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Early onset or syndromic epilepsy v9.94 SCN1A Benito Banos Pinero changed review comment from: Review collated by C&S GLH.
Gene associated with AD SCN1A-related seizure disorder. AR inheritance not considered but there is sufficient evidence to support AR inheritance. At least 11 families with 16 patients affected by epilepsy +/- developmental delay and ID and biallelic SCN1A variants resported in the literature. There is limited evidence of epilepsy phenotype in heterozygous parents.
PMID: 25795284 described two families with two affected homozygous siblings each and parents unaffected. No functional work. Variants were c.1198A>G, p.(Met400Val) and c.1852C>T, p.(Arg618Cys). Phenotype was infantile seizures with one patient showing learning difficulties and another one developmental regression.
PMID: 33042244 - described a homozygous frameshift (c.4796del, p.(Tyr1599Phefs*19)) in a patient with seizures and ID. Variant tested in parents and siblings and detected in het state but no mention if they had seizures.
PMID: 34174751 - two additional families with homozygous SCN1A variants - c.2768T>G p.(Ile923Ser) and c.824A>G p.(Asn275Ser). Phenotype – seizures and cognitive impairment, parents were unaffected.
PMID: 34917021 - one homozygous variant in two siblings from a consanguineous family, c.4513A > C (p.Lys1505Gln). Phenotype: genetic epilepsy with febrile seizures plus. Parents unaffected.
PMID: 33674996 - described a homozygous de novo variant c.4319C>T (p.Ala1440Val), likely caused by gene conversion in a proband with epilespsy and profound dev delay. Parents and unaffected sister did not have the variant and were unaffected.
PMID: 39200163 - two siblings with comp het variants in this gene c.2770A>T, p.(Asn935Tyr) and c.4146T>A p.(His1393Gln), parents were unaffected and functional work proved that the combined action of those two variants were causing the pathogenic effect but not the variants separately. Phenotype: drug-responsive developmental and epileptic encephalopathy.
PMID: 40120363 - two consanguineous family with one affected proband each with SCN1A-related disorder. Phenotype: epilepsy and developmental delay. All parents were unaffected, variants were c. 1676T>A, (p. Ile559Asn) and c. 4970G>A, (p. Arg1657His).
PMID: 37955180 described a consanguineous family with two affected siblings with dravet syndrome, parents had seizures, variant is c.473A>G (p.Glu158Gly).
Multiple patients in CVA with phenotype consistent with SCN1A-related seizure disorder and homozygous and comp het SCN1A variants.
MOI should be changed from monoallelic to monoallelic and biallelic for this gene in the R59 panel.; to: Review collated by C&S GLH.
Gene associated with AD SCN1A-related seizure disorder. AR inheritance not considered but there is sufficient evidence to support AR inheritance. At least 11 families with 16 patients affected by epilepsy +/- developmental delay and ID and biallelic SCN1A variants resported in the literature. There is limited evidence of epilepsy phenotype in heterozygous parents.
PMID: 25795284 described two families with two affected homozygous siblings each and parents unaffected. No functional work. Variants were c.1198A>G, p.(Met400Val) and c.1852C>T, p.(Arg618Cys). Phenotype was infantile seizures with one patient showing learning difficulties and another one developmental regression.
PMID: 33042244 - described a homozygous frameshift (c.4796del, p.(Tyr1599Phefs*19)) in a patient with seizