence is most compelling for an epilepsy phenotype associated with heterozygous LOF de novo variants at present.
Early onset or syndromic epilepsy v1.28 NUS1 Eleanor Williams commented on gene: NUS1: NUS1 is associated with Mental retardation, autosomal dominant 55, with seizures (AD inheritance) and ?Congenital disorder of glycosylation, type 1aa (AR inheritance) in OMIM. It is associated with Epilepsy and intellectual disability in Gene2Phenotype (probable) with monoallelic inheritance.

PMID: 25066056 (Park et al 2014) - 2 sibs, born of unrelated Czech parents of Roma descent, with congenital disorder of glycosylation type Iaa - a homozygous missense mutation in the NUS1 gene (p.Arg290His (R290H), which is located in the evolutionarily conserved C-terminal domain of NgBR) . The siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. Functional studies with WT and mutant fibroblasts show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR.

PMID: 29100083 (Hamdan et al 2017) - performed whole-genome sequencing (WGS) on 197 developmental and epileptic encephalopathy individuals and their unaffected parents. 3 unrelated individuals identified with de novo changes in NUS1 - p.Asp248Alafs), p.Val48Profs)∗7, exon 2 deletion. All had seizures and mild to severe ID.
Early onset or syndromic epilepsy v1.28 NUS1 Eleanor Williams gene: NUS1 was added
gene: NUS1 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: NUS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function
Review for gene: NUS1 was set to AMBER
Added comment: Adding NUS1 to this panel following review of the gene by Konstantinos Varvagiannis on the Intellectual Disability panel https://panelapp.genomicsengland.co.uk/panels/285/gene/NUS1/.
Sources: Expert Review
Early onset or syndromic epilepsy v1.27 CTNNA2 Louise Daugherty Classified gene: CTNNA2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.27 CTNNA2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Early onset or syndromic epilepsy v1.27 CTNNA2 Louise Daugherty Gene: ctnna2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.26 CTNNA2 Louise Daugherty Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 4, 618174 to Cortical dysplasia, complex, with other brain malformations 4, 618174, seizures
Early onset or syndromic epilepsy v1.25 CTNNA2 Louise Daugherty commented on gene: CTNNA2
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Classified gene: SMARCC2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green following review from Konstantinos Varvagiannis highlighting recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with harbouring one of 13 heterozygous pathogenic SMARCC2 variants, with seizures reported in 4 of the individuals. Therefore sufficient unrelated cases of seizures in this paper for diagnostic-rating. Konstantinos Varvagiannis notes that SMARCC2 is not yet associated with a phenotype in OMIM or Gene2Phenotype, but this is most likely because the 2019 paper PMID:30580808 has not yet been curated in these databases.
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Gene: smarcc2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.24 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Early onset or syndromic epilepsy v1.23 SMARCC2 Rebecca Foulger Added comment: Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Early onset or syndromic epilepsy v1.23 SMARCC2 Rebecca Foulger Mode of inheritance for gene: SMARCC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.22 SMARCC2 Rebecca Foulger Added comment: Comment on publications: PMID:27392482 (Tuoc et al., 2017, demonstrating a mouse model of learning and memory as included in the review by Konstantinos Varvagiannis) use BAF170 nomenclature; BAF170 is a synonym of SMARCC2.
Early onset or syndromic epilepsy v1.22 SMARCC2 Rebecca Foulger Publications for gene: SMARCC2 were set to 27392482
Early onset or syndromic epilepsy v1.21 WARS2 Konstantinos Varvagiannis gene: WARS2 was added
gene: WARS2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS2 were set to 28236339; 28650581; 28905505; 29783990; 29120065
Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710
Penetrance for gene: WARS2 were set to unknown
Review for gene: WARS2 was set to GREEN
Added comment: Several individuals with biallelic pathogenic WARS2 variants have been published to date. DD and ID have been reported among others in most of the affected individuals (only the respective features are commented on below):

PMID: 28236339 (Musante et al. 2017) : 2 sibs compound heterozygous for NM_201263.2:c.325delA (p.Ser109Alafs*159) and c.37T>G (p.Trp13Gly). DD with ID were features in both.

PMID: 28650581 (Theisen et al. 2017) : The authors report on 1 individual with DD, ID and seizures was found to harbor in the compound heterozygous state NM_0158360.3:c.938A>T (p.K313M) and c.298_300delCTT (p.L100del).

PMID: 28905505 (Wortmann et al. 2017) : Details on 6 individuals from 5 unrelated families are provided. DD and ID were observed in 5 of these individuals (Fam 2-5). Severe, neonatal presentation was the case for an additional subject. Confirmed occurrence of epilepsy was reported for 3 individuals from 2 families (and suspected in a further one). Using NM_0158360.3 variants were the following :
Fam1 : c.91-8725_348+27113del36096 (p.Lys31_Glndel116) in trans with c.1045G>C (p.Val349Leu)
Fam2 : c.797del (p.Pro266Argfs*10) in trans with c.938A>T (p.Lys313met) [in 2 individuals]
Fam3 : c.231C>G (p.His77Gln) in trans with c.1054G>A (p.Glu352Lys)
Fam4 : c.532G>C (p.Val178Leu) in homozygous state
Fam5 : c.134G>T (p.Gly45Val) in trans with c.938A>T (p.Lys313Met)

PMID: 29783990 (Vantroys et al. 2018) : The authors report on 1 individual with DD, ID and seizures (among other features), compound heterozygous for c.797del (p.Pro266Argfs*10) and c.938A>T (p.Lys313met), similar to subjects from family 2 in PMID: 28905505.

PMID: 29120065 (Burke et al. 2018) : One 17-year-old boy with infantile-onset Parkinsonism but not DD/ID is described in this study. This individuals was found to harbor in the following variants in the compound heterozygous state: NM_015836.3: c.37T>G (p.Trp13Gly) and c.683C>G (p.Ser228Trp).

Probably 7 missense variants, 3 frameshift ones and an intragenic deletion have been reported in individuals with DD/ID (overview in fig 4. - in PMID: 29783990).
- p.Pro266Argfs*10 is located in the last exon of the gene (NM_015836.3).
- p.Trp13Gly (c.37T>G using either NM_201263.2 or NM_015836.3 as ref) has been commented to be a functional polymorphism 'uncovered' by the presence of a LoF allele in trans in affected individuals (AF : 0.003265 and 6 homozygotes in gnomAD)
- p.Lys313Met is possibly the most frequently reported variant as discussed by Vantroys et al.

WARS2 encodes mitochondrial tryptophanyl-tRNA synthetase (a cytoplasmic form is encoded by WARS). As commented in most of the articles, aminoacyl-tRNA synthetases (ARS) are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in mitochondrial ARSs lead to impaired intramitochondrial translation affecting OXPHOS complexes (with mitochondrial-encoded subunits). Mutations in all 19 mitochondrial ARSs have been linked to disorders affecting different organ systems with variable severity and phenotypic presentation (summarized by Vantroys et al.).

Several lines of evidence have been provided to support a role for specific variants (eg. reduced WARS2 amounts upon Western blot, or impaired mitochondrial localization depending on the different variants and their effect) or WARS2 (expression in brain, impaired aminoacylation, abnormalities in OXPHOS enzymes/biosynthesis , etc).

Alternative causes (disorders of the differential diagnosis) have been ruled out on most - if not all - occasions.

As commented by Wortmann et al. the clinical spectrum appears to be broad as for the age of onset, features and clinical course (as happens to be the case for some other disorders due deficiencies of other ARSs). The same authors state that apart from elevated lactate which is suggestive of mitochondrial dysfunction, no specific metabolite was found to be altered in affected individuals.

Phenotypic variability even between individuals with the same genotype has been reported. Eg. severe neonatal presentation with lactic acidosis/hypoglycaemia was the case for 2 sibs in family 2 from Wortmann et al. but the clinical course was different for the subject reported by Vantroys et al. (DD/ID with seizure onset at the age of 6 yrs).

As a result, investigations (and selection of gene panel) may not be straightforward.

In addition consideration of this gene in the epilepsy panel seems to be relevant given that seizures were noted in at least 5 individuals (from 4 families - 28650581, 28905505, 29783990) and severe adverse effects of valproate administration occurred in the subject reported by Vantroys et al.
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The associated phenotype in OMIM is Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (# 617710). WARS2 is not associated with any disorder in G2P.
This gene is included in panels for ID offered by some diagnostic laboratories.
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As a result, WARS2 can be considered for inclusion in the ID and epilepsy panels as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.21 ZDHHC9 Deb Pal gene: ZDHHC9 was added
gene: ZDHHC9 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ZDHHC9 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZDHHC9 were set to 26000327
Phenotypes for gene: ZDHHC9 were set to intellectual disability; epilepsy
Penetrance for gene: ZDHHC9 were set to unknown
Review for gene: ZDHHC9 was set to GREEN
gene: ZDHHC9 was marked as current diagnostic
Added comment: Amplexa CHE-114 epilepsy panel
Sources: Literature
Early onset or syndromic epilepsy v1.21 SMC1A Deb Pal reviewed gene: SMC1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28677859, 28548707, 28166369, 26752331, 26386245, 26358754; Phenotypes: Rett-like phenotype; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Early onset or syndromic epilepsy v1.21 SLC35A3 Deb Pal reviewed gene: SLC35A3: Rating: RED; Mode of pathogenicity: None; Publications: 28328131; Phenotypes: epilepsy, arthrogryposis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.21 SLC35A2 Deb Pal reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30746764, 30584598, 29679388, 27743886, 24115232; Phenotypes: epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.21 PIGQ Deb Pal reviewed gene: PIGQ: Rating: RED; Mode of pathogenicity: None; Publications: 24463883; Phenotypes: epilepsy, Ohtahara syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.21 NPRL2 Deb Pal reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30093711; Phenotypes: epilepsy, intellectual disability, focal cortical dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.21 KCNT2 Deb Pal gene: KCNT2 was added
gene: KCNT2 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNT2 were set to 29740868; 29069600
Phenotypes for gene: KCNT2 were set to epilepsy
Penetrance for gene: KCNT2 were set to unknown
Review for gene: KCNT2 was set to GREEN
gene: KCNT2 was marked as current diagnostic
Added comment: Amplexa CHE-114 epilepsy panel
Sources: Expert list
Early onset or syndromic epilepsy v1.21 KCNMA1 Deb Pal reviewed gene: KCNMA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.21 KCNH5 Deb Pal gene: KCNH5 was added
gene: KCNH5 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH5 were set to 23647072
Phenotypes for gene: KCNH5 were set to epilepsy
Penetrance for gene: KCNH5 were set to unknown
Review for gene: KCNH5 was set to RED
gene: KCNH5 was marked as current diagnostic
Added comment: Amplexa CHE-114 epilepsy panel
Sources: Expert list
Early onset or syndromic epilepsy v1.21 KCND2 Deb Pal gene: KCND2 was added
gene: KCND2 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND2 were set to 24501278
Phenotypes for gene: KCND2 were set to autism; epilepsy
Penetrance for gene: KCND2 were set to unknown
Review for gene: KCND2 was set to RED
gene: KCND2 was marked as current diagnostic
Added comment: Amplexa CHE-114 epilepsy panel
Sources: Expert list
Early onset or syndromic epilepsy v1.21 AIMP2 Louise Daugherty Classified gene: AIMP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.21 AIMP2 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene currently as Amber
Early onset or syndromic epilepsy v1.21 AIMP2 Louise Daugherty Gene: aimp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.20 AIMP2 Louise Daugherty Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17 (MIM 618006) to Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Early onset or syndromic epilepsy v1.19 SLC35A1 Rebecca Foulger commented on gene: SLC35A1: Removed watchlist tag after promotion of SLC35A1 to Green.
Early onset or syndromic epilepsy v1.19 SLC35A1 Rebecca Foulger Tag watchlist was removed from gene: SLC35A1.
Early onset or syndromic epilepsy v1.19 SLC35A1 Rebecca Foulger Classified gene: SLC35A1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.19 SLC35A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following clinical agreement from Helen Brittain: A recent PMID:30115659 paper (Kauskot et al. 2018) provides a third SLC35A1 case with a seizure phenotype (the first two cases coming from PMID:23873973 and PMID:28856833).
Early onset or syndromic epilepsy v1.19 SLC35A1 Rebecca Foulger Gene: slc35a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.18 SLC35A1 Rebecca Foulger commented on gene: SLC35A1
Early onset or syndromic epilepsy v1.18 SLC35A1 Rebecca Foulger Phenotypes for gene: SLC35A1 were changed from Congenital disorder of glycosylation, type IIf 603585 to Congenital disorder of glycosylation, type IIf, 603585; seizures
Early onset or syndromic epilepsy v1.17 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973; 15576474; 28856833
Early onset or syndromic epilepsy v1.16 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Added watchlist tag.
Early onset or syndromic epilepsy v1.16 SLC35A3 Rebecca Foulger Tag watchlist tag was added to gene: SLC35A3.
Early onset or syndromic epilepsy v1.16 SLC35A3 Rebecca Foulger Classified gene: SLC35A3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.16 SLC35A3 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Green by Konstantinos Varvagiannis. 1 case (multiple individuals from Ashkenazi Jewish kindred) in PMID:24031089 with epilepsy in many individuals. A second epilepsy case comes from PMID:28328131 (Marini et al. 2017). Epilepsy is not recorded in the SLC35A3‐related skeletal dysplasia patient from PMID:28777481 who died at 21days. ClinVar submissions weren't included as additional cases as individual phenotypes were not recorded. Therefore rated Amber awaiting further published or clinical cases.
Early onset or syndromic epilepsy v1.16 SLC35A3 Rebecca Foulger Gene: slc35a3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.15 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: The 2013 (SCV000108589.2) and 2016 (SCV000699337.1) ClinVar submissions reported in the review by Konstantinos Varvagiannis link to the same publication: Edvardson et al. (2013, PMID:24031089).
Early onset or syndromic epilepsy v1.15 SLC35A3 Rebecca Foulger Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553) to ?Arthrogryposis, mental retardation, and seizures (MIM 615553); Early onset epileptic encephalopathy with skeletal defects
Early onset or syndromic epilepsy v1.14 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Marini et al. 2017 (PMID: 28328131) provide a second case. They report a non-consanguineous Italian family with two siblings manifesting severe EE. Both siblings exhibited infantile spasms associated with focal and tonic seizures from early infancy. In addition, both had quadriplegia, acquired microcephaly and severe ID. WGS identified novel compound het variants in SLC35A3 in both children.
Early onset or syndromic epilepsy v1.14 SLC35A3 Rebecca Foulger commented on gene: SLC35A3
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Classified gene: PAK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. 2 cases to date. Appears to be gain of function. Both missense variants.
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Gene: pak1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.13 PAK1 Eleanor Williams commented on gene: PAK1
Early onset or syndromic epilepsy v1.13 LSS Konstantinos Varvagiannis gene: LSS was added
gene: LSS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 30723320
Phenotypes for gene: LSS were set to Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly
Penetrance for gene: LSS were set to unknown
Review for gene: LSS was set to AMBER
Added comment: Epilepsy was observed in at least 6 individuals from 4 unrelated families (7 different variants). However other individuals with biallelic LSS mutations and primarily neuroectodermal phenotype or others (hypotrichosis or congenital cataract) did not manifest seizures. As a result this gene can be considered for inclusion possibly as amber.

Copied from the ID panel (only the relevant publication included here):
DD and ID seem to be among the features observed in some individuals with biallelic LSS mutations, although the clinical presentation appears to be highly variable.

PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants. One additional subject from a seventh family was found to harbor only a missense SNV (in the maternal allele) while the transcript corresponding to the other (/paternal) allele was less expressed upon RNA studies from patient fibroblasts. The allelic imbalance and the phenotypic overlap with the other individuals of the study were thought to be explained by an LSS defect.

The phenotype consisted of total alopecia (11/11) with additional dermatological features in most (9/11), hypotonia (7/11), DD with variable degrees of ID (11/11 both), epilepsy (8/11), microcephaly and genital anomalies in few. Cataracts were not noted in any individuals. The authors suggest that the phenotype corresponds to that observed in a neuroectodermal syndrome previously known as APMR (alopecia with mental retardation - other genes or loci earlier proposed).

Variants included: 7 missense SNVs, 1 nonsense, 1 frameshift, 2 splice variants (c.1109+2T>C / c.1194+5G>A - using NM_002340.5).

Using a minigene assay the latter variants were confirmhed (both) to affect splicing, at least to some important extent. However the splicing defect for one SNV (c.1194+5G>A - skipping of exon 12) was not confirmed upon RNA studies from blood samples of the respective individuals but an allelic balance in favor of the other allele instead (due to presumed utilisation of an alternative splice site, introduction of a premature stop codon and NMD).

Allelic imbalance is discussed for the individual with the single LSS variant but not shown.

Variants did not show clustering (also upon 3D modelling).

Lanosterol synthase converts (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Quantification of cholesterol and its precursors in affected individuals did not however reveal any important imbalance.

As most individuals harbored an allele with missense variant, and mice homozygous for an allele with absent LSS activity show variable lethality, residual LSS activity is suggested for the individuals studied.

Several other disorders affecting cholesterol biosynthesis present overlapping features eg. DD/ID in Lathosterolosis, Desmosterolosis, Smith-Lemli-Opitz syndrome (in this case also genital anomalies), etc or cutaneous anomalies in others.

A neurodevelopmental phenotype in animal models for LSS deficiency is not commented.
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Based on the discussion of the current article (and OMIM):

Earlier studies [PMIDs : 26200341, 29016354 - Zhao et al 2015 and Chen and Liu 2017 respectively] found biallelic missense in individuals with congenital cataracts. DD/ID were not commented/observed. The subject reported by Chen had baldness and genital defects. Shumiya cataract rats due to mutation in Lss gene recapitulate the specific human phenotype [PMID: 16440058 and OMIM]. Cataract was not a feature in any of the individuals of the present study. The corresponding entry for this phenotype in OMIM is Cataract 44 (#616509).

PMID: 30401459 [Romano et al, 2018] reported biallelic LSS mutations in 3 unrelated families with hypotrichosis. Intellectual disability was a feature in 2 sibs from 1 non-consanguineous family (among the three). ID was considered to be coincidental by the authors. The respective entry in OMIM is Hypotrichosis 14 (#618275).
Sources: Literature
Early onset or syndromic epilepsy v1.13 GATM Deb Pal reviewed gene: GATM: Rating: RED; Mode of pathogenicity: None; Publications: 26490222; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.13 GABRD Deb Pal reviewed gene: GABRD: Rating: RED; Mode of pathogenicity: None; Publications: 15115768; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.13 CUX2 Deb Pal reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29630738; Phenotypes: infantile onset myoclonic DEE; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.13 CACNB4 Deb Pal reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: 20561025, 20378313, 10762541; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.13 CACNA1A Deb Pal reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11564488, 20071244, 15452324; Phenotypes: Absence epilepsy, Familial hemiplegic migraine 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.13 ATP1A2 Deb Pal edited their review of gene: ATP1A2: Changed publications: 18028407, 9579893, 12953268
Early onset or syndromic epilepsy v1.13 ATP1A2 Deb Pal reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18028407; Phenotypes: Familial hemiplegic migraine, Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v1.13 NECAP1 Konstantinos Varvagiannis reviewed gene: NECAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24399846, 30525121, 30626896; Phenotypes: ?Epileptic encephalopathy, early infantile 21, 615833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.13 ISPD Louise Daugherty commented on gene: ISPD
Early onset or syndromic epilepsy v1.13 ISPD Louise Daugherty Tag new-gene-name tag was added to gene: ISPD.
Early onset or syndromic epilepsy v1.13 USP7 Konstantinos Varvagiannis gene: USP7 was added
gene: USP7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: USP7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: USP7 were set to 26365382; 19946331
Phenotypes for gene: USP7 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Seizures; Abnormality of brain morphology; Hypogonadism
Penetrance for gene: USP7 were set to unknown
Review for gene: USP7 was set to GREEN
Added comment: Fountain et al. (2019 - doi.org/10.1038/s41436-019-0433-1 - PMID: NA) report on 23 individuals, all of whom harbored pathogenic de novo variants affecting USP7.

Variants included 8 deletions spanning USP7 (and other proximal genes - the gene is located at 16p13.2), 4 nonsense, 8 missense and 3 splice site mutations.

Haploinsufficiency appears to be the underlying mechanism (as suggested by the type of variants reported).

The common phenotype consisted of DD/ID (almost universal feature - 22/23) with prominent speech delay (23/23). Other features included seizures (10/22 - seen in all categories of USP7 variants), variable behavioral anomalies (incl. aggressive behavior, temper tantrums, ASD, ADHD), brain MRI abnormalities, as well as hypogonadism in some.

7 of these (23) individuals (6 with deletions, 1 with nonsense variant) were previously reported by the same group (2015 - Hao et al. - PMID: 26365382). In this study, the authors provided evidence that USP7 encodes a deubiquitinating enzyme, component of the MAGEL2/TRIM27 ubiquitin ligase complex. USP7 is involved in fine-tuning of the WASH activity - a protein involved in endosomal actin assembly and protein recycling - by promoting or limiting WASH ubiquitination (the former achieved by preventing TRIM27 autoubiquitination and degradation and the latter by direct WASH deubiquitination).

Overlap to some extent of the USP7-related phenotype with Schaaf-Yang syndrome (due to MAGEL2 mutations - MIM615547) is suggested.

In mice, Usp7 (or Hausp - herpesvirus-associated ubiquitin-specific protease) conditional knockout in brain results in neonatal lethality (PMID cited: 19946331).
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USP7 is not associated with any phenotype in OMIM.
This gene is part of the DD panel of G2P, associated with "Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism" (Disease confidence: possible).
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As a result, this gene can be considered for inlusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.13 CYFIP2 Konstantinos Varvagiannis reviewed gene: CYFIP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29534297, 29667327, 30664714; Phenotypes: Epileptic encephalopathy, early infantile 65, 618008; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.13 DHPS Konstantinos Varvagiannis gene: DHPS was added
gene: DHPS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHPS were set to 21389784; 21850436
Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck
Penetrance for gene: DHPS were set to Complete
Review for gene: DHPS was set to GREEN
Added comment: Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS.

The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features.

Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing.

All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference].

Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2).

eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article).

Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders.

Concerning the DHPS variants reported:

cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site.

The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells).

In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells.

Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436).
---------
DHPS is not associated with any phenotype in G2P, nor in OMIM.
---------
As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.13 ZMIZ1 Konstantinos Varvagiannis gene: ZMIZ1 was added
gene: ZMIZ1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843
Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck; Seizures
Penetrance for gene: ZMIZ1 were set to unknown
Review for gene: ZMIZ1 was set to AMBER
Added comment: Gene added in the ID panel. Seizures were noted in 3 unrelated individuals (with different variants) of the 19 reported to date. If the proportion of individuals with this feature is sufficient then this gene can be considered for inclusion in this panel.

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From the ID panel:

Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10).

Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants).

Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations.

In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report.

One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769).

The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors.

ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators.

Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain.

This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization.

As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients.

Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel].
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One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843).
[ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ]
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ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P.
This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories.
------------
As a result, ZMIZ1 can be considered for inclusion in the ID panel as green.
Sources: Literature
Early onset or syndromic epilepsy v1.13 CLN6 Louise Daugherty Phenotypes for gene: CLN6 were changed from to Ceroid lipofuscinosis, neuronal, 6, 601780; Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, 204300
Early onset or syndromic epilepsy v1.12 GLRA1 Louise Daugherty Phenotypes for gene: GLRA1 were changed from Hyperekplexia 1 149400 to Hyperekplexia, hereditary 1, 149400; Hyperekplexia; developmental delay; infantile spasms and generalized tonic-clonic seizures
Early onset or syndromic epilepsy v1.11 GLRB Louise Daugherty Phenotypes for gene: GLRB were changed from Hyperekplexia 2 614619 to Hyperekplexia 2, 614619
Early onset or syndromic epilepsy v1.10 HEXA Louise Daugherty Phenotypes for gene: HEXA were changed from Tay-Sachs disease, 272800 to GM2-gangliosidosis, several forms, 272800; Tay-Sachs disease, 272800
Early onset or syndromic epilepsy v1.9 HEXB Louise Daugherty Mode of inheritance for gene: HEXB was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.8 HEXB Louise Daugherty Publications for gene: HEXB were set to
Early onset or syndromic epilepsy v1.7 HEXB Louise Daugherty Phenotypes for gene: HEXB were changed from to Sandhoff disease, infantile, juvenile, and adult forms, 268800
Early onset or syndromic epilepsy v1.6 RNF13 Konstantinos Varvagiannis gene: RNF13 was added
gene: RNF13 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment
Penetrance for gene: RNF13 were set to unknown
Mode of pathogenicity for gene: RNF13 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RNF13 was set to GREEN
Added comment: Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants.

Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment.

One individual harbored the p.Leu311Ser variant while 2 others the p.Leu312Pro.

RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor.

The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser:
- Protein levels were similar to controls upon Western blotting in patient fibroblasts.
- Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function.
- Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders.

Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed.

Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones).
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RNF13 is not associated with any phenotype in OMIM, nor in G2P.
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As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.6 PPP2CA Konstantinos Varvagiannis gene: PPP2CA was added
gene: PPP2CA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2CA were set to 29274472; 30030003
Phenotypes for gene: PPP2CA were set to Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology
Penetrance for gene: PPP2CA were set to unknown
Review for gene: PPP2CA was set to GREEN
Added comment: Reynhout et al. (doi.org/10.1016/j.ajhg.2018.12.002 - PMID not available) report on 16 individuals with heterozygous pathogenic PPP2CA variants.

Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability (probably 15/16 - a single individual developped cognitive dysfunction following a psychotic episode), language impairment, behavioral problems, seizures (10/16), brain abnormalities and variable other features.

The variants reported included 3 nonsense mutations, 1 frameshift, 1 duplication of one amino acid, 9 missense variants (of which one was observed twice and 2 affected Asp223) as well as a partial gene deletion (spanning also CDKL3).

Various mechanisms seemed to explain the effect of the different variants - among others - haploinsufficiency for some or a dominant negative effect for others, etc.

Type 2A protein phosphatases (PP2As) comprise 3 subunits, a catalytic C-type subunit (PPP2CA encodes the Cα subunit), a scaffolding A-type subunit as well as a regulatory B-type subunit important for their function. Impairment of PP2A-B56δ (encoded by PPP2R5D) binding/functionality was suggested for most of the variants. Similar dysfunction has been observed - among others - upon loss of one functional allele of PPP2R1A.

The effect of 2 variants affecting Asp223 (Asp223Val and Asp233His) was unclear as they largely behaved similar to wild-type in various functional assays. The authors argue that contribution of mutations in other genes could not be ruled out for the individuals harboring these variants, as could also be the case for the subject with disruption of (also) CDKL3.

The authors note overlapping phenotype with PPP2R1A and PPP2R5D-related ID (MIM 616362 and 616355 respectively - genes rated green in this panel).

Brain-specific Ppp2ca knockout in mice (PMID: 29274472) resulted in morphological and behavioral abnormalities partly overlapping with features observed in individuals with PPP2CA mutations. However mice heterozygous for null mutations have not been phenotypically examined (PMID: 30030003).
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PPP2CA is not associated with any phenotype in OMIM, nor in G2P.
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As a result, PPP2CA can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.6 CTNNA2 Konstantinos Varvagiannis gene: CTNNA2 was added
gene: CTNNA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNA2 were set to 30013181
Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 4, 618174
Penetrance for gene: CTNNA2 were set to Complete
Review for gene: CTNNA2 was set to GREEN
Added comment: Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174).
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Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all.

CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration.
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CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry).

This gene is not commonly included in gene panels for intellectual disability.
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As a result CTNNA2 could be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.6 SLC35A3 Konstantinos Varvagiannis gene: SLC35A3 was added
gene: SLC35A3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to 24031089; 28328131; 28777481; 16344554
Phenotypes for gene: SLC35A3 were set to ?Arthrogryposis, mental retardation, and seizures (MIM 615553)
Penetrance for gene: SLC35A3 were set to Complete
Review for gene: SLC35A3 was set to GREEN
Added comment: Biallelic pathogenic variants in SLC35A3 cause Arthrogryposis, mental retardation, and seizures (MIM 615553).
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Edvardson et al. (PMID: 24031089) report on 8 affected individuals from 3 nuclear Ashkenazi Jewish families. All harbored a nonsense [NM_012243.1:c.514C>T / p.(Gln172*)] as well as a missense variant [NM_012243.1:c.886A>G / p.(Ser296Gly)] in the compound heterozygous state. Most of the parents, who were heterozygous for the one or the other variant, were distantly related.

Common features included ASD (8/8), arthrogryposis (8/8), seizures (6/8) and intellectual disability (6/8 - variable degrees).

Upon cDNA studies, the (predicted) missense variant led to skipping of exon 8 and there was no normal size transcript (as would be expected for a variant of this type). Introduction of a premature stop codon due to this variant as well instability of the mRNA from the Gln172Ter allele was presumed to lead to absence of functional SLC35A3 protein.

Testing of 2045 Ashkenazi Jewish individuals revealed a carrier frequency of 1/205 for the missense variant in this community (with no occurrence of the nonsense variant).

SLC35A3 is a nucleotide sugar transporter that transports (uniquely) UDP-N-acetylglucosamine (UDP-GlcNAc) from the cytoplasm where it is synthesized to its site of use in the Golgi. Proper function of such transporters is essential for biosynthesis of glycoproteins, glycolipids and proteoglycans.

Although the transport of UDP-GlcNAc is mediated also by other less specific transporters, members of the SLC35 family, reduced transport was shown in patient fibroblasts compared to controls. In addition an abnormal N-glycan profile was shown in patient fibroblasts (but was not the case in serum).

Biallelic SLC35A3 mutations in cattle were previously shown to cause a Complex Vertebral Malformation (CVM) syndrome characterized by abnormal growth, vertebral and heart malformations as well as arthrogryposis (Thomsen et al. - PMID: 16344554). Arthrogryposis as well as some skeletal features observed in patients were similar to those of the animal model.
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Marini et al. (PMID: 28328131) report on 2 sibs compound heterozygous for a missense and a frameshift variant [NM_012243.2:c.73C>T or p.(Arg25Cys) and c.899_900delTTinsA or p.(Leu300Glnfs*6)]. Hypotonia, DD with ID, early-onset seizures and arthrogryposis were features in both. Severe scoliosis was also noted in the younger sib.
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Edmondson et al. (PMID: 28777481) report on a neonate (follow-up till the 21st day of life) with extensive vertebral anomalies (butterfly vertebrae, hemibertebrae, sagittal clefts, scoliosis), heart defects (PFO, PDA) and arthrogryposis. Presence of hypotonia or other neurologic features (eg. seizures) is not commented on. Conventional caryotype and SNP-array analysis were normal apart from the presence of ROH regions due to parental consanguinity. Exome sequencing revealed only a homozygous missense SNV [c.74G>T or p.(Arg25Leu) - NP_036375.1] which was supported by an abnormal N-glycan profile. As proposed for the bovine model (PMID: 16344554) and discussed in this article, similarity of the skeletal/congenital heart defects with those observed in Alagille syndrome might be due to some of the Notch functions being dependent upon N-acetylglucosamine modification.
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In ClinVar :

There is a further submission of p.Ser296Gly as pathogenic (SCV000699337.1 - 2016) apart from the submission by OMIM (SCV000108589.2 - 2013). The associated condition is Arthrogryposis, mental retardation, and seizures.

A frameshift variant [NM_012243.2(SLC35A3):c.680dup (p.Asp227Glufs)- SCV000826704.1 - April 2018] as well as an intragenic deletion [NC_000001.10:g.(?_100472570)_(100477109_?)del (GRCh37) - SCV000837123.1 - June 2018] have both been submitted as pathogenic, associated with Arthrogryposis, mental retardation, and seizures. (Note: due to the different submission dates, one can presume that these variants were found in different individuals).
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SLC35A3 is not associated with any phenotype in G2P.
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As a result, this gene can be considered for inclusion in the epilepsy panel probably as green (or amber)
[Consider upgrade of this gene to green in other panels (eg. CDGs, arthrogryposis, IEMs) and/or inclusion in other possibly relevant panels.]
Sources: Literature
Early onset or syndromic epilepsy v1.6 SMARCC2 Konstantinos Varvagiannis gene: SMARCC2 was added
gene: SMARCC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SMARCC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCC2 were set to 27392482
Phenotypes for gene: SMARCC2 were set to Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures
Penetrance for gene: SMARCC2 were set to unknown
Review for gene: SMARCC2 was set to AMBER
Added comment: Gene present in the ID panel :

Machol et al. (https://doi.org/10.1016/j.ajhg.2018.11.007) report on 15 unrelated individuals with heterozygous pathogenic SMARCC2 variants.

SMARCC2 (BAF170) is one of the subunits of the chromatin remodeling BAF complex and the phenotype of these subjects resembled the phenotype of other "BAFopathies", notably Coffin-Siris and Nicolaides-Baraitser syndrome. DD and/or ID were universal features (a few individuals were too young). Other common features included speech impairment, hypotonia, feeding problems, behavioral anomalies as well as some overlapping facial features (similar to other BAFopathies).

** Seizures were noted in 4/15 individuals. **

8 missense variants, 1 in-frame deletion, 4 splice-site variants, 1 frameshift and 1 nonsense variant are reported. De novo occurrence was the case for 12 of these variants while for 2 individuals one/both parents were unavailable. One subject with mild DD had inherited a nonsense variant from his affected father (with borderline ID) in whom the mutation had occurred as a de novo event.

Several of the missense variants (but not all) clustered in the SANT domain, while individuals with the specific variants seemed to present with a more severe phenotype.

The de novo in-frame deletion, which was observed in one mildly affected individual, has been reported once in gnomAD.

Exon skipping was demonstrated for 1 splice-site variant while expression studies for another splice-site variant showed reduced mRNA expression. mRNA expression was normal for the in-frame deletion.

Similarly to what has been observed in other disorders of this group, some mutations are thought to act through a dominant-negative mechanism.

Transcriptome analysis in fibroblasts from affected individuals suggested the presence of a group of differentially expressed genes possibly involved in regulation of neuronal development/function.

As the authors note, studies in Smarcc2-deficient mice suggest a role in learning as well as behavioral adaptation (PMID: 27392482).

SMARCC2 is not associated with any phenotype in OMIM, nor in G2P.

As a result, this gene should be considered for inclusion in this panel as amber (or green).
Sources: Literature
Early onset or syndromic epilepsy v1.6 ATN1_CAG Louise Daugherty GRCh38 position for ATN1_CAG was changed from 6936717-6936742 to 6936717-6936772.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v1.5 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease; Component Of Super Panel
Early onset or syndromic epilepsy v1.4 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease
Early onset or syndromic epilepsy v1.3 TIMM50 Sarah Leigh reviewed gene: TIMM50: Rating: ; Mode of pathogenicity: None; Publications: 27573165; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.3 PROSC Ellen McDonagh Classified gene: PROSC as No list
Early onset or syndromic epilepsy v1.3 PROSC Ellen McDonagh Added comment: Comment on list classification: Demoting from Green to Grey, as this gene is represented by PLPBP in this panel: https://panelapp.genomicsengland.co.uk/panels/402/gene/PLPBP/.
Early onset or syndromic epilepsy v1.3 PROSC Ellen McDonagh Gene: prosc has been removed from the panel.
Early onset or syndromic epilepsy v1.2 PLPBP Ellen McDonagh commented on gene: PLPBP
Early onset or syndromic epilepsy v1.1 AIMP2 Konstantinos Varvagiannis gene: AIMP2 was added
gene: AIMP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AIMP2 were set to 29215095
Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 (MIM 618006)
Penetrance for gene: AIMP2 were set to Complete
Review for gene: AIMP2 was set to AMBER
Added comment: Biallelic pathogenic variants in AIMP2 cause Leukodystrophy, hypomyelinating, 17 (MIM 618006).

3 individuals from 2 unrelated consanguineous families, of Indian origin have been reported (all in PMID: 29215095).

The phenotype consisted of feeding difficulties, lack of development with intellectual disability and seizures (3/3) as well as brain MRI abnormalities (cerebral and cerebellar atrophy, hypo-intensities of the basal ganglia on T2w sequences). Severe microcephaly was observed in 2 patients for whom this information was available (birth measurements not specified).

All patients described to date were homozygous for a nonsense variant [NM_006303.3:c.105C>A or p.(Tyr35Ter)] which appears to be a founder mutation in this population.

Quantitative reverse transcription PCR demonstrated reduced mRNA levels in peripheral lymphocytes, but this decrease was not significant compared to controls (the authors presume low level of NMD).

Previous mouse models provide some - but not substantial - support.

The authors note marked similarity with the phenotype associated with AIMP1 (Leukodystrophy, hypomyelinating, 3 - MIM 260600), another auxiliary protein of the macromolecular multienzyme multi-tRNA synthetase complex. AIMP1 is listed in the current panel as green.

AIMP2 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel probably as amber.
Sources: Literature
Early onset or syndromic epilepsy v1.1 VPS11 Konstantinos Varvagiannis gene: VPS11 was added
gene: VPS11 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: VPS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS11 were set to 27120463; 26307567; 27473128
Phenotypes for gene: VPS11 were set to Leukodystrophy, hypomyelinating, 12 (MIM 616683)
Penetrance for gene: VPS11 were set to Complete
Review for gene: VPS11 was set to GREEN
Added comment: Biallelic mutations in VPS11 cause Leukodystrophy, hypomyelinating, 12 (MIM 616683).

PMIDs: 27120463, 26307567, 27473128 all report on this disorder.

The phenotype consists of global DD, ID, (variable) acquired microcephaly with hypomyelination upon brain MRI. Seizures appear to be a feature in several individuals.

Almost all individuals appear to be of Ashkenazi Jewish descent, homozygous for a founder mutation (NM_021729.5:c.2536T>G or p.Cys846Gly). PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families.

A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents. Seizures were also noted in these individuals.

Pathogenicity is supported by extensive functional studies in all relevant articles.

VPS11 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel probably as green (or amber).

[Please consider inclusion in the lysosomal disorders panel as well as in the undiagnosed metabolic disorders panel].
Sources: Literature
Early onset or syndromic epilepsy v1.1 PAK1 Konstantinos Varvagiannis gene: PAK1 was added
gene: PAK1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PAK1 were set to 30290153
Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158)
Penetrance for gene: PAK1 were set to unknown
Mode of pathogenicity for gene: PAK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PAK1 was set to AMBER
Added comment: Heterozygous pathogenic PAK1 variants cause Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158).

Harms et al. (PMID: 30290153) report on two unrelated individuals with de novo missense mutations in PAK1. Common features included developmental delay with associated intellectual disability, seizures, ataxic gait. Postnatal-onset microcephaly as well as some facial features were also common to both subjects.

Each patient was found to harbour a (private) de novo missense variant [NM_001128620.1:c.392A>G or p.(Tyr131Cys) - c.1286A>G or p.(Tyr429Cys)]. Expression studies demonstrated similar levels for the mutant and wt transcript and Western blot confirmed similar amounts of protein in patient fibroblasts when compared to controls. Functional studies suggest that gain-of-function is the underlying mechanism for both variants.

PAK1 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel as amber.
Sources: Literature
Early onset or syndromic epilepsy v1.1 FUK Konstantinos Varvagiannis gene: FUK was added
gene: FUK was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUK were set to 30503518
Phenotypes for gene: FUK were set to Feeding difficulties; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision
Penetrance for gene: FUK were set to Complete
Review for gene: FUK was set to AMBER
Added comment: Ng et al. (PMID: 30503518) report on 2 unrelated individuals with biallelic pathogenic variants in FUK. The common features consisted of feeding difficulties, hypotonia, global developmental delay with severe intellectual disability, seizures as well as visual impairment.

The first patient was compound heterozygous for 2 missense variants (Ser223Pro and Arg683Cys) while the second - born to consanguineous parents - was homozygous for Lys994Gln.

Significant reduction in the FUK protein amount was demonstrated upon Western blot for the first individual for whom fibroblast and lymphoblast cell lines were available.

Fucokinase (FUK) is an enzyme of the fucose salvage pathway, one of the mechanisms (the other and main contributor being the de novo pathway) for synthesis of GDP-fucose. GDP-fucose is a donor substrate for fucosylation, a form of glycosylation. Significant decrease of fucokinase activity was shown for this individual when compared to controls.

Cell lines from the second individual were not available for expression/functional studies.

Overall the authors suggest that loss-of-function variants cause a congenital disorder of glycosylation with ID and seizures.

There are no further cases published in the literature.

FUK is not associated with any phenotype in OMIM nor in G2P.

As a result this gene can be considered for inclusion in this panel as amber.

[You might consider inclusion of this gene also in the CDG gene panel].
Sources: Literature
Early onset or syndromic epilepsy v1.1 Sarah Leigh List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus
Early onset or syndromic epilepsy v1.0 Sarah Leigh promoted panel to version 1.0
Early onset or syndromic epilepsy v0.1591 PAH Eleanor Williams Marked gene: PAH as ready
Early onset or syndromic epilepsy v0.1591 PAH Eleanor Williams Gene: pah has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1591 PAH Eleanor Williams Publications for gene: PAH were set to
Early onset or syndromic epilepsy v0.1590 PAH Eleanor Williams Phenotypes for gene: PAH were changed from to Phenylketonuria 261600
Early onset or syndromic epilepsy v0.1589 COX15 Sarah Leigh Marked gene: COX15 as ready
Early onset or syndromic epilepsy v0.1589 COX15 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1589 COX15 Sarah Leigh Gene: cox15 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1589 COX10 Sarah Leigh Marked gene: COX10 as ready
Early onset or syndromic epilepsy v0.1589 COX10 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1589 COX10 Sarah Leigh Gene: cox10 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1589 COG8 Sarah Leigh Marked gene: COG8 as ready
Early onset or syndromic epilepsy v0.1589 COG8 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1589 COG8 Sarah Leigh Gene: cog8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1589 COG6 Sarah Leigh Marked gene: COG6 as ready
Early onset or syndromic epilepsy v0.1589 COG6 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1589 COG6 Sarah Leigh Gene: cog6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1589 COG6 Sarah Leigh Publications for gene: COG6 were set to
Early onset or syndromic epilepsy v0.1588 PAH Eleanor Williams Mode of inheritance for gene: PAH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1587 PAH Eleanor Williams Classified gene: PAH as Green List (high evidence)
Early onset or syndromic epilepsy v0.1587 PAH Eleanor Williams Added comment: Comment on list classification: Two cases reported in recent literature of variants in PAH in patients that show Phenylketonuria with seizures. Few cases of untreated PKU since newborn screen is now routine in most countries. But many publications state that seizures are a feature of untreated PKU so rating this gene green.
Early onset or syndromic epilepsy v0.1587 PAH Eleanor Williams Gene: pah has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1586 COG4 Sarah Leigh Marked gene: COG4 as ready
Early onset or syndromic epilepsy v0.1586 COG4 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1586 COG4 Sarah Leigh Gene: cog4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1586 VLDLR Sarah Leigh Marked gene: VLDLR as ready
Early onset or syndromic epilepsy v0.1586 VLDLR Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least two variants reported in two unrelated cases in which seizures are a phenotypic feature.
PMID: 16174313 reports seizures in 5/19 cases with autosomal recessivecerebellar hypoplasiain the Hutterite population, but does not include any genetic evidence. PMID: 18326629 reports VLDLR a c.769C>T variant in Family A, where seizures are a rare ocurrance and also a deletion including VLDLR and LOC401491 in the family described in PMID: 16080122.
Early onset or syndromic epilepsy v0.1586 VLDLR Sarah Leigh Gene: vldlr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1586 VLDLR Sarah Leigh Tag watchlist tag was added to gene: VLDLR.
Early onset or syndromic epilepsy v0.1586 PAH Eleanor Williams commented on gene: PAH
Early onset or syndromic epilepsy v0.1586 VLDLR Sarah Leigh Publications for gene: VLDLR were set to 27000652; 27108886; 27251579; 16174313; 16080122; 18326629
Early onset or syndromic epilepsy v0.1585 PTF1A Rebecca Foulger commented on gene: PTF1A: Added watchlist tag.
Early onset or syndromic epilepsy v0.1585 PTF1A Rebecca Foulger Tag watchlist tag was added to gene: PTF1A.
Early onset or syndromic epilepsy v0.1585 PTF1A Rebecca Foulger Classified gene: PTF1A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1585 PTF1A Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: Variants in PTF1A can cause Pancreatic agenesis 2, 615935 and Pancreatic and cerebellar agenesis, 609069. MIM:609069 can present with seizures, but hard to find individual cases in literature where epilepsy/seizures are recorded. Therefore Amber awaiting further cases.
Early onset or syndromic epilepsy v0.1585 PTF1A Rebecca Foulger Gene: ptf1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1584 CYP27A1 Sarah Leigh gene: CYP27A1 was added
gene: CYP27A1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CYP27A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP27A1 were set to 18227423
Phenotypes for gene: CYP27A1 were set to Cerebrotendinous xanthomatosis 213700
Review for gene: CYP27A1 was set to RED
Added comment: Not associated with phenotype in OMIM or in Gen2Phen. At least one variant in a single case in which seizures are a phenotypic feature.
Sources: Literature
Early onset or syndromic epilepsy v0.1583 PTF1A Rebecca Foulger Mode of inheritance for gene: PTF1A was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1582 VLDLR Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v0.1582 VLDLR Sarah Leigh Added comment: Comment on publications: Seizures were not evident in cases reported in PMIDs
Early onset or syndromic epilepsy v0.1582 VLDLR Sarah Leigh Publications for gene: VLDLR were set to 27000652; 27108886; 27251579; 16174313; 16080122; 18326629
Early onset or syndromic epilepsy v0.1581 PTF1A Rebecca Foulger Publications for gene: PTF1A were set to
Early onset or syndromic epilepsy v0.1580 PTF1A Rebecca Foulger Phenotypes for gene: PTF1A were changed from to Pancreatic and cerebellar agenesis, 609069
Early onset or syndromic epilepsy v0.1579 PSPH Ellen McDonagh Marked gene: PSPH as ready
Early onset or syndromic epilepsy v0.1579 PSPH Ellen McDonagh Added comment: Comment when marking as ready: Kept as Amber due to expert review.
Early onset or syndromic epilepsy v0.1579 PSPH Ellen McDonagh Gene: psph has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1579 PSPH Ellen McDonagh Tag watchlist tag was added to gene: PSPH.
Early onset or syndromic epilepsy v0.1579 PSPH Ellen McDonagh Phenotypes for gene: PSPH were changed from to Phosphoserine phosphatase deficiency 614023
Early onset or syndromic epilepsy v0.1578 PSPH Ellen McDonagh Publications for gene: PSPH were set to
Early onset or syndromic epilepsy v0.1577 PSPH Ellen McDonagh Mode of inheritance for gene: PSPH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1576 KIF1A Ellen McDonagh Marked gene: KIF1A as ready
Early onset or syndromic epilepsy v0.1576 KIF1A Ellen McDonagh Gene: kif1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1576 KIF1A Ellen McDonagh Classified gene: KIF1A as Green List (high evidence)
Early onset or syndromic epilepsy v0.1576 KIF1A Ellen McDonagh Added comment: Comment on list classification: Promoted to Green due to expert review and enough evidence for inclusion of this gene on this panel. More than 3 unrelated cases reported.
Early onset or syndromic epilepsy v0.1576 KIF1A Ellen McDonagh Gene: kif1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1575 KIF1A Ellen McDonagh Added comment: Comment on publications: PMID: 25265257 - five cases of 14 reported with de novo KIF1A variants were epileptic or had epileptic abnormalities (infantile spasms, partial complex and myoclinic seizures).
Early onset or syndromic epilepsy v0.1575 KIF1A Ellen McDonagh Publications for gene: KIF1A were set to
Early onset or syndromic epilepsy v0.1574 KIF2A Rebecca Foulger Marked gene: KIF2A as ready
Early onset or syndromic epilepsy v0.1574 KIF2A Rebecca Foulger Gene: kif2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1574 KIF2A Rebecca Foulger Classified gene: KIF2A as Green List (high evidence)
Early onset or syndromic epilepsy v0.1574 KIF2A Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: 5 unrelated patients with seizures amongst their phenotypes and heterozygous variants in KIF2A from PMIDs:
27896282, 27747449 and 23603762.
Early onset or syndromic epilepsy v0.1574 KIF2A Rebecca Foulger Gene: kif2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1573 KIF1A Ellen McDonagh Phenotypes for gene: KIF1A were changed from to Mental retardation, autosomal dominant 9 614255
Early onset or syndromic epilepsy v0.1572 KIF2A Rebecca Foulger commented on gene: KIF2A: PMID:23603762 (Poirier et al., 2013) report neontal onset seizures in two patients with heterozygous KIF2A variants: patient P462 with a heterozygous variant c.961C>G, p.H321D in KIF2A, and patient p147 with a heterozygous c.950G>A (p.S317N) variant in KIF2A (supplementary Table 4).
Early onset or syndromic epilepsy v0.1572 KIF2A Rebecca Foulger commented on gene: KIF2A: PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 2 had tonic-clonic seizures and the c.962A>C (p.His321Pro) variant in KIF2A.
Early onset or syndromic epilepsy v0.1572 KIF2A Rebecca Foulger commented on gene: KIF2A
Early onset or syndromic epilepsy v0.1572 PIGQ Louise Daugherty Marked gene: PIGQ as ready
Early onset or syndromic epilepsy v0.1572 PIGQ Louise Daugherty Gene: pigq has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1572 PIGQ Louise Daugherty Classified gene: PIGQ as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1572 PIGQ Louise Daugherty Added comment: Comment on list classification: changed from Red to Amber Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1572 PIGQ Louise Daugherty Gene: pigq has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1571 VLDLR Sarah Leigh Added comment: Comment on publications: Seizures not evident in cases reported in PMID: 18043714
Early onset or syndromic epilepsy v0.1571 VLDLR Sarah Leigh Publications for gene: VLDLR were set to 27000652; 27108886; 27251579; 16174313; 16080122; 18326629
Early onset or syndromic epilepsy v0.1570 KIF1A Ellen McDonagh Mode of inheritance for gene: KIF1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1569 PIGQ Louise Daugherty Publications for gene: PIGQ were set to Martin et al (2014) Hum Mol Genet 23(12).3200-3211; 25558065
Early onset or syndromic epilepsy v0.1568 PIGQ Louise Daugherty Added comment: Comment on phenotypes: added phenotype from expert review
Early onset or syndromic epilepsy v0.1568 PIGQ Louise Daugherty Phenotypes for gene: PIGQ were changed from BIALLELIC, autosomal or pseudoautosomal to Intractable seizures; developmental delay; optic atrophy
Early onset or syndromic epilepsy v0.1567 NDUFA2 Ellen McDonagh Marked gene: NDUFA2 as ready
Early onset or syndromic epilepsy v0.1567 NDUFA2 Ellen McDonagh Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1567 NDUFA2 Ellen McDonagh Classified gene: NDUFA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1567 NDUFA2 Ellen McDonagh Added comment: Comment on list classification: Keep as amber for now on this panel, as it is unclear whether variants in this gene directly cause epilepsy/seizures. This gene is Green on the Mitochondrial panel Version 1.75, which would be applied to all patients who receive the epilepsy panel.
Early onset or syndromic epilepsy v0.1567 NDUFA2 Ellen McDonagh Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1566 NDUFA2 Ellen McDonagh Classified gene: NDUFA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1566 NDUFA2 Ellen McDonagh Added comment: Comment on list classification: Keep as amber for now on this panel, as it is unclear whether variants in this gene directly cause epilepsy/seizures. This gene is Green on the Mitochondrial panel Version 1.75, which would be applied to all patients who receive the epilepsy panel.
Early onset or syndromic epilepsy v0.1566 NDUFA2 Ellen McDonagh Gene: ndufa2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1565 PIGQ Louise Daugherty Mode of inheritance for gene: PIGQ was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1564 PIGQ Louise Daugherty Phenotypes for gene: PIGQ were changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1563 NDUFA2 Ellen McDonagh Phenotypes for gene: NDUFA2 were changed from to Leigh syndrome due to mitochondrial complex I deficiency 256000
Early onset or syndromic epilepsy v0.1562 NDUFA2 Ellen McDonagh Mode of inheritance for gene: NDUFA2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1561 NDUFA2 Ellen McDonagh Added comment: Comment on publications: PMID: 28857146 - unclear whether either of the genotyped cases displayed seizures/epilepsy.
Early onset or syndromic epilepsy v0.1561 NDUFA2 Ellen McDonagh Publications for gene: NDUFA2 were set to 28857146; 18513682
Early onset or syndromic epilepsy v0.1560 KIF2A Rebecca Foulger Mode of inheritance for gene: KIF2A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1559 KIF2A Rebecca Foulger Publications for gene: KIF2A were set to
Early onset or syndromic epilepsy v0.1558 KIF2A Rebecca Foulger Phenotypes for gene: KIF2A were changed from to Cortical dysplasia, complex, with other brain malformations 3, 615411
Early onset or syndromic epilepsy v0.1557 PIGQ Louise Daugherty Added comment: Comment on publications: added publication suggested by external reviewer
Early onset or syndromic epilepsy v0.1557 PIGQ Louise Daugherty Publications for gene: PIGQ were set to Martin et al (2014) Hum Mol Genet 23(12).3200-3211
Early onset or syndromic epilepsy v0.1556 PIGQ Louise Daugherty reviewed gene: PIGQ: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Marked gene: HOXA1 as ready
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Gene: hoxa1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger commented on gene: HOXA1: Added watchlist tag.
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Tag watchlist tag was added to gene: HOXA1.
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Classified gene: HOXA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber. HOXA1 is a Confirmed DD-G2P gene for Athabaskan brainstem dysgenesis syndrome and Bosley-Salih-Alorainy syndrome; seizures are a variable feature of these HOXA1 spectrum disorders but aren't present in all affected individuals. Reported individuals so far are all from Saudi families or the Athabascan Indian population. Of the 5 BSAS or ABDS individuals summarised with seizures in PMID:18412118, it's unclear how many are related and therefore how many individual cases there are. Therefore rated Amber awaiting further clear cases.
Early onset or syndromic epilepsy v0.1556 HOXA1 Rebecca Foulger Gene: hoxa1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1555 NDUFA2 Ellen McDonagh Added comment: Comment on publications: PMID: 18513682 - the case reported developed seizures after a varicella infection, with severe acidosis.
Early onset or syndromic epilepsy v0.1555 NDUFA2 Ellen McDonagh Publications for gene: NDUFA2 were set to
Early onset or syndromic epilepsy v0.1554 HOXA1 Rebecca Foulger commented on gene: HOXA1: PMID:18412118 (Bosley et al 2008) report 9 new individuals from 6 families (3 consanguineous Saudi families and 3 Native American families) who have homozygous variants of HOXA1 with either the Bosley-Salih-Alorainy Syndrome (BSAS) or the Athabascan Brainstem Dysgenesis Syndrome (ABDS). Seizures were seen in 2 patients (Saudi patients B1 and C1). Patient B1 had 2 unaffected siblings and six unaffected half siblings. Patients C1-C4 came from a consanguineous extended family, and seizures weren't noted in C2-C4. The Authors provide a summary, reporting seizures in 1/16 BSAS patients and 4/13 ABDS patients (it's unclear which of these patients are related).
Early onset or syndromic epilepsy v0.1554 HOXA1 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v0.1554 HOXA1 Rebecca Foulger Publications for gene: HOXA1 were set to 18412118
Early onset or syndromic epilepsy v0.1553 HOXA1 Rebecca Foulger commented on gene: HOXA1: Holve et al., 2003 (PMID:12833395): Seizures reported in 4/10 ABDS patients, all of which are Athabascan Indian children. Genetic analysis was not performed.
Early onset or syndromic epilepsy v0.1553 SHH Sarah Leigh Marked gene: SHH as ready
Early onset or syndromic epilepsy v0.1553 SHH Sarah Leigh Added comment: Comment when marking as ready: Associated with somatic variants and so not relevant to this panel.
Early onset or syndromic epilepsy v0.1553 SHH Sarah Leigh Gene: shh has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1553 SHH Sarah Leigh Classified gene: SHH as Red List (low evidence)
Early onset or syndromic epilepsy v0.1553 SHH Sarah Leigh Gene: shh has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1552 NDUFS8 Ellen McDonagh Marked gene: NDUFS8 as ready
Early onset or syndromic epilepsy v0.1552 NDUFS8 Ellen McDonagh Gene: ndufs8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1552 NDUFS8 Ellen McDonagh Classified gene: NDUFS8 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1552 NDUFS8 Ellen McDonagh Gene: ndufs8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1551 NDUFS8 Ellen McDonagh Added comment: Comment on mode of inheritance: Promoted to Green due to evidence of a seizures/epilepsy phenotype in two unrelated cases with variants in this gene.
Early onset or syndromic epilepsy v0.1551 NDUFS8 Ellen McDonagh Mode of inheritance for gene: NDUFS8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1550 NDUFS8 Ellen McDonagh Deleted their comment
Early onset or syndromic epilepsy v0.1550 SMC1A Sarah Leigh Marked gene: SMC1A as ready
Early onset or syndromic epilepsy v0.1550 SMC1A Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported four unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1550 SMC1A Sarah Leigh Gene: smc1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1550 NDUFS8 Ellen McDonagh Deleted their comment
Early onset or syndromic epilepsy v0.1550 NDUFS8 Ellen McDonagh commented on gene: NDUFS8: Comment on publications: PMID: 22499348 - of three patients (2 related) reported with homozygous or compound heterozygous variants in this gene, one was reported with epilepsy with a clinical diagnosis of Leigh syndrome...this patient also had a homozygous variant in NDUFS7, however the variant in NDUFS8 was attributed to the disease as their affected sister also carried this homozygous variant. She had a clinical diagnosis of Leigh syndrome, decribed with Muscular hypotonia, lactic acidosis blood and CSF, MRI lesions basal ganglia and brainstem, hypertrophic cardiomyopathy (seizures or epilepsy were not mentioned). In the other unrelated case, a clinical diagnosis of mitochondrial encephalopathy and hypertrophic cardiomyopathy was given, with Muscular hypotonia, respiratory insufficiency as other features.
Early onset or syndromic epilepsy v0.1550 SMC1A Sarah Leigh Publications for gene: SMC1A were set to 16604071
Early onset or syndromic epilepsy v0.1549 NDUFS8 Ellen McDonagh Added comment: Comment on publications: PMID: 22499348 - of three patients reported with homozygous or compound heterozygous variants in this gene, one was reported with epilepsy with a clinical diagnosis of Leigh syndrome. The other two cases had a clinical diagnosis of mitochondrial encephalopathy and hypertrophic cardiomyopathy, and Leigh syndrome, respectively.
Early onset or syndromic epilepsy v0.1549 NDUFS8 Ellen McDonagh Publications for gene: NDUFS8 were set to 15159508; 22499348; 9837812
Early onset or syndromic epilepsy v0.1548 NDUFS8 Ellen McDonagh Added comment: Comment on publications: PMID: 22499348 - of three patients reported with homozygous or compound heterozygous variants in this gene, one was reported with epilepsy with a clinical diagnosis of Leigh syndrome. The other two cases had a clinical diagnosis of mitochondrial encephalopathy and hypertrophic cardiomyopathy, and Leigh syndrome, respectively.
Early onset or syndromic epilepsy v0.1548 NDUFS8 Ellen McDonagh Publications for gene: NDUFS8 were set to 15159508; 22499348; 9837812
Early onset or syndromic epilepsy v0.1547 SMC1A Sarah Leigh Publications for gene: SMC1A were set to
Early onset or syndromic epilepsy v0.1546 SMC1A Sarah Leigh Phenotypes for gene: SMC1A were changed from to Cornelia de Lange syndrome 2 300590
Early onset or syndromic epilepsy v0.1545 SMC1A Sarah Leigh Mode of inheritance for gene: SMC1A was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.1544 NDUFS8 Ellen McDonagh Added comment: Comment on publications: PMID: 9837812 - erratic seizures reported in a case who was compound heterozygous for variants in NDUFS8 "At admission, the main symptoms were mild cyanosis, severe hypercarbia, a cardiac murmur, drowsiness with absent optical and acoustical blink, eye flutter, intense hypotonia, brisk tendon reflexes with ankle clonus, and erratic seizures".
Early onset or syndromic epilepsy v0.1544 NDUFS8 Ellen McDonagh Publications for gene: NDUFS8 were set to 15159508; 22499348; 9837812
Early onset or syndromic epilepsy v0.1543 SLC45A1 Sarah Leigh Marked gene: SLC45A1 as ready
Early onset or syndromic epilepsy v0.1543 SLC45A1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least three homozygous variants reported in three unrelated cases, however, seizures were only a phenotypic feature in two of the unrelated cases.
Early onset or syndromic epilepsy v0.1543 SLC45A1 Sarah Leigh Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1543 HOXA1 Rebecca Foulger Added comment: Comment on mode of inheritance: Biallelic MOI supported by the literature (e.g. PMID:18412118)
Early onset or syndromic epilepsy v0.1543 HOXA1 Rebecca Foulger Mode of inheritance for gene: HOXA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1542 HOXA1 Rebecca Foulger Publications for gene: HOXA1 were set to
Early onset or syndromic epilepsy v0.1541 HOXA1 Rebecca Foulger commented on gene: HOXA1
Early onset or syndromic epilepsy v0.1541 SLC45A1 Sarah Leigh Tag watchlist tag was added to gene: SLC45A1.
Early onset or syndromic epilepsy v0.1541 NDUFS8 Ellen McDonagh Added comment: Comment on publications: PMID: 15159508 - does not mention seizures in the case.
Early onset or syndromic epilepsy v0.1541 NDUFS8 Ellen McDonagh Publications for gene: NDUFS8 were set to
Early onset or syndromic epilepsy v0.1540 SLC45A1 Sarah Leigh Phenotypes for gene: SLC45A1 were changed from to Intellectual developmental disorder with neuropsychiatric features 617532
Early onset or syndromic epilepsy v0.1539 SLC45A1 Sarah Leigh Mode of inheritance for gene: SLC45A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1538 NDUFS8 Ellen McDonagh Classified gene: NDUFS8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1538 NDUFS8 Ellen McDonagh Added comment: Comment on list classification: Curated in OMIM for Leigh syndrome due to mitochondrial complex I deficiency and in Gene2Phenotype for MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY, which include seizures as a phenotype.
Early onset or syndromic epilepsy v0.1538 NDUFS8 Ellen McDonagh Gene: ndufs8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1537 HOXA1 Rebecca Foulger Phenotypes for gene: HOXA1 were changed from to Athabaskan brainstem dysgenesis syndrome, 601536; Bosley-Salih-Alorainy syndrome, 601536
Early onset or syndromic epilepsy v0.1536 SLC45A1 Sarah Leigh Publications for gene: SLC45A1 were set to
Early onset or syndromic epilepsy v0.1535 NDUFS7 Ellen McDonagh Marked gene: NDUFS7 as ready
Early onset or syndromic epilepsy v0.1535 NDUFS7 Ellen McDonagh Gene: ndufs7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1535 NDUFS7 Ellen McDonagh Tag watchlist tag was added to gene: NDUFS7.
Early onset or syndromic epilepsy v0.1535 NDUFS7 Ellen McDonagh Mode of inheritance for gene: NDUFS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1534 NDUFS7 Ellen McDonagh Mode of inheritance for gene: NDUFS7 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1533 NDUFS7 Ellen McDonagh Publications for gene: NDUFS7 were set to
Early onset or syndromic epilepsy v0.1532 NDUFS7 Ellen McDonagh commented on gene: NDUFS7: Though variants in this gene cause Leigh syndrome, there does not seem to be enough evidence for variants in this gene to be directly attributed to seizures/epilepsy from these publications.
Early onset or syndromic epilepsy v0.1532 NDUFS7 Ellen McDonagh commented on gene: NDUFS7: PMID: 10330338 - seizures not mentioned in the patients reported with NDUFS7.
Early onset or syndromic epilepsy v0.1532 SETD1B Sarah Leigh Marked gene: SETD1B as ready
Early onset or syndromic epilepsy v0.1532 SETD1B Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 SETD1B Sarah Leigh Gene: setd1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 NDUFS7 Ellen McDonagh commented on gene: NDUFS7
Early onset or syndromic epilepsy v0.1532 RYR2 Sarah Leigh Marked gene: RYR2 as ready
Early onset or syndromic epilepsy v0.1532 RYR2 Sarah Leigh Gene: ryr2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 RUSC2 Sarah Leigh Marked gene: RUSC2 as ready
Early onset or syndromic epilepsy v0.1532 RUSC2 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 RUSC2 Sarah Leigh Gene: rusc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 RAB3GAP2 Sarah Leigh Marked gene: RAB3GAP2 as ready
Early onset or syndromic epilepsy v0.1532 RAB3GAP2 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 RAB3GAP2 Sarah Leigh Gene: rab3gap2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 RAB3GAP1 Sarah Leigh Marked gene: RAB3GAP1 as ready
Early onset or syndromic epilepsy v0.1532 RAB3GAP1 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 RAB3GAP1 Sarah Leigh Gene: rab3gap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 PSAT1 Sarah Leigh Marked gene: PSAT1 as ready
Early onset or syndromic epilepsy v0.1532 PSAT1 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 PSAT1 Sarah Leigh Gene: psat1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 NDP Sarah Leigh Marked gene: NDP as ready
Early onset or syndromic epilepsy v0.1532 NDP Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 NDP Sarah Leigh Gene: ndp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 MAST1 Sarah Leigh Marked gene: MAST1 as ready
Early onset or syndromic epilepsy v0.1532 MAST1 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 MAST1 Sarah Leigh Gene: mast1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 MANBA Sarah Leigh Marked gene: MANBA as ready
Early onset or syndromic epilepsy v0.1532 MANBA Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 MANBA Sarah Leigh Gene: manba has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 HPRT1 Sarah Leigh Marked gene: HPRT1 as ready
Early onset or syndromic epilepsy v0.1532 HPRT1 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 HPRT1 Sarah Leigh Gene: hprt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 HEXB Sarah Leigh Marked gene: HEXB as ready
Early onset or syndromic epilepsy v0.1532 HEXB Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 HEXB Sarah Leigh Gene: hexb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 GLI3 Sarah Leigh Marked gene: GLI3 as ready
Early onset or syndromic epilepsy v0.1532 GLI3 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 GLI3 Sarah Leigh Gene: gli3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1532 GCSH Sarah Leigh Classified gene: GCSH as Red List (low evidence)
Early onset or syndromic epilepsy v0.1532 GCSH Sarah Leigh Added comment: Comment on list classification: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1532 GCSH Sarah Leigh Gene: gcsh has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1531 FOXRED1 Sarah Leigh Marked gene: FOXRED1 as ready
Early onset or syndromic epilepsy v0.1531 FOXRED1 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1531 FOXRED1 Sarah Leigh Gene: foxred1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1531 FIG4 Sarah Leigh Classified gene: FIG4 as Red List (low evidence)
Early onset or syndromic epilepsy v0.1531 FIG4 Sarah Leigh Gene: fig4 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1530 FIG4 Sarah Leigh Classified gene: FIG4 as Red List (low evidence)
Early onset or syndromic epilepsy v0.1530 FIG4 Sarah Leigh Added comment: Comment on list classification: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1530 FIG4 Sarah Leigh Gene: fig4 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1529 FIG4 Sarah Leigh Marked gene: FIG4 as ready
Early onset or syndromic epilepsy v0.1529 FIG4 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 FIG4 Sarah Leigh Gene: fig4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 FASTKD2 Sarah Leigh Marked gene: FASTKD2 as ready
Early onset or syndromic epilepsy v0.1529 FASTKD2 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 FASTKD2 Sarah Leigh Gene: fastkd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 DNAJC6 Sarah Leigh Marked gene: DNAJC6 as ready
Early onset or syndromic epilepsy v0.1529 DNAJC6 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 DNAJC6 Sarah Leigh Gene: dnajc6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 DPM2 Sarah Leigh Marked gene: DPM2 as ready
Early onset or syndromic epilepsy v0.1529 DPM2 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 DPM2 Sarah Leigh Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 PDSS2 Sarah Leigh Marked gene: PDSS2 as ready
Early onset or syndromic epilepsy v0.1529 PDSS2 Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 PDSS2 Sarah Leigh Gene: pdss2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 PCLO Sarah Leigh Marked gene: PCLO as ready
Early onset or syndromic epilepsy v0.1529 PCLO Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 PCLO Sarah Leigh Gene: pclo has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1529 NRAS Sarah Leigh Marked gene: NRAS as ready
Early onset or syndromic epilepsy v0.1529 NRAS Sarah Leigh Gene: nras has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1529 NRAS Sarah Leigh Classified gene: NRAS as Red List (low evidence)
Early onset or syndromic epilepsy v0.1529 NRAS Sarah Leigh Added comment: Comment on list classification: Based on reviewers' comments.
Early onset or syndromic epilepsy v0.1529 NRAS Sarah Leigh Gene: nras has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1528 NECAP1 Sarah Leigh Marked gene: NECAP1 as ready
Early onset or syndromic epilepsy v0.1528 NECAP1 Sarah Leigh Added comment: Comment when marking as ready: Single family reported.
Early onset or syndromic epilepsy v0.1528 NECAP1 Sarah Leigh Gene: necap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1528 OTX2 Sarah Leigh Marked gene: OTX2 as ready
Early onset or syndromic epilepsy v0.1528 OTX2 Sarah Leigh Gene: otx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1528 NDUFAF4 Sarah Leigh Marked gene: NDUFAF4 as ready
Early onset or syndromic epilepsy v0.1528 NDUFAF4 Sarah Leigh Gene: ndufaf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1528 PIGC Sarah Leigh Marked gene: PIGC as ready
Early onset or syndromic epilepsy v0.1528 PIGC Sarah Leigh Gene: pigc has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1528 NDUFAF4 Sarah Leigh Tag watchlist tag was added to gene: NDUFAF4.
Early onset or syndromic epilepsy v0.1528 DHDDS Rebecca Foulger Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb; 613861 to Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb,613861
Early onset or syndromic epilepsy v0.1526 DHDDS Rebecca Foulger Marked gene: DHDDS as ready
Early onset or syndromic epilepsy v0.1526 DHDDS Rebecca Foulger Gene: dhdds has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1526 DHDDS Rebecca Foulger Classified gene: DHDDS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1526 DHDDS Rebecca Foulger Added comment: Comment on list classification: Added gene to panel and rated green based on literature evidence (PMID:29100083) and relevant OMIM phenotype (MIM:617836). 5 unrelated heterozygous cases in PMID:29100083 plus 1 compound het case in PMID:27343064 for a patient with a glycosylation disorder including seizures. Therefore sufficient (>3) unrelated seizure cases for a diagnostic rating.
Early onset or syndromic epilepsy v0.1526 DHDDS Rebecca Foulger Gene: dhdds has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1525 DHDDS Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM (and PMID:29100083) report AD inheritance for Developmental delay and seizures with or without movement abnormalities, 617836. In addition, Sabry et al (PMID:27343064) report one individual with a glycosylation disorder (MIM:613861) and epilepsy, carrying compound heterozygous variants in DHDDS. Therefore selected 'both monoallelic and biallelic' MOI.
Early onset or syndromic epilepsy v0.1525 DHDDS Rebecca Foulger Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1524 DHDDS Rebecca Foulger commented on gene: DHDDS: Sabry et al (PMID:27343064) report a patient with DHDDS deficiency and epilepsy amongst his phenotypes. The patient died at 8 months during a status epilepticus. The patient was compound heterozygous for variants in the DHDDS gene. The patient is also homozygous for the c.911 T>C (p.F304S) ALG6 variant that occurs in about one third of the population and does not cause CDG (but is a disease modifier to exacerbate symptoms in patients with glycosylation pathway defects).
Early onset or syndromic epilepsy v0.1524 DHDDS Rebecca Foulger gene: DHDDS was added
gene: DHDDS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHDDS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHDDS were set to 27343064; 29100083
Phenotypes for gene: DHDDS were set to Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb; 613861
Review for gene: DHDDS was set to GREEN
Added comment: In 5 unrelated patients with developmental delay and seizures with or without movement abnormalities (DEDSM; 617836), Hamdan et al. (2017, PMID:29100083) identified 2 different de novo heterozygous missense mutations in the DHDDS gene (R37H and R211Q). These five individuals with de novo variants in DHDDS presented with a generalized epilepsy disorder with myoclonic seizures, either as myoclonic absences or as isolated cortical myoclonus, and sometimes with light sensitivity or fever susceptibility. Two of these individuals also presented with other generalized seizure types, including atonic seizures or generalized tonic-clonic seizures. In three individuals, EEG revealed clear generalized spike-wave discharges (and additional photosensitivity in one individual).
Sources: Literature
Early onset or syndromic epilepsy v0.1523 RALA Sarah Leigh Marked gene: RALA as ready
Early onset or syndromic epilepsy v0.1523 RALA Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least seven apparetly gain of function variants identified in eleven unrelated cases, with seizures reported in six of these cases.
Early onset or syndromic epilepsy v0.1523 RALA Sarah Leigh Gene: rala has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1523 RALA Sarah Leigh Added comment: Comment on publications: PMID for doi.org/10.1371/journal.pgen.1007671 not yet available
Early onset or syndromic epilepsy v0.1523 RALA Sarah Leigh Publications for gene: RALA were set to
Early onset or syndromic epilepsy v0.1522 NTRK2 Rebecca Foulger Marked gene: NTRK2 as ready
Early onset or syndromic epilepsy v0.1522 NTRK2 Rebecca Foulger Gene: ntrk2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1522 NTRK2 Rebecca Foulger Classified gene: NTRK2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1522 NTRK2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: Added and reviewed Green by Konstantinos Varvagiannis. Although probable rating in DD-G2P for 'Epilepsy and ID', there are sufficient unrelated cases (>3) of patients with NTRK2 variants and seizures from PMID:29100083 and PMID:15494731 (2 variants) for both EE and obesity/hyperphagia phenotypes.
Early onset or syndromic epilepsy v0.1522 NTRK2 Rebecca Foulger Gene: ntrk2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1521 NTRK2 Rebecca Foulger commented on gene: NTRK2
Early onset or syndromic epilepsy v0.1521 RALA Sarah Leigh Classified gene: RALA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1521 RALA Sarah Leigh Added comment: Comment on list classification: Based on reviewers' comments and sufficient cases.
Early onset or syndromic epilepsy v0.1521 RALA Sarah Leigh Gene: rala has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1520 RPIA Sarah Leigh Marked gene: RPIA as ready
Early onset or syndromic epilepsy v0.1520 RPIA Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least five variants identified in three unrelated cases, with seizures as a phenotypic feature in two of these cases.
Early onset or syndromic epilepsy v0.1520 RPIA Sarah Leigh Gene: rpia has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1520 MAST1 Rebecca Foulger commented on gene: MAST1: Added 'watchlist' tag.
Early onset or syndromic epilepsy v0.1520 MAST1 Rebecca Foulger Tag watchlist tag was added to gene: MAST1.
Early onset or syndromic epilepsy v0.1520 MAST1 Rebecca Foulger Classified gene: MAST1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1520 MAST1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. 6 individuals in PMID:30449657 with MAST1 variants, and seizures in 2/6 patients. DDD participant DDD4K.02310 has a synonymous variant in RXRG and a missense variant in MAST (Supplementary material of PMID:28135719). 1 individual in PMID:23934111 (Epi4K encephalopathies) had seizures- listed as benign variant from Polyphen in the paper tables. The phenotype appears complex, and MAST1 is not yet linked to epilepsy in OMIM, and is not yet on the DD-G2P list. Therefore rated as Amber awaiting further confirmed cases from the literature or clinic.
Early onset or syndromic epilepsy v0.1520 MAST1 Rebecca Foulger Gene: mast1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1519 RPIA Sarah Leigh Phenotypes for gene: RPIA were changed from Ribose 5-phosphate isomerase deficiency, MIM 608611 to ?Ribose 5-phosphate isomerase deficiency 608611
Early onset or syndromic epilepsy v0.1518 RPIA Sarah Leigh Classified gene: RPIA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1518 RPIA Sarah Leigh Added comment: Comment on list classification: Based on reviewers' comments and number of cases reported.
Early onset or syndromic epilepsy v0.1518 RPIA Sarah Leigh Gene: rpia has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1517 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to 29369572; 30245509
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Marked gene: TANGO2 as ready
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least three variants reported 7 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Gene: tango2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Classified gene: TANGO2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Added comment: Comment on list classification: Based on reviewer's comments and sufficient evidence from the literature.
Early onset or syndromic epilepsy v0.1516 TANGO2 Sarah Leigh Gene: tango2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1515 TANGO2 Sarah Leigh Phenotypes for gene: TANGO2 were changed from Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM 616878 to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger Marked gene: CAD as ready
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger Gene: cad has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger commented on gene: CAD: Confirmed DD-G2P gene for Uridine-responsive epileptic encephalopathy.
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger Classified gene: CAD as Green List (high evidence)
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: 5 patients from 4 families in total (1 patient from PMID:25678555 and 4 more patients from 28007989) all with epileptic seizures (generalized tonic clonic seizures, severe epilepsy, generalised/focal seizures). Note that 2 of the families in PMID:28007989 were Serbian Roma descent with the same homozygous c.98T>G (Met33Arg) transversion, although listed as unrelated. Overall sufficient (>3) unrelated cases of epileptic seizures in patients with CAD variants, for inclusion on diagnostic panel.
Early onset or syndromic epilepsy v0.1514 CAD Rebecca Foulger Gene: cad has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1514 TXNRD1 Sarah Leigh Added comment: Comment on phenotypes: Seizures, myoclonic seizures and generalized tonic-clonic seizures which disappeared progressively
Early onset or syndromic epilepsy v0.1514 TXNRD1 Sarah Leigh Phenotypes for gene: TXNRD1 were changed from genetic generalized epilepsy to genetic generalized epilepsy
Early onset or syndromic epilepsy v0.1513 TXNRD1 Sarah Leigh Marked gene: TXNRD1 as ready
Early onset or syndromic epilepsy v0.1513 TXNRD1 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. Based on single report of homozygous variants in five siblings three of whom have genetic generalized epilepsy (PMID 28232204), thus suggestive of incomplete penetrance. In vitro functional studies demonstrate the pathogenicity of the variant c.569 C>T, p.Pro190Leu, NM_182743.2, NP_877393.1. Furthermore, mouse models provide some evidence for the potential role of TXNRD1 in epilepsy, with nervous system-specific inactivation of Txnrd1 in mice resulting in ataxia, tremor and cerebellar hypoplasia. Although, cerebellar development was not impaired in neuron-specific Txnrd1 knockout mice. (PMID 18350150).
Early onset or syndromic epilepsy v0.1513 TXNRD1 Sarah Leigh Gene: txnrd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1513 TXNRD1 Sarah Leigh Penetrance for gene TXNRD1 was set from to None
Early onset or syndromic epilepsy v0.1512 TXNRD1 Sarah Leigh Added comment: Comment on publications: PMID 18350150 Nervous system-specific inactivation of Txnrd1 in mice led to ataxia, tremor and cerebellar hypoplasia. However, cerebellar development was not impaired in neuron-specific Txnrd1 knockout mice.
Early onset or syndromic epilepsy v0.1512 TXNRD1 Sarah Leigh Publications for gene: TXNRD1 were set to 28232204
Early onset or syndromic epilepsy v0.1511 TXNRD1 Sarah Leigh Classified gene: TXNRD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1511 TXNRD1 Sarah Leigh Gene: txnrd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1510 TXNRD1 Sarah Leigh gene: TXNRD1 was added
gene: TXNRD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TXNRD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXNRD1 were set to 28232204
Phenotypes for gene: TXNRD1 were set to genetic generalized epilepsy
Review for gene: TXNRD1 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v0.1509 SIX3 Sarah Leigh Added comment: Comment on publications: PMID 18791198 discusses incomplete penetrance.
Early onset or syndromic epilepsy v0.1509 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 28670735; 20157829; 19346217
Early onset or syndromic epilepsy v0.1508 NPRL2 Ellen McDonagh Marked gene: NPRL2 as ready
Early onset or syndromic epilepsy v0.1508 NPRL2 Ellen McDonagh Gene: nprl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1508 NPRL2 Ellen McDonagh Classified gene: NPRL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1508 NPRL2 Ellen McDonagh Added comment: Comment on list classification: At this time, as there are many unaffected family members with the variants identified in affected patients, Arianna Tucci (Genomics England Clinical Team) agrees that it is best to keep this gene amber for now, due to lack of enough evidence for a monogenic role of this gene in epilepsy.
Early onset or syndromic epilepsy v0.1508 NPRL2 Ellen McDonagh Gene: nprl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1507 NPRL2 Ellen McDonagh Classified gene: NPRL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1507 NPRL2 Ellen McDonagh Added comment: Comment on list classification: Knockout mice do not seem to have a seizure phenotype: http://www.informatics.jax.org/marker/phenotypes/MGI:1914482
Early onset or syndromic epilepsy v0.1507 NPRL2 Ellen McDonagh Gene: nprl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1506 SIX3 Sarah Leigh Marked gene: SIX3 as ready
Early onset or syndromic epilepsy v0.1506 SIX3 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, however, seizures have only been reported in two cases of SIX3 variant carriers. In PMID: 20157829, patient 4 had a seizure but certain epilepsy characteristic activity in the subsequent electroencephalogram (EEG) was not met. The variants (c.618C>A + c.621G>A; p.Gly206Gly + p.Glu207Glu) were found in this case. The synonymous variant c.621G>A, was not predicted to effect splicing, although it was was predicted to create a consensus sequence motif for an additional SF2/ASF (score 2.71378; threshold 1.956) as well as SRp40 (score 2.98263; threshold 2.67) splice enhancer. Both consensus sequences are recognized by the human proteins SF2/ASF or SRp40, respectively, and are important for the recognition and utilization of regular as well as alternative splice sites (Wang et al. 2005), and these may be considered to be pathogenic.
In PMID 28670735 a deletion of SIX3 gene was reported in a case with seizures, but incomplete penetrance has been suggested. The publication PMID 19346217 mentions seizures as a clinical feature, however, precise details about cases cannot be found as the supplementary material tables 1a & b are no longer available (the authors have been contacted, December 2018).
Early onset or syndromic epilepsy v0.1506 SIX3 Sarah Leigh Gene: six3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1506 NPRL2 Ellen McDonagh Tag watchlist tag was added to gene: NPRL2.
Early onset or syndromic epilepsy v0.1506 NPRL2 Ellen McDonagh Classified gene: NPRL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1506 NPRL2 Ellen McDonagh Added comment: Comment on list classification: Four families reported (see publications), however the same variants were identified in unaffected family members, with the publications stating this is due to incomplete penetrance.
Early onset or syndromic epilepsy v0.1506 NPRL2 Ellen McDonagh Gene: nprl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1505 NPRL2 Ellen McDonagh Source Victorian Clinical Genetics Services was removed from NPRL2.
Source Expert Review was added to NPRL2.
Penetrance for gene NPRL2 was set from to None
Early onset or syndromic epilepsy v0.1504 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 28670735; 20157829
Early onset or syndromic epilepsy v0.1503 NPRL2 Ellen McDonagh Mode of inheritance for gene: NPRL2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1502 NPRL2 Ellen McDonagh Publications for gene: NPRL2 were set to
Early onset or syndromic epilepsy v0.1501 NPRL2 Ellen McDonagh Phenotypes for gene: NPRL2 were changed from to Epilepsy, familial focal, with variable foci 2 617116
Early onset or syndromic epilepsy v0.1500 NGLY1 Ellen McDonagh Classified gene: NGLY1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1500 NGLY1 Ellen McDonagh Added comment: Comment on list classification: Promoted to Green due to expert review and enough evidence for N-glycanase 1 deficiency to cause seizures.
Early onset or syndromic epilepsy v0.1500 NGLY1 Ellen McDonagh Gene: ngly1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1499 NGLY1 Ellen McDonagh Marked gene: NGLY1 as ready
Early onset or syndromic epilepsy v0.1499 NGLY1 Ellen McDonagh Gene: ngly1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1499 NGLY1 Ellen McDonagh Classified gene: NGLY1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1499 NGLY1 Ellen McDonagh Added comment: Comment on list classification: Promoted to Green due to expert review and enough evidence for N-glycanase 1 deficiency to cause seizures.
Early onset or syndromic epilepsy v0.1499 NGLY1 Ellen McDonagh Gene: ngly1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1498 NGLY1 Ellen McDonagh Added comment: Comment on publications: PMID: 24651605 - 4 out of 8 patients with deficiency of N-glycanase 1 had seizures as a clinical feature.
Early onset or syndromic epilepsy v0.1498 NGLY1 Ellen McDonagh Publications for gene: NGLY1 were set to 22581936; 24651605
Early onset or syndromic epilepsy v0.1496 NGLY1 Ellen McDonagh Added comment: Comment on publications: PMID: 22581936 - describes a male patient with developmental delay, multifocal epilepsy, involuntary movements, abnormal liver function, absent tears. Sequencing revealed a frameshift variant inherited from his mother and a nonsense mutation from his father.
Early onset or syndromic epilepsy v0.1496 NGLY1 Ellen McDonagh Publications for gene: NGLY1 were set to
Early onset or syndromic epilepsy v0.1495 NGLY1 Ellen McDonagh Mode of inheritance for gene: NGLY1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1493 NGLY1 Ellen McDonagh Classified gene: NGLY1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1493 NGLY1 Ellen McDonagh Added comment: Comment on list classification: This is a Green gene on the Congenital disorders of glycosylation (Version 1.20) gene panel, with more than 4 families/cases with Congenital disorder of deglycosylation reported with variants in this gene.
Early onset or syndromic epilepsy v0.1493 NGLY1 Ellen McDonagh Gene: ngly1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1492 NGLY1 Ellen McDonagh Phenotypes for gene: NGLY1 were changed from to Congenital disorder of deglycosylation 615273
Early onset or syndromic epilepsy v0.1488 NTRK2 Konstantinos Varvagiannis gene: NTRK2 was added
gene: NTRK2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NTRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NTRK2 were set to 29100083; 15494731
Phenotypes for gene: NTRK2 were set to Epileptic encephalopathy, early infantile, 58 (MIM 617830); Obesity, hyperphagia, and developmental delay (MIM 613886)
Penetrance for gene: NTRK2 were set to unknown
Review for gene: NTRK2 was set to GREEN
Added comment: Heterozygous pathogenic variants in NTRK2 cause Epileptic encephalopathy, early infantile, 58 (EIEE58 - MIM 617830) or Obesity, hyperphagia, and developmental delay (MIM 613886).

Seizures can be noted in individuals falling into either diagnosis [eg. observed in the individuals with obesity and hyperphagia as in PMIDs: 15494731 and 29100083 (individual with Thr720Ile)].

Concerning EIEE58 Tyr434Cys appears to be a recurrent variant that has been observed in 4 unrelated individuals (summary in table 2 from PMID: 29100083).

NTRK2 is a probable DD gene in G2P associated with epilepsy and ID.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature
Early onset or syndromic epilepsy v0.1488 ALDH7A1 Ellen McDonagh commented on gene: ALDH7A1
Early onset or syndromic epilepsy v0.1488 ALDH7A1 Ellen McDonagh Tag treatable tag was added to gene: ALDH7A1.
Early onset or syndromic epilepsy v0.1488 TANGO2 Konstantinos Varvagiannis gene: TANGO2 was added
gene: TANGO2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 29369572; 30245509
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM 616878
Penetrance for gene: TANGO2 were set to Complete
Review for gene: TANGO2 was set to GREEN
gene: TANGO2 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in TANGO2 cause Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM 616878

PMIDs: 29369572 and 30245509 are both reviews on the disorder. Epilepsy is a feature in 70-80% of the patients (29 individuals reviewed in the second article).

According to PMID: 29369572 "Seizures are observed outside the periods of crises in more than 75% of individuals". PMID 30245509 notes that seizures occurred in a small minority of patients only during periods of crises secondary to hypoglycemia or associated with arrhythmia.

TANGO2 is included in gene panels for epilepsy offered by (few) diagnostic laboratories. The gene is already present in the ID and mitochondrial disorders panels as green.

As a result, this gene can also be considered for inclusion in this panel as green.
Sources: Literature
Early onset or syndromic epilepsy v0.1488 MAST1 Konstantinos Varvagiannis gene: MAST1 was added
gene: MAST1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST1 were set to 30449657; 23934111
Phenotypes for gene: MAST1 were set to Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures
Penetrance for gene: MAST1 were set to unknown
Review for gene: MAST1 was set to GREEN
Added comment: PMID: 30449657 reports on 6 unrelated individuals with de novo mutations in MAST1. All these 6 individuals were investigated for a strikingly similar phenotype of enlarged corpus callosum (CC), cerebellar hypoplasia, cortical malformation with associated DD/ID. Seizures were a feature in 2/6 (one further had EEG anomalies without clinical seizures).

Three of them harbored an in-frame deletion of 1 amino-acid (3 different indels reported - all in a specific domain) while 3 others had a missense variant (NM_014975.2:c.1549G>A or p.Gly517Ser).

Mast1 has embryonic expression in murine models with postnatal decrease. Similarly qPCR of human fetal brain cDNA demonstrated expression at 13 and 22 gestational weeks. A murine model for L278del recapitulated the brain (incl. CC) and cerebellar phenotype while Mast1 knockout mice do not present similar morphological defects. While Western blot in murine brain lysates demonstrated absence of Mast1 in knockout and reduction in the L278del, Mast1 transcript levels for L278del were similar to wildtype. Other Mast proteins (Mast1 & Mast2) were significantly reduced upon western blot while this was not reflected in their mRNA levels, suggesting a dominant-negative effect, at least for the L278del.

4 additional individuals with somewhat different phenotype consisting DD/ID and microcephaly/autism are described in the supplement. All 4 had de novo missense variants but did not display the CC-cerebral and cerebellar anomalies. Four different (additional to Gly517Ser) missense SNVs were observed.

Several additional individuals exist in the denovo-db (among others DDD participant DDD4K.02310 published in 28135719, 25666757 - McMichael et al. commented in the article, 27479843, etc.). [http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=Mast1]

Epilepsy was a feature in 4/10 individuals (with an additional one with EEG anomalies without clinical seizures). One further individual from PMID:23934111 (in denovo-db) had seizures.

As the authors comment (and as evident from the 6+4 reported patients) the related neurodevelopmental phenotype may be more complex.

MAST1 is not related to any phenotype in G2P, nor in OMIM.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v0.1488 RPIA Konstantinos Varvagiannis gene: RPIA was added
gene: RPIA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 14988808; 20499043; 28801340; 30088433
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611
Penetrance for gene: RPIA were set to unknown
Review for gene: RPIA was set to AMBER
Added comment: Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611.

PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T / NP_653164.2:p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG / NP_653164.2:p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548].

PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis.

PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis.

2 of the 3 patients described in the literature presented seizures.

As a result this gene can be considered for inclusion in this panel as amber.
Sources: Literature
Early onset or syndromic epilepsy v0.1488 CSTB_CCCCGCCCCGCG Arianna Tucci Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800
Early onset or syndromic epilepsy v0.1487 ATN1_CAG Arianna Tucci Phenotypes for STR: ATN1_CAG were changed from to Dentatorubro-pallidoluysian atrophy 125370
Early onset or syndromic epilepsy v0.1486 NDUFS6 Sarah Leigh Marked gene: NDUFS6 as ready
Early onset or syndromic epilepsy v0.1486 NDUFS6 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least two homozygous variants identified in two unrelated cases with abnormal, slowly drifting eye movements, rolling nystagmus, thought to indicate possible seizures, as well as overt seizures occurred on day 1 of life (PMID: 15372108). Other variants reported, but no association with epilepsy, seizures or convulsions could be found.
Early onset or syndromic epilepsy v0.1486 NDUFS6 Sarah Leigh Gene: ndufs6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1486 NDUFS6 Sarah Leigh Phenotypes for gene: NDUFS6 were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1485 NDUFS6 Sarah Leigh Publications for gene: NDUFS6 were set to
Early onset or syndromic epilepsy v0.1484 NDUFS6 Sarah Leigh Mode of inheritance for gene: NDUFS6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1483 NDUFS4 Sarah Leigh Marked gene: NDUFS4 as ready
Early onset or syndromic epilepsy v0.1483 NDUFS4 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least three biallelic variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1483 NDUFS4 Sarah Leigh Gene: ndufs4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1483 NDUFS4 Sarah Leigh Classified gene: NDUFS4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1483 NDUFS4 Sarah Leigh Gene: ndufs4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1482 NDUFS4 Sarah Leigh Mode of inheritance for gene: NDUFS4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1481 NDUFS4 Sarah Leigh Publications for gene: NDUFS4 were set to 28371352; 27671926; 27079373; 19107570; 9463323
Early onset or syndromic epilepsy v0.1480 NDUFS4 Sarah Leigh Phenotypes for gene: NDUFS4 were changed from to Leigh syndrome 256000; Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1479 NDUFS4 Sarah Leigh Publications for gene: NDUFS4 were set to
Early onset or syndromic epilepsy v0.1478 NDUFA11 Sarah Leigh Classified gene: NDUFA11 as Red List (low evidence)
Early onset or syndromic epilepsy v0.1478 NDUFA11 Sarah Leigh Added comment: Comment on list classification: Based on single case and the observation that not all the carriers manifested with convulsive disorder
Early onset or syndromic epilepsy v0.1478 NDUFA11 Sarah Leigh Gene: ndufa11 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1477 NDUFA11 Sarah Leigh Marked gene: NDUFA11 as ready
Early onset or syndromic epilepsy v0.1477 NDUFA11 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least one homozygous variant identified in a large consanguineous Bedoin family, convulsive disorder appeared at 4 months in one patient (PMID 18306244).
Early onset or syndromic epilepsy v0.1477 NDUFA11 Sarah Leigh Gene: ndufa11 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1477 NDUFA11 Sarah Leigh Publications for gene: NDUFA11 were set to
Early onset or syndromic epilepsy v0.1476 NDUFA11 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v0.1476 NDUFA11 Sarah Leigh Added comment: Comment on phenotypes: Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1476 NDUFA11 Sarah Leigh Phenotypes for gene: NDUFA11 were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1475 LIPT2 Sarah Leigh Marked gene: LIPT2 as ready
Early onset or syndromic epilepsy v0.1475 LIPT2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in one case
in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1475 LIPT2 Sarah Leigh Gene: lipt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1475 LIPT2 Sarah Leigh Phenotypes for gene: LIPT2 were changed from to Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities 617668
Early onset or syndromic epilepsy v0.1474 LIPT2 Sarah Leigh Mode of inheritance for gene: LIPT2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1473 LIPT2 Sarah Leigh Publications for gene: LIPT2 were set to
Early onset or syndromic epilepsy v0.1472 LIPT2 Sarah Leigh Tag watchlist tag was added to gene: LIPT2.
Early onset or syndromic epilepsy v0.1472 KIAA1109 Sarah Leigh Marked gene: KIAA1109 as ready
Early onset or syndromic epilepsy v0.1472 KIAA1109 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene (although not for seizures in Gen2Phen). At least 2 variants reported in Lithuanian siblings with Alkuraya-Kucinskas syndrome in which seizures were a phenotypic feature (PMID 29290337). Rare drosophila idividuals that are homozygous for a "tweek" variant (ortholog KIAA1109) survive to adulthood and are unable to walk or stand upright for long periods, plus they exhibit seizures, suggestive of severe neurological defects and similar to the reported phenotype of the Lithuanian siblings mentioned (PMID 19640479).
Early onset or syndromic epilepsy v0.1472 KIAA1109 Sarah Leigh Gene: kiaa1109 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1472 KIAA1109 Sarah Leigh Tag watchlist tag was added to gene: KIAA1109.
Early onset or syndromic epilepsy v0.1472 KIAA1109 Sarah Leigh Mode of inheritance for gene: KIAA1109 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1471 KIAA1109 Sarah Leigh Phenotypes for gene: KIAA1109 were changed from to Alkuraya-Kucinskas syndrome 617822
Early onset or syndromic epilepsy v0.1470 KIAA1109 Sarah Leigh Publications for gene: KIAA1109 were set to
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Classified gene: KAT5 as Red List (low evidence)
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Added comment: Comment on list classification: Based on expert reviewers' comments.
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Gene: kat5 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1468 H3F3B Sarah Leigh Classified gene: H3F3B as Red List (low evidence)
Early onset or syndromic epilepsy v0.1468 H3F3B Sarah Leigh Added comment: Comment on list classification: Based on expert reviewers' comments
Early onset or syndromic epilepsy v0.1468 H3F3B Sarah Leigh Gene: h3f3b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1467 H3F3A Sarah Leigh Classified gene: H3F3A as Red List (low evidence)
Early onset or syndromic epilepsy v0.1467 H3F3A Sarah Leigh Added comment: Comment on list classification: Based on expert reviewers' comments
Early onset or syndromic epilepsy v0.1467 H3F3A Sarah Leigh Gene: h3f3a has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1466 H3F3A Sarah Leigh Classified gene: H3F3A as Red List (low evidence)
Early onset or syndromic epilepsy v0.1466 H3F3A Sarah Leigh Gene: h3f3a has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1465 H3F3B Sarah Leigh Classified gene: H3F3B as Red List (low evidence)
Early onset or syndromic epilepsy v0.1465 H3F3B Sarah Leigh Gene: h3f3b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1464 GRIN2D Sarah Leigh Marked gene: GRIN2D as ready
Early onset or syndromic epilepsy v0.1464 GRIN2D Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in five unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1464 GRIN2D Sarah Leigh Gene: grin2d has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1464 GRIN2D Sarah Leigh Mode of inheritance for gene: GRIN2D was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1463 GRIN2D Sarah Leigh Added comment: Comment on phenotypes: Epileptic encephalopathy, early infantile, 46 617162
Early onset or syndromic epilepsy v0.1463 GRIN2D Sarah Leigh Phenotypes for gene: GRIN2D were changed from to Epileptic encephalopathy, early infantile, 46 617162
Early onset or syndromic epilepsy v0.1462 GRIN2D Sarah Leigh Publications for gene: GRIN2D were set to
Early onset or syndromic epilepsy v0.1461 GRIN2D Sarah Leigh Classified gene: GRIN2D as Green List (high evidence)
Early onset or syndromic epilepsy v0.1461 GRIN2D Sarah Leigh Gene: grin2d has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1460 GNAQ Sarah Leigh Marked gene: GNAQ as ready
Early onset or syndromic epilepsy v0.1460 GNAQ Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least one variant (rs397514698) was identified in at least 12/15 cases of Sturge-Weber syndrome, somatic, mosaic, 185300 (PMID 25374402). The percentage of the gain of function variant in brain tissues of these 12 patients ranged from 3.6 to 8.9%.
Early onset or syndromic epilepsy v0.1460 GNAQ Sarah Leigh Gene: gnaq has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1460 GNAQ Sarah Leigh Classified gene: GNAQ as Green List (high evidence)
Early onset or syndromic epilepsy v0.1460 GNAQ Sarah Leigh Gene: gnaq has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1459 AIMP1 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from monoallelic to biallelic to match OMIM, Gene2Phenotype, and other relevant panels.
Early onset or syndromic epilepsy v0.1459 AIMP1 Rebecca Foulger Mode of inheritance for gene: AIMP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1458 GNAQ Sarah Leigh Publications for gene: GNAQ were set to
Early onset or syndromic epilepsy v0.1457 GRIN2D Konstantinos Varvagiannis reviewed gene: GRIN2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616483, 30280376; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Early onset or syndromic epilepsy v0.1457 GNAQ Sarah Leigh Added comment: Comment on mode of pathogenicity: Somatic gain of function
Early onset or syndromic epilepsy v0.1457 GNAQ Sarah Leigh Mode of pathogenicity for gene: GNAQ was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.1456 GNAQ Sarah Leigh Mode of inheritance for gene: GNAQ was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1455 NDUFS2 Eleanor Williams Marked gene: NDUFS2 as ready
Early onset or syndromic epilepsy v0.1455 NDUFS2 Eleanor Williams Gene: ndufs2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1455 NDUFS2 Eleanor Williams Phenotypes for gene: NDUFS2 were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1454 NDUFS2 Eleanor Williams Publications for gene: NDUFS2 were set to
Early onset or syndromic epilepsy v0.1453 NDUFS2 Eleanor Williams Mode of inheritance for gene: NDUFS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1452 NDUFS2 Eleanor Williams Classified gene: NDUFS2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1452 NDUFS2 Eleanor Williams Added comment: Comment on list classification: Keep as Amber. Although there are sufficient cases to associate this gene with Mitochondrial complex I deficiency there is only 1 report of a patient with seizures.
Early onset or syndromic epilepsy v0.1452 NDUFS2 Eleanor Williams Gene: ndufs2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1451 NDUFS2 Eleanor Williams commented on gene: NDUFS2
Early onset or syndromic epilepsy v0.1451 GNAQ Sarah Leigh Phenotypes for gene: GNAQ were changed from to Sturge-Weber syndrome, somatic, mosaic, 185300
Early onset or syndromic epilepsy v0.1450 GFM1 Sarah Leigh Classified gene: GFM1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1450 GFM1 Sarah Leigh Gene: gfm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1449 GFM1 Sarah Leigh Marked gene: GFM1 as ready
Early onset or syndromic epilepsy v0.1449 GFM1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in at least three unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1449 GFM1 Sarah Leigh Gene: gfm1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1449 GFM1 Sarah Leigh Mode of inheritance for gene: GFM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1448 GFM1 Sarah Leigh Phenotypes for gene: GFM1 were changed from to Combined oxidative phosphorylation deficiency 1 609060
Early onset or syndromic epilepsy v0.1447 GFM1 Sarah Leigh Publications for gene: GFM1 were set to
Early onset or syndromic epilepsy v0.1446 DPM2 Sarah Leigh Phenotypes for gene: DPM2 were changed from to Congenital disorder of glycosylation, type Iu 615042
Early onset or syndromic epilepsy v0.1445 DPM2 Sarah Leigh Publications for gene: DPM2 were set to
Early onset or syndromic epilepsy v0.1444 DPM2 Sarah Leigh Mode of inheritance for gene: DPM2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1443 COX15 Sarah Leigh Mode of inheritance for gene: COX15 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1442 COX15 Sarah Leigh Phenotypes for gene: COX15 were changed from to Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 615119; Leigh syndrome 256000
Early onset or syndromic epilepsy v0.1441 COX15 Sarah Leigh Publications for gene: COX15 were set to
Early onset or syndromic epilepsy v0.1440 COG6 Sarah Leigh Mode of inheritance for gene: COG6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1439 COG6 Sarah Leigh Added comment: Comment on phenotypes: Congenital disorder of glycosylation, type Iil 614576
Early onset or syndromic epilepsy v0.1439 COG6 Sarah Leigh Phenotypes for gene: COG6 were changed from to Congenital disorder of glycosylation, type Iil 614576
Early onset or syndromic epilepsy v0.1438 CNPY3 Sarah Leigh Marked gene: CNPY3 as ready
Early onset or syndromic epilepsy v0.1438 CNPY3 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least three variants identified in two unrelated cases.
Early onset or syndromic epilepsy v0.1438 CNPY3 Sarah Leigh Gene: cnpy3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1438 CNPY3 Sarah Leigh Tag watchlist tag was added to gene: CNPY3.
Early onset or syndromic epilepsy v0.1438 CNPY3 Sarah Leigh Publications for gene: CNPY3 were set to
Early onset or syndromic epilepsy v0.1437 CNPY3 Sarah Leigh Mode of inheritance for gene: CNPY3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1436 CNPY3 Sarah Leigh Phenotypes for gene: CNPY3 were changed from to Epileptic encephalopathy, early infantile, 60 617929
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Marked gene: NDUFV1 as ready
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least six variants reported in at least three unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Gene: ndufv1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Classified gene: NDUFV1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Added comment: Comment on list classification: Sufficient variants in unrelated cases displaying seizures.
Early onset or syndromic epilepsy v0.1435 NDUFV1 Sarah Leigh Gene: ndufv1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1434 NDUFV1 Sarah Leigh Mode of inheritance for gene: NDUFV1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1433 NDUFV1 Sarah Leigh Phenotypes for gene: NDUFV1 were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1432 NDUFV1 Sarah Leigh Publications for gene: NDUFV1 were set to
Early onset or syndromic epilepsy v0.1431 NDUFV1 Eleanor Williams reviewed gene: NDUFV1: Rating: ; Mode of pathogenicity: None; Publications: 25615419; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v0.1431 COG8 Sarah Leigh Phenotypes for gene: COG8 were changed from to Congenital disorder of glycosylation, type IIh 611182
Early onset or syndromic epilepsy v0.1430 COG8 Sarah Leigh Publications for gene: COG8 were set to
Early onset or syndromic epilepsy v0.1429 COG8 Sarah Leigh Mode of inheritance for gene: COG8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1428 NDUFS1 Eleanor Williams Marked gene: NDUFS1 as ready
Early onset or syndromic epilepsy v0.1428 NDUFS1 Eleanor Williams Gene: ndufs1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1428 MAP2K2 Sarah Leigh Mode of inheritance for gene: MAP2K2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1427 NDUFS1 Eleanor Williams Phenotypes for gene: NDUFS1 were changed from to Mitochondrial complex I deficiency, 252010; LEIGH SYNDROME; MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY
Early onset or syndromic epilepsy v0.1426 NDUFS1 Eleanor Williams Mode of inheritance for gene: NDUFS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1425 NDUFS1 Eleanor Williams Publications for gene: NDUFS1 were set to
Early onset or syndromic epilepsy v0.1424 NDUFS1 Eleanor Williams Classified gene: NDUFS1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1424 NDUFS1 Eleanor Williams Added comment: Comment on list classification: Keeping this gene amber on this panel, because although there are enough cases to associate the gene with the disease possible epilepsy/seizures have only been observed in 2 cases.
Early onset or syndromic epilepsy v0.1424 NDUFS1 Eleanor Williams Gene: ndufs1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1423 NDUFS1 Eleanor Williams commented on gene: NDUFS1
Early onset or syndromic epilepsy v0.1423 SCO2 Sarah Leigh Marked gene: SCO2 as ready
Early onset or syndromic epilepsy v0.1423 SCO2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported as compound heterozygotes in three unrelated cases of Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377 in which seizures were a phenotypic feature. It appears from the literature that seizures are not commonly reported in this phenotype (PMIDs 14994243, 12020273).
Early onset or syndromic epilepsy v0.1423 SCO2 Sarah Leigh Gene: sco2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1423 SCO2 Sarah Leigh Classified gene: SCO2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1423 SCO2 Sarah Leigh Gene: sco2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1422 NDUFAF5 Eleanor Williams Marked gene: NDUFAF5 as ready
Early onset or syndromic epilepsy v0.1422 NDUFAF5 Eleanor Williams Gene: ndufaf5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1422 SCO2 Sarah Leigh Publications for gene: SCO2 were set to 10545952; 10749987
Early onset or syndromic epilepsy v0.1421 NDUFAF5 Eleanor Williams Phenotypes for gene: NDUFAF5 were changed from to Mitochondrial complex 1 deficiency 252010
Early onset or syndromic epilepsy v0.1420 NDUFAF5 Eleanor Williams Publications for gene: NDUFAF5 were set to
Early onset or syndromic epilepsy v0.1419 NDUFAF5 Eleanor Williams Mode of inheritance for gene: NDUFAF5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1418 NDUFAF5 Eleanor Williams Classified gene: NDUFAF5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1418 NDUFAF5 Eleanor Williams Added comment: Comment on list classification: Variants in this gene reported in more than 3 families with affected individuals. Seizures seen in 5 families.
Early onset or syndromic epilepsy v0.1418 NDUFAF5 Eleanor Williams Gene: ndufaf5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1417 NDUFAF5 Eleanor Williams commented on gene: NDUFAF5
Early onset or syndromic epilepsy v0.1417 NDUFAF3 Eleanor Williams Marked gene: NDUFAF3 as ready
Early onset or syndromic epilepsy v0.1417 NDUFAF3 Eleanor Williams Gene: ndufaf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1417 NDUFAF3 Eleanor Williams Phenotypes for gene: NDUFAF3 were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.1416 NDUFAF3 Eleanor Williams Publications for gene: NDUFAF3 were set to
Early onset or syndromic epilepsy v0.1415 NDUFAF3 Eleanor Williams Mode of inheritance for gene: NDUFAF3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1414 NDUFAF3 Eleanor Williams Classified gene: NDUFAF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1414 NDUFAF3 Eleanor Williams Added comment: Comment on list classification: There are 3 cases supporting the association of NDUFAF3 with Mitochondrial complex I deficiency, but only two cases with seizures to date so keeping this gene Amber until further cases verify the association with seizures.
Early onset or syndromic epilepsy v0.1414 NDUFAF3 Eleanor Williams Gene: ndufaf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1413 NDUFAF3 Eleanor Williams commented on gene: NDUFAF3
Early onset or syndromic epilepsy v0.1413 ATN1_CAG Louise Daugherty Tag STR tag was added to STR: ATN1_CAG.
Early onset or syndromic epilepsy v0.1413 PSAP Eleanor Williams Classified gene: PSAP as Green List (high evidence)
Early onset or syndromic epilepsy v0.1413 PSAP Eleanor Williams Added comment: Comment on list classification: Promoting to green after gaining access to PMID: 2514102 and confirming a second case of a patient showing seizures, which along with the mouse knockout model confirms the association with seizures. In addition there is a green expert review.
Early onset or syndromic epilepsy v0.1413 PSAP Eleanor Williams Gene: psap has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1412 CSTB_CCCCGCCCCGCG Louise Daugherty Tag STR tag was added to STR: CSTB_CCCCGCCCCGCG.
Early onset or syndromic epilepsy v0.1412 PSAP Eleanor Williams Added comment: Comment on phenotypes: Only added Combined SAP deficiency as a phenotype as evidence for seizures only found for this disorder.
Early onset or syndromic epilepsy v0.1412 PSAP Eleanor Williams Phenotypes for gene: PSAP were changed from to Combined SAP deficiency 611721
Early onset or syndromic epilepsy v0.1411 PSAP Eleanor Williams Publications for gene: PSAP were set to
Early onset or syndromic epilepsy v0.1410 PSAP Eleanor Williams Mode of inheritance for gene: PSAP was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1409 CSTB_CCCCGCCCCGCG Arianna Tucci Marked STR: CSTB_CCCCGCCCCGCG as ready
Early onset or syndromic epilepsy v0.1409 CSTB_CCCCGCCCCGCG Arianna Tucci Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1409 CSTB_CCCCGCCCCGCG Arianna Tucci Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Early onset or syndromic epilepsy v0.1409 CSTB_CCCCGCCCCGCG Arianna Tucci Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1408 CSTB_CCCCGCCCCGCG Arianna Tucci STR: CSTB_CCCCGCCCCGCG was added
STR: CSTB_CCCCGCCCCGCG was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for STR: CSTB_CCCCGCCCCGCG was set to BIALLELIC, autosomal or pseudoautosomal
Added comment: Added to the panel following the Webex discussion with experts from the GMCs (6/09/2018) about feeding back STR results
Sources: Expert list
Early onset or syndromic epilepsy v0.1407 PSAP Eleanor Williams Classified gene: PSAP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1407 PSAP Eleanor Williams Added comment: Comment on list classification: Keeping Amber rating, as only 1 confirmed case of a variant in PSAP in a n individual with seizures. A mouse model which does develop seizures also exists.
Early onset or syndromic epilepsy v0.1407 PSAP Eleanor Williams Gene: psap has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Marked STR: ATN1_CAG as ready
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Added comment: Comment when marking as ready: Added to the panel following the Webex discussion with experts from the GMCs (6/09/2018) about feeding back STR results
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1406 PSAP Eleanor Williams commented on gene: PSAP: A mouse SAP -/- knockout exists (PMID: 8776585) and surviving mice develop intermittent seizures and progress to continual tonic status epilepticus.
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Classified STR: ATN1_CAG as Green List (high evidence)
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1405 ATN1_CAG Arianna Tucci STR: ATN1_CAG was added
STR: ATN1_CAG was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for STR: ATN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for STR: ATN1_CAG was set to GREEN
Added comment: Sources: Expert Review
Early onset or syndromic epilepsy v0.1404 PSAP Eleanor Williams commented on gene: PSAP: Metachromatic leukodystrophy due to SAP-b deficiency
2 cases of children with variants in PSAP and saposin B deficiency have been reported in PMID: 8554069 (Henseler et al. 1996) and PMID: 10682309 (Wrobe et al. 2000). Neither child was reported to have seizures.
Early onset or syndromic epilepsy v0.1404 PSAP Eleanor Williams commented on gene: PSAP: Combined SAP deficiency
PMIDs: 2514102 (Harzer et al. 1989) and 1371116 (Schnabel et al. 1992) report 2 sibs with combined SAP deficiency with a homozygous mutation resulting in a M1L substitution. No precursor and no mature SAPs were detected in the patient's cells. Both parents were heterozygous for the mutation. Can't access full text for PMID: 2514102 to assess phenotype.

PMID: 11309366 (Hulkova et al. 2001) - In a Slovakian patient with fatal infantile combined SAP deficiency, a homozygous for a 1 bp deletion in the PSAP gene, inherited from both his parents . Immunohistochemical investigations indicated that saposins A, B, C, and D were all deficient. Generalized seizures developed within minutes of birth.
Early onset or syndromic epilepsy v0.1404 PSAP Eleanor Williams commented on gene: PSAP
Early onset or syndromic epilepsy v0.1404 PPP3CA Eleanor Williams Marked gene: PPP3CA as ready
Early onset or syndromic epilepsy v0.1404 PPP3CA Eleanor Williams Gene: ppp3ca has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1404 PPP3CA Eleanor Williams Publications for gene: PPP3CA were set to
Early onset or syndromic epilepsy v0.1403 PPP3CA Eleanor Williams Phenotypes for gene: PPP3CA were changed from to Epileptic encephalopathy, infantile or early childhood, 1 617711
Early onset or syndromic epilepsy v0.1402 PPP3CA Eleanor Williams Mode of inheritance for gene: PPP3CA was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1401 PPP3CA Eleanor Williams Classified gene: PPP3CA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1401 PPP3CA Eleanor Williams Added comment: Comment on list classification: > 3 cases of de novo variants in this gene associated with Epileptic encephalopathy. Note variants in the catalytic domain result in loss of function and are associated with this phenotype. Variants in the AI domain of the protein are not thought to be loss of function and the clinical phenotype does not always include seizures.
Early onset or syndromic epilepsy v0.1401 PPP3CA Eleanor Williams Gene: ppp3ca has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1400 PPP3CA Eleanor Williams commented on gene: PPP3CA
Early onset or syndromic epilepsy v0.1400 POMT1 Eleanor Williams Marked gene: POMT1 as ready
Early onset or syndromic epilepsy v0.1400 POMT1 Eleanor Williams Gene: pomt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1400 POMT1 Eleanor Williams Phenotypes for gene: POMT1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670
Early onset or syndromic epilepsy v0.1399 POMT1 Eleanor Williams Publications for gene: POMT1 were set to
Early onset or syndromic epilepsy v0.1398 POMT1 Eleanor Williams Mode of inheritance for gene: POMT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1397 POMT1 Eleanor Williams Classified gene: POMT1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1397 POMT1 Eleanor Williams Added comment: Comment on list classification: >3 cases of variants in this gene in patients with a relevant phenotype. £ patients reported with seizures.
Early onset or syndromic epilepsy v0.1397 POMT1 Eleanor Williams Gene: pomt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1396 POMT1 Eleanor Williams commented on gene: POMT1
Early onset or syndromic epilepsy v0.1396 PMM2 Eleanor Williams Classified gene: PMM2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1396 PMM2 Eleanor Williams Added comment: Comment on list classification: > 3 cases of variants in this gene associated with the phenotype, and presenting with seizures.
Early onset or syndromic epilepsy v0.1396 PMM2 Eleanor Williams Gene: pmm2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1395 PMM2 Eleanor Williams Classified gene: PMM2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1395 PMM2 Eleanor Williams Added comment: Comment on list classification: > 3 cases associating variants in this gene with the phenotype and presenting with seizures.
Early onset or syndromic epilepsy v0.1395 PMM2 Eleanor Williams Gene: pmm2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1394 PMM2 Eleanor Williams Marked gene: PMM2 as ready
Early onset or syndromic epilepsy v0.1394 PMM2 Eleanor Williams Gene: pmm2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1394 PMM2 Eleanor Williams Mode of inheritance for gene: PMM2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1393 PMM2 Eleanor Williams Phenotypes for gene: PMM2 were changed from to Congenital disorder of glycosylation, type Ia 212065
Early onset or syndromic epilepsy v0.1392 PMM2 Eleanor Williams Publications for gene: PMM2 were set to
Early onset or syndromic epilepsy v0.1391 PMM2 Eleanor Williams commented on gene: PMM2
Early onset or syndromic epilepsy v0.1391 POMGNT1 Eleanor Williams Marked gene: POMGNT1 as ready
Early onset or syndromic epilepsy v0.1391 POMGNT1 Eleanor Williams Gene: pomgnt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1391 POMGNT1 Eleanor Williams Phenotypes for gene: POMGNT1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3 253280
Early onset or syndromic epilepsy v0.1390 POMGNT1 Eleanor Williams Mode of inheritance for gene: POMGNT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1389 POMGNT1 Eleanor Williams Publications for gene: POMGNT1 were set to
Early onset or syndromic epilepsy v0.1388 POMGNT1 Eleanor Williams Classified gene: POMGNT1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1388 POMGNT1 Eleanor Williams Added comment: Comment on list classification: > 3 cases with variants in this gene and seizures so rating green.
Early onset or syndromic epilepsy v0.1388 POMGNT1 Eleanor Williams Gene: pomgnt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1387 POMGNT1 Eleanor Williams commented on gene: POMGNT1
Early onset or syndromic epilepsy v0.1387 PPT1 Eleanor Williams Marked gene: PPT1 as ready
Early onset or syndromic epilepsy v0.1387 PPT1 Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases
Early onset or syndromic epilepsy v0.1387 PPT1 Eleanor Williams Gene: ppt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1387 PPT1 Eleanor Williams Phenotypes for gene: PPT1 were changed from to Ceroid lipofuscinosis, neuronal, 1 256730
Early onset or syndromic epilepsy v0.1386 PPT1 Eleanor Williams Publications for gene: PPT1 were set to
Early onset or syndromic epilepsy v0.1385 PPT1 Eleanor Williams Mode of inheritance for gene: PPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1384 PPT1 Eleanor Williams Classified gene: PPT1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1384 PPT1 Eleanor Williams Added comment: Comment on list classification: Numerous variants and cases presenting with seizures.
Early onset or syndromic epilepsy v0.1384 PPT1 Eleanor Williams Gene: ppt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1383 PPT1 Eleanor Williams commented on gene: PPT1
Early onset or syndromic epilepsy v0.1383 PROSC Eleanor Williams Marked gene: PROSC as ready
Early onset or syndromic epilepsy v0.1383 PROSC Eleanor Williams Added comment: Comment when marking as ready: > 3 cases
Early onset or syndromic epilepsy v0.1383 PROSC Eleanor Williams Gene: prosc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1383 PROSC Eleanor Williams Phenotypes for gene: PROSC were changed from to Epilepsy, early-onset, vitamin B6-dependent 617290
Early onset or syndromic epilepsy v0.1382 PROSC Eleanor Williams Publications for gene: PROSC were set to
Early onset or syndromic epilepsy v0.1381 PROSC Eleanor Williams Mode of inheritance for gene: PROSC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1380 PROSC Eleanor Williams Classified gene: PROSC as Green List (high evidence)
Early onset or syndromic epilepsy v0.1380 PROSC Eleanor Williams Added comment: Comment on list classification: > 3 cases reported
Early onset or syndromic epilepsy v0.1380 PROSC Eleanor Williams Gene: prosc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1379 PROSC Eleanor Williams commented on gene: PROSC
Early onset or syndromic epilepsy v0.1379 PROSC Eleanor Williams Tag new-gene-name tag was added to gene: PROSC.
Early onset or syndromic epilepsy v0.1379 NARS2 Louise Daugherty Marked gene: NARS2 as ready
Early onset or syndromic epilepsy v0.1379 NARS2 Louise Daugherty Gene: nars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1379 NARS2 Louise Daugherty Classified gene: NARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1379 NARS2 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1379 NARS2 Louise Daugherty Gene: nars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1378 NARS2 Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1378 NARS2 Louise Daugherty Publications for gene: NARS2 were set to
Early onset or syndromic epilepsy v0.1377 SIX3 Sarah Leigh Added comment: Comment on publications: Variants reported in following articles in either Holoprosencephaly 2 157170 or Schizencephaly 269160 however, seizures are not mentioned in the patients being reported PMID: 19353631, 17001667, 10369266, 15523651.
Early onset or syndromic epilepsy v0.1377 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 28670735; 20157829
Early onset or syndromic epilepsy v0.1376 PTEN Eleanor Williams Phenotypes for gene: PTEN were changed from to Cowden syndrome 1 158350; Lhermitte-Duclos syndrome; BANNAYAN-RILEY-RUVALCABA SYNDROME
Early onset or syndromic epilepsy v0.1375 PTEN Eleanor Williams Marked gene: PTEN as ready
Early onset or syndromic epilepsy v0.1375 PTEN Eleanor Williams Gene: pten has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1375 PTEN Eleanor Williams Mode of inheritance for gene: PTEN was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1374 PTEN Eleanor Williams Publications for gene: PTEN were set to
Early onset or syndromic epilepsy v0.1373 PTEN Eleanor Williams Classified gene: PTEN as Green List (high evidence)
Early onset or syndromic epilepsy v0.1373 PTEN Eleanor Williams Added comment: Comment on list classification: 3 cases in which a variant in PTEN is reported in individuals with Bannayan-Riley-Ruvalcaba syndrome with clinical phenotype that includes seizures.
Early onset or syndromic epilepsy v0.1373 PTEN Eleanor Williams Gene: pten has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1372 NARS2 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1372 NARS2 Louise Daugherty Phenotypes for gene: NARS2 were changed from to Combined oxidative phosphorylation deficiency 24, 616239; seizures
Early onset or syndromic epilepsy v0.1371 PTEN Eleanor Williams commented on gene: PTEN
Early onset or syndromic epilepsy v0.1371 MTHFR Louise Daugherty Marked gene: MTHFR as ready
Early onset or syndromic epilepsy v0.1371 MTHFR Louise Daugherty Gene: mthfr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1371 MTR Louise Daugherty Marked gene: MTR as ready
Early onset or syndromic epilepsy v0.1371 MTR Louise Daugherty Gene: mtr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1371 NAGA Louise Daugherty Marked gene: NAGA as ready
Early onset or syndromic epilepsy v0.1371 NAGA Louise Daugherty Gene: naga has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1371 NAGA Louise Daugherty Classified gene: NAGA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1371 NAGA Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1371 NAGA Louise Daugherty Gene: naga has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1370 NAGA Louise Daugherty Added comment: Comment on publications: Added publications to support gene-disease association, and upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1370 NAGA Louise Daugherty Publications for gene: NAGA were set to
Early onset or syndromic epilepsy v0.1369 SIX3 Sarah Leigh Publications for gene: SIX3 were set to
Early onset or syndromic epilepsy v0.1368 SIX3 Sarah Leigh Source Victorian Clinical Genetics Services was removed from SIX3.
Source Literature was added to SIX3.
Penetrance for gene SIX3 was set from to None
Early onset or syndromic epilepsy v0.1367 PCCB Eleanor Williams Classified gene: PCCB as Green List (high evidence)
Early onset or syndromic epilepsy v0.1367 PCCB Eleanor Williams Added comment: Comment on list classification: Promoted to green on the basis that there are sufficient cases of variants in this gene in patients with a relevant phenotype, and that seizures are reported in 12-53% of patients.
Early onset or syndromic epilepsy v0.1367 PCCB Eleanor Williams Gene: pccb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1366 PCCA Eleanor Williams Classified gene: PCCA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1366 PCCA Eleanor Williams Added comment: Comment on list classification: Promoted to green on the basis that there are sufficient cases of variants in this gene in patients with a relevant phenotype, and that seizures are reported in 12-53% of patients.
Early onset or syndromic epilepsy v0.1366 PCCA Eleanor Williams Gene: pcca has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1365 SIX3 Sarah Leigh Added comment: Comment on phenotypes: Schizencephaly 269160
Early onset or syndromic epilepsy v0.1365 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from Holoprosencephaly 2 157170 to Holoprosencephaly 2 157170; Schizencephaly 269160
Early onset or syndromic epilepsy v0.1364 NAGA Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1364 NAGA Louise Daugherty Mode of inheritance for gene: NAGA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1363 SDHA Sarah Leigh Marked gene: SDHA as ready
Early onset or syndromic epilepsy v0.1363 SDHA Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported in two unrelated cases, one of autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency and the other of Leigh syndrome. Seizures do not appear to be a common feature of either phenotype as there are numerous reports of biallelic SDHA variants in cases with out seizures (PMIDs: 22972948, 16798039,12794685, 10746566 & 7550341).
Early onset or syndromic epilepsy v0.1363 SDHA Sarah Leigh Gene: sdha has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1363 NAGA Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1363 NAGA Louise Daugherty Phenotypes for gene: NAGA were changed from to Schindler disease, type I, 609241; seizures
Early onset or syndromic epilepsy v0.1362 CAD Konstantinos Varvagiannis gene: CAD was added
gene: CAD was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 25678555; 28007989
Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50 - MIM 616457
Penetrance for gene: CAD were set to Complete
Review for gene: CAD was set to GREEN
Added comment: Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457.

Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary).

The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset.

CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis.

In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway.

CAD mutations have previously been studied in other model organisms.

Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes.

The disorder appears to be amenable to dietary intervention (uridine supplementation).

As a result, this gene can be considered for inclusion in the epilepsy panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v0.1362 SDHA Sarah Leigh Added comment: Comment on publications: PMIDs: 22972948, 16798039,12794685, 10746566 & 7550341 report biallelic variants, but no seizures.
Early onset or syndromic epilepsy v0.1362 SDHA Sarah Leigh Publications for gene: SDHA were set to
Early onset or syndromic epilepsy v0.1361 MTR Louise Daugherty Classified gene: MTR as Green List (high evidence)
Early onset or syndromic epilepsy v0.1361 MTR Louise Daugherty Gene: mtr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1360 MTR Louise Daugherty Publications for gene: MTR were set to 9453374; 12068375; 9683607; 28666289
Early onset or syndromic epilepsy v0.1359 MTR Louise Daugherty Publications for gene: MTR were set to 12068375; 9683607; 28666289
Early onset or syndromic epilepsy v0.1358 MTR Louise Daugherty Classified gene: MTR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1358 MTR Louise Daugherty Added comment: Comment on list classification: Not enough evidence to date to rate this gene green, kept this gene Amber on this panel until further evidence.
Early onset or syndromic epilepsy v0.1358 MTR Louise Daugherty Gene: mtr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1357 MTR Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Early onset or syndromic epilepsy v0.1357 MTR Louise Daugherty Publications for gene: MTR were set to
Early onset or syndromic epilepsy v0.1356 MTHFR Louise Daugherty Publications for gene: MTHFR were set to 29391032; 21778025; 12406076; 12840091; 9587029; 30267335; 24556013
Early onset or syndromic epilepsy v0.1355 SDHA Sarah Leigh Added comment: Comment on phenotypes: Mitochondrial respiratory chain complex II deficiency 252011
Early onset or syndromic epilepsy v0.1355 SDHA Sarah Leigh Phenotypes for gene: SDHA were changed from to Leigh syndrome 256000; Mitochondrial respiratory chain complex II deficiency 252011
Early onset or syndromic epilepsy v0.1354 SDHA Sarah Leigh Mode of inheritance for gene: SDHA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1353 SEPSECS Sarah Leigh Marked gene: SEPSECS as ready
Early onset or syndromic epilepsy v0.1353 SEPSECS Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least three variants identified in unrelated cases of Pontocerebellar hypoplasia type 2D 613811, however, the majority of published cases of this condition do not include seizures.
Early onset or syndromic epilepsy v0.1353 SEPSECS Sarah Leigh Gene: sepsecs has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1353 SEPSECS Sarah Leigh Classified gene: SEPSECS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1353 SEPSECS Sarah Leigh Gene: sepsecs has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1352 SEPSECS Sarah Leigh Publications for gene: SEPSECS were set to 20920667; 25044680
Early onset or syndromic epilepsy v0.1351 SEPSECS Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v0.1351 SEPSECS Sarah Leigh Added comment: Comment on publications: No seizures reported in two milder cases of Pontocerebellar hypoplasia type 2D 613811 in PMID: 26888482. SEPSECS variants not reported in the cases that have seizures (21 trios) in PMID: 25590979. PMID: 26805434 case report of pontocerebellar hypoplasia type 2D and optic nerve atrophy, with homozygous SEPSECS variannt, but no seizures.
Early onset or syndromic epilepsy v0.1351 SEPSECS Sarah Leigh Publications for gene: SEPSECS were set to 20920667; 25044680
Early onset or syndromic epilepsy v0.1350 MTR Louise Daugherty Phenotypes for gene: MTR were changed from Homocystinuria-megaloblastic anemia, cblG complementation type, 250940; seizures to Homocystinuria-megaloblastic anemia, cblG complementation type, 250940; methionine synthase deficiency type cblG; seizures
Early onset or syndromic epilepsy v0.1349 MTR Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1349 MTR Louise Daugherty Phenotypes for gene: MTR were changed from to Homocystinuria-megaloblastic anemia, cblG complementation type, 250940; seizures
Early onset or syndromic epilepsy v0.1348 MTR Louise Daugherty Mode of inheritance for gene: MTR was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1347 SEPSECS Sarah Leigh Added comment: Comment on publications: No seizures reported in two milder cases of Pontocerebellar hypoplasia type 2D 613811 in PMID: 26888482.
Early onset or syndromic epilepsy v0.1347 SEPSECS Sarah Leigh Publications for gene: SEPSECS were set to 20920667; 25044680
Early onset or syndromic epilepsy v0.1346 SEPSECS Sarah Leigh Mode of inheritance for gene: SEPSECS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1345 SEPSECS Sarah Leigh Mode of inheritance for gene: SEPSECS was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1344 SEPSECS Sarah Leigh Publications for gene: SEPSECS were set to
Early onset or syndromic epilepsy v0.1343 SEPSECS Sarah Leigh Phenotypes for gene: SEPSECS were changed from to Pontocerebellar hypoplasia type 2D 613811
Early onset or syndromic epilepsy v0.1342 SETBP1 Sarah Leigh Marked gene: SETBP1 as ready
Early onset or syndromic epilepsy v0.1342 SETBP1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in twelve unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1342 SETBP1 Sarah Leigh Gene: setbp1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1342 SETBP1 Sarah Leigh Classified gene: SETBP1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1342 SETBP1 Sarah Leigh Gene: setbp1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1341 SETBP1 Sarah Leigh Publications for gene: SETBP1 were set to
Early onset or syndromic epilepsy v0.1340 SETBP1 Sarah Leigh Mode of inheritance for gene: SETBP1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1339 SETBP1 Sarah Leigh Phenotypes for gene: SETBP1 were changed from to Schinzel-Giedion midface retraction syndrome 269150
Early onset or syndromic epilepsy v0.1338 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from to Holoprosencephaly 2 157170
Early onset or syndromic epilepsy v0.1337 SIX3 Sarah Leigh Mode of inheritance for gene: SIX3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1336 SLC25A12 Sarah Leigh Marked gene: SLC25A12 as ready
Early onset or syndromic epilepsy v0.1336 SLC25A12 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least three homozygous variants identified in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1336 SLC25A12 Sarah Leigh Gene: slc25a12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1336 SLC25A12 Sarah Leigh Classified gene: SLC25A12 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1336 SLC25A12 Sarah Leigh Gene: slc25a12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1335 SLC25A12 Sarah Leigh Added comment: Comment on publications: Homozygous missense variants: c.1058G>A; p.Arg353Gln, segregated with disease in this kindred in a child with epilepsy (PMID 24515575);
c.1769A>G, p.Gln590Arg in a 3 year old girl (PMID: 19641205); de novo in an infant c.1335C>A, p.Asn445Lys (PMID 27290639).
Early onset or syndromic epilepsy v0.1335 SLC25A12 Sarah Leigh Publications for gene: SLC25A12 were set to 24515575; 19641205; 27290639
Early onset or syndromic epilepsy v0.1334 SLC25A12 Sarah Leigh Publications for gene: SLC25A12 were set to
Early onset or syndromic epilepsy v0.1333 SLC25A12 Sarah Leigh Phenotypes for gene: SLC25A12 were changed from to Epileptic encephalopathy, early infantile, 39 612949
Early onset or syndromic epilepsy v0.1332 SLC25A12 Sarah Leigh Mode of inheritance for gene: SLC25A12 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1331 SLC6A8 Sarah Leigh Classified gene: SLC6A8 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1331 SLC6A8 Sarah Leigh Gene: slc6a8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1330 SLC6A8 Sarah Leigh Marked gene: SLC6A8 as ready
Early onset or syndromic epilepsy v0.1330 SLC6A8 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported
in at least four unrelated male cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1330 SLC6A8 Sarah Leigh Gene: slc6a8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1330 SLC6A8 Sarah Leigh Publications for gene: SLC6A8 were set to
Early onset or syndromic epilepsy v0.1329 SLC6A8 Sarah Leigh Phenotypes for gene: SLC6A8 were changed from to Cerebral creatine deficiency syndrome 1 300352
Early onset or syndromic epilepsy v0.1328 SLC6A8 Sarah Leigh Mode of inheritance for gene: SLC6A8 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.1327 SNORD118 Sarah Leigh Marked gene: SNORD118 as ready
Early onset or syndromic epilepsy v0.1327 SNORD118 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and in Gen2Phen gene (Plausible disease-causing mutations within, affecting or encompassing the coding region of a single gene identified in multiple (>3) unrelated cases/families with both the relevant disease (RD) and an incidental disorder). At least 13 variants reported in 13 cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1327 SNORD118 Sarah Leigh Gene: snord118 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1327 SNORD118 Sarah Leigh Mode of inheritance for gene: SNORD118 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1326 SNORD118 Sarah Leigh Classified gene: SNORD118 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1326 SNORD118 Sarah Leigh Gene: snord118 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1325 SNORD118 Sarah Leigh Publications for gene: SNORD118 were set to
Early onset or syndromic epilepsy v0.1324 DOLK Konstantinos Varvagiannis reviewed gene: DOLK: Rating: AMBER; Mode of pathogenicity: None; Publications: 24144945, 28816422; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v0.1324 SNORD118 Sarah Leigh Phenotypes for gene: SNORD118 were changed from to Leukoencephalopathy, brain calcifications, and cysts 614561
Early onset or syndromic epilepsy v0.1323 MTHFR Louise Daugherty Classified gene: MTHFR as Green List (high evidence)
Early onset or syndromic epilepsy v0.1323 MTHFR Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1323 MTHFR Louise Daugherty Gene: mthfr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1322 MTHFR Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1322 MTHFR Louise Daugherty Publications for gene: MTHFR were set to
Early onset or syndromic epilepsy v0.1321 EIF2B3 Rebecca Foulger Marked gene: EIF2B3 as ready
Early onset or syndromic epilepsy v0.1321 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1321 EIF2B1 Rebecca Foulger Marked gene: EIF2B1 as ready
Early onset or syndromic epilepsy v0.1321 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1321 ETHE1 Rebecca Foulger Marked gene: ETHE1 as ready
Early onset or syndromic epilepsy v0.1321 ETHE1 Rebecca Foulger Gene: ethe1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1321 DNM1L Rebecca Foulger Added comment: Comment on mode of inheritance: Both autosomal dominant and autosomal recessive inheritance reported by OMIM for 'Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, 614388'.
Early onset or syndromic epilepsy v0.1321 DNM1L Rebecca Foulger Mode of inheritance for gene: DNM1L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1320 MMACHC Rebecca Foulger Marked gene: MMACHC as ready
Early onset or syndromic epilepsy v0.1320 MMACHC Rebecca Foulger Gene: mmachc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1320 MPDU1 Rebecca Foulger Marked gene: MPDU1 as ready
Early onset or syndromic epilepsy v0.1320 MPDU1 Rebecca Foulger Gene: mpdu1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1320 MPDU1 Rebecca Foulger Classified gene: MPDU1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1320 MPDU1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza plus sufficient (>3) cases of seizures in CDG patients with MPDU1 variants from PMIDs:11733556, 11733564 and 28122681.
Early onset or syndromic epilepsy v0.1320 MPDU1 Rebecca Foulger Gene: mpdu1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1319 MPDU1 Rebecca Foulger Publications for gene: MPDU1 were set to
Early onset or syndromic epilepsy v0.1318 MPDU1 Rebecca Foulger commented on gene: MPDU1: PMID:28122681 (Al Teneiji et al. 2017) report 15 patients, 1 of which had MPDU1-CDG. The patient had a homozygous c.218G>A (p.G73E) variant in MPDU1, and seizures were reported amongst the phenotypes (Table 2).
Early onset or syndromic epilepsy v0.1318 MTHFR Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1318 MTHFR Louise Daugherty Mode of inheritance for gene: MTHFR was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1317 MTHFR Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1317 MTHFR Louise Daugherty Phenotypes for gene: MTHFR were changed from to Homocystinuria due to MTHFR deficiency, 236250; seizures
Early onset or syndromic epilepsy v0.1316 MPDU1 Rebecca Foulger commented on gene: MPDU1: Schenk et al 2001 (PMID:11733564) report 3 unrelated patients with congenital disorder of glycosylation CDG-If, and variants in MPDU1. Patient S had severed intractable seizures from birth, which worsened up to his death age 10 months. Patient A had generalized seizures from age 15 months that responded well to valproate (listed as generalized febrile seizures in Table 1). Patient L had hypertonic attacks in infancy.
Early onset or syndromic epilepsy v0.1316 MPDU1 Rebecca Foulger commented on gene: MPDU1
Early onset or syndromic epilepsy v0.1316 MPDU1 Rebecca Foulger Mode of inheritance for gene: MPDU1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1315 MPDU1 Rebecca Foulger Phenotypes for gene: MPDU1 were changed from to Congenital disorder of glycosylation, type If, 609180
Early onset or syndromic epilepsy v0.1314 MMADHC Rebecca Foulger Marked gene: MMADHC as ready
Early onset or syndromic epilepsy v0.1314 MMADHC Rebecca Foulger Gene: mmadhc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1314 MMADHC Rebecca Foulger Classified gene: MMADHC as Green List (high evidence)
Early onset or syndromic epilepsy v0.1314 MMADHC Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Green rating by Zornitza, and sufficient unrelated cases of patients with MMADHC variants and seizures (4 cases in PMID:18385497) for inclusion on panel.
Early onset or syndromic epilepsy v0.1314 MMADHC Rebecca Foulger Gene: mmadhc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1313 MMADHC Rebecca Foulger commented on gene: MMADHC
Early onset or syndromic epilepsy v0.1313 MMADHC Rebecca Foulger Mode of inheritance for gene: MMADHC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1312 SPR Sarah Leigh Marked gene: SPR as ready
Early onset or syndromic epilepsy v0.1312 SPR Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, however, the associated seizures appear to have been misdiagnosed and are infact myoclonic movements (PMIDs 16650784;21431957;28189489).
Early onset or syndromic epilepsy v0.1312 SPR Sarah Leigh Gene: spr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1312 SPR Sarah Leigh Publications for gene: SPR were set to
Early onset or syndromic epilepsy v0.1311 SPR Sarah Leigh reviewed gene: SPR: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v0.1311 MMADHC Rebecca Foulger Phenotypes for gene: MMADHC were changed from to Methylmalonic aciduria and homocystinuria, cblD type, 277410
Early onset or syndromic epilepsy v0.1310 EXOSC3 Rebecca Foulger Publications for gene: EXOSC3 were set to 25144110; 25149867; 23975261
Early onset or syndromic epilepsy v0.1309 MMACHC Rebecca Foulger Publications for gene: MMACHC were set to
Early onset or syndromic epilepsy v0.1308 MMACHC Rebecca Foulger Marked gene: MMACHC as ready
Early onset or syndromic epilepsy v0.1308 MMACHC Rebecca Foulger Gene: mmachc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1308 MMACHC Rebecca Foulger Classified gene: MMACHC as Green List (high evidence)
Early onset or syndromic epilepsy v0.1308 MMACHC Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza plus sufficient (>3) cases of cblC disease patients with MMACHC variants and seizures from PMIDs 17431913 and 20924684).
Early onset or syndromic epilepsy v0.1308 MMACHC Rebecca Foulger Gene: mmachc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1307 MMACHC Rebecca Foulger commented on gene: MMACHC: PMID:20924684 (Wang et al, 2010) report 43 patients with combined methylmalonic acidemia and hyperhomocysteinemia (cblC type), 50% of which presented with seizures. Homozygous MMACHC variants are listed in Table 4.
Early onset or syndromic epilepsy v0.1307 SPR Sarah Leigh Mode of inheritance for gene: SPR was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1306 DBT Rebecca Foulger Marked gene: DBT as ready
Early onset or syndromic epilepsy v0.1306 DBT Rebecca Foulger Gene: dbt has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1306 DBT Rebecca Foulger Classified gene: DBT as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1306 DBT Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: DBT encodes the E2 subunit of the BCKD complex. The other complex subunits (BCKDHA and BCKDHB) are Green on this panel, and all 3 genes are associated with Maple syrup urine disease (MSUD, MIM:248600). Seizures are a recognised symptom of MSUD, and although there is generalized information about DBT causing intermediate forms of the disease with later-onset seizures, specific cases with DBT variants are required before promoting to Green.
Early onset or syndromic epilepsy v0.1306 DBT Rebecca Foulger Gene: dbt has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1305 DBT Rebecca Foulger Tag watchlist tag was added to gene: DBT.
Early onset or syndromic epilepsy v0.1305 EIF2B1 Rebecca Foulger Classified gene: EIF2B1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1305 EIF2B1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber after discussion in Genomics England Curation team. Although other EIF2B subunits are also associated with Vanishing white matter (VWM) and rated Green on the panel, there are currently insufficient clinical/literature cases of patients with EIF2B1 and seizures (2 patients in PMIDs 25761052 and 25843247). Therefore added 'watchlist' tag while awaiting further cases.
Early onset or syndromic epilepsy v0.1305 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Marked gene: EIF2B3 as ready
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Tag watchlist tag was added to gene: EIF2B3.
Early onset or syndromic epilepsy v0.1304 EIF2B1 Rebecca Foulger Tag watchlist tag was added to gene: EIF2B1.
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Classified gene: EIF2B3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber after discussion in Genomics England Curation team. Although other EIF2B subunits are also associated with Vanishing white matter (VWM) and rated Green on the panel, there are currently insufficient clinical/literature cases of patients with EIF2B3 and seizures (1 patient in 19158808). Therefore added 'watchlist' tag while awaiting further cases.
Early onset or syndromic epilepsy v0.1304 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1303 SPR Sarah Leigh Phenotypes for gene: SPR were changed from to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716
Early onset or syndromic epilepsy v0.1302 STAG1 Sarah Leigh Marked gene: STAG1 as ready
Early onset or syndromic epilepsy v0.1302 STAG1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Three missense variants and one copy number event that deletes STAG1 & PCCB genes were reported in four unrelated cases in which seizures were a phenotypic feature.
Early onset or syndromic epilepsy v0.1302 STAG1 Sarah Leigh Gene: stag1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1302 STAG1 Sarah Leigh Classified gene: STAG1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1302 STAG1 Sarah Leigh Gene: stag1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1301 STAG1 Sarah Leigh Publications for gene: STAG1 were set to
Early onset or syndromic epilepsy v0.1300 STAG1 Sarah Leigh Phenotypes for gene: STAG1 were changed from to Mental retardation, autosomal dominant 47 617635
Early onset or syndromic epilepsy v0.1299 STAG1 Sarah Leigh Mode of inheritance for gene: STAG1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1298 STAMBP Sarah Leigh Classified gene: STAMBP as Green List (high evidence)
Early onset or syndromic epilepsy v0.1298 STAMBP Sarah Leigh Gene: stambp has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1297 STAMBP Sarah Leigh Marked gene: STAMBP as ready
Early onset or syndromic epilepsy v0.1297 STAMBP Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in at least 6 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1297 STAMBP Sarah Leigh Gene: stambp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1297 STAMBP Sarah Leigh Publications for gene: STAMBP were set to
Early onset or syndromic epilepsy v0.1296 MMACHC Rebecca Foulger commented on gene: MMACHC
Early onset or syndromic epilepsy v0.1296 LARGE1 Ivone Leong Marked gene: LARGE1 as ready
Early onset or syndromic epilepsy v0.1296 LARGE1 Ivone Leong Added comment: Comment when marking as ready: Seizures are more common features of other dystroglycanopathies, therefore LARGE1 will remain an amber gene as there is not enough evidence to promote it to a green gene currently. I have added the 'watchlist' tag.
Early onset or syndromic epilepsy v0.1296 LARGE1 Ivone Leong Gene: large1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1296 LARGE1 Ivone Leong Tag watchlist tag was added to gene: LARGE1.
Early onset or syndromic epilepsy v0.1296 ISPD Ivone Leong Marked gene: ISPD as ready
Early onset or syndromic epilepsy v0.1296 ISPD Ivone Leong Added comment: Comment when marking as ready: Seizures are more common features of other dystroglycanopathies, therefore ISPD will remain an amber gene as there is not enough evidence to promote it to a green gene currently. I have added the 'watchlist' tag.
Early onset or syndromic epilepsy v0.1296 ISPD Ivone Leong Gene: ispd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1296 ISPD Ivone Leong Tag watchlist tag was added to gene: ISPD.
Early onset or syndromic epilepsy v0.1296 STAMBP Sarah Leigh Phenotypes for gene: STAMBP were changed from to Microcephaly-capillary malformation syndrome 614261
Early onset or syndromic epilepsy v0.1295 HSPD1 Ivone Leong Marked gene: HSPD1 as ready
Early onset or syndromic epilepsy v0.1295 HSPD1 Ivone Leong Added comment: Comment when marking as ready: HSPD1 remains as an amber gene as there is not enough evidence to promote it to a green gene. I have added the watchlist tag.
Early onset or syndromic epilepsy v0.1295 HSPD1 Ivone Leong Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1295 STAMBP Sarah Leigh Mode of inheritance for gene: STAMBP was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1294 HCCS Ivone Leong Marked gene: HCCS as ready
Early onset or syndromic epilepsy v0.1294 HCCS Ivone Leong Added comment: Comment when marking as ready: Despite seizures being listed as a common feature in GeneReviews, there is only 1 reported case of epilepsy with with HCCS gene. Therefore, it will remain as an amber gene. I have added the 'watchlist' tag.
Early onset or syndromic epilepsy v0.1294 HCCS Ivone Leong Gene: hccs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1294 HCCS Ivone Leong Tag watchlist tag was added to gene: HCCS.
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Marked gene: DOLK as ready
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Gene: dolk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger commented on gene: DOLK: Added 'watchlist' tag.
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Tag watchlist tag was added to gene: DOLK.
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Classified gene: DOLK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: 2 families reported so far (2 siblings from PMID:23890587 and 1 of 2 cousins in PMID:17273964). Zornitza confirmed (via email on Dec 1st 2018) that there's no further known cases.
Early onset or syndromic epilepsy v0.1294 DOLK Rebecca Foulger Gene: dolk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1293 GTPBP3 Ivone Leong Marked gene: GTPBP3 as ready
Early onset or syndromic epilepsy v0.1293 GTPBP3 Ivone Leong Added comment: Comment when marking as ready: GTPBP3 remains an amber gene as there are only 2 reported cases of epilepsy for this gene. I have put the 'watchlist' tag on so that if new cases appear this gene will be updated accordingly.
Early onset or syndromic epilepsy v0.1293 GTPBP3 Ivone Leong Gene: gtpbp3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1293 GTPBP3 Ivone Leong Tag watchlist tag was added to gene: GTPBP3.
Early onset or syndromic epilepsy v0.1293 EXOSC3 Rebecca Foulger Marked gene: EXOSC3 as ready
Early onset or syndromic epilepsy v0.1293 EXOSC3 Rebecca Foulger Gene: exosc3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1293 EXOSC3 Rebecca Foulger Classified gene: EXOSC3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1293 EXOSC3 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza plus sufficient unrelated cases (>3) of seizures in patients with EXOSC3 variants from PMIDs:24524299 and 23284067 for inclusion on panel.
Early onset or syndromic epilepsy v0.1293 EXOSC3 Rebecca Foulger Gene: exosc3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1292 EXOSC3 Rebecca Foulger commented on gene: EXOSC3: Rudnik-Schoneborn et al 2013 (PMID:23284067) detected biallelic variants in EXOSC3 in 15 patients (10 of 27 families). Epileptic seizures occurred in 3 patients in 2 families, including absence epilepsy in patient 2-1 and infantile spasms in 2 sisters (5-1 and 5-2).
Early onset or syndromic epilepsy v0.1292 MMACHC Rebecca Foulger Mode of inheritance for gene: MMACHC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1291 MMACHC Rebecca Foulger Phenotypes for gene: MMACHC were changed from to Methylmalonic aciduria and homocystinuria, cblC type, 277400
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger Marked gene: MLC1 as ready
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger Gene: mlc1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger commented on gene: MLC1: In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004), Lopez-Hernandez et al. (2011, PMID:21624973) identified a homozygous misssense 206C-T variant in the MLC1 gene (p.S69L). The patient had epilepsy amongst her symptoms.
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger Classified gene: MLC1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza. Plus the onset of epileptic seizures is an integral part of the MLC phenotype (PMID:29466841) with plenty of seizure cases in MLC1 patients in PMIDs:29466841 and 21624973.
Early onset or syndromic epilepsy v0.1290 MLC1 Rebecca Foulger Gene: mlc1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1289 MLC1 Rebecca Foulger commented on gene: MLC1
Early onset or syndromic epilepsy v0.1289 MLC1 Rebecca Foulger Publications for gene: MLC1 were set to 21624973; 2946684
Early onset or syndromic epilepsy v0.1288 MLC1 Rebecca Foulger commented on gene: MLC1
Early onset or syndromic epilepsy v0.1288 MLC1 Rebecca Foulger Publications for gene: MLC1 were set to
Early onset or syndromic epilepsy v0.1287 MLC1 Rebecca Foulger Phenotypes for gene: MLC1 were changed from Megalencephalic leukoencephalopathy with subcortical cysts, 604004 to Megalencephalic leukoencephalopathy with subcortical cysts, 604004; generalized tonic-clonic seizures; focal seizures
Early onset or syndromic epilepsy v0.1286 MLC1 Rebecca Foulger Mode of inheritance for gene: MLC1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1285 MLC1 Rebecca Foulger Phenotypes for gene: MLC1 were changed from to Megalencephalic leukoencephalopathy with subcortical cysts, 604004
Early onset or syndromic epilepsy v0.1284 RALA Konstantinos Varvagiannis gene: RALA was added
gene: RALA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology
Penetrance for gene: RALA were set to unknown
Mode of pathogenicity for gene: RALA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RALA was set to GREEN
Added comment: Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although appart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GTP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS.

Seizures were a feature in most (6/11) individuals (5 different variants incl. R176X). Discordance for this feature was however noted for individuals with the same variant.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v0.1284 SCO2 Sarah Leigh Mode of inheritance for gene: SCO2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1283 SCO2 Sarah Leigh Publications for gene: SCO2 were set to
Early onset or syndromic epilepsy v0.1282 SCO2 Sarah Leigh Phenotypes for gene: SCO2 were changed from to Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377
Early onset or syndromic epilepsy v0.1281 SCO1 Sarah Leigh Classified gene: SCO1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1281 SCO1 Sarah Leigh Gene: sco1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1280 SCO1 Sarah Leigh Marked gene: SCO1 as ready
Early onset or syndromic epilepsy v0.1280 SCO1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in unrelated cases
Early onset or syndromic epilepsy v0.1280 SCO1 Sarah Leigh Gene: sco1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1280 SCO1 Sarah Leigh Phenotypes for gene: SCO1 were changed from to Mitochondrial complex IV deficiency, 220110
Early onset or syndromic epilepsy v0.1279 SCO1 Sarah Leigh Publications for gene: SCO1 were set to 23878101; 11013136; 19295170
Early onset or syndromic epilepsy v0.1279 SCO1 Sarah Leigh Publications for gene: SCO1 were set to
Early onset or syndromic epilepsy v0.1278 SCO1 Sarah Leigh Mode of inheritance for gene: SCO1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1277 RORB Sarah Leigh Marked gene: RORB as ready
Early onset or syndromic epilepsy v0.1277 RORB Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. Three variants reported in three unrelated cases of generalized epilepsies with predominant absence seizures. The variant c.196C>T/p.(Arg66*) segregates with the condition in four affected members of a three generation family. Variants c.218T>C/p.(Leu73Pro), c.1249_1251delACG/p.(Thr417del) appeared to be the result of de novo events in sporadic cases. Furthermore, two de novo deletions were identified in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion (PMID: 27352968).
Early onset or syndromic epilepsy v0.1277 RORB Sarah Leigh Gene: rorb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1277 RORB Sarah Leigh Classified gene: RORB as Green List (high evidence)
Early onset or syndromic epilepsy v0.1277 RORB Sarah Leigh Gene: rorb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1276 RORB Sarah Leigh Mode of inheritance for gene: RORB was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1275 FUCA1 Louise Daugherty Marked gene: FUCA1 as ready
Early onset or syndromic epilepsy v0.1275 FUCA1 Louise Daugherty Gene: fuca1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1275 FRRS1L Louise Daugherty Marked gene: FRRS1L as ready
Early onset or syndromic epilepsy v0.1275 FRRS1L Louise Daugherty Gene: frrs1l has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1275 FOLR1 Louise Daugherty Marked gene: FOLR1 as ready
Early onset or syndromic epilepsy v0.1275 FOLR1 Louise Daugherty Gene: folr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1275 FKTN Louise Daugherty Marked gene: FKTN as ready
Early onset or syndromic epilepsy v0.1275 FKTN Louise Daugherty Gene: fktn has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1275 FKRP Louise Daugherty Marked gene: FKRP as ready
Early onset or syndromic epilepsy v0.1275 FKRP Louise Daugherty Gene: fkrp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1275 FKRP Louise Daugherty Publications for gene: FKRP were set to 14652796; 234206531; 11741828; 11592034
Early onset or syndromic epilepsy v0.1274 FKRP Louise Daugherty Added comment: Comment on publications: MDC1C is a form of congenital muscular dystrophy with mental retardation and structural brain abnormalities and belongs to a group of disorders resulting from defective glycosylation of dystrophin-associated glycoprotein-1, collectively known as dystroglycanopathies. External expert review notes Green status, but there is not enough evidence to date to asocaited this gene with seizures so I have kept this gene Amber on this panel until further evidence.
Early onset or syndromic epilepsy v0.1274 FKRP Louise Daugherty Publications for gene: FKRP were set to 14652796
Early onset or syndromic epilepsy v0.1273 CCDC88A Sarah Leigh Publications for gene: CCDC88A were set to 26917597
Early onset or syndromic epilepsy v0.1272 RORB Sarah Leigh Phenotypes for gene: RORB were changed from to generalized epilepsies with predominant absence seizures
Early onset or syndromic epilepsy v0.1271 RORB Sarah Leigh Publications for gene: RORB were set to
Early onset or syndromic epilepsy v0.1270 ROGDI Sarah Leigh Classified gene: ROGDI as Green List (high evidence)
Early onset or syndromic epilepsy v0.1270 ROGDI Sarah Leigh Gene: rogdi has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1269 ROGDI Sarah Leigh Marked gene: ROGDI as ready
Early onset or syndromic epilepsy v0.1269 ROGDI Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported in at least 7 unrelated cases.
Early onset or syndromic epilepsy v0.1269 ROGDI Sarah Leigh Gene: rogdi has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1269 ROGDI Sarah Leigh Publications for gene: ROGDI were set to
Early onset or syndromic epilepsy v0.1268 ROGDI Sarah Leigh Mode of inheritance for gene: ROGDI was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1267 ROGDI Sarah Leigh Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome 226750
Early onset or syndromic epilepsy v0.1266 RNU4ATAC Sarah Leigh Marked gene: RNU4ATAC as ready
Early onset or syndromic epilepsy v0.1266 RNU4ATAC Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Three case reported of Microcephalic osteodysplastic primordial dwarfism, type I 210710 ()MOPD1 with seizures as part of their phenotype (PMID 21474761;23794361;22786707) . However, not clear from pmid 23794361 & 22786707 whether the cases were related or not. Thirteen more cases of MOPD1 with RNU4ATAC variants were reported (PMID 29370840, 27591150, 27312855, 26641461, 27040866, 25735804, 22581640), but seizures were not reported in any of these.
Early onset or syndromic epilepsy v0.1266 RNU4ATAC Sarah Leigh Gene: rnu4atac has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1266 FKRP Louise Daugherty Phenotypes for gene: FKRP were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153; seizures; Walker-warburg syndrome or muscle-eye-brain disease to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153; seizures; Walker-warburg syndrome or muscle-eye-brain disease; Muscular dystrophy, congenital, 1c
Early onset or syndromic epilepsy v0.1265 FKRP Louise Daugherty Publications for gene: FKRP were set to
Early onset or syndromic epilepsy v0.1264 RNU4ATAC Sarah Leigh Publications for gene: RNU4ATAC were set to 21474761; 23794361; 22786707
Early onset or syndromic epilepsy v0.1263 RNU4ATAC Sarah Leigh Publications for gene: RNU4ATAC were set to
Early onset or syndromic epilepsy v0.1262 FKRP Louise Daugherty Phenotypes for gene: FKRP were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153; seizures to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153; seizures; Walker-warburg syndrome or muscle-eye-brain disease
Early onset or syndromic epilepsy v0.1261 FKRP Louise Daugherty Phenotypes for gene: FKRP were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153; seizures
Early onset or syndromic epilepsy v0.1260 FKRP Louise Daugherty Mode of inheritance for gene: FKRP was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1259 FARS2 Rebecca Foulger Marked gene: FARS2 as ready
Early onset or syndromic epilepsy v0.1259 FARS2 Rebecca Foulger Gene: fars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1259 FARS2 Rebecca Foulger Classified gene: FARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1259 FARS2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza- seizures are a common phentoype of MIM:614946. Plenty of unrelated (>3) cases of seizures in FARS2 patients from the literature (PMIDs 24161539, 22833457, 22499341, 28043061) as summarised in 29126765.
Early onset or syndromic epilepsy v0.1259 FARS2 Rebecca Foulger Gene: fars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1258 FARS2 Rebecca Foulger commented on gene: FARS2: PMID:22499341 (Shamseldin et al 2012) report an index patient and her two siblings with a homozygous FARS2 variant c.431A>G (p.Y144C). The patients had uncontrolled seizures starting in infancy.
Early onset or syndromic epilepsy v0.1258 FARS2 Rebecca Foulger commented on gene: FARS2: Cho et al, 2017 (PMID:28043061) report a novel homozgyous c.925G>A (G309S) missense variant in FARS2 in 4 patients from 2 nonconsanguineous Korean families. All 4 patients had intractable seizures.
Early onset or syndromic epilepsy v0.1258 FARS2 Rebecca Foulger commented on gene: FARS2: PMID:22833457 (Elo et al 2012) discovered compound het FARS2 variants in two siblings with fatal epileptic mitochondrial encephalopathy (p.I329T and p.D391V).
Early onset or syndromic epilepsy v0.1258 FARS2 Rebecca Foulger commented on gene: FARS2
Early onset or syndromic epilepsy v0.1258 FARS2 Rebecca Foulger Publications for gene: FARS2 were set to 24161539, 22833457, 22499341, 29126765
Early onset or syndromic epilepsy v0.1257 FARS2 Rebecca Foulger Publications for gene: FARS2 were set to
Early onset or syndromic epilepsy v0.1256 FARS2 Rebecca Foulger Mode of inheritance for gene: FARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1255 FARS2 Rebecca Foulger Phenotypes for gene: FARS2 were changed from to Combined oxidative phosphorylation deficiency 14, 614946
Early onset or syndromic epilepsy v0.1254 EXOSC3 Rebecca Foulger commented on gene: EXOSC3: PMID:24524299 (Eggens et al, 2014) summarise 14 patients with the EXOSC3 variants out of a cohort of 99 PCH patients (90 families). Seizures are reported in patients 7-I and Patient 8. Seizures were not recorded in the p.G31A group (6 patients, 5 families).
Early onset or syndromic epilepsy v0.1254 EXOSC3 Rebecca Foulger commented on gene: EXOSC3: PMID:23883322: states that Epileptic seizures were not noted in any of their patients.
Early onset or syndromic epilepsy v0.1254 EXOSC3 Rebecca Foulger Publications for gene: EXOSC3 were set to
Early onset or syndromic epilepsy v0.1253 EXOSC3 Rebecca Foulger commented on gene: EXOSC3: PMID:25144110 summary confirms that epileptic seizures are reported in some patients.
Early onset or syndromic epilepsy v0.1253 EXOSC3 Rebecca Foulger commented on gene: EXOSC3: PMID:25149867 (Halevy et al, 2014): Of the 4 patients, 1 patient had a single atonic seizure age 12 years.
Early onset or syndromic epilepsy v0.1253 EXOSC3 Rebecca Foulger commented on gene: EXOSC3
Early onset or syndromic epilepsy v0.1253 NSD1 Ivone Leong Marked gene: NSD1 as ready
Early onset or syndromic epilepsy v0.1253 NSD1 Ivone Leong Gene: nsd1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1253 RNU4ATAC Sarah Leigh Mode of inheritance for gene: RNU4ATAC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1252 RNU4ATAC Sarah Leigh Phenotypes for gene: RNU4ATAC were changed from to Microcephalic osteodysplastic primordial dwarfism, type I 210710
Early onset or syndromic epilepsy v0.1251 RNASET2 Sarah Leigh Marked gene: RNASET2 as ready
Early onset or syndromic epilepsy v0.1251 RNASET2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 6 variants reported in 5 unrelated cases, seizures were a phenotypic feature in 4 cases. Supportive functional studies were also presented (PMID 19525954).
Early onset or syndromic epilepsy v0.1251 RNASET2 Sarah Leigh Gene: rnaset2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1251 RNASET2 Sarah Leigh Classified gene: RNASET2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1251 RNASET2 Sarah Leigh Gene: rnaset2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1250 FKTN Louise Daugherty Classified gene: FKTN as Green List (high evidence)
Early onset or syndromic epilepsy v0.1250 FKTN Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1250 FKTN Louise Daugherty Gene: fktn has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1249 FKTN Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Early onset or syndromic epilepsy v0.1249 FKTN Louise Daugherty Publications for gene: FKTN were set to 30220444; 9690476
Early onset or syndromic epilepsy v0.1248 FKTN Louise Daugherty Phenotypes for gene: FKTN were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, 253800; seizures to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, 253800; seizures; Walker-warburg syndrome or muscle-eye-brain disease; Fukuyama congenital muscular dystrophy
Early onset or syndromic epilepsy v0.1247 RNASET2 Sarah Leigh Mode of inheritance for gene: RNASET2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1246 RNASET2 Sarah Leigh Publications for gene: RNASET2 were set to
Early onset or syndromic epilepsy v0.1245 RNASET2 Sarah Leigh Phenotypes for gene: RNASET2 were changed from to Leukoencephalopathy, cystic, without megalencephaly 612951
Early onset or syndromic epilepsy v0.1244 FKTN Louise Daugherty Publications for gene: FKTN were set to
Early onset or syndromic epilepsy v0.1243 NSD1 Ivone Leong Classified gene: NSD1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1243 NSD1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. NSD1 is confirmed to be associated with Sotos syndrome on OMIM and Gene2Phenotype, and both databases have listed seizures as a phenotype. GeneReviews stated that ~25% of Sotos syndrome patients have seizures. A large multicentre gene-phenotype association study showed that there are multiple cases (>3) of Sotos syndrome patients who have seizures.
Early onset or syndromic epilepsy v0.1243 NSD1 Ivone Leong Gene: nsd1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1242 NSD1 Ivone Leong Publications for gene: NSD1 were set to
Early onset or syndromic epilepsy v0.1241 EXOSC3 Rebecca Foulger Mode of inheritance for gene: EXOSC3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1240 FKTN Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1240 FKTN Louise Daugherty Phenotypes for gene: FKTN were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, 253800; seizures
Early onset or syndromic epilepsy v0.1239 FKTN Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1239 FKTN Louise Daugherty Mode of inheritance for gene: FKTN was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1238 FOLR1 Louise Daugherty Classified gene: FOLR1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1238 FOLR1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1238 FOLR1 Louise Daugherty Gene: folr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1237 FOLR1 Louise Daugherty Added comment: Comment on publications: Added publications to support gene-disease association, and upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1237 FOLR1 Louise Daugherty Publications for gene: FOLR1 were set to
Early onset or syndromic epilepsy v0.1236 FOLR1 Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1236 FOLR1 Louise Daugherty Mode of inheritance for gene: FOLR1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1235 FOLR1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1235 FOLR1 Louise Daugherty Phenotypes for gene: FOLR1 were changed from to Neurodegeneration due to cerebral folate transport deficiency, 613068; seizures
Early onset or syndromic epilepsy v0.1234 FRRS1L Louise Daugherty Classified gene: FRRS1L as Green List (high evidence)
Early onset or syndromic epilepsy v0.1234 FRRS1L Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1234 FRRS1L Louise Daugherty Gene: frrs1l has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1233 FRRS1L Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1233 FRRS1L Louise Daugherty Publications for gene: FRRS1L were set to
Early onset or syndromic epilepsy v0.1232 NSD1 Ivone Leong Mode of inheritance for gene: NSD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1231 FRRS1L Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1231 FRRS1L Louise Daugherty Mode of inheritance for gene: FRRS1L was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1230 FRRS1L Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1230 FRRS1L Louise Daugherty Phenotypes for gene: FRRS1L were changed from to Epileptic encephalopathy, early infantile 37, 616981
Early onset or syndromic epilepsy v0.1229 FUCA1 Louise Daugherty Classified gene: FUCA1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1229 FUCA1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.1229 FUCA1 Louise Daugherty Gene: fuca1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1228 FUCA1 Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease association
Early onset or syndromic epilepsy v0.1228 FUCA1 Louise Daugherty Publications for gene: FUCA1 were set to
Early onset or syndromic epilepsy v0.1227 EXOSC3 Rebecca Foulger Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, 614678
Early onset or syndromic epilepsy v0.1226 ETHE1 Rebecca Foulger Classified gene: ETHE1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1226 ETHE1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza. Confirmed DD-G2P gene for Ethylmalonic encephalopathy (EE) which can present with seizures. Sufficient cases of patients with EE and seizures for inclusion on panel (as summarised by PMID:26194623).
Early onset or syndromic epilepsy v0.1226 ETHE1 Rebecca Foulger Gene: ethe1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1225 ETHE1 Rebecca Foulger Marked gene: ETHE1 as ready
Early onset or syndromic epilepsy v0.1225 ETHE1 Rebecca Foulger Gene: ethe1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1225 ETHE1 Rebecca Foulger commented on gene: ETHE1: PMID:26194623 (Papetti et al 2015) report on a baby with severe early onset EE associated with a novel ETHE1 gene variant and a an early pure epileptic onset. They also provide a summary of all previous EE cases. A large proportion report seizures- although the earlier cases don't report a ETHE1 gene defect, there are sufficient cases with both seizures and an ETHE1 variant reported.
Early onset or syndromic epilepsy v0.1225 ETHE1 Rebecca Foulger commented on gene: ETHE1
Early onset or syndromic epilepsy v0.1225 NSD1 Ivone Leong Phenotypes for gene: NSD1 were changed from to Sotos syndrome 1, 117550
Early onset or syndromic epilepsy v0.1224 NPRL3 Ivone Leong Marked gene: NPRL3 as ready
Early onset or syndromic epilepsy v0.1224 NPRL3 Ivone Leong Gene: nprl3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1224 NPRL3 Ivone Leong Classified gene: NPRL3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1224 NPRL3 Ivone Leong Added comment: Comment on list classification: NPRL3 is confirmed to be associated with Epilepsy, familial focal on OMIM but not on Gene2Phenotype. There are >3 cases (PMID: 26505888; 26285051; 27173016) of patients from unrelated families who have familial focal epilepsy with variants in NPRL3.
Early onset or syndromic epilepsy v0.1224 NPRL3 Ivone Leong Gene: nprl3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1223 ETHE1 Rebecca Foulger Mode of inheritance for gene: ETHE1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1222 ETHE1 Rebecca Foulger Phenotypes for gene: ETHE1 were changed from to Ethylmalonic encephalopathy, 602473
Early onset or syndromic epilepsy v0.1221 EMX2 Rebecca Foulger Marked gene: EMX2 as ready
Early onset or syndromic epilepsy v0.1221 EMX2 Rebecca Foulger Gene: emx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1221 EMX2 Rebecca Foulger Classified gene: EMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1221 EMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza and 3 cases of Schizencephaly patients with EMX2 variants and partial epilepsy in PMID:9359037. PMID:15921232 (2005) report that half of Schizencephaly patients show epilepsy. Therefore sufficient evidence for inclusion on panel.
Early onset or syndromic epilepsy v0.1221 EMX2 Rebecca Foulger Gene: emx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1220 EMX2 Rebecca Foulger commented on gene: EMX2: Faiella et al., 1997 (PMID:9359037) summarise 10 patients with Schizencephaly. 6 patients were heterozygous for de novo variants in EMX2 (including 2 brothers). 3 of these unrelated patients have EMX2 variants (patients VF, MB and PB).
Early onset or syndromic epilepsy v0.1220 EMX2 Rebecca Foulger Added comment: Comment on mode of inheritance: Monoallelic MOI supported by Gene2Phenotype, which provide a 'possible' rating for Familial Schizencephaly.
Early onset or syndromic epilepsy v0.1220 EMX2 Rebecca Foulger Mode of inheritance for gene: EMX2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1219 NPRL3 Ivone Leong Added comment: Comment on mode of inheritance: Incomplete penetrance was observed in some of the studies (PMID: 265005888,26285051).
Early onset or syndromic epilepsy v0.1219 NPRL3 Ivone Leong Mode of inheritance for gene: NPRL3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1218 EMX2 Rebecca Foulger commented on gene: EMX2
Early onset or syndromic epilepsy v0.1218 EMX2 Rebecca Foulger Publications for gene: EMX2 were set to
Early onset or syndromic epilepsy v0.1217 EMX2 Rebecca Foulger commented on gene: EMX2
Early onset or syndromic epilepsy v0.1217 NPRL3 Ivone Leong Publications for gene: NPRL3 were set to
Early onset or syndromic epilepsy v0.1216 EMX2 Rebecca Foulger Phenotypes for gene: EMX2 were changed from to Schizencephaly, 269160
Early onset or syndromic epilepsy v0.1215 EIF2S3 Rebecca Foulger Marked gene: EIF2S3 as ready
Early onset or syndromic epilepsy v0.1215 EIF2S3 Rebecca Foulger Gene: eif2s3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1215 EIF2S3 Rebecca Foulger Classified gene: EIF2S3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1215 EIF2S3 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Probable rating in Gene2Phenotype for 'Syndromic ID with severe microcephaly' but sufficient unrelated cases (>3) of seizures in MEHMO patients from literature (PMIDs 23063529,27333055,28055140).
Early onset or syndromic epilepsy v0.1215 EIF2S3 Rebecca Foulger Gene: eif2s3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1214 EIF2S3 Rebecca Foulger Added comment: Comment on mode of inheritance: X-linked recessive MOI supported by OMIM and literature.
Early onset or syndromic epilepsy v0.1214 EIF2S3 Rebecca Foulger Mode of inheritance for gene: EIF2S3 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.1213 EIF2S3 Rebecca Foulger Publications for gene: EIF2S3 were set to
Early onset or syndromic epilepsy v0.1212 EIF2S3 Rebecca Foulger commented on gene: EIF2S3: Skopkova et al 2017 (PMID:28055140) identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. Two of the families had members with seizures amongst their phenotypes.
Early onset or syndromic epilepsy v0.1212 EIF2S3 Rebecca Foulger commented on gene: EIF2S3: Moortgat et al, 2016 (PMID:27333055) examined syndromic intellectual disability in two unrelated families with suspected X-linked inheritance. In both families, affected males presented with severe intellectual disability, microcephaly, growth retardation, and epilepsy in most individuals. A missense variant(c.777T>G p.(Ile259Met)) and a frameshift variant (c.1394_1397del p.(Ile465Serfs*4)) were identified in the EIF2S3 gene in the hemizygous state in affected patients, and in the heterozygous states female obligate carriers.
Early onset or syndromic epilepsy v0.1212 EIF2S3 Rebecca Foulger commented on gene: EIF2S3: Borck et al., 2012 (PMID:23063529) ascertained a family of Morocco Jewish ancestry in which three male individuals were affected by X-linked intellectual disability (ID). Individual III:2 had generalized seizures.
Early onset or syndromic epilepsy v0.1212 EIF2S3 Rebecca Foulger commented on gene: EIF2S3
Early onset or syndromic epilepsy v0.1212 NPRL3 Ivone Leong Phenotypes for gene: NPRL3 were changed from to Epilepsy, familial focal, with variable foci 3, 617118
Early onset or syndromic epilepsy v0.1211 EIF2S3 Rebecca Foulger Phenotypes for gene: EIF2S3 were changed from to MEHMO syndrome, 300148
Early onset or syndromic epilepsy v0.1210 FUCA1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1210 FUCA1 Louise Daugherty Phenotypes for gene: FUCA1 were changed from to Fucosidosis, 230000; seizures
Early onset or syndromic epilepsy v0.1209 FUCA1 Louise Daugherty Added comment: Comment on mode of inheritance: changed MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1209 FUCA1 Louise Daugherty Mode of inheritance for gene: FUCA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1208 NDUFAF2 Ivone Leong Marked gene: NDUFAF2 as ready
Early onset or syndromic epilepsy v0.1208 NDUFAF2 Ivone Leong Gene: ndufaf2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1208 NDUFAF2 Ivone Leong Classified gene: NDUFAF2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1208 NDUFAF2 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. NDUFAF2 is confirmed to be associated with complex I deficiency on OMIM and listed as a probable causative gene on Gene2Phenotype. Both websites list seizures as a phenotype of the disease.
There are reports (PMID: 18180188, 26795593, 22644603) of 3 unrelated patients diagnosed with Leigh syndrome or mitochondrial complex I deficiency with different NDUFAF2 variants who have seizures.
Early onset or syndromic epilepsy v0.1208 NDUFAF2 Ivone Leong Gene: ndufaf2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1207 NDUFAF2 Ivone Leong Publications for gene: NDUFAF2 were set to
Early onset or syndromic epilepsy v0.1206 NDUFAF2 Ivone Leong Mode of inheritance for gene: NDUFAF2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1205 EIF2B5 Rebecca Foulger Publications for gene: EIF2B5 were set to 17646634; 21484434; 15136690; 29995139; 18266750
Early onset or syndromic epilepsy v0.1204 EIF2B3 Rebecca Foulger Publications for gene: EIF2B3 were set to
Early onset or syndromic epilepsy v0.1203 EIF2B3 Rebecca Foulger commented on gene: EIF2B3
Early onset or syndromic epilepsy v0.1203 EIF2B3 Rebecca Foulger Phenotypes for gene: EIF2B3 were changed from to Leukoencephalopathy with vanishing white matter, 603896
Early onset or syndromic epilepsy v0.1202 EIF2B3 Rebecca Foulger Mode of inheritance for gene: EIF2B3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1201 EIF2B4 Rebecca Foulger Marked gene: EIF2B4 as ready
Early onset or syndromic epilepsy v0.1201 EIF2B4 Rebecca Foulger Gene: eif2b4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1201 EIF2B4 Rebecca Foulger Classified gene: EIF2B4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1201 EIF2B4 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza, and sufficient cases of epilepsy in Vanishing White Matter (VWM) patients with EIF2B4 variants from the literature (3 cases in PMIDs 25843247, 26043506 and 29331873) for inclusion on the panel.
Early onset or syndromic epilepsy v0.1201 EIF2B4 Rebecca Foulger Gene: eif2b4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1200 EIF2B4 Rebecca Foulger Publications for gene: EIF2B4 were set to 25843247; 26043506
Early onset or syndromic epilepsy v0.1199 EIF2B4 Rebecca Foulger commented on gene: EIF2B4: Herrera-García et al, 2018 (PMID:29331873) describe a 41-year-old woman and her 37-year-old sister who developed epilepsy in association with premature ovarian failure at the age of 13 and 18 respectively. In both patients they found the c.1117C>T (p.Arg373Cys) homozygous variant in EIF2B4.
Early onset or syndromic epilepsy v0.1199 EIF2B4 Rebecca Foulger Phenotypes for gene: EIF2B4 were changed from to Leukoencephalopathy with vanishing white matter, 603896
Early onset or syndromic epilepsy v0.1198 EIF2B4 Rebecca Foulger Publications for gene: EIF2B4 were set to 25843247
Early onset or syndromic epilepsy v0.1197 EIF2B4 Rebecca Foulger commented on gene: EIF2B4: Gungor et al (PMID:26043506) report a 12-month old boy presented with intractable seizures present since 3-months of age. A homozygous c.1091G>A variant was detected in the EIF2B4 gene.
Early onset or syndromic epilepsy v0.1197 EIF2B2 Rebecca Foulger Publications for gene: EIF2B2 were set to
Early onset or syndromic epilepsy v0.1196 EIF2B4 Rebecca Foulger Mode of inheritance for gene: EIF2B4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1195 EIF2B4 Rebecca Foulger Publications for gene: EIF2B4 were set to
Early onset or syndromic epilepsy v0.1194 EIF2B4 Rebecca Foulger commented on gene: EIF2B4
Early onset or syndromic epilepsy v0.1194 EIF2B2 Rebecca Foulger Marked gene: EIF2B2 as ready
Early onset or syndromic epilepsy v0.1194 EIF2B2 Rebecca Foulger Gene: eif2b2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1194 EIF2B2 Rebecca Foulger Classified gene: EIF2B2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1194 EIF2B2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review from Zornitza. Seizures are seen in some patients with Vanishing White Matter Disease (VWM). Sufficient cases of seizures in patients from the literature (2 in PMID:25843247 and 1 in PMID:22678813) for inclusion on the panel.
Early onset or syndromic epilepsy v0.1194 EIF2B2 Rebecca Foulger Gene: eif2b2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1193 EIF2B2 Rebecca Foulger commented on gene: EIF2B2: Shimada et al, 2012 (PMID:22678813) report an 11-month-old patient with intractable epilepsy amongst her symptoms. A Submicroscopic deletion at 14q24.3 that included EIF2B2 was found in compound heterozygous state for a missense variant in EIF2B2 (V85W). The p.V85E variant may be common in individuals of E. Asian origin (Chinese and Japanese).
Early onset or syndromic epilepsy v0.1193 EIF2B2 Rebecca Foulger commented on gene: EIF2B2
Early onset or syndromic epilepsy v0.1193 EIF2B2 Rebecca Foulger Mode of inheritance for gene: EIF2B2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1192 EIF2B2 Rebecca Foulger Phenotypes for gene: EIF2B2 were changed from to Leukoencephalopathy with vanishing white matter, 603896
Early onset or syndromic epilepsy v0.1191 NDUFAF2 Ivone Leong Phenotypes for gene: NDUFAF2 were changed from to Mitochondrial complex I deficiency, 252010
Early onset or syndromic epilepsy v0.1190 NDUFA10 Ivone Leong Classified gene: NDUFA10 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1190 NDUFA10 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Both OMIM and Gene2Phenotype have confirmed that NDUFA10 is associated with Leigh syndrome, and both have listed seizures as a phenotype.
There are 3 studies (PMID: 21150889; 26741492; 28247337) reporting 3 patients who have different variants in the NDUFA10 gene and have seizures.
Early onset or syndromic epilepsy v0.1190 NDUFA10 Ivone Leong Gene: ndufa10 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1189 NDUFA10 Ivone Leong Classified gene: NDUFA10 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1189 NDUFA10 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Both OMIM and Gene2Phenotype confirm that NDUFA10 is associated with Leigh syndrome and both databases list seizures as a phenotype.
There are 3 studies (PMID: 21150889, 26741492, 28247337) describing 3 patients who have different variants in NDUFA10 who have seizures.
Early onset or syndromic epilepsy v0.1189 NDUFA10 Ivone Leong Gene: ndufa10 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1188 NDUFA10 Ivone Leong Marked gene: NDUFA10 as ready
Early onset or syndromic epilepsy v0.1188 NDUFA10 Ivone Leong Gene: ndufa10 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1188 NDUFA10 Ivone Leong Publications for gene: NDUFA10 were set to
Early onset or syndromic epilepsy v0.1187 NDUFA10 Ivone Leong Mode of inheritance for gene: NDUFA10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1186 NDUFA10 Ivone Leong Phenotypes for gene: NDUFA10 were changed from to Leigh syndrome, 256000
Early onset or syndromic epilepsy v0.1185 NDUFA1 Ivone Leong Marked gene: NDUFA1 as ready
Early onset or syndromic epilepsy v0.1185 NDUFA1 Ivone Leong Gene: ndufa1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1185 NDUFA1 Ivone Leong Classified gene: NDUFA1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1185 NDUFA1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Both OMIM and Gene2Phenotype confirm that NDUFA1 is associated with Mitochondrial complex I deficiency and seizures is listed on both databases as a phenotype. There are three papers (PMID: 17262856,19185523, 29272804) reporting on 4 individuals with variants in the NDUFA1 gene and have seizures. There are currently 2 different NDUFA1 variants reported that are associated with Mitochondrial complex I deficiency.
Early onset or syndromic epilepsy v0.1185 NDUFA1 Ivone Leong Gene: ndufa1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1184 NDUFA1 Ivone Leong Publications for gene: NDUFA1 were set to
Early onset or syndromic epilepsy v0.1183 NDUFA1 Ivone Leong Mode of inheritance for gene: NDUFA1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.1182 UFM1 Sarah Leigh Marked gene: UFM1 as ready
Early onset or syndromic epilepsy v0.1182 UFM1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in 3 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1182 UFM1 Sarah Leigh Gene: ufm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1182 UFM1 Sarah Leigh Mode of inheritance for gene: UFM1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1181 UFM1 Sarah Leigh Classified gene: UFM1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1181 UFM1 Sarah Leigh Gene: ufm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1180 UFC1 Sarah Leigh Marked gene: UFC1 as ready
Early onset or syndromic epilepsy v0.1180 UFC1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 2 variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1180 UFC1 Sarah Leigh Gene: ufc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1180 UFC1 Sarah Leigh Classified gene: UFC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1180 UFC1 Sarah Leigh Gene: ufc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1179 UFC1 Sarah Leigh Publications for gene: UFC1 were set to 29868776
Early onset or syndromic epilepsy v0.1178 TELO2 Sarah Leigh Marked gene: TELO2 as ready
Early onset or syndromic epilepsy v0.1178 TELO2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 7 variants reported in 7 unrelated cases, two of whome had seizures.
Early onset or syndromic epilepsy v0.1178 TELO2 Sarah Leigh Gene: telo2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1178 TELO2 Sarah Leigh Classified gene: TELO2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1178 TELO2 Sarah Leigh Gene: telo2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1177 TELO2 Sarah Leigh Publications for gene: TELO2 were set to
Early onset or syndromic epilepsy v0.1176 TELO2 Sarah Leigh Phenotypes for gene: TELO2 were changed from to You-Hoover-Fong syndrome 616954
Early onset or syndromic epilepsy v0.1175 PHACTR1 Sarah Leigh Marked gene: PHACTR1 as ready
Early onset or syndromic epilepsy v0.1175 PHACTR1 Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. At least 3 variants reported in unrelated cases, together with supportive functional studies (PMIDs: 23033978, 28135719), which support a dominant negative mode of action or incomplete penetrance.
Early onset or syndromic epilepsy v0.1175 PHACTR1 Sarah Leigh Gene: phactr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1175 PHACTR1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719)
Early onset or syndromic epilepsy v0.1175 PHACTR1 Sarah Leigh Mode of pathogenicity for gene: PHACTR1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.1174 PHACTR1 Sarah Leigh Classified gene: PHACTR1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1174 PHACTR1 Sarah Leigh Gene: phactr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1173 MACF1 Sarah Leigh Marked gene: MACF1 as ready
Early onset or syndromic epilepsy v0.1173 MACF1 Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM (last updated for this gene 05/17/2011) or in Gen2Phen. At least 7 variants reported in unrelated cases with intellectual disability, seizures, lissencephalyand brainstem dysplasia.
Early onset or syndromic epilepsy v0.1173 MACF1 Sarah Leigh Gene: macf1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1173 MACF1 Sarah Leigh Added comment: Comment on mode of inheritance: Authors of PMID 30471716 suggest that a gain of function or dominant negative mode of action as truncating variant are reported in EXAC
Early onset or syndromic epilepsy v0.1173 MACF1 Sarah Leigh Mode of inheritance for gene: MACF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1172 MACF1 Sarah Leigh Publications for gene: MACF1 were set to doi.org/10.1016/j.ajhg.2018.10.019
Early onset or syndromic epilepsy v0.1171 MACF1 Sarah Leigh Classified gene: MACF1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1171 MACF1 Sarah Leigh Gene: macf1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1170 MACF1 Sarah Leigh Mode of inheritance for gene: MACF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1169 MACF1 Sarah Leigh Publications for gene: MACF1 were set to
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Marked gene: GNB5 as ready
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. Sufficient variants and unrelated cases for this gene to be rated green.
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Classified gene: GNB5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Added comment: Comment on list classification: Based on cited literature and review by Konstantinos Varvagiannis.
Early onset or syndromic epilepsy v0.1168 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1167 GNB5 Sarah Leigh Classified gene: GNB5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1167 GNB5 Sarah Leigh Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1166 RMND1 Sarah Leigh Marked gene: RMND1 as ready
Early onset or syndromic epilepsy v0.1166 RMND1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in 3 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1166 RMND1 Sarah Leigh Gene: rmnd1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1166 RMND1 Sarah Leigh Classified gene: RMND1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1166 RMND1 Sarah Leigh Gene: rmnd1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1165 RMND1 Sarah Leigh Publications for gene: RMND1 were set to
Early onset or syndromic epilepsy v0.1164 NDUFA1 Ivone Leong Phenotypes for gene: NDUFA1 were changed from to Mitochondrial complex I deficiency, 252010
Early onset or syndromic epilepsy v0.1163 NDE1 Ivone Leong Marked gene: NDE1 as ready
Early onset or syndromic epilepsy v0.1163 NDE1 Ivone Leong Gene: nde1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1163 NDE1 Ivone Leong Classified gene: NDE1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1163 NDE1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. NDE1 is confirmed to be a causative gene of Lissencephaly by OMIM and Gene2Phenotype. Both sources list seizures as a phenotype of the disease. There are 3 papers (PMID:21529752, 21529751, 22526350) reporting on 5 unrelated families with 8 affected individuals who have Lissencephaly and have different variants in the NDE1 gene. All patients are of Pakistani, Turkish or Saudi Arabian descent.
Early onset or syndromic epilepsy v0.1163 NDE1 Ivone Leong Gene: nde1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1162 NDE1 Ivone Leong Publications for gene: NDE1 were set to
Early onset or syndromic epilepsy v0.1161 RMND1 Sarah Leigh Phenotypes for gene: RMND1 were changed from to Combined oxidative phosphorylation deficiency 11, 614922
Early onset or syndromic epilepsy v0.1160 RMND1 Sarah Leigh Mode of inheritance for gene: RMND1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1159 RFT1 Sarah Leigh Marked gene: RFT1 as ready
Early onset or syndromic epilepsy v0.1159 RFT1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 7 variants reported in at least 6 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1159 RFT1 Sarah Leigh Gene: rft1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1159 RFT1 Sarah Leigh Classified gene: RFT1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1159 RFT1 Sarah Leigh Gene: rft1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1158 RFT1 Sarah Leigh Mode of inheritance for gene: RFT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1157 RFT1 Sarah Leigh Publications for gene: RFT1 were set to
Early onset or syndromic epilepsy v0.1156 NDE1 Ivone Leong Mode of inheritance for gene: NDE1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1155 RFT1 Sarah Leigh Phenotypes for gene: RFT1 were changed from to Congenital disorder of glycosylation, type In, 612015
Early onset or syndromic epilepsy v0.1154 NDE1 Ivone Leong Phenotypes for gene: NDE1 were changed from to Lissencephaly 4 (with microcephaly), 614019
Early onset or syndromic epilepsy v0.1153 MED12 Ivone Leong Marked gene: MED12 as ready
Early onset or syndromic epilepsy v0.1153 MED12 Ivone Leong Gene: med12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1153 MED12 Ivone Leong Classified gene: MED12 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1153 MED12 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green, based on the information provided previously.
Early onset or syndromic epilepsy v0.1153 MED12 Ivone Leong Gene: med12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1152 RARS2 Sarah Leigh Mode of inheritance for gene: RARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1151 RARS2 Sarah Leigh Classified gene: RARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1151 RARS2 Sarah Leigh Gene: rars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Marked gene: RARS2 as ready
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 4 unrelated cases, in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Gene: rars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6, 611523
Early onset or syndromic epilepsy v0.1149 RARS2 Sarah Leigh Publications for gene: RARS2 were set to
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Marked gene: KRAS as ready
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Gene: kras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Classified gene: KRAS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Added comment: Comment on list classification: Promoted from amber to green as an additional report on a patient with a variant in the KRAS gene who also has seizures (PMID: 17601930).
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Gene: kras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1147 KRAS Ivone Leong Publications for gene: KRAS were set to 21871821; 23059812; 16474405; 21871821
Early onset or syndromic epilepsy v0.1146 RAB18 Sarah Leigh Marked gene: RAB18 as ready
Early onset or syndromic epilepsy v0.1146 RAB18 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 4 variants reported 3 unrelated cases, each of the variants was associated with at least one case in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1146 RAB18 Sarah Leigh Gene: rab18 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1146 HCN2 Ivone Leong Marked gene: HCN2 as ready
Early onset or syndromic epilepsy v0.1146 HCN2 Ivone Leong Gene: hcn2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1146 RAB18 Sarah Leigh Publications for gene: RAB18 were set to 15216543
Early onset or syndromic epilepsy v0.1145 RAB18 Sarah Leigh Mode of inheritance for gene: RAB18 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1144 RAB18 Sarah Leigh Classified gene: RAB18 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1144 RAB18 Sarah Leigh Gene: rab18 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1143 RAB18 Sarah Leigh Phenotypes for gene: RAB18 were changed from to Warburg micro syndrome 3, 614222
Early onset or syndromic epilepsy v0.1142 RAB18 Sarah Leigh Publications for gene: RAB18 were set to
Early onset or syndromic epilepsy v0.1141 RAB11B Sarah Leigh Marked gene: RAB11B as ready
Early onset or syndromic epilepsy v0.1141 RAB11B Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 5 unrelated cases, of which epileptic seizures were reported in three cases. Protein modeling suggested that both variants alter the GTP/GDP binding pocket and reveal that they both have localization patterns similar to inactive RAB11B (PMID 29106825).
Early onset or syndromic epilepsy v0.1141 RAB11B Sarah Leigh Gene: rab11b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1141 RAB11B Sarah Leigh Publications for gene: RAB11B were set to
Early onset or syndromic epilepsy v0.1140 RAB11B Sarah Leigh Classified gene: RAB11B as Green List (high evidence)
Early onset or syndromic epilepsy v0.1140 RAB11B Sarah Leigh Gene: rab11b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1139 QDPR Sarah Leigh Marked gene: QDPR as ready
Early onset or syndromic epilepsy v0.1139 QDPR Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 16 variants reported as in unrelated cases. PMID 26006720 reports seizures in 83% (20 cases) of Hyperphenylalaninemia, BH4-deficient, C, 261630.
Early onset or syndromic epilepsy v0.1139 QDPR Sarah Leigh Gene: qdpr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1139 QDPR Sarah Leigh Classified gene: QDPR as Green List (high evidence)
Early onset or syndromic epilepsy v0.1139 QDPR Sarah Leigh Gene: qdpr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1138 QDPR Sarah Leigh Publications for gene: QDPR were set to
Early onset or syndromic epilepsy v0.1137 QDPR Sarah Leigh Phenotypes for gene: QDPR were changed from to Hyperphenylalaninemia, BH4-deficient, C, 261630
Early onset or syndromic epilepsy v0.1136 QDPR Sarah Leigh Mode of inheritance for gene: QDPR was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1135 PTS Sarah Leigh Marked gene: PTS as ready
Early onset or syndromic epilepsy v0.1135 PTS Sarah Leigh Gene: pts has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1135 PTS Sarah Leigh Classified gene: PTS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1135 PTS Sarah Leigh Gene: pts has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1134 PTS Sarah Leigh Publications for gene: PTS were set to 11916314; 16364672
Early onset or syndromic epilepsy v0.1133 EIF2B5 Rebecca Foulger Publications for gene: EIF2B5 were set to 17646634; 21484434; 15136690; 29995139
Early onset or syndromic epilepsy v0.1132 EIF2B5 Rebecca Foulger Publications for gene: EIF2B5 were set to 17646634; 21484434; 15136690
Early onset or syndromic epilepsy v0.1131 EIF2B1 Rebecca Foulger Publications for gene: EIF2B1 were set to
Early onset or syndromic epilepsy v0.1130 EIF2B1 Rebecca Foulger commented on gene: EIF2B1: In a 2-year-old Chinese girl (case 29) with MIM:603896, Zhang et al. (2015, PMID:25761052) identified a homozygous c(c.328A-G, NM_001414) in exon 4 of the EIF2B1 gene (KL110E). The patient had seizures.
Early onset or syndromic epilepsy v0.1130 EIF2B1 Rebecca Foulger commented on gene: EIF2B1
Early onset or syndromic epilepsy v0.1130 EIF2B1 Rebecca Foulger Mode of inheritance for gene: EIF2B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1129 EIF2B1 Rebecca Foulger Phenotypes for gene: EIF2B1 were changed from to Leukoencephalopathy with vanishing white matter, 603896
Early onset or syndromic epilepsy v0.1128 EARS2 Rebecca Foulger Marked gene: EARS2 as ready
Early onset or syndromic epilepsy v0.1128 EARS2 Rebecca Foulger Gene: ears2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1128 EARS2 Rebecca Foulger Classified gene: EARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1128 EARS2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review from Zornitza plus sufficient cases (>3) of seizures and/or epilepsy in patients from the literature (PMIDs:22492562, 26619324, 27117034, 27206875) for inclusion on panel.
Early onset or syndromic epilepsy v0.1128 EARS2 Rebecca Foulger Gene: ears2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1127 EARS2 Rebecca Foulger Publications for gene: EARS2 were set to
Early onset or syndromic epilepsy v0.1126 EARS2 Rebecca Foulger Phenotypes for gene: EARS2 were changed from Combined oxidative phosphorylation deficiency 12, 614924; Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) to Combined oxidative phosphorylation deficiency 12, 614924; Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL); Drug-refractory seizures; Epilepsy
Early onset or syndromic epilepsy v0.1125 EARS2 Rebecca Foulger commented on gene: EARS2
Early onset or syndromic epilepsy v0.1125 EARS2 Rebecca Foulger Phenotypes for gene: EARS2 were changed from Combined oxidative phosphorylation deficiency 12, 614924 to Combined oxidative phosphorylation deficiency 12, 614924; Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)
Early onset or syndromic epilepsy v0.1124 EARS2 Rebecca Foulger Mode of inheritance for gene: EARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1123 EARS2 Rebecca Foulger Phenotypes for gene: EARS2 were changed from to Combined oxidative phosphorylation deficiency 12, 614924
Early onset or syndromic epilepsy v0.1122 DYNC1H1 Rebecca Foulger Marked gene: DYNC1H1 as ready
Early onset or syndromic epilepsy v0.1122 DYNC1H1 Rebecca Foulger Gene: dync1h1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1122 DYNC1H1 Rebecca Foulger Classified gene: DYNC1H1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1122 DYNC1H1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza and sufficient unrelated cases (7 sporadic cases plus two brothers and their mother) in PMID:23603762 of patients with epilepsy for inclusion on panel.
Early onset or syndromic epilepsy v0.1122 DYNC1H1 Rebecca Foulger Gene: dync1h1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1121 DYNC1H1 Rebecca Foulger Phenotypes for gene: DYNC1H1 were changed from Mental retardation, autosomal dominant 13, 614563; Lennox Gastaut; Early-onset epilepsy; Late-onset epilepsy; Focal seizures to Mental retardation, autosomal dominant 13, 614563; malformations of cortical development (MCD); Lennox Gastaut; Early-onset epilepsy; Late-onset epilepsy; Focal seizures
Early onset or syndromic epilepsy v0.1120 DYNC1H1 Rebecca Foulger Phenotypes for gene: DYNC1H1 were changed from Mental retardation, autosomal dominant 13, 614563 to Mental retardation, autosomal dominant 13, 614563; Lennox Gastaut; Early-onset epilepsy; Late-onset epilepsy; Focal seizures
Early onset or syndromic epilepsy v0.1119 DYNC1H1 Rebecca Foulger commented on gene: DYNC1H1
Early onset or syndromic epilepsy v0.1119 DYNC1H1 Rebecca Foulger Mode of inheritance for gene: DYNC1H1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1118 DYNC1H1 Rebecca Foulger Publications for gene: DYNC1H1 were set to
Early onset or syndromic epilepsy v0.1117 DYNC1H1 Rebecca Foulger Phenotypes for gene: DYNC1H1 were changed from to Mental retardation, autosomal dominant 13, 614563
Early onset or syndromic epilepsy v0.1116 DPM1 Rebecca Foulger Marked gene: DPM1 as ready
Early onset or syndromic epilepsy v0.1116 DPM1 Rebecca Foulger Gene: dpm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1116 DPM1 Rebecca Foulger Added comment: Comment on publications: Epilepsy is not reported in all patients. Severe epilepsy was not present in 2 French siblings with CDG1E, born of consanguineous Algerian parents, as reported Dancourt et al. (2006, PMID:16641202).
Early onset or syndromic epilepsy v0.1116 DPM1 Rebecca Foulger Publications for gene: DPM1 were set to 23856421; 10642597; 10642602
Early onset or syndromic epilepsy v0.1115 DPM1 Rebecca Foulger Classified gene: DPM1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1115 DPM1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza. Confirmed DD-G2P gene for congenital disorder of glycosylation, which can present with seizures. Sufficient cases of seizures in patients with CDG1E (MIM:608799) for inclusion on panel: 4 unrelated cases in PMIDs 23856421, 10642597 and 10642602, several of which are compound heterozygous for a substitution AND a deletion in DPM1.
Early onset or syndromic epilepsy v0.1115 DPM1 Rebecca Foulger Gene: dpm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1114 DPM1 Rebecca Foulger Publications for gene: DPM1 were set to
Early onset or syndromic epilepsy v0.1113 DPM1 Rebecca Foulger commented on gene: DPM1: Imbach et al. (2000, PMID:10642602) report a brother and sister with severe developmental delay, repeated seizures, and dysmorphic features. Both sibs were compound heterozygous for the 274C>G (R92G) transversion and a 628delC deletion in DPM1.
Early onset or syndromic epilepsy v0.1113 DPM1 Rebecca Foulger commented on gene: DPM1: Kim et al., 2000 (PMID:10642597) report a patient with CDG1E and a homozygous 274C-G transversion in the DPM1 gene (p.R92G). Another unrelated patient was compound heterozygous for the R92G variant and a 13-bp deletion in exon 4 that may result in an unstable transcript. Both patients were recorded with medically intractable seizures
Early onset or syndromic epilepsy v0.1113 DPM1 Rebecca Foulger commented on gene: DPM1
Early onset or syndromic epilepsy v0.1113 DPM1 Rebecca Foulger Mode of inheritance for gene: DPM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1112 DPM1 Rebecca Foulger Phenotypes for gene: DPM1 were changed from to Congenital disorder of glycosylation, type Ie, 608799
Early onset or syndromic epilepsy v0.1111 TELO2 Konstantinos Varvagiannis reviewed gene: TELO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27132593, 28944240; Phenotypes: You-Hoover-Fong syndrome, MIM 616954; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1111 TELO2 Konstantinos Varvagiannis Deleted their review
Early onset or syndromic epilepsy v0.1111 TELO2 Konstantinos Varvagiannis gene: TELO2 was added
gene: TELO2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal
Penetrance for gene: TELO2 were set to Complete
Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). //

PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype.

Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures.

5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported.

As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed.

Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function.

PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (ID and microcephaly) with additional features (dwarfism, renal anomalies, retinitis pigmentosa, etc) compared to previously reported patients. //

As a result this gene could possibly be considered for inclusion in this panel as amber (seizures in 3/8 patients reported to date - these individuals belonged to 2 different families) .
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.1111 DPAGT1 Rebecca Foulger Marked gene: DPAGT1 as ready
Early onset or syndromic epilepsy v0.1111 DPAGT1 Rebecca Foulger Gene: dpagt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1111 DPAGT1 Rebecca Foulger Classified gene: DPAGT1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1111 DPAGT1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green review. Confirmed DD-G2P gene for Congenital disorder of glycosylation (CDG), which can present with seizures. Sufficient cases of seizures from the literature (3 cases from PMIDs:22304930, 23249953, 12872255) for inclusion on panel.
Early onset or syndromic epilepsy v0.1111 DPAGT1 Rebecca Foulger Gene: dpagt1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1110 DPAGT1 Rebecca Foulger commented on gene: DPAGT1: In a patient with central disorder of glycosylation type Ij, Wu et al. (2003, PMID:12872255) identified reduced DPAGT1 enzymatic activity. In the paternal allele, a variant Y170C was identified. Although no variant was identified in the maternal allele, it produced only 12% of the normal amount of mRNA. She had severe hypotonia and medically intractable seizures amongst her phenotypes.
Early onset or syndromic epilepsy v0.1110 DPAGT1 Rebecca Foulger commented on gene: DPAGT1: In a Pakistani brother and sister born of unrelated patients with a mild form of CDG Ij, Iqbal et al. (2013, PMID:23249953) identified compound heterozygous mutations in the DPAGT1 gene (I29F and L168P). The patients had normal psychomotor development until ages 2 and 5 years, respectively, when they both developed seizures, hypotonia, and aggressive behavior. Seizures and additional phenotypes continued into adulthood.
Early onset or syndromic epilepsy v0.1110 DPAGT1 Rebecca Foulger commented on gene: DPAGT1
Early onset or syndromic epilepsy v0.1110 HCN2 Ivone Leong Classified gene: HCN2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1110 HCN2 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. No phenotypes have been associated with HCN2 in OMIM or Gene2Phenotype. There are 2 papers (PMID: 29064616, 17931874) reporting misssense, frameshift and small deletion variants in HCN2 associated with Genetic epilepsy with febrile seizures plus disorders and other epilepsy/seizure disorders (e.g. Idiopathic generalized epilepsy). There is also evidence that these variants cause gain-of-function effects (PMID: 29064616). Another study reported on a patient with sporadic idiopathic generalised seizures who had a recessive loss-of-function missense variant. An HCN2 knockout mouse model (PMID: 12514127) had absence seizures.
Early onset or syndromic epilepsy v0.1110 HCN2 Ivone Leong Gene: hcn2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1109 HCN2 Ivone Leong Phenotypes for gene: HCN2 were changed from Genetic epilepsy with efbrile seizures plus; Other seizure disorders to Genetic epilepsy with febrile seizures plus; Other seizure disorders
Early onset or syndromic epilepsy v0.1108 HCN2 Ivone Leong Phenotypes for gene: HCN2 were changed from to Genetic epilepsy with efbrile seizures plus; Other seizure disorders
Early onset or syndromic epilepsy v0.1107 HCN2 Ivone Leong Mode of inheritance for gene: HCN2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1106 HCN2 Ivone Leong Publications for gene: HCN2 were set to 29064616; 20437590; 12514127; 17931874
Early onset or syndromic epilepsy v0.1105 HCN2 Ivone Leong Publications for gene: HCN2 were set to
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Marked gene: GPHN as ready
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Added comment: Comment when marking as ready: Gene is ready as there is enough evidence. All cases were selected based on the fact that patients were diagnosed with Molybdenum cofactor deficiency C or are positive for molybdenum cofactor deficiency who have a causative variant in the GPHN gene, who also have seizures. This is why PMID: 24561070, 23393157 were not included as publication sources.
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Gene: gphn has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Classified gene: GPHN as Green List (high evidence)
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. GPHN is confirmed to be associated with Molybdenum cofactor deficiency C on OMIM, with seizures listed as a phenotype; however, there is nothing listed in Gene2Phenotype.
There are 3 papers (PMID: 26613940,12684523,11095995) reporting patients who have Molybdenum cofactor deficiency C with different variants in the GPHN gene. All of these patients are of different ethnicity and all have seizures.
Early onset or syndromic epilepsy v0.1104 GPHN Ivone Leong Gene: gphn has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1103 GPHN Ivone Leong Publications for gene: GPHN were set to
Early onset or syndromic epilepsy v0.1102 MED12 Ivone Leong commented on gene: MED12
Early onset or syndromic epilepsy v0.1102 MED12 Ivone Leong Publications for gene: MED12 were set to
Early onset or syndromic epilepsy v0.1101 MED12 Ivone Leong Phenotypes for gene: MED12 were changed from Lujan-Fryns syndrome, 309520 to Lujan-Fryns syndrome, 309520; Opitz-Kaveggia syndrome, 305450
Early onset or syndromic epilepsy v0.1100 MED12 Ivone Leong Mode of inheritance for gene: MED12 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.1099 MED12 Ivone Leong Phenotypes for gene: MED12 were changed from to Lujan-Fryns syndrome, 309520
Early onset or syndromic epilepsy v0.1098 MAP2K2 Ivone Leong Marked gene: MAP2K2 as ready
Early onset or syndromic epilepsy v0.1098 MAP2K2 Ivone Leong Gene: map2k2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1098 MAP2K2 Ivone Leong Classified gene: MAP2K2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1098 MAP2K2 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. MAP2K2 is confirmed to be associated with Cardiofaciocutaneous syndrome 4 in both OMIM and Gene2Phenotype. Only Gene2Phenotype lists seizures as a phenotype.
There are three reported cases (PMID: 29799162, 24719372, 27799067)
of unrelated probands with different variants (2 missense and one deletion) who have seizures. It should be noted that not all patients with a MAP2K2 variant experience seizures.
Early onset or syndromic epilepsy v0.1098 MAP2K2 Ivone Leong Gene: map2k2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1097 MAP2K2 Ivone Leong Publications for gene: MAP2K2 were set to 29799162; 2471937; 27799067
Early onset or syndromic epilepsy v0.1096 MAP2K2 Ivone Leong Publications for gene: MAP2K2 were set to
Early onset or syndromic epilepsy v0.1095 MACF1 Konstantinos Varvagiannis gene: MACF1 was added
gene: MACF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia
Penetrance for gene: MACF1 were set to unknown
Mode of pathogenicity for gene: MACF1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MACF1 was set to GREEN
Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1.

All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9).

Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle.

5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total.

The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration.

Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation.

The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0.

As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism.

Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures.

As a result, this gene can be considered for inclusion in this panel probably as green.
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.1095 DPAGT1 Rebecca Foulger Mode of inheritance for gene: DPAGT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1094 DPAGT1 Rebecca Foulger Phenotypes for gene: DPAGT1 were changed from to Congenital disorder of glycosylation, type Ij, 608093
Early onset or syndromic epilepsy v0.1093 DOLK Rebecca Foulger commented on gene: DOLK: Lebfer et al, 2011 (PMID:22242004) say epilepsy was not present in their patients with DOLK variants and dilated cardiomyopathy.
Early onset or syndromic epilepsy v0.1093 DOLK Rebecca Foulger Publications for gene: DOLK were set to 23890587
Early onset or syndromic epilepsy v0.1092 DOLK Rebecca Foulger commented on gene: DOLK: PMID:17273964 (Kranz et al. 2007) report 2 affected first cousins in a consanguineous German family with homozygosity for a 295T-A transversion in the DOLK gene (C99S). For subject GH, seizures due to hypsarrhythmia started at age 7 wk. Subject NB, a first cousin of GH, had no seizures. The authors also report 2 Turkish siblings from consanguineous parents with a 1322A-C transversion in the DOLK gene (Y441S). No epilepsy was mentioned, although death occured age 7 mo and 4 mo.
Early onset or syndromic epilepsy v0.1092 MAP2K2 Ivone Leong Phenotypes for gene: MAP2K2 were changed from to Cardiofaciocutaneous syndrome 4, 615280
Early onset or syndromic epilepsy v0.1091 DOLK Rebecca Foulger Publications for gene: DOLK were set to
Early onset or syndromic epilepsy v0.1090 DOLK Rebecca Foulger commented on gene: DOLK
Early onset or syndromic epilepsy v0.1090 MAP2K1 Ivone Leong Marked gene: MAP2K1 as ready
Early onset or syndromic epilepsy v0.1090 MAP2K1 Ivone Leong Gene: map2k1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1090 MAP2K1 Ivone Leong Classified gene: MAP2K1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1090 MAP2K1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Both Omim and Gene2Phenotype confirmed that MAP2K1 is associated with Cardiofaciocutaneous syndrome and seizure is listed as a phenotype by Gene2Phenotype but not OMIM.
A study (PMID: 27862862) reported a proband with a missense variant who has seizures. A large study (PMID: 18039235) examining patients from North America, Australia and UK found that 4 out of 5 patients with different missense variants in MAP2K1 had seizures.
Early onset or syndromic epilepsy v0.1090 MAP2K1 Ivone Leong Gene: map2k1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1089 DOLK Rebecca Foulger Mode of inheritance for gene: DOLK was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1088 DOLK Rebecca Foulger Phenotypes for gene: DOLK were changed from to Congenital disorder of glycosylation, type Im, 610768
Early onset or syndromic epilepsy v0.1087 DNM1L Rebecca Foulger Marked gene: DNM1L as ready
Early onset or syndromic epilepsy v0.1087 DNM1L Rebecca Foulger Gene: dnm1l has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1087 DNM1L Rebecca Foulger Classified gene: DNM1L as Green List (high evidence)
Early onset or syndromic epilepsy v0.1087 DNM1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Green rating by Zornitza. At least 3 cases in the literature of unrelated patients with DNM1L variants and seizures (1 in PMID:26604000 and 2 in PMID:27145208).
Early onset or syndromic epilepsy v0.1087 DNM1L Rebecca Foulger Gene: dnm1l has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1086 DNM1L Rebecca Foulger Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, 614388 to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, 614388; refractory epilepsy; refractory focal status epilepticus
Early onset or syndromic epilepsy v0.1085 DNM1L Rebecca Foulger commented on gene: DNM1L
Early onset or syndromic epilepsy v0.1085 DNM1L Rebecca Foulger Publications for gene: DNM1L were set to 26604000
Early onset or syndromic epilepsy v0.1084 MAP2K1 Ivone Leong Publications for gene: MAP2K1 were set to 18039235
Early onset or syndromic epilepsy v0.1083 DNM1L Rebecca Foulger Publications for gene: DNM1L were set to
Early onset or syndromic epilepsy v0.1082 DNM1L Rebecca Foulger Mode of inheritance for gene: DNM1L was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1081 DNM1L Rebecca Foulger Phenotypes for gene: DNM1L were changed from to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, 614388
Early onset or syndromic epilepsy v0.1080 DHCR24 Rebecca Foulger Marked gene: DHCR24 as ready
Early onset or syndromic epilepsy v0.1080 DHCR24 Rebecca Foulger Gene: dhcr24 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1080 DHCR24 Rebecca Foulger Tag watchlist tag was added to gene: DHCR24.
Early onset or syndromic epilepsy v0.1080 DHCR24 Rebecca Foulger commented on gene: DHCR24: Added 'watchlist' tag.
Early onset or syndromic epilepsy v0.1080 DHCR24 Rebecca Foulger Publications for gene: DHCR24 were set to
Early onset or syndromic epilepsy v0.1079 DHCR24 Rebecca Foulger Classified gene: DHCR24 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1079 DHCR24 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: Confirmed DD-G2P gene for Desmosterolosis but only 2 families reported so far in the literature with seizures as part of the desmosterolosis phenotype: PMIDs:21559050 and 24961299.
Early onset or syndromic epilepsy v0.1079 DHCR24 Rebecca Foulger Gene: dhcr24 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1078 DHCR24 Rebecca Foulger commented on gene: DHCR24: Epilepsy not reported as part of phenotype in patients from PMID:21671375 (Schaaf et al 2011) and PMID:11519011 (Waterham et al.2001).
Early onset or syndromic epilepsy v0.1078 DHCR24 Rebecca Foulger commented on gene: DHCR24: Dias et al, 2014 report two sisters homozygous for the 571G>A (E191K) DHCR24 variant with syndromic ID and desmosterolosis. Each had transient neonatal seizures. The authors also provide a summary table of 9 patients to-date (2014) with DHCR24 and Desmosterolosis. Only this family and the kindred reported by PMID:21559050 exhibit seizures as part of their phenotype.
Early onset or syndromic epilepsy v0.1078 DHCR24 Rebecca Foulger commented on gene: DHCR24
Early onset or syndromic epilepsy v0.1078 DHCR24 Rebecca Foulger Phenotypes for gene: DHCR24 were changed from to Desmosterolosis, 602398
Early onset or syndromic epilepsy v0.1077 DHCR24 Rebecca Foulger Mode of inheritance for gene: DHCR24 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1076 DENND5A Rebecca Foulger Marked gene: DENND5A as ready
Early onset or syndromic epilepsy v0.1076 DENND5A Rebecca Foulger Gene: dennd5a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1076 DENND5A Rebecca Foulger Classified gene: DENND5A as Green List (high evidence)
Early onset or syndromic epilepsy v0.1076 DENND5A Rebecca Foulger Gene: dennd5a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1075 DENND5A Rebecca Foulger Classified gene: DENND5A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1075 DENND5A Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Although only Probable confidence level in DD-G2P for EPILEPTIC ENCEPHALOPATHY, there are suffcient cases from PMIDs 27866705 and 27431290 (5 individuals from 4 unrelated families) to support gene:disease association and diagnostic rating.
Early onset or syndromic epilepsy v0.1075 DENND5A Rebecca Foulger Gene: dennd5a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1074 DENND5A Rebecca Foulger Publications for gene: DENND5A were set to
Early onset or syndromic epilepsy v0.1073 DENND5A Rebecca Foulger Mode of inheritance for gene: DENND5A was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1072 DENND5A Rebecca Foulger commented on gene: DENND5A
Early onset or syndromic epilepsy v0.1072 DENND5A Rebecca Foulger Phenotypes for gene: DENND5A were changed from to Epileptic encephalopathy, early infantile, 49, 617281
Early onset or syndromic epilepsy v0.1071 DDX3X Rebecca Foulger Marked gene: DDX3X as ready
Early onset or syndromic epilepsy v0.1071 DDX3X Rebecca Foulger Gene: ddx3x has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1071 DDX3X Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM and Gene2Phenotype list MOI as both XLR and XLD.
Early onset or syndromic epilepsy v0.1071 DDX3X Rebecca Foulger Mode of inheritance for gene: DDX3X 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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.1070 DDX3X Rebecca Foulger Classified gene: DDX3X as Green List (high evidence)
Early onset or syndromic epilepsy v0.1070 DDX3X Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Confirmed DD-G2P for X-linked intellectual disability. MIM:300958 disease includes seizures in some patients. 6 females in PMID:26235985 with 6 different DDX3X variants showed seizures (16%). Therefore sufficient cases for diagnostic rating.
Early onset or syndromic epilepsy v0.1070 DDX3X Rebecca Foulger Gene: ddx3x has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1069 DDX3X Rebecca Foulger Mode of inheritance for gene: DDX3X was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.1068 DDX3X Rebecca Foulger commented on gene: DDX3X
Early onset or syndromic epilepsy v0.1068 DDX3X Rebecca Foulger Phenotypes for gene: DDX3X were changed from to Mental retardation, X-linked 102, 300958
Early onset or syndromic epilepsy v0.1067 PLAA Eleanor Williams Marked gene: PLAA as ready
Early onset or syndromic epilepsy v0.1067 PLAA Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases for disease association, >3 cases with seizures
Early onset or syndromic epilepsy v0.1067 PLAA Eleanor Williams Gene: plaa has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1067 PLAA Eleanor Williams Phenotypes for gene: PLAA were changed from to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies 617527; Lethal Infantile Epileptic Encephalopathy
Early onset or syndromic epilepsy v0.1066 PLAA Eleanor Williams Publications for gene: PLAA were set to
Early onset or syndromic epilepsy v0.1065 DBT Rebecca Foulger Phenotypes for gene: DBT were changed from to Maple syrup urine disease, type II, 248600
Early onset or syndromic epilepsy v0.1064 PLAA Eleanor Williams Mode of inheritance for gene: PLAA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1063 PLAA Eleanor Williams Classified gene: PLAA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1063 PLAA Eleanor Williams Added comment: Comment on list classification: 3 variants found in 5 families (but two families likely to have common ancestral haplotype). Seizures reported in all families.
Early onset or syndromic epilepsy v0.1063 PLAA Eleanor Williams Gene: plaa has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1062 HEXA Ivone Leong commented on gene: HEXA: Tay-Sachs disease is rare in the general population but has increased frequency in Ashkenazi Jews. Many of the papers do not specify whether patients have seizures/epilpsy and many report on the patient's phenotype as classic infantile (seizures can be a symptom), juvenile or adult late-onset (seizures can be a symptom), which may or may not necessarily mean patients have seizures. I have only included studies that mention seizures/epilepsy specifically.
Three studies have reported 3 patients with different variants in HEXA gene who have seizures (PMID: 30006889, 21937992, 7551830). PMID: 14972682 describe a mouse model of HEXA which also exhibited seizure/epilpsy phenotype.
Early onset or syndromic epilepsy v0.1062 PLAA Eleanor Williams commented on gene: PLAA
Early onset or syndromic epilepsy v0.1062 DBT Rebecca Foulger Mode of inheritance for gene: DBT was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1061 HEXA Ivone Leong Publications for gene: HEXA were set to
Early onset or syndromic epilepsy v0.1060 GABRB2 Louise Daugherty Marked gene: GABRB2 as ready
Early onset or syndromic epilepsy v0.1060 GABRB2 Louise Daugherty Gene: gabrb2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1060 PHACTR1 Konstantinos Varvagiannis gene: PHACTR1 was added
gene: PHACTR1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: PHACTR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHACTR1 were set to 30256902; 23033978; 28135719
Phenotypes for gene: PHACTR1 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: PHACTR1 were set to unknown
Review for gene: PHACTR1 was set to GREEN
Added comment: PMID: 30256902 (Hamada et al., 2018) reports on the phenotype of 2 unrelated individuals with de novo missense variants in PHACTR1. Both had a diagnosis of West syndrome (infantile spasms and intellectual disability).

As the authors note, 3 individuals with missense variants in this gene (in 2 of whom as a de novo occurrence) were previously identified :
- In PMID: 23033978 (de Ligt et al., 2012) one patient with ID and epilepsy and a de novo missense variant.
- In PMID: 28135719 (DDD study in 2017) one individual with developmental disorder and a further de novo missense SNV.
- PMID: 27457812 (Riazuddin et al., 2017) is an exome sequencing study for intellectual disability. (NB. In the supplement of this study, the consanguineous parents of the affected individuals appear to be heterozygous for this variant but the affected children non-carriers).

Extensive functional studies for the 2 novel as the 2 previously reported variants (from PMIDs: 23033978, 28135719) support a dominant negative effect for all 4 variants.

One of these variants (reported by de Ligt al.) for which pathogenicity is suggested has however been reported 4 times in gnomAD. The authors discuss the possibility of reduced penetrance and/or other phenotypes in the individuals from gnomAD.

Although all the variants studied appear to have a dominant negative effect, Phactr1-knockdown neurons seem to display aberrant migration and morphological phenotype. As a result, the eventual effect of haploinsufficiency probably needs to be further clarified. (Still PHACTR1 has a pLI score of 0.66 in ExAC).

At least 3 individuals appeared to have epilepsy (as this information is not available for the DDD participant).

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.1060 HCFC1 Ivone Leong Publications for gene: HCFC1 were set to 24011988; 23000143; 25740848
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Marked gene: PIK3CA as ready
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Gene: pik3ca has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Classified gene: PIK3CA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Added comment: Comment on list classification: > 3 cases of variants in this gene associated with phenotype, and with seizures
Early onset or syndromic epilepsy v0.1059 PIK3CA Eleanor Williams Gene: pik3ca has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1058 PIK3CA Eleanor Williams Phenotypes for gene: PIK3CA were changed from to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic 602501
Early onset or syndromic epilepsy v0.1057 PIK3CA Eleanor Williams Publications for gene: PIK3CA were set to
Early onset or syndromic epilepsy v0.1056 PIK3CA Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function
Early onset or syndromic epilepsy v0.1056 PIK3CA Eleanor Williams Mode of pathogenicity for gene: PIK3CA was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.1055 GABRB2 Louise Daugherty Marked gene: GABRB2 as ready
Early onset or syndromic epilepsy v0.1055 GABRB2 Louise Daugherty Gene: gabrb2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1055 GABRB2 Louise Daugherty Classified gene: GABRB2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1055 GABRB2 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1055 GABRB2 Louise Daugherty Gene: gabrb2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1054 GABRB2 Louise Daugherty Mode of inheritance for gene: GABRB2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1053 GABRB2 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green. Hamdan et al. (2017) PMID 29100083 reported 3 unrelated cases with de novo missense variants in GABRB2 who had developmental and epileptic encephalopathy. Srivastava et al. (2014) PMID 25124326 . Ishii et al. (2017) PMID: 27789573 describes a 12-year old girl with intellectual disability and epilepsy due to another de novo missense variant in GABRB2 epileptic seizures. Ishii et al. (2017) PMID 27789573 describes a patient with early myoclonic encephalopathy and severe psycomotor delay, due to a de novo heterozygous missense mutation in GABRB2.
Early onset or syndromic epilepsy v0.1053 GABRB2 Louise Daugherty Publications for gene: GABRB2 were set to
Early onset or syndromic epilepsy v0.1052 GABRB2 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1052 GABRB2 Louise Daugherty Phenotypes for gene: GABRB2 were changed from to Epileptic encephalopathy, infantile or early childhood, 2, 617829
Early onset or syndromic epilepsy v0.1051 GALC Louise Daugherty Marked gene: GALC as ready
Early onset or syndromic epilepsy v0.1051 GALC Louise Daugherty Gene: galc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1051 GALC Louise Daugherty Classified gene: GALC as Green List (high evidence)
Early onset or syndromic epilepsy v0.1051 GALC Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1051 GALC Louise Daugherty Gene: galc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1050 PTS Sarah Leigh Classified gene: PTS as Red List (low evidence)
Early onset or syndromic epilepsy v0.1050 PTS Sarah Leigh Added comment: Comment on list classification: Although the phenotype in OMIM and Gen2Phen gene. However, unable to find reports of seizures in variant carriers.
Early onset or syndromic epilepsy v0.1050 PTS Sarah Leigh Gene: pts has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.1049 GALC Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1049 GALC Louise Daugherty Publications for gene: GALC were set to
Early onset or syndromic epilepsy v0.1048 GALC Louise Daugherty Added comment: Comment on mode of inheritance: changed MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1048 GALC Louise Daugherty Mode of inheritance for gene: GALC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1047 GALC Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1047 GALC Louise Daugherty Phenotypes for gene: GALC were changed from to Krabbe disease, 245200; seizures; CALC deficiency; Galactosylceramide beta-galactosidase deficiency
Early onset or syndromic epilepsy v0.1046 GAMT Louise Daugherty Marked gene: GAMT as ready
Early onset or syndromic epilepsy v0.1046 GAMT Louise Daugherty Gene: gamt has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1046 PIK3CA Eleanor Williams Added comment: Comment on mode of inheritance: Note somatic mosiacism
Early onset or syndromic epilepsy v0.1046 PIK3CA Eleanor Williams Mode of inheritance for gene: PIK3CA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1045 PIK3CA Eleanor Williams Tag mosaicism tag was added to gene: PIK3CA.
Tag somatic tag was added to gene: PIK3CA.
Early onset or syndromic epilepsy v0.1045 PIK3CA Eleanor Williams commented on gene: PIK3CA
Early onset or syndromic epilepsy v0.1045 KCNQ5 Ivone Leong Classified gene: KCNQ5 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1045 KCNQ5 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Have checked with Eleanor Williams (Genomic England) that two probands with different variants who have the same ethnic background is accepted as two separate pieces of evidence.
Early onset or syndromic epilepsy v0.1045 KCNQ5 Ivone Leong Gene: kcnq5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1044 GAMT Louise Daugherty Added comment: Comment on phenotypes: added synonyms
Early onset or syndromic epilepsy v0.1044 GAMT Louise Daugherty Phenotypes for gene: GAMT were changed from Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase to Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase; GAMT deficiency
Early onset or syndromic epilepsy v0.1043 GAMT Louise Daugherty Publications for gene: GAMT were set to 15651030; 17101918; 15108290; 19027335
Early onset or syndromic epilepsy v0.1042 GAMT Louise Daugherty Classified gene: GAMT as Green List (high evidence)
Early onset or syndromic epilepsy v0.1042 GAMT Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1042 GAMT Louise Daugherty Gene: gamt has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1041 GAMT Louise Daugherty Added comment: Comment on publications: Added publications s to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1041 GAMT Louise Daugherty Publications for gene: GAMT were set to
Early onset or syndromic epilepsy v0.1040 MAP2K1 Ivone Leong Publications for gene: MAP2K1 were set to
Early onset or syndromic epilepsy v0.1039 GAMT Louise Daugherty Phenotypes for gene: GAMT were changed from Cerebral creatine deficiency syndrome 2, 612736; Seizures to Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase
Early onset or syndromic epilepsy v0.1038 GAMT Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.1038 GAMT Louise Daugherty Mode of inheritance for gene: GAMT was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1037 GAMT Louise Daugherty Added comment: Comment on phenotypes: Not added the expert review phenotype Krabbe disease as it related to the previously reviewed gene GALC. Cerebral creatine deficiency syndrome 2, 612736 is the disorder associated to variants of this gene, and is relevant for inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.1037 GAMT Louise Daugherty Phenotypes for gene: GAMT were changed from to Cerebral creatine deficiency syndrome 2, 612736; Seizures
Early onset or syndromic epilepsy v0.1036 MAP2K1 Ivone Leong Mode of inheritance for gene: MAP2K1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.1035 MAP2K1 Ivone Leong Phenotypes for gene: MAP2K1 were changed from to Cardiofaciocutaneous syndrome 3, 615279
Early onset or syndromic epilepsy v0.1034 PIGW Eleanor Williams Marked gene: PIGW as ready
Early onset or syndromic epilepsy v0.1034 PIGW Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases to make green
Early onset or syndromic epilepsy v0.1034 PIGW Eleanor Williams Gene: pigw has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1034 PIGW Eleanor Williams Phenotypes for gene: PIGW were changed from to Glycosylphosphatidylinositol biosynthesis defect 11, 616025; HYPERPHOSPHATASIA WITH MENTAL RETARDATION SYNDROME 5
Early onset or syndromic epilepsy v0.1033 PIGW Eleanor Williams Publications for gene: PIGW were set to 24367057; 27626616; 30078644
Early onset or syndromic epilepsy v0.1032 PIGW Eleanor Williams Publications for gene: PIGW were set to
Early onset or syndromic epilepsy v0.1031 LIAS Ivone Leong Marked gene: LIAS as ready
Early onset or syndromic epilepsy v0.1031 LIAS Ivone Leong Gene: lias has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1031 LIAS Ivone Leong Classified gene: LIAS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1031 LIAS Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Phenotype confirmed by both OMIM and Gene2Phenotype.

There are only 4 reported cases of this disease in 3 papers (PMID: 24334290, 22152680, 26108146). Of the three cases, all patients (2 of Turkish descent and 1 of Somali descent) have different variants in the LIAS gene and they all have seizures (PMID: 24334290, 22152680).
Early onset or syndromic epilepsy v0.1031 LIAS Ivone Leong Gene: lias has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1030 PIGW Eleanor Williams Mode of inheritance for gene: PIGW was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1029 PIGW Eleanor Williams Classified gene: PIGW as Green List (high evidence)
Early onset or syndromic epilepsy v0.1029 PIGW Eleanor Williams Added comment: Comment on list classification: 3 cases/families reported, all with seizures
Early onset or syndromic epilepsy v0.1029 PIGW Eleanor Williams Gene: pigw has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1028 PIGW Eleanor Williams commented on gene: PIGW
Early onset or syndromic epilepsy v0.1028 PIGO Eleanor Williams Marked gene: PIGO as ready
Early onset or syndromic epilepsy v0.1028 PIGO Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases with compound heterozygous mutations in PIGO and 3 cases with seizures.
Early onset or syndromic epilepsy v0.1028 PIGO Eleanor Williams Gene: pigo has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1028 PIGO Eleanor Williams Publications for gene: PIGO were set to 22683086; 24049131; 24417746; 28900819
Early onset or syndromic epilepsy v0.1027 PIGO Eleanor Williams Phenotypes for gene: PIGO were changed from to Hyperphosphatasia with mental retardation syndrome 2, 614749
Early onset or syndromic epilepsy v0.1026 PIGO Eleanor Williams Added comment: Comment on publications: Further cases reported in PMIDs: 28900819 and 28337824
Early onset or syndromic epilepsy v0.1026 PIGO Eleanor Williams Publications for gene: PIGO were set to
Early onset or syndromic epilepsy v0.1025 PIGO Eleanor Williams Mode of inheritance for gene: PIGO was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1024 PIGO Eleanor Williams Classified gene: PIGO as Green List (high evidence)
Early onset or syndromic epilepsy v0.1024 PIGO Eleanor Williams Added comment: Comment on list classification: Sufficient cases with compound heterogzyous mutations in PIGO and 3 cases with seizures.
Early onset or syndromic epilepsy v0.1024 PIGO Eleanor Williams Gene: pigo has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1023 PIGO Eleanor Williams commented on gene: PIGO
Early onset or syndromic epilepsy v0.1023 LARGE1 Ivone Leong Marked gene: LARGE1 as ready
Early onset or syndromic epilepsy v0.1023 LARGE1 Ivone Leong Gene: large1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1023 LARGE1 Ivone Leong Classified gene: LARGE1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1023 LARGE1 Ivone Leong Added comment: Comment on list classification: Phenotype confirmed by both OMIM and Gene2Phenotype. However, there is only one reported case of a patient with mutations in LARGE1 who also have seizures (PMID: 24709677). Therefore not enough evidence to promote to green status.
Early onset or syndromic epilepsy v0.1023 LARGE1 Ivone Leong Gene: large1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1022 LARGE1 Ivone Leong Publications for gene: LARGE1 were set to
Early onset or syndromic epilepsy v0.1021 PHGDH Eleanor Williams Marked gene: PHGDH as ready
Early onset or syndromic epilepsy v0.1021 PHGDH Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases reported with seizures.
Early onset or syndromic epilepsy v0.1021 PHGDH Eleanor Williams Gene: phgdh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1021 PHGDH Eleanor Williams Phenotypes for gene: PHGDH were changed from to Phosphoglycerate dehydrogenase deficiency 601815
Early onset or syndromic epilepsy v0.1020 PHGDH Eleanor Williams Publications for gene: PHGDH were set to
Early onset or syndromic epilepsy v0.1019 PHGDH Eleanor Williams Mode of inheritance for gene: PHGDH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1018 PHGDH Eleanor Williams Classified gene: PHGDH as Green List (high evidence)
Early onset or syndromic epilepsy v0.1018 PHGDH Eleanor Williams Added comment: Comment on list classification: More than 3 variants associated with the disorder. Patients from 7 families present with seizures.
Early onset or syndromic epilepsy v0.1018 PHGDH Eleanor Williams Gene: phgdh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1017 PHGDH Eleanor Williams commented on gene: PHGDH
Early onset or syndromic epilepsy v0.1017 PDHX Eleanor Williams Marked gene: PDHX as ready
Early onset or syndromic epilepsy v0.1017 PDHX Eleanor Williams Added comment: Comment when marking as ready: Sufficient variants to associate with disorder. At least 3 cases where seizures are part of the phenotype.
Early onset or syndromic epilepsy v0.1017 PDHX Eleanor Williams Gene: pdhx has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1017 PDHX Eleanor Williams Phenotypes for gene: PDHX were changed from to Lacticacidemia due to PDX1 deficiency 245349
Early onset or syndromic epilepsy v0.1016 PDHX Eleanor Williams Publications for gene: PDHX were set to
Early onset or syndromic epilepsy v0.1015 PDHX Eleanor Williams Mode of inheritance for gene: PDHX was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1014 PDHX Eleanor Williams Classified gene: PDHX as Green List (high evidence)
Early onset or syndromic epilepsy v0.1014 PDHX Eleanor Williams Added comment: Comment on list classification: Numerous variants in this gene associated with Lacticacidemia are reported. 3 cases where seizures are part of the phenotype.
Early onset or syndromic epilepsy v0.1014 PDHX Eleanor Williams Gene: pdhx has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1013 PDHX Eleanor Williams commented on gene: PDHX
Early onset or syndromic epilepsy v0.1013 GBA Louise Daugherty Marked gene: GBA as ready
Early onset or syndromic epilepsy v0.1013 GBA Louise Daugherty Gene: gba has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Marked gene: PDHA1 as ready
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases.
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Gene: pdha1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Classified gene: PDHA1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Added comment: Comment on list classification: > 3 cases of patients with variants in this gene with Pyruvate dehydrogenase E1-alpha deficiency and with seizures as part of the phenotype.
Early onset or syndromic epilepsy v0.1013 PDHA1 Eleanor Williams Gene: pdha1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1012 GBA Louise Daugherty Classified gene: GBA as Green List (high evidence)
Early onset or syndromic epilepsy v0.1012 GBA Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.1012 GBA Louise Daugherty Gene: gba has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1011 PDHA1 Eleanor Williams Added comment: Comment on mode of inheritance: Heterozygous mutations seen in females showing phenotype.
Early onset or syndromic epilepsy v0.1011 PDHA1 Eleanor Williams Mode of inheritance for gene: PDHA1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.1010 PDHA1 Eleanor Williams Added comment: Comment on phenotypes: Siezures are listed as part of the phenotype for X-LINKED LEIGH SYNDROME, PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY IN FEMALES and INTELLECTUAL DISABILTIY in Gene2Phenotype
Early onset or syndromic epilepsy v0.1010 PDHA1 Eleanor Williams Phenotypes for gene: PDHA1 were changed from to Pyruvate dehydrogenase E1-alpha deficiency 312170; X-LINKED LEIGH SYNDROME; PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY IN FEMALES; INTELLECTUAL DISABILTIY
Early onset or syndromic epilepsy v0.1009 PDHA1 Eleanor Williams Publications for gene: PDHA1 were set to
Early onset or syndromic epilepsy v0.1008 PDHA1 Eleanor Williams commented on gene: PDHA1
Early onset or syndromic epilepsy v0.1008 GBA Louise Daugherty Publications for gene: GBA were set to 8929950; 15214004; 12838552; 8829654; 8118460
Early onset or syndromic epilepsy v0.1007 LIAS Ivone Leong Mode of inheritance for gene: LIAS was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1006 LIAS Ivone Leong Phenotypes for gene: LIAS were changed from to Hyperglycinemia, lactic acidosis, and seizures, 614462
Early onset or syndromic epilepsy v0.1005 LARGE1 Ivone Leong Mode of inheritance for gene: LARGE1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1004 LARGE1 Ivone Leong Phenotypes for gene: LARGE1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6, 613154; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6, 608840
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Classified gene: KRAS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Added comment: Comment on list classification: Cardiofaciocutaneous syndrome 2 was confirmed on both OMIM and Gene2Phenotype. One report (PMID: 16474405) found one proband with a missense variant in the KRAS gene that had seizures, and another study (PMID: 21871821) found 2 unrelated Japanese probands with missense mutations who have seizures. There is not enough evidence to promote the gene.
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Gene: kras has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1002 GBA Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.1002 GBA Louise Daugherty Publications for gene: GBA were set to
Early onset or syndromic epilepsy v0.1001 KRAS Ivone Leong Publications for gene: KRAS were set to
Early onset or syndromic epilepsy v0.1000 KRAS Ivone Leong Added comment: Comment on mode of pathogenicity: Variants cause gain-of-function effects (PMID: 21871821, 23059812).
Early onset or syndromic epilepsy v0.1000 KRAS Ivone Leong Mode of pathogenicity for gene: KRAS was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.999 GBA Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.999 GBA Louise Daugherty Mode of inheritance for gene: GBA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.998 GBA Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review and reviewed literature that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.998 GBA Louise Daugherty Phenotypes for gene: GBA were changed from to Gaucher disease, perinatal lethal, 608013; Gaucher disease, type II, 230900; Gaucher disease, type III, 231000; Gaucher disease, type IIIC, 231005; seizures
Early onset or syndromic epilepsy v0.997 GCH1 Louise Daugherty Marked gene: GCH1 as ready
Early onset or syndromic epilepsy v0.997 GCH1 Louise Daugherty Gene: gch1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.997 GCH1 Louise Daugherty Classified gene: GCH1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.997 GCH1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.997 GCH1 Louise Daugherty Gene: gch1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.996 GCH1 Louise Daugherty Mode of inheritance for gene: GCH1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.995 GCH1 Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.995 GCH1 Louise Daugherty Publications for gene: GCH1 were set to
Early onset or syndromic epilepsy v0.994 PCCB Eleanor Williams Phenotypes for gene: PCCB were changed from to Propionicacidemia 606054
Early onset or syndromic epilepsy v0.993 PCCB Eleanor Williams Publications for gene: PCCB were set to
Early onset or syndromic epilepsy v0.992 PCCB Eleanor Williams commented on gene: PCCB
Early onset or syndromic epilepsy v0.992 PCCB Eleanor Williams Mode of inheritance for gene: PCCB was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.991 GCH1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.991 GCH1 Louise Daugherty Phenotypes for gene: GCH1 were changed from to Hyperphenylalaninemia, BH4-deficient, B, 233910; seizures
Early onset or syndromic epilepsy v0.990 PTS Sarah Leigh Classified gene: PTS as Green List (high evidence)
Early onset or syndromic epilepsy v0.990 PTS Sarah Leigh Gene: pts has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.989 PCCB Eleanor Williams commented on gene: PCCB
Early onset or syndromic epilepsy v0.989 PTS Sarah Leigh Phenotypes for gene: PTS were changed from to Hyperphenylalaninemia, BH4-deficient, A, 261640
Early onset or syndromic epilepsy v0.988 PTS Sarah Leigh Publications for gene: PTS were set to
Early onset or syndromic epilepsy v0.987 GFAP Louise Daugherty Marked gene: GFAP as ready
Early onset or syndromic epilepsy v0.987 GFAP Louise Daugherty Gene: gfap has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.987 PTS Sarah Leigh Mode of inheritance for gene: PTS was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.986 GFAP Louise Daugherty Classified gene: GFAP as Green List (high evidence)
Early onset or syndromic epilepsy v0.986 GFAP Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.986 GFAP Louise Daugherty Gene: gfap has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.985 GFAP Louise Daugherty Mode of inheritance for gene: GFAP was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.984 GFAP Louise Daugherty Phenotypes for gene: GFAP were changed from to Alexander disease, 203450; seizures
Early onset or syndromic epilepsy v0.983 GFAP Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green. From OMIM PMID: 12034785 Gorospe et al. (2002) reported 12 genetically confirmed cases of Alexander disease. Seven of the 12 had onset in infancy (range 2-18 months), with seizures being the most common presenting sign, followed by failure to thrive and delayed motor development.
Early onset or syndromic epilepsy v0.983 GFAP Louise Daugherty Publications for gene: GFAP were set to
Early onset or syndromic epilepsy v0.982 KRAS Ivone Leong Mode of inheritance for gene: KRAS was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.981 PCCA Eleanor Williams Publications for gene: PCCA were set to 2213454; 25875215; 30014764
Early onset or syndromic epilepsy v0.980 D2HGDH Rebecca Foulger Marked gene: D2HGDH as ready
Early onset or syndromic epilepsy v0.980 D2HGDH Rebecca Foulger Gene: d2hgdh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.980 D2HGDH Rebecca Foulger Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures, to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures
Early onset or syndromic epilepsy v0.979 D2HGDH Rebecca Foulger Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721 to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures,
Early onset or syndromic epilepsy v0.978 D2HGDH Rebecca Foulger Classified gene: D2HGDH as Green List (high evidence)
Early onset or syndromic epilepsy v0.978 D2HGDH Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Green review, and as Zornitza reports, epilepsy is a phenotype of D-2-hydroxyglutaric aciduria. Sufficient unrelated epileptic cases from the literature (2 from PMID:15609246 and 1 from PMID:16037974) to support a diagnostic rating.
Early onset or syndromic epilepsy v0.978 D2HGDH Rebecca Foulger Gene: d2hgdh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.977 D2HGDH Rebecca Foulger commented on gene: D2HGDH: Struys et al 2005 (PMID:15609246) report two unrelated patients affected with severe D-2-hydroxyglutaric aciduria and disease-causing variants in D2HGDH. Patient one suffered tonic, tonic-clonic, and myoclonic seizures, and was homozygous for missense variant in D2HGDH (c.1331T-->C; p.Val444Ala). Patient 2 presented with generalized tonic-clonic seizures and infantile spasms amongst her symptoms. She was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele.
Early onset or syndromic epilepsy v0.977 D2HGDH Rebecca Foulger commented on gene: D2HGDH
Early onset or syndromic epilepsy v0.977 PCCA Eleanor Williams Phenotypes for gene: PCCA were changed from to Propionicacidemia 606054
Early onset or syndromic epilepsy v0.976 PCCA Eleanor Williams Publications for gene: PCCA were set to
Early onset or syndromic epilepsy v0.975 PCCA Eleanor Williams Mode of inheritance for gene: PCCA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.974 PCCA Eleanor Williams commented on gene: PCCA
Early onset or syndromic epilepsy v0.974 GLB1 Louise Daugherty Marked gene: GLB1 as ready
Early onset or syndromic epilepsy v0.974 GLB1 Louise Daugherty Gene: glb1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.974 GLB1 Louise Daugherty Classified gene: GLB1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.974 GLB1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.974 GLB1 Louise Daugherty Gene: glb1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.973 GLB1 Louise Daugherty Publications for gene: GLB1 were set to
Early onset or syndromic epilepsy v0.972 UFM1 Konstantinos Varvagiannis reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28931644, 29868776; Phenotypes: Leukodystrophy hypomyelinating 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.972 UFM1 Konstantinos Varvagiannis Deleted their review
Early onset or syndromic epilepsy v0.972 UFM1 Konstantinos Varvagiannis gene: UFM1 was added
gene: UFM1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: UFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UFM1 were set to 28931644; 29868776
Phenotypes for gene: UFM1 were set to Leukodystrophy hypomyelinating 14, 617899
Penetrance for gene: UFM1 were set to Complete
Review for gene: UFM1 was set to GREEN
Added comment: Biallelic UFM1 mutations cause Leukodystrophy hypomyelinating 14, MIM 617899.

PMID: 28931644 is the first report on 16 individuals from 14 families with shared Roma ethnic background. All subjects were found to harbor a UFM1 promoter 3 basepair deletion in the homozygous state.

All patients demonstrated a severe phenotype including lack of development and severe epileptic encephalopathy while their MRI images demonstrated hypomyelination with atrophy of the basal ganglia and the cerebellum.

The promoter deletion was detected by exome sequencing. Previously a 0.8 Mb homozygous region (encompassing UFM1) was identified to be shared by all the patients in whom a SNP array was performed. Alternative causes, notably TUBB4A mutations and deletions/duplications were excluded. 3 individuals had Sanger sequencing of all coding regions within the homozygous interval to rule out other - eventually missed - variants.

PMID: 29868776 reports 4 additional individuals from 2 consanguineous families (one from Ethiopia, for the other this was not specified). All 4 patients were homozygous for the c.241C>T (NM_016617.3) or p.(Arg81Cys) variant which was shown to be hypomorphic upon functional studies.

The phenotype consisted of developmental delay (4/4 or 20/20 including the patients from the previous report with which comparison is made in table 2 of the article) with microcephaly (4/4 or 20/20) and seizures (4/4 or 16/20) as well as MRI abnormalities. Failure to thrive and/or short stature were also among the most common features.

UFM1 (as well as UFC1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.972 GLB1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotype suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.972 GLB1 Louise Daugherty Phenotypes for gene: GLB1 were changed from to GM1-gangliosidosis, type II, 230600; seizures
Early onset or syndromic epilepsy v0.971 GLB1 Louise Daugherty Mode of inheritance for gene: GLB1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.970 D2HGDH Rebecca Foulger Mode of inheritance for gene: D2HGDH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.969 D2HGDH Rebecca Foulger Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria, 600721
Early onset or syndromic epilepsy v0.968 GLDC Louise Daugherty Marked gene: GLDC as ready
Early onset or syndromic epilepsy v0.968 GLDC Louise Daugherty Gene: gldc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.968 GLDC Louise Daugherty Classified gene: GLDC as Green List (high evidence)
Early onset or syndromic epilepsy v0.968 GLDC Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Early onset or syndromic epilepsy v0.968 GLDC Louise Daugherty Gene: gldc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.967 GLDC Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.967 GLDC Louise Daugherty Publications for gene: GLDC were set to
Early onset or syndromic epilepsy v0.966 CTSD Rebecca Foulger Marked gene: CTSD as ready
Early onset or syndromic epilepsy v0.966 CTSD Rebecca Foulger Gene: ctsd has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.966 CTSD Rebecca Foulger Classified gene: CTSD as Green List (high evidence)
Early onset or syndromic epilepsy v0.966 CTSD Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Epileptic seizures are an accepted phenotype of CLN10 disease (MIM:610127). Epilepsy reported as part of the symptoms in at least 2 families in literature (PMID:16670177 and PMID:26059544) PLUS animal model of epilepsy (PMID:10995834). Therefore 2 cases + clear animal model is sufficient evidence for diagnostic rating.
Early onset or syndromic epilepsy v0.966 CTSD Rebecca Foulger Gene: ctsd has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.965 CTSD Rebecca Foulger commented on gene: CTSD: PMID:26059544 (Meyer et al 2015) report 2 siblings with CLN10 disease who showed intractable seizures and respiratory insufficiency immediately after birth. A homozygous insertion (c.268_269insC) in exon 3 of the cathepsin D gene was found in both infants.
Early onset or syndromic epilepsy v0.965 CTSD Rebecca Foulger commented on gene: CTSD: Animal mode: CatD-deficient mice develop seizures and progressive retinal atrophy, becoming blind (See PMIDs:10995834 and 16685649).
Early onset or syndromic epilepsy v0.965 CTSD Rebecca Foulger commented on gene: CTSD
Early onset or syndromic epilepsy v0.965 CTSD Rebecca Foulger Publications for gene: CTSD were set to
Early onset or syndromic epilepsy v0.964 KRAS Ivone Leong Phenotypes for gene: KRAS were changed from to Cardiofaciocutaneous syndrome 2, 615278
Early onset or syndromic epilepsy v0.963 KIF5C Ivone Leong Classified gene: KIF5C as Green List (high evidence)
Early onset or syndromic epilepsy v0.963 KIF5C Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Phenotype is confirmed in both OMIM and Gene2Phenotype.
There are 3 studies (PMID: 23603762, 23033978, 29048727) that have reported, in total, 3 unrelated families (5 patients) who have various missense variants in this gene who have Cortical dysplasia and also seizures.
Early onset or syndromic epilepsy v0.963 KIF5C Ivone Leong Gene: kif5c has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.962 GLDC Louise Daugherty Mode of inheritance for gene: GLDC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.961 GLDC Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.961 GLDC Louise Daugherty Phenotypes for gene: GLDC were changed from to Glycine encephalopathy, 605899; seizures
Early onset or syndromic epilepsy v0.960 KIF5C Ivone Leong Publications for gene: KIF5C were set to
Early onset or syndromic epilepsy v0.959 GLUD1 Louise Daugherty Marked gene: GLUD1 as ready
Early onset or syndromic epilepsy v0.959 GLUD1 Louise Daugherty Gene: glud1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.959 GLUD1 Louise Daugherty Classified gene: GLUD1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.959 GLUD1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.959 GLUD1 Louise Daugherty Gene: glud1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.958 GLUD1 Louise Daugherty Phenotypes for gene: GLUD1 were changed from Hyperinsulinism-hyperammonemia syndrome, 606762 to Hyperinsulinism-hyperammonemia syndrome, 606762; epilepsy
Early onset or syndromic epilepsy v0.957 GLUD1 Louise Daugherty Publications for gene: GLUD1 were set to 19046187
Early onset or syndromic epilepsy v0.956 CTSD Rebecca Foulger Mode of inheritance for gene: CTSD was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.955 CTSD Rebecca Foulger Phenotypes for gene: CTSD were changed from to Ceroid lipofuscinosis, neuronal, 10, 610127
Early onset or syndromic epilepsy v0.954 GLUL Louise Daugherty Marked gene: GLUL as ready
Early onset or syndromic epilepsy v0.954 GLUL Louise Daugherty Gene: glul has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.954 GLUL Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.954 GLUL Louise Daugherty Publications for gene: GLUL were set to
Early onset or syndromic epilepsy v0.953 GLUL Louise Daugherty Classified gene: GLUL as Green List (high evidence)
Early onset or syndromic epilepsy v0.953 GLUL Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.953 GLUL Louise Daugherty Gene: glul has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.952 KIF5C Ivone Leong Mode of inheritance for gene: KIF5C was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.951 KIF5C Ivone Leong Phenotypes for gene: KIF5C were changed from to Cortical dysplasia, complex, with other brain malformations 2, 615282
Early onset or syndromic epilepsy v0.950 KCTD3 Ivone Leong Marked gene: KCTD3 as ready
Early onset or syndromic epilepsy v0.950 KCTD3 Ivone Leong Gene: kctd3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.950 KCTD3 Ivone Leong Classified gene: KCTD3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.950 KCTD3 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. No phenotypes are associated with this gene OMIM or Gene2Phenotype.
One study (PMID: 29406573) reported various mutations in this gene for 7 probands from 4 consanguineous families who all have epilepsy. The families are from the same geographical location. The study did show that the variants segregated with the phenotype. Two other large (PMID: 27848944, 25558065) screening studies reported 3 probands with frameshift variants in this gene who have epilepsy.
Early onset or syndromic epilepsy v0.950 KCTD3 Ivone Leong Gene: kctd3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.949 GLUD1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.949 GLUD1 Louise Daugherty Phenotypes for gene: GLUD1 were changed from to Hyperinsulinism-hyperammonemia syndrome, 606762
Early onset or syndromic epilepsy v0.948 GLUD1 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.948 GLUD1 Louise Daugherty Publications for gene: GLUD1 were set to
Early onset or syndromic epilepsy v0.947 GLUD1 Louise Daugherty Added comment: Comment on mode of inheritance: Changed MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.947 GLUD1 Louise Daugherty Mode of inheritance for gene: GLUD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.946 KCTD3 Ivone Leong Phenotypes for gene: KCTD3 were changed from to No OMIM number; Epileptic encephalopathy
Early onset or syndromic epilepsy v0.945 KCTD3 Ivone Leong Publications for gene: KCTD3 were set to
Early onset or syndromic epilepsy v0.944 KCTD3 Ivone Leong Mode of inheritance for gene: KCTD3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.943 UFC1 Konstantinos Varvagiannis gene: UFC1 was added
gene: UFC1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth, 618076
Penetrance for gene: UFC1 were set to Complete
Review for gene: UFC1 was set to GREEN
Added comment: Biallelic UFC1 mutations cause Neurodevelopmental disorder with spasticity and poor growth, MIM 618076.

PMID: 29868776 describes 7 individuals (most) born to consanguineous Saudi families (in one case the parents were not consanguineous but originated from the same tribe) as well as a further individual born to distantly related Swiss parents. One of these patients was previously briefly published by the same authors (PMID: 27431290).

The phenotype consisted of developmental delay (8/8 - usually profound), failure to thrive (8/8), short stature and microcephaly (both observed in 7/8), seizures (4/8) and variable brain MRI anomalies in some of these subjects.

Overall, two UFC1 missense variants are reported [NM_016406.3:c.317C>T or p.(Thr106Ile) and c.68G>A or p.(Arg23Gln) the former in the Saudi individuals]. Functional studies demonstrated the hypomorphic nature of the variants.

UFC1 (as well as UFM1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

Epilepsy was a feature in 50% (4/8) of the individuals reported.

As a result this gene can be considered for inclusion in the epilepsy panel as green (or amber).
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.943 KCNQ5 Ivone Leong Marked gene: KCNQ5 as ready
Early onset or syndromic epilepsy v0.943 KCNQ5 Ivone Leong Added comment: Comment when marking as ready: Phenotype conformed on OMIM and Gene2Phenotype. KCNQ5 is a green gene on the Intellectual disability panel.

As stated by Zornitza Stark (Australian Genomics), the original paper (PMID: 28669405) describes 2 of 4 patients with variants in this gene who have seizures (both are are South East Asian decent). Another paper (PMID: 30359776) describes a patient with an intragenic duplication variant in this gene who has seizures. However, as there's just not quit nough evidence I have put the Watchlist tag on.
Early onset or syndromic epilepsy v0.943 KCNQ5 Ivone Leong Gene: kcnq5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.943 KCNQ5 Ivone Leong Tag watchlist tag was added to gene: KCNQ5.
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Marked gene: CSNK2B as ready
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Added comment: Comment when marking as ready: Marked as Ready: November 19th 2018.
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Gene: csnk2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger commented on gene: CSNK2B: Added watchlist tag.
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Tag watchlist tag was added to gene: CSNK2B.
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Classified gene: CSNK2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: As summarised by Zornitza, currently 2 epileptic patients with de novo CSNK2B variants (PMID:28762608 and PMID:28585349). The third patient was reported with intellectual disability but not epilepsy. At least one further epileptic case required for diagnostic rating.
Early onset or syndromic epilepsy v0.943 CSNK2B Rebecca Foulger Gene: csnk2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.942 CSNK2B Rebecca Foulger commented on gene: CSNK2B
Early onset or syndromic epilepsy v0.942 CSNK2B Rebecca Foulger Phenotypes for gene: CSNK2B were changed from to Myoclonic epilepsy and intellectual disability
Early onset or syndromic epilepsy v0.941 CSNK2B Rebecca Foulger Publications for gene: CSNK2B were set to
Early onset or syndromic epilepsy v0.940 CSNK2B Rebecca Foulger Mode of inheritance for gene: CSNK2B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.939 KCNQ5 Ivone Leong Publications for gene: KCNQ5 were set to
Early onset or syndromic epilepsy v0.938 KCNQ5 Ivone Leong Mode of inheritance for gene: KCNQ5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.937 KCNQ5 Ivone Leong Phenotypes for gene: KCNQ5 were changed from to Mental retardation, autosomal dominant 46, 617601
Early onset or syndromic epilepsy v0.936 KCNJ11 Ivone Leong Classified gene: KCNJ11 as Green List (high evidence)
Early onset or syndromic epilepsy v0.936 KCNJ11 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Conformed for Diabetes, permanent neonatal, with or without neurologic features (PNDM) on OMIM but not on Gene2Phenotype, which lists only Diabetes mellitus, kcnj11-related transient neonatal. It should be noted that in the OMIM (606176), developmental delay, epilepsy, and neonatal diabetes (DEND) is also included, which is a more severe form of the disease.
KCNJ11 is also a green gene in the Intellectual disability gene panel.
There are 4 studies (PMID: 25678012,
16670688,16609879,27681997) describing, in total, 27 unrelated probands with DEND or PNDM who have seizures.
Early onset or syndromic epilepsy v0.936 KCNJ11 Ivone Leong Gene: kcnj11 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.935 KCNJ11 Ivone Leong Publications for gene: KCNJ11 were set to
Early onset or syndromic epilepsy v0.934 KCNJ11 Ivone Leong Added comment: Comment on mode of pathogenicity: Gain-of-function mutations are responsible for the phenotype (PMID: 17065345).
Early onset or syndromic epilepsy v0.934 KCNJ11 Ivone Leong Mode of pathogenicity for gene: KCNJ11 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.933 KCNJ11 Ivone Leong Mode of inheritance for gene: KCNJ11 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.932 CCDC88A Konstantinos Varvagiannis reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: None; Publications: 26917597, 30392057; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v0.932 KCNJ11 Ivone Leong Phenotypes for gene: KCNJ11 were changed from Diabetes, permanent neonatal, with or without neurologic features, 606176 to Diabetes, permanent neonatal, with or without neurologic features, 606176; DEND syndrome
Early onset or syndromic epilepsy v0.931 FUT8 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Intellectual Disability panel
Early onset or syndromic epilepsy v0.931 FUT8 Louise Daugherty Phenotypes for gene: FUT8 were changed from Congenital disorder of glycosylation with defective fucosylation, 618005 to Congenital disorder of glycosylation with defective fucosylation, 618005; Intellectual disability
Early onset or syndromic epilepsy v0.930 KCNJ11 Ivone Leong Phenotypes for gene: KCNJ11 were changed from to Diabetes, permanent neonatal, with or without neurologic features, 606176
Early onset or syndromic epilepsy v0.929 ISPD Ivone Leong Marked gene: ISPD as ready
Early onset or syndromic epilepsy v0.929 ISPD Ivone Leong Added comment: Comment when marking as ready: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 confirmed on OMIM but listed as Walker-Warburg syndrome, which comes under Muscular dystrophy-dystroglycanopathy, on Gene2Phenotype. Only one report of a patient with a large deletion in the ISPD gene having seizures (24120487).
Early onset or syndromic epilepsy v0.929 ISPD Ivone Leong Gene: ispd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.929 ISPD Ivone Leong Publications for gene: ISPD were set to
Early onset or syndromic epilepsy v0.928 ISPD Ivone Leong Phenotypes for gene: ISPD were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, 614643 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, 614643; Walker-Warburg syndrome
Early onset or syndromic epilepsy v0.927 GNB5 Konstantinos Varvagiannis gene: GNB5 was added
gene: GNB5 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331
Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182
Penetrance for gene: GNB5 were set to Complete
Review for gene: GNB5 was set to GREEN
Added comment: Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182).

PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described.

The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux).

The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L).

Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one.

As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability.

Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes.

Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out.

Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies.

PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies.

PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing.

PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599.

PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion.

Epilepsy was a feature in at least 6 individuals reported.

As a result this gene can be considered for inclusion in this panel as green or amber.
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.927 ISPD Ivone Leong Mode of inheritance for gene: ISPD was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.926 ISPD Ivone Leong Phenotypes for gene: ISPD were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, 614643
Early onset or syndromic epilepsy v0.925 IKBKG Ivone Leong Marked gene: IKBKG as ready
Early onset or syndromic epilepsy v0.925 IKBKG Ivone Leong Gene: ikbkg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.925 IKBKG Ivone Leong Publications for gene: IKBKG were set to
Early onset or syndromic epilepsy v0.924 IKBKG Ivone Leong Classified gene: IKBKG as Green List (high evidence)
Early onset or syndromic epilepsy v0.924 IKBKG Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Incontinentia pigmenti is confirmed by OMIM and Gene2Phenotype. There are >3 unrelated families with a variant in this gene diagnosed with incontinentia pigmenti who have seizures (PMID: 30151858,28794079,24339369). Neurological symptoms (including seizures) are affect ~30% of patients with incontinentia pigmenti (PMID:28870493).
Early onset or syndromic epilepsy v0.924 IKBKG Ivone Leong Gene: ikbkg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.923 EIF3F Sarah Leigh Marked gene: EIF3F as ready
Early onset or syndromic epilepsy v0.923 EIF3F Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. A single variant (rs141976414, ENSP00000310040.4:p.Phe232Val) has been identified as a homozygote in 9 subjects with intellectual disability and other phenotypic features, 6/9 have seizures. rs141976414 has a frequency of 0.12% in non-Finnish Europeans, however, it is not found as a homozygote in gnomAD (http://gnomad.broadinstitute.org). Supportive functional studies were also provided (PMID 30409806).
Early onset or syndromic epilepsy v0.923 EIF3F Sarah Leigh Gene: eif3f has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.923 EIF3F Sarah Leigh Classified gene: EIF3F as Green List (high evidence)
Early onset or syndromic epilepsy v0.923 EIF3F Sarah Leigh Gene: eif3f has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.922 EIF3F Sarah Leigh Classified gene: EIF3F as Green List (high evidence)
Early onset or syndromic epilepsy v0.922 EIF3F Sarah Leigh Gene: eif3f has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.921 IKBKG Ivone Leong Mode of inheritance for gene: IKBKG was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.920 RHOBTB2 Sarah Leigh Marked gene: RHOBTB2 as ready
Early onset or syndromic epilepsy v0.920 RHOBTB2 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 6 variants identified in 8 unrelated cases. In vitro functional studies suggest that pathogenicity results from increased expression or reduced degradation of the variant peptides in affected individuals (PMID 29276004).
Early onset or syndromic epilepsy v0.920 RHOBTB2 Sarah Leigh Gene: rhobtb2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.920 RHOBTB2 Sarah Leigh Classified gene: RHOBTB2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.920 RHOBTB2 Sarah Leigh Gene: rhobtb2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.919 RHOBTB2 Sarah Leigh Phenotypes for gene: RHOBTB2 were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly to Epileptic encephalopathy, early infantile, 64 618004
Early onset or syndromic epilepsy v0.918 FUT8 Sarah Leigh Marked gene: FUT8 as ready
Early onset or syndromic epilepsy v0.918 FUT8 Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants identified in 3 unrelated cases, supportive segregation and in vitro data was also presented.
Early onset or syndromic epilepsy v0.918 FUT8 Sarah Leigh Gene: fut8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.918 FUT8 Sarah Leigh Classified gene: FUT8 as Green List (high evidence)
Early onset or syndromic epilepsy v0.918 FUT8 Sarah Leigh Gene: fut8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.917 ATP6V1A Sarah Leigh Marked gene: ATP6V1A as ready
Early onset or syndromic epilepsy v0.917 ATP6V1A Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants were identified in unrelated cases of Epileptic encephalopathy, infantile or early childhood, 3 618012, one variant (c.1045G>A, NM_001690.3, p.D349N) appear give gain of function results in in vitro analysis, whereas the others had loss of function. Two homozygous variants were reported in two unrelated cases of Cutis laxa, autosomal recessive, type IID 617403 who both had seizures as part of their phenotypes.
Early onset or syndromic epilepsy v0.917 ATP6V1A Sarah Leigh Gene: atp6v1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.917 ATP6V1A Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants associated with Epileptic encephalopathy, infantile or early childhood, 3 618012 and biallelic variants associated with Cutis laxa, autosomal recessive, type IID 617403. Both phenotypes include seizures.
Early onset or syndromic epilepsy v0.917 ATP6V1A Sarah Leigh Phenotypes for gene: ATP6V1A were changed from # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3 - IECEE3; # 617403 CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID - ARCL2D to Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403
Early onset or syndromic epilepsy v0.916 ATP6V1A Sarah Leigh Classified gene: ATP6V1A as Green List (high evidence)
Early onset or syndromic epilepsy v0.916 ATP6V1A Sarah Leigh Gene: atp6v1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.915 ATP1A1 Sarah Leigh Marked gene: ATP1A1 as ready
Early onset or syndromic epilepsy v0.915 ATP1A1 Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. Three heterozygous de novo variants reported in three unrelated cases manifesting with refractory seizures, severe hypomagnesemia and severe intellectual disability. Supportive in vitro studies were also presented.
Early onset or syndromic epilepsy v0.915 ATP1A1 Sarah Leigh Gene: atp1a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.915 ATP1A1 Sarah Leigh Classified gene: ATP1A1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.915 ATP1A1 Sarah Leigh Gene: atp1a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.914 EIF3F Konstantinos Varvagiannis gene: EIF3F was added
gene: EIF3F was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF3F were set to 30409806
Phenotypes for gene: EIF3F were set to Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment
Penetrance for gene: EIF3F were set to Complete
Review for gene: EIF3F was set to GREEN
Added comment: EIF3F was identified in a recent DDD publication (PMID: 30409806) as a cause of autosomal recessive intellectual disability.

All 9 individuals reported were homozygous for a missense variant (Phe232Val - rs141976414) which has a frequency of 0.12% in non-Finnish Europeans.

Features included intellectual disability (9/9), seizures (6/9), behavioral problems (3/9) and sensorineural hearing loss (3/9). Facial features were not specific.

Extensive functional studies were performed and support pathogenicity of the variant in the homozygous state (reduced protein levels, reduced translation rate in line with the role of EIF3F encoding a subunit for eukaryotic translation initiation factor 3, as well as reduced proliferation rates).

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.914 FUT8 Konstantinos Varvagiannis gene: FUT8 was added
gene: FUT8 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT8 were set to 29304374
Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005
Penetrance for gene: FUT8 were set to Complete
Review for gene: FUT8 was set to GREEN
Added comment: PMID: 29304374 reports on 3 unrelated individuals with biallelic pathogenic variants in FUT8.

Two of the patients were born to consanguineous parents and were found to be homozygous for stopgain variants (p.Arg239* in one family and p.Arg315* in the other). A third patient was compound heterozygous for a missense as well as a splice variant.

All three presented with similar phenotype consisting of polyhydramnios (2 out of 3), IUGR and failure to thrive with short stature (3/3), severe developmental delay (3/3) with microcephaly (3/3) and seizures (3/3). Variable respiratory problems were also noted in all.

Western blot demonstrated loss of FUT8 protein expression in one individual homozygous for a stopgain mutation as well as the patient who was compound heterozygous for the missense and the splice variant. The splice variant was further shown to produce a shorter transcript due to lack of exon 9, leading to an in-frame deletion of 59 residues critical for the protein function.

Additional studies confirmed the fucosylation defect compared to controls.

The authors note that while Fut8 knockout mice are born normal, 70% die within the first 3 days due to severe growth retardation and respiratory deficiency (similarly to what is observed in humans, though to a lesser extent).

As a result this gene can be considered for inclusion in this panel probably as green (3 unrelated families, strong additional functional data, consistent phenotype) or amber.
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.914 ATP6V1A Konstantinos Varvagiannis gene: ATP6V1A was added
gene: ATP6V1A was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: ATP6V1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATP6V1A were set to 29668857; 28065471
Phenotypes for gene: ATP6V1A were set to # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3 - IECEE3; # 617403 CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID - ARCL2D
Penetrance for gene: ATP6V1A were set to unknown
Review for gene: ATP6V1A was set to GREEN
Added comment: Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012).

PMID: 29668857 reports 4 individuals from 4 families with de novo pathogenic variants in ATP6V1A. The phenotype was consistent with a developmental encephalopathy with epilepsy.

All patients were found to harbor missense variants. The variants resulted in altered lysosomal homeostasis, abnormal neuritogenesis and synaptic density. However in one of the variants tested (p.Asp100Tyr) pathogenicity was mediated by loss-of-function mechanism while for another (p.Asp349Asn) by gain-of-function mechanism.

Differences in severity were noted, with two variants (incl. Asp100Tyr) being associated with a more severe phenotype and the two other (incl. Asp349Asn) with milder degrees of ID and epilepsy.

Biallelic ATP6V1A mutations cause Cutis laxa type IID (MIM 617403). PMID: 28065471 is the first report on 3 individuals from 3 different families (2 of which were consanguineous). All patients were homozygous for ATP6V1A pathogenic variants. All three presented with hypotonia, one (or possibly two) with developmental delay and two with seizures although the developmental phenotype is not further commented on. (Additional patients described in the article harbored mutations in other genes and were not considered).

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.914 ATP1A1 Konstantinos Varvagiannis gene: ATP1A1 was added
gene: ATP1A1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP1A1 were set to 30388404
Phenotypes for gene: ATP1A1 were set to Hypomagnesemia; Seizures; Intellectual disability
Penetrance for gene: ATP1A1 were set to unknown
Review for gene: ATP1A1 was set to GREEN
Added comment: PMID: 30388404 reports on 3 subjects from 3 families with de novo pathogenic variants in ATP1A1. All 3 presented with similar phenotype consisting of hypomagnesemia, early onset refractory seizures as well as intellectual disability.

Alternative causes of hypomagnesemia with seizures (eg. due to TRPM6 mutations) were excluded while the phenotype of the 3 patients differed from similar disorder in that hypomagnesemia as well as seizures were not responsive to magnesium supplementation.

Three different missense variants are reported (L302R, G303R, M859R) all as de novo occurences and after confirmation of paternity.

Functional studies were suggestive of loss of the ATPase function, abnormal cation permeabilities as well as reduced level of expression (the latter was significant for at least for 2 of the 3 variants).

Mutations in ATP1A1 have also been reported in patients with Charcot-Marie-Tooth type 2 (CMT2DD - MIM: 618036) although the variants reported to date map seem to cluster within the helical linker region (residues 592 to 608). The young age of the patients with epilepsy and intellectual disability did not allow conclusions on eventual peripheral neuropathy in these individuals.

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.914 GLUL Louise Daugherty Added comment: Comment on mode of inheritance: changed MOI from OMIM and publication PMID:16267323
Early onset or syndromic epilepsy v0.914 GLUL Louise Daugherty Mode of inheritance for gene: GLUL was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.913 GLUL Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.913 GLUL Louise Daugherty Phenotypes for gene: GLUL were changed from to Glutamine deficiency, congenital, 610015; seizures
Early onset or syndromic epilepsy v0.912 GM2A Louise Daugherty Marked gene: GM2A as ready
Early onset or syndromic epilepsy v0.912 GM2A Louise Daugherty Gene: gm2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.912 GM2A Louise Daugherty Classified gene: GM2A as Green List (high evidence)
Early onset or syndromic epilepsy v0.912 GM2A Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.912 GM2A Louise Daugherty Gene: gm2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.911 GM2A Louise Daugherty Added comment: Comment on publications: Publications added support gene-disease association and rating of this gene to Green.
Early onset or syndromic epilepsy v0.911 GM2A Louise Daugherty Publications for gene: GM2A were set to
Early onset or syndromic epilepsy v0.910 GM2A Louise Daugherty Phenotypes for gene: GM2A were changed from GM2-gangliosidosis, AB variant, 272750; seizures to GM2-gangliosidosis, AB variant, 272750; seizures; Hexosaminidase activator deficiency; Tay-Sachs disease
Early onset or syndromic epilepsy v0.909 GM2A Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.909 GM2A Louise Daugherty Phenotypes for gene: GM2A were changed from to GM2-gangliosidosis, AB variant, 272750; seizures
Early onset or syndromic epilepsy v0.908 GM2A Louise Daugherty Mode of inheritance for gene: GM2A was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.907 GNB1 Louise Daugherty Marked gene: GNB1 as ready
Early onset or syndromic epilepsy v0.907 GNB1 Louise Daugherty Gene: gnb1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.907 GNB1 Louise Daugherty Classified gene: GNB1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.907 GNB1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases (more than 20), and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.907 GNB1 Louise Daugherty Gene: gnb1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.906 GNB1 Louise Daugherty Mode of inheritance for gene: GNB1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.905 GNB1 Louise Daugherty Publications for gene: GNB1 were set to 27108799; 25529582; 27108799
Early onset or syndromic epilepsy v0.904 GNB1 Louise Daugherty Added comment: Comment on publications: 13 unrelated patients with autosomal dominant mental retardation-42 Petrovski et al. (2016) PMID:27108799 identified 9 different de novo heterozygous missense mutations in the GNB1 gene, the variants were confirmed by Sanger sequencing.
Early onset or syndromic epilepsy v0.904 GNB1 Louise Daugherty Publications for gene: GNB1 were set to
Early onset or syndromic epilepsy v0.903 GNB1 Louise Daugherty Added comment: Comment on phenotypes: correction of the MIMid
Early onset or syndromic epilepsy v0.903 GNB1 Louise Daugherty Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 614018; seizures to Mental retardation, autosomal dominant 42, 616973; seizures
Early onset or syndromic epilepsy v0.902 GNB1 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.902 GNB1 Louise Daugherty Phenotypes for gene: GNB1 were changed from to Mental retardation, autosomal dominant 42, 614018; seizures
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Marked gene: GOSR2 as ready
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Gene: gosr2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty commented on gene: GOSR2: added founder-effect tag. Even though there is a founder effect in this population, there is further evidence for it being the gene of interest by the fact that there is more than one variant identified so supports a green rating on the current evidence.
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Tag founder-effect tag was added to gene: GOSR2.
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Classified gene: GOSR2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.901 GOSR2 Louise Daugherty Gene: gosr2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.900 GOSR2 Louise Daugherty edited their review of gene: GOSR2: Added comment: External review notes that there are Corbett et al., 2011 (PMID: 21549339) reported five unrelated individuals reported with bi-allelic variants and denoted a founder effect.
To date, 17 reported patients with GOSR2‐mediated Progressive myoclonic epilepsy have been shown to carry the same homozygous c.430G>T (p.G144W) mutation, the result of a founder effect 21549339, 23449775, 24458321. However, Praschberger et al., (2015) PMID: 30363482 described a 61‐year‐old female patient suffering from progressive myoclonus epilepsy and was found to be compound heterozygous for the known c.430G>T and a novel c.491_493delAGA (p.K164del) GOSR2 mutation.; Changed rating: GREEN
Early onset or syndromic epilepsy v0.900 GOSR2 Louise Daugherty Publications for gene: GOSR2 were set to 21549339; 30363482; 24458321; 27618868
Early onset or syndromic epilepsy v0.899 GOSR2 Louise Daugherty Publications for gene: GOSR2 were set to 21549339; 30363482; 24458321
Early onset or syndromic epilepsy v0.898 GOSR2 Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review and additional publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.898 GOSR2 Louise Daugherty Publications for gene: GOSR2 were set to
Early onset or syndromic epilepsy v0.897 GOSR2 Louise Daugherty Added comment: Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel
Early onset or syndromic epilepsy v0.897 GOSR2 Louise Daugherty Phenotypes for gene: GOSR2 were changed from to Epilepsy, progressive myoclonic 6, 614018
Early onset or syndromic epilepsy v0.896 GOSR2 Louise Daugherty Added comment: Comment on mode of inheritance: added MOI suggested by external review, confirmed with OMIM/publications
Early onset or syndromic epilepsy v0.896 GOSR2 Louise Daugherty Mode of inheritance for gene: GOSR2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.895 Ellen McDonagh Panel name changed from Genetic Epilepsy Syndromes to Genetic epilepsy syndromes
List of related panels changed from Epilepsy Plus;Epilepsy plus other features to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Early onset or syndromic epilepsy v0.894 IKBKG Ivone Leong Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, 308300
Early onset or syndromic epilepsy v0.893 HSPD1 Ivone Leong Marked gene: HSPD1 as ready
Early onset or syndromic epilepsy v0.893 HSPD1 Ivone Leong Added comment: Comment when marking as ready: Leukodystrophy, hypomyelinating, 4 is associated with the gene on OMIM and Gene2Phenotype. However, there are only 2 reported families with variants in this gene. In one large family (PMID:18571143) 6 of 10 affected members have seizures. In another study (PMID:30083362) one patient with a variant in this gene has seizures.
Early onset or syndromic epilepsy v0.893 HSPD1 Ivone Leong Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.893 HSPD1 Ivone Leong Tag watchlist tag was added to gene: HSPD1.
Early onset or syndromic epilepsy v0.893 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to
Early onset or syndromic epilepsy v0.892 HSPD1 Ivone Leong Mode of inheritance for gene: HSPD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.891 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from to Leukodystrophy, hypomyelinating, 4, 612233
Early onset or syndromic epilepsy v0.890 HSD17B4 Ivone Leong Marked gene: HSD17B4 as ready
Early onset or syndromic epilepsy v0.890 HSD17B4 Ivone Leong Gene: hsd17b4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.890 HSD17B4 Ivone Leong Classified gene: HSD17B4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.890 HSD17B4 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green as 3+ unrelated patients reported with D-bifunctional protein deficiency have variants in this gene and also have seizures. D-bifunctional protein deficiency is conformed to be associated with this gene on both OMIM and Gene2Phenotype.
Early onset or syndromic epilepsy v0.890 HSD17B4 Ivone Leong Gene: hsd17b4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.889 HSD17B4 Ivone Leong Publications for gene: HSD17B4 were set to 9345094; 9482850; 9915948; 11743515
Early onset or syndromic epilepsy v0.888 HSD17B4 Ivone Leong Publications for gene: HSD17B4 were set to
Early onset or syndromic epilepsy v0.887 HSD17B4 Ivone Leong Mode of inheritance for gene: HSD17B4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.886 HSD17B4 Ivone Leong Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, 261515
Early onset or syndromic epilepsy v0.885 HRAS Ivone Leong Marked gene: HRAS as ready
Early onset or syndromic epilepsy v0.885 HRAS Ivone Leong Gene: hras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.885 HRAS Ivone Leong Publications for gene: HRAS were set to
Early onset or syndromic epilepsy v0.884 HRAS Ivone Leong Classified gene: HRAS as Green List (high evidence)
Early onset or syndromic epilepsy v0.884 HRAS Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. There are 3+ cases reporting of patients with Costello syndrome who have seizures (PMID: 28337834, 27195699, 26888048, 22926243) and all patients have HRAS heterozygous variants.

It is also confirmed as being associated with Costello syndrome on OMIM and Gene2Phenotype.
Early onset or syndromic epilepsy v0.884 HRAS Ivone Leong Gene: hras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.883 FKRP Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested from external reviewer
Early onset or syndromic epilepsy v0.883 FKRP Louise Daugherty Phenotypes for gene: FKRP were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, 613153
Early onset or syndromic epilepsy v0.882 HRAS Ivone Leong Mode of inheritance for gene: HRAS was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.881 HRAS Ivone Leong Phenotypes for gene: HRAS were changed from Costello syndrome, 218040 to Costello syndrome, 218040; Schimmelpenning-Feuerstein-Mims syndrome, 218040
Early onset or syndromic epilepsy v0.880 HRAS Ivone Leong Phenotypes for gene: HRAS were changed from to Costello syndrome, 218040
Early onset or syndromic epilepsy v0.879 HEXA Ivone Leong Marked gene: HEXA as ready
Early onset or syndromic epilepsy v0.879 HEXA Ivone Leong Gene: hexa has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.879 HEXA Ivone Leong Classified gene: HEXA as Green List (high evidence)
Early onset or syndromic epilepsy v0.879 HEXA Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as seizures is a phenotype of
Tay-Sachs disease in accordance with the review by Zornitza Stark (Australian Genomics). Tay-Sachs disease is confirmed to be associated with this gene by both OMIM and Gene2Phenotype.
Early onset or syndromic epilepsy v0.879 HEXA Ivone Leong Gene: hexa has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.878 HEXA Ivone Leong Mode of inheritance for gene: HEXA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.877 HEXA Ivone Leong Mode of inheritance for gene: HEXA was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.876 HEXA Ivone Leong Phenotypes for gene: HEXA were changed from to Tay-Sachs disease, 272800
Early onset or syndromic epilepsy v0.875 HEPACAM Ivone Leong Marked gene: HEPACAM as ready
Early onset or syndromic epilepsy v0.875 HEPACAM Ivone Leong Gene: hepacam has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.875 HEPACAM Ivone Leong Classified gene: HEPACAM as Green List (high evidence)
Early onset or syndromic epilepsy v0.875 HEPACAM Ivone Leong Added comment: Comment on list classification: Promoted from amber to green based on evidence in the literature. One study (PMID: 21419380) reported 8 families with 10 patients with either homozygous or compound heterozygous variants in this gene having epilepsy. Another study (PMID: 27389245) reported on a patient with a homozygous variant in this gene having generalized tonic-clonic seizure.
Megalencephalic leukoencephalopathy with subcortical cysts 2A confirmed to be associated with this gene on OMIM but not Gene2Phenotype.
Early onset or syndromic epilepsy v0.875 HEPACAM Ivone Leong Gene: hepacam has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.874 EFHC1 Sarah Leigh Marked gene: EFHC1 as ready
Early onset or syndromic epilepsy v0.874 EFHC1 Sarah Leigh Gene: efhc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.874 EFHC1 Sarah Leigh Classified gene: EFHC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.874 EFHC1 Sarah Leigh Added comment: Comment on list classification: As this gene is associated with susceptibility to juvenile absence epilepsy (MIM 607631) and juvenile myoclonic epilepsy 1 (MIM 254770), EFHC1 has been rated at amber in consultation with Arianna Tucci (GEL Clinical Fellow).
Early onset or syndromic epilepsy v0.874 EFHC1 Sarah Leigh Gene: efhc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.873 HEPACAM Ivone Leong Publications for gene: HEPACAM were set to
Early onset or syndromic epilepsy v0.872 PAFAH1B1 Eleanor Williams Marked gene: PAFAH1B1 as ready
Early onset or syndromic epilepsy v0.872 PAFAH1B1 Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases with PAFAH1B1 variants in Lissencephaly 1 and reports of seizures.
Early onset or syndromic epilepsy v0.872 PAFAH1B1 Eleanor Williams Gene: pafah1b1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.872 PAFAH1B1 Eleanor Williams Phenotypes for gene: PAFAH1B1 were changed from to Lissencephaly 1 607432
Early onset or syndromic epilepsy v0.871 PAFAH1B1 Eleanor Williams Publications for gene: PAFAH1B1 were set to
Early onset or syndromic epilepsy v0.870 PAFAH1B1 Eleanor Williams Mode of inheritance for gene: PAFAH1B1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.869 PAFAH1B1 Eleanor Williams Classified gene: PAFAH1B1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.869 PAFAH1B1 Eleanor Williams Added comment: Comment on list classification: Numerous cases of variants in the PAFAH1B1 gene in patients with Lissencephaly 1 and reporting seizures.
Early onset or syndromic epilepsy v0.869 PAFAH1B1 Eleanor Williams Gene: pafah1b1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.868 PAFAH1B1 Eleanor Williams commented on gene: PAFAH1B1
Early onset or syndromic epilepsy v0.868 OPHN1 Eleanor Williams Marked gene: OPHN1 as ready
Early onset or syndromic epilepsy v0.868 OPHN1 Eleanor Williams Added comment: Comment when marking as ready: 3 cases of patients with SNVs in OPHN1 and a phenotype that includes epilepsy/seizures. Carrier females may show milder phenotype.
Early onset or syndromic epilepsy v0.868 OPHN1 Eleanor Williams Gene: ophn1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.868 OPHN1 Eleanor Williams Added comment: Comment on mode of inheritance: Note OMIM reports an XLR mode of inheritance. But evidence from PMIDs: 16221952, 29510240 suggest that carrier females can show phenotypic traits although in milder form.
Early onset or syndromic epilepsy v0.868 OPHN1 Eleanor Williams Mode of inheritance for gene: OPHN1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.867 OPHN1 Eleanor Williams Classified gene: OPHN1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.867 OPHN1 Eleanor Williams Added comment: Comment on list classification: 3 cases of patients with SNVs in OPHN1 and a phenotype that includes epilepsy/seizures. Seizures not seen in every case.
Early onset or syndromic epilepsy v0.867 OPHN1 Eleanor Williams Gene: ophn1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.866 OPHN1 Eleanor Williams Phenotypes for gene: OPHN1 were changed from to Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance 300486; MENTAL RETARDATION X-LINKED OPHN1-RELATED
Early onset or syndromic epilepsy v0.865 OPHN1 Eleanor Williams Publications for gene: OPHN1 were set to
Early onset or syndromic epilepsy v0.864 OPHN1 Eleanor Williams commented on gene: OPHN1
Early onset or syndromic epilepsy v0.864 HEPACAM Ivone Leong Mode of inheritance for gene: HEPACAM was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.863 HEPACAM Ivone Leong Phenotypes for gene: HEPACAM were changed from to Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925
Early onset or syndromic epilepsy v0.862 OCLN Eleanor Williams Marked gene: OCLN as ready
Early onset or syndromic epilepsy v0.862 OCLN Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases with variants in OCLN and seizures reported.
Early onset or syndromic epilepsy v0.862 OCLN Eleanor Williams Gene: ocln has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.862 OCLN Eleanor Williams Phenotypes for gene: OCLN were changed from to Pseudo-TORCH syndrome 1 251290
Early onset or syndromic epilepsy v0.861 OCLN Eleanor Williams Publications for gene: OCLN were set to
Early onset or syndromic epilepsy v0.860 OCLN Eleanor Williams Mode of inheritance for gene: OCLN was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.859 OCLN Eleanor Williams Classified gene: OCLN as Green List (high evidence)
Early onset or syndromic epilepsy v0.859 OCLN Eleanor Williams Added comment: Comment on list classification: More than 3 cases/variants reported in OCLN in patients with Pseudo-TORCH syndrome 1. At least 3 families with reports of seizures in newborns.
Early onset or syndromic epilepsy v0.859 OCLN Eleanor Williams Gene: ocln has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.858 OCLN Eleanor Williams commented on gene: OCLN
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Marked gene: HCFC1 as ready
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Added comment: Comment when marking as ready: Mental retardation, X-linked 3 is associated with HCFC1 and is confirmed in both OMIM and Gene2Phenotype. >3 unrelated probands have been found to have a mutation in this gene and also have epilepsy.
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Gene: hcfc1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Classified gene: HCFC1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green as >3 unrelated probands have been found to have a mutation in this gene and also have epilepsy.
Early onset or syndromic epilepsy v0.858 HCFC1 Ivone Leong Gene: hcfc1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.857 HCFC1 Ivone Leong Publications for gene: HCFC1 were set to
Early onset or syndromic epilepsy v0.856 NUBPL Eleanor Williams Marked gene: NUBPL as ready
Early onset or syndromic epilepsy v0.856 NUBPL Eleanor Williams Added comment: Comment when marking as ready: Sufficient cases associating NUBPL with Mitochondrial complex I deficiency but not sufficient cases with epilepsy/seizure phenotype to rate this gene green on this panel.
Early onset or syndromic epilepsy v0.856 NUBPL Eleanor Williams Gene: nubpl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.856 NUBPL Eleanor Williams Phenotypes for gene: NUBPL were changed from to Mitochondrial complex I deficiency 252010
Early onset or syndromic epilepsy v0.855 NUBPL Eleanor Williams Publications for gene: NUBPL were set to
Early onset or syndromic epilepsy v0.854 NUBPL Eleanor Williams Mode of inheritance for gene: NUBPL was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.853 NUBPL Eleanor Williams Classified gene: NUBPL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.853 NUBPL Eleanor Williams Added comment: Comment on list classification: Keeping Amber as only 1 confirmed case of patient with epilepsy
Early onset or syndromic epilepsy v0.853 NUBPL Eleanor Williams Gene: nubpl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.852 NUBPL Eleanor Williams commented on gene: NUBPL
Early onset or syndromic epilepsy v0.852 HCCS Ivone Leong Marked gene: HCCS as ready
Early onset or syndromic epilepsy v0.852 HCCS Ivone Leong Added comment: Comment when marking as ready: 'Linear skin defects with multiple congenital anomalies 1' confirmed in both OMIM and Gene2Phenotype. However, seizures is not a common feature. Only found one patient with who had a seizure (17033964).
Early onset or syndromic epilepsy v0.852 HCCS Ivone Leong Gene: hccs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.852 HCCS Ivone Leong Publications for gene: HCCS were set to
Early onset or syndromic epilepsy v0.851 FH Louise Daugherty Marked gene: FH as ready
Early onset or syndromic epilepsy v0.851 FH Louise Daugherty Gene: fh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.851 FH Louise Daugherty Classified gene: FH as Green List (high evidence)
Early onset or syndromic epilepsy v0.851 FH Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.851 FH Louise Daugherty Gene: fh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.850 FH Louise Daugherty Publications for gene: FH were set to 2314594; 10805328; 10805328; 20301679
Early onset or syndromic epilepsy v0.849 HCFC1 Ivone Leong Mode of inheritance for gene: HCFC1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.848 HCFC1 Ivone Leong Phenotypes for gene: HCFC1 were changed from Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ), 309541 to Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type), 309541
Early onset or syndromic epilepsy v0.847 FH Louise Daugherty edited their review of gene: FH: Added comment: From GeneReview PMID: 20301679. Fumarate hydratase deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Epileptic seizures are common (40%-80%), although age of onset and seizure type are variable (PMID:10805328, PMID:20549362). Infantile spasms (epileptic spasms) accompanied by hypsarrhythmia on EEG have been reported (PMID:15221078, PMID:16151915).; Changed rating: GREEN
Early onset or syndromic epilepsy v0.847 HCFC1 Ivone Leong Phenotypes for gene: HCFC1 were changed from Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ) to Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type ), 309541
Early onset or syndromic epilepsy v0.846 HCFC1 Ivone Leong Phenotypes for gene: HCFC1 were changed from to Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type )
Early onset or syndromic epilepsy v0.845 FH Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green
Early onset or syndromic epilepsy v0.845 FH Louise Daugherty Publications for gene: FH were set to
Early onset or syndromic epilepsy v0.844 FH Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.844 FH Louise Daugherty Mode of inheritance for gene: FH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.843 FH Louise Daugherty Added comment: Comment on phenotypes: Added phenotype suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel.
Early onset or syndromic epilepsy v0.843 FH Louise Daugherty Phenotypes for gene: FH were changed from to Fumarase deficiency, 606812; Seizures
Early onset or syndromic epilepsy v0.842 NSDHL Eleanor Williams Marked gene: NSDHL as ready
Early onset or syndromic epilepsy v0.842 NSDHL Eleanor Williams Added comment: Comment when marking as ready: 3 cases/variants in unrelated families where male show seizures. One SNV is missense but it segregates with the disease in the family, is predicted to affect protein function and is not found in dbSNP.
Early onset or syndromic epilepsy v0.842 NSDHL Eleanor Williams Gene: nsdhl has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.842 NSDHL Eleanor Williams Phenotypes for gene: NSDHL were changed from to CK syndrome 300831
Early onset or syndromic epilepsy v0.841 NSDHL Eleanor Williams Mode of inheritance for gene: NSDHL was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.840 NSDHL Eleanor Williams Publications for gene: NSDHL were set to
Early onset or syndromic epilepsy v0.839 NSDHL Eleanor Williams Classified gene: NSDHL as Green List (high evidence)
Early onset or syndromic epilepsy v0.839 NSDHL Eleanor Williams Added comment: Comment on list classification: 3 cases reported of variants in this gene in males with CK syndrome.
Early onset or syndromic epilepsy v0.839 NSDHL Eleanor Williams Gene: nsdhl has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.838 NSDHL Eleanor Williams commented on gene: NSDHL
Early onset or syndromic epilepsy v0.838 FGFR3 Louise Daugherty Publications for gene: FGFR3 were set to 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976; http://doi.org/10.15844/pedneurbriefs-26-12-6; http://www.ashg.org/genetics/ashg07s/f20570.htm
Early onset or syndromic epilepsy v0.837 FGFR3 Louise Daugherty Publications for gene: FGFR3 were set to 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976; http://doi.org/10.15844/pedneurbriefs-26-12-6
Early onset or syndromic epilepsy v0.836 FGFR3 Louise Daugherty Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, 146000; Focal Epilepsy; Muenke syndrome 602849, Epilepsy to Hypochondroplasia, 146000; Focal Epilepsy; Muenke syndrome, 602849; Epilepsy
Early onset or syndromic epilepsy v0.835 FGFR3 Louise Daugherty Marked gene: FGFR3 as ready
Early onset or syndromic epilepsy v0.835 FGFR3 Louise Daugherty Gene: fgfr3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.835 FGFR3 Louise Daugherty Classified gene: FGFR3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.835 FGFR3 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.835 FGFR3 Louise Daugherty Gene: fgfr3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.834 FGFR3 Louise Daugherty edited their review of gene: FGFR3: Changed rating: GREEN
Early onset or syndromic epilepsy v0.834 FGFR3 Louise Daugherty Publications for gene: FGFR3 were set to 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976
Early onset or syndromic epilepsy v0.833 FGFR3 Louise Daugherty Added comment: Comment on phenotypes: added additional relevant phenotype Muenke syndrome Millichap, J.G., 2012. Epilepsy in Muenke Syndrome. Pediatric Neurology Briefs, 26(12), pp.93–93. DOI: http://doi.org/10.15844/pedneurbriefs-26-12-6 : A review of 789 published cases of Muenke syndrome with neurological complications identified epilepsy in 6 cases, with intracranial anomalies in 5. The intracranial anomalies were agenesis of the corpus callosum, hemimegalencephaly, and porencephaly. In the review of 58 patients with Muenke syndrome in the Washington, DC cohort, 7 (12%) had epilepsy and 4 survived neonatal apnea. Patients with Muenke syndrome should be monitored for apnea and seizures.
Early onset or syndromic epilepsy v0.833 FGFR3 Louise Daugherty Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, 146000; Focal epilepsy to Hypochondroplasia, 146000; Focal Epilepsy; Muenke syndrome 602849, Epilepsy
Early onset or syndromic epilepsy v0.832 FGFR3 Louise Daugherty Mode of inheritance for gene: FGFR3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.831 FGFR3 Louise Daugherty Added comment: Comment on publications: Hypochondroplasia and FGFR3 variants are associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy and was first reported PMID: 24630288 (2014). Subsequent cases PMID: 27485793, PMID:23649205, PMID:12794698. In addition, patients with with Muenke syndrome (MS) also show similarities in early-onset temporal lobe-related seizures PMID:23044018, PMID:12794698, PMID:18000976.
Early onset or syndromic epilepsy v0.831 FGFR3 Louise Daugherty Publications for gene: FGFR3 were set to
Early onset or syndromic epilepsy v0.830 FGFR3 Louise Daugherty Added comment: Comment on phenotypes: Added phenotype suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel.
Early onset or syndromic epilepsy v0.830 FGFR3 Louise Daugherty Phenotypes for gene: FGFR3 were changed from to Hypochondroplasia, 146000; Focal epilepsy
Early onset or syndromic epilepsy v0.829 HCCS Ivone Leong Mode of inheritance for gene: HCCS was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v0.828 FBXL4 Louise Daugherty Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471 to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; Seizures
Early onset or syndromic epilepsy v0.827 HCCS Ivone Leong Phenotypes for gene: HCCS were changed from to Linear skin defects with multiple congenital anomalies 1, 309801
Early onset or syndromic epilepsy v0.826 FGF12 Louise Daugherty Marked gene: FGF12 as ready
Early onset or syndromic epilepsy v0.826 FGF12 Louise Daugherty Gene: fgf12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.826 FGF12 Louise Daugherty Classified gene: FGF12 as Green List (high evidence)
Early onset or syndromic epilepsy v0.826 FGF12 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Early onset or syndromic epilepsy v0.826 FGF12 Louise Daugherty Gene: fgf12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.825 FGF12 Louise Daugherty Added comment: Comment on mode of inheritance: changed MOI from external clinical review and publications
Early onset or syndromic epilepsy v0.825 FGF12 Louise Daugherty Mode of inheritance for gene: FGF12 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.824 FGF12 Louise Daugherty Added comment: Comment on publications: Added publications that support the association with the phenotype suggested by external reviewer and recent publication PMID:29699863 that describes two unrelated cases, 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). Both patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole-exome sequencing. The mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy.
Early onset or syndromic epilepsy v0.824 FGF12 Louise Daugherty Publications for gene: FGF12 were set to
Early onset or syndromic epilepsy v0.823 FBXL4 Louise Daugherty Marked gene: FBXL4 as ready
Early onset or syndromic epilepsy v0.823 FBXL4 Louise Daugherty Gene: fbxl4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.823 FBXL4 Louise Daugherty Classified gene: FBXL4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.823 FBXL4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Early onset or syndromic epilepsy v0.823 FBXL4 Louise Daugherty Gene: fbxl4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.822 FBXL4 Louise Daugherty Publications for gene: FBXL4 were set to 23993193; 23993194; 25868664; 26404457; 27182039; 27290639; 27099744; 27743463
Early onset or syndromic epilepsy v0.821 FBXL4 Louise Daugherty edited their review of gene: FBXL4: Added comment: FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome, seizures are part of the clinical phenotype and can start at age four months (Dai et al 2017 PMID: 27743463). Seizure types reported include complex partial seizures (Baroy et al 2016 PMID:27182039) and absence and generalized seizures (Gai et al 2013 PMID:23993194). The clinical manifestations of FBXL4-Related mtDNA Depletion Syndrome with seizures occurs at a frequency of approximately 33% of cases (Almannai et al 2017 PMID:28383868); Changed rating: GREEN
Early onset or syndromic epilepsy v0.821 FBXL4 Louise Daugherty Added comment: Comment on publications: FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals to date. Added publications suggested to support upgrading of the gene to Green.
Early onset or syndromic epilepsy v0.821 FBXL4 Louise Daugherty Publications for gene: FBXL4 were set to
Early onset or syndromic epilepsy v0.820 FGF12 Louise Daugherty Added comment: Comment on phenotypes: added phenotype from external review and checked with OMIM
Early onset or syndromic epilepsy v0.820 FGF12 Louise Daugherty Phenotypes for gene: FGF12 were changed from to Epileptic encephalopathy, early infantile, 47, 617166
Early onset or syndromic epilepsy v0.819 GPHN Ivone Leong Mode of inheritance for gene: GPHN was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.818 GPHN Ivone Leong Phenotypes for gene: GPHN were changed from to Molybdenum cofactor deficiency C, 615501
Early onset or syndromic epilepsy v0.817 GTPBP3 Ivone Leong Publications for gene: GTPBP3 were set to
Early onset or syndromic epilepsy v0.816 GTPBP3 Ivone Leong Mode of inheritance for gene: GTPBP3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.815 FBXL4 Louise Daugherty Added comment: Comment on phenotypes: added OMIM phenotype and MIMid
Early onset or syndromic epilepsy v0.815 FBXL4 Louise Daugherty Phenotypes for gene: FBXL4 were changed from to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471
Early onset or syndromic epilepsy v0.814 GTPBP3 Ivone Leong Phenotypes for gene: GTPBP3 were changed from to Combined oxidative phosphorylation deficiency 23, 616198
Early onset or syndromic epilepsy v0.813 FBXL4 Louise Daugherty Added comment: Comment on mode of inheritance: Added MOI from external review and checked with PMID
Early onset or syndromic epilepsy v0.813 FBXL4 Louise Daugherty Mode of inheritance for gene: FBXL4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.812 GTPBP3 Ivone Leong Marked gene: GTPBP3 as ready
Early onset or syndromic epilepsy v0.812 GTPBP3 Ivone Leong Added comment: Comment when marking as ready: Associated with 'mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy' in Gene2phenotype. Only 2 unrelated families have been reported to have seizures.
Early onset or syndromic epilepsy v0.812 GTPBP3 Ivone Leong Gene: gtpbp3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.812 TIMM50 Rebecca Foulger commented on gene: TIMM50: Added 'watchlist' tag.
Early onset or syndromic epilepsy v0.812 TIMM50 Rebecca Foulger Tag watchlist tag was added to gene: TIMM50.
Early onset or syndromic epilepsy v0.812 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: Added 'watchlist' tag.
Early onset or syndromic epilepsy v0.812 SUCLG1 Rebecca Foulger Tag watchlist tag was added to gene: SUCLG1.
Early onset or syndromic epilepsy v0.812 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: PMID:26475597 (Carrozzo et al 2016) report 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. Epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations: Only 1 patient with the SUCLG1 variant had epilepsy.
Early onset or syndromic epilepsy v0.812 SUCLA2 Rebecca Foulger Marked gene: SUCLA2 as ready
Early onset or syndromic epilepsy v0.812 SUCLA2 Rebecca Foulger Gene: sucla2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.812 SUCLA2 Rebecca Foulger Classified gene: SUCLA2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.812 SUCLA2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Green review plus sufficient cases (>3) of seizures in MMA patients (At least 3 new patients in PMID:26475597, 2 cousins from 1 family in PMID:15877282, and 1 Faroe Island patient in PMID:17287286/17301081).
Early onset or syndromic epilepsy v0.812 SUCLA2 Rebecca Foulger Gene: sucla2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.811 SUCLA2 Rebecca Foulger commented on gene: SUCLA2: PMID:26475597 (Carrozzo et al 2016) report 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. Epilepsy reported as generalized seizures, unspecified epilesy or infantile spasms was mainly reported in patients with SUCLA2 variants. Only 1 patient with the SUCLG1 variant had epilepsy (5%). At least 3 cases of epilepsy listed in new patients with SUCLA2 variants (supplementary material).
Early onset or syndromic epilepsy v0.811 SUCLA2 Rebecca Foulger Publications for gene: SUCLA2 were set to 17301081; 17287286; 15877282; 23759946
Early onset or syndromic epilepsy v0.810 COQ9 Sarah Leigh Marked gene: COQ9 as ready
Early onset or syndromic epilepsy v0.810 COQ9 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Coenzyme Q10 deficiency, primary, 5, 614654, although seizures are not mentioned. At least 2 loss of function variants have been reported in two unrelated cases. In vitro studies show that expression of wildtype COQ9 in patient cells carrying homozygous c.521+1del can rescue reduced activity of mitochondrial complex II/III and restore CoQ10 and COQ7 levels (PMID 26081641)
Early onset or syndromic epilepsy v0.810 COQ9 Sarah Leigh Gene: coq9 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.810 COQ9 Sarah Leigh Publications for gene: COQ9 were set to
Early onset or syndromic epilepsy v0.809 COQ9 Sarah Leigh Classified gene: COQ9 as Green List (high evidence)
Early onset or syndromic epilepsy v0.809 COQ9 Sarah Leigh Gene: coq9 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.808 COQ9 Sarah Leigh Mode of inheritance for gene: COQ9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.807 COQ9 Sarah Leigh Phenotypes for gene: COQ9 were changed from to Coenzyme Q10 deficiency, primary, 5, 614654
Early onset or syndromic epilepsy v0.806 COQ6 Sarah Leigh Marked gene: COQ6 as ready
Early onset or syndromic epilepsy v0.806 COQ6 Sarah Leigh Gene: coq6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.806 COQ6 Sarah Leigh Mode of inheritance for gene: COQ6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.805 COQ6 Sarah Leigh Phenotypes for gene: COQ6 were changed from to Coenzyme Q10 deficiency, primary, 6, 614650
Early onset or syndromic epilepsy v0.804 COQ4 Sarah Leigh Marked gene: COQ4 as ready
Early onset or syndromic epilepsy v0.804 COQ4 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.804 COQ4 Sarah Leigh Gene: coq4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.804 COQ4 Sarah Leigh Classified gene: COQ4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.804 COQ4 Sarah Leigh Gene: coq4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.803 COQ4 Sarah Leigh Phenotypes for gene: COQ4 were changed from to Coenzyme Q10 deficiency, primary, 7 616276
Early onset or syndromic epilepsy v0.802 COQ4 Sarah Leigh Publications for gene: COQ4 were set to
Early onset or syndromic epilepsy v0.801 COQ4 Sarah Leigh Mode of inheritance for gene: COQ4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.800 COQ2 Sarah Leigh Marked gene: COQ2 as ready
Early onset or syndromic epilepsy v0.800 COQ2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.800 COQ2 Sarah Leigh Gene: coq2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.800 COQ2 Sarah Leigh Classified gene: COQ2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.800 COQ2 Sarah Leigh Gene: coq2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.799 COQ2 Sarah Leigh Publications for gene: COQ2 were set to
Early onset or syndromic epilepsy v0.798 SUCLA2 Rebecca Foulger Publications for gene: SUCLA2 were set to
Early onset or syndromic epilepsy v0.797 SUCLA2 Rebecca Foulger commented on gene: SUCLA2: Jaberi et al 2013 (PMID:23759946) identified a homozygous c.751G>A transition in SUCLA2 (D251N) in 2 Iranian cousins with MIM:612073. No sign of epilepsy was seen in Patient 1. Epilepsy was not mentioned for the cousin (Patient 2).
Early onset or syndromic epilepsy v0.797 SUCLA2 Rebecca Foulger commented on gene: SUCLA2: Elpeleg et al 2005 (PMID:15877282) identified a homozgyous deletion/insertion in SUCLA2 in 2 first cousins from a consanguineous Muslim family. Both cousins had generalized seizures from age 1 and age 3.
Early onset or syndromic epilepsy v0.797 SUCLA2 Rebecca Foulger commented on gene: SUCLA2
Early onset or syndromic epilepsy v0.797 COQ2 Sarah Leigh Phenotypes for gene: COQ2 were changed from to Coenzyme Q10 deficiency, primary, 1 607426
Early onset or syndromic epilepsy v0.796 COQ2 Sarah Leigh Mode of inheritance for gene: COQ2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.795 COL4A2 Sarah Leigh Marked gene: COL4A2 as ready
Early onset or syndromic epilepsy v0.795 COL4A2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as both DD and IF Gen2Phen gene. At least 3 variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.795 COL4A2 Sarah Leigh Gene: col4a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.795 COL4A2 Sarah Leigh Classified gene: COL4A2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.795 COL4A2 Sarah Leigh Gene: col4a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.794 COL4A2 Sarah Leigh Publications for gene: COL4A2 were set to
Early onset or syndromic epilepsy v0.793 COL4A2 Sarah Leigh Phenotypes for gene: COL4A2 were changed from to Porencephaly 2 614483
Early onset or syndromic epilepsy v0.792 COL4A2 Sarah Leigh Mode of inheritance for gene: COL4A2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.791 SUCLA2 Rebecca Foulger Mode of inheritance for gene: SUCLA2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.790 SUCLA2 Rebecca Foulger Phenotypes for gene: SUCLA2 were changed from to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), 612073
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Marked gene: SUCLG1 as ready
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Added comment: Comment when marking as ready: Marked as Ready: November 13th 2018.
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Gene: suclg1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.789 COL4A1 Sarah Leigh Marked gene: COL4A1 as ready
Early onset or syndromic epilepsy v0.789 COL4A1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 4 variants reported in unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.789 COL4A1 Sarah Leigh Gene: col4a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: PMID:22231385 (Honzik et al 2012) report 1 patient with SUCLG1 variant, who did not have seizures.
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Classified gene: SUCLG1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber. Confirmed DD-G2P gene for FATAL INFANTILE LACTIC ACIDOSIS. Although patients with SUCLG1 variants can report with seizures (1 of 3 patients in PMID:26028457 plus EEG abnormalities in PMID:27484306), there are currently insufficient cases to rate as diagnostic.
Early onset or syndromic epilepsy v0.789 SUCLG1 Rebecca Foulger Gene: suclg1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.788 COL4A1 Sarah Leigh Classified gene: COL4A1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.788 COL4A1 Sarah Leigh Gene: col4a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.787 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: PMID:28358460 gives an overview of treatment of seizures when present in SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome patients.
Early onset or syndromic epilepsy v0.787 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: Seizures are not reported in the clinical phenotype of patients in PMIDs 17668387, 19526370 and 20693550, which report patients with SUCLG1 variants.
Early onset or syndromic epilepsy v0.787 SUCLG1 Rebecca Foulger Added comment: Comment on publications: PMID:27143079 article is in Chinese. See PMID:26028457 for a description of the same patients.
Early onset or syndromic epilepsy v0.787 SUCLG1 Rebecca Foulger Publications for gene: SUCLG1 were set to 28358460; 27143079; 26028457; 27484306
Early onset or syndromic epilepsy v0.786 COL4A1 Sarah Leigh Publications for gene: COL4A1 were set to
Early onset or syndromic epilepsy v0.785 COL4A1 Sarah Leigh Phenotypes for gene: COL4A1 were changed from to Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps 611773; Brain small vessel disease with or without ocular anomalies 607595; Porencephaly 1 175780; Schizencephaly 269160
Early onset or syndromic epilepsy v0.784 SUCLG1 Rebecca Foulger commented on gene: SUCLG1: PMID:26028457 (Liu et al 2016) report 3 unrelated Chinese patients with severe psychomotor retardation, hypotonia, dystonia and athetoid movements, and homozygous/compound het variants in SUCLG1. Patient 2 had Epilepsy (Table 1).
Early onset or syndromic epilepsy v0.784 SUCLG1 Rebecca Foulger commented on gene: SUCLG1
Early onset or syndromic epilepsy v0.784 SUCLG1 Rebecca Foulger Publications for gene: SUCLG1 were set to
Early onset or syndromic epilepsy v0.783 COL4A1 Sarah Leigh Mode of inheritance for gene: COL4A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.782 COL18A1 Sarah Leigh Marked gene: COL18A1 as ready
Early onset or syndromic epilepsy v0.782 COL18A1 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 4 truncating variants reported in 3 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.782 COL18A1 Sarah Leigh Gene: col18a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.782 COL18A1 Sarah Leigh Classified gene: COL18A1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.782 COL18A1 Sarah Leigh Gene: col18a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.781 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to
Early onset or syndromic epilepsy v0.780 SUCLG1 Rebecca Foulger Mode of inheritance for gene: SUCLG1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.779 SUCLG1 Rebecca Foulger Phenotypes for gene: SUCLG1 were changed from to Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria), 245400
Early onset or syndromic epilepsy v0.778 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from to Knobloch syndrome, type 1 267750
Early onset or syndromic epilepsy v0.777 COL18A1 Sarah Leigh Mode of inheritance for gene: COL18A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.776 CLN3 Sarah Leigh Marked gene: CLN3 as ready
Early onset or syndromic epilepsy v0.776 CLN3 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in 3 unrelated cases in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.776 CLN3 Sarah Leigh Gene: cln3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.776 CLN3 Sarah Leigh Classified gene: CLN3 as Green List (high evidence)
Early onset or syndromic epilepsy v0.776 CLN3 Sarah Leigh Gene: cln3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.775 CLN3 Sarah Leigh Publications for gene: CLN3 were set to
Early onset or syndromic epilepsy v0.774 CLN3 Sarah Leigh Phenotypes for gene: CLN3 were changed from to Ceroid lipofuscinosis, neuronal, 3 204200
Early onset or syndromic epilepsy v0.773 CLN3 Sarah Leigh Mode of inheritance for gene: CLN3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.772 CLCN4 Sarah Leigh Marked gene: CLCN4 as ready
Early onset or syndromic epilepsy v0.772 CLCN4 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for INFANTILE EPILEPTIC ENCEPHALOPATHY AND/OR INTELLECTUAL DISABILITY. At least 2 variants reported in 3 unrelated cases in whom seizures are included in their phenotypic features. Supportive functional studies are also reported (PMID 27550844).
Early onset or syndromic epilepsy v0.772 CLCN4 Sarah Leigh Gene: clcn4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.772 CLCN4 Sarah Leigh Mode of inheritance for gene: CLCN4 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v0.771 CLCN4 Sarah Leigh Publications for gene: CLCN4 were set to
Early onset or syndromic epilepsy v0.770 CLCN4 Sarah Leigh Phenotypes for gene: CLCN4 were changed from to Raynaud-Claes syndrome 300114; Mental retardation, X-linked 49/15
Early onset or syndromic epilepsy v0.769 CLCN4 Sarah Leigh Classified gene: CLCN4 as Green List (high evidence)
Early onset or syndromic epilepsy v0.769 CLCN4 Sarah Leigh Gene: clcn4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.768 STRADA Sarah Leigh edited their review of gene: STRADA: Changed rating: GREEN
Early onset or syndromic epilepsy v0.768 CACNA1G Sarah Leigh edited their review of gene: CACNA1G: Changed rating: GREEN
Early onset or syndromic epilepsy v0.768 CCDC88A Sarah Leigh Marked gene: CCDC88A as ready
Early onset or syndromic epilepsy v0.768 CCDC88A Sarah Leigh Added comment: Comment when marking as ready: Insufficient evidence at present for gene to be green (13/11/2018)
Early onset or syndromic epilepsy v0.768 CCDC88A Sarah Leigh Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.768 CCDC88A Sarah Leigh Tag watchlist tag was added to gene: CCDC88A.
Early onset or syndromic epilepsy v0.768 CCDC88A Sarah Leigh Phenotypes for gene: CCDC88A were changed from to ?PEHO syndrome-like 617507
Early onset or syndromic epilepsy v0.767 CCDC88A Sarah Leigh Publications for gene: CCDC88A were set to
Early onset or syndromic epilepsy v0.766 CCDC88A Sarah Leigh Mode of inheritance for gene: CCDC88A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal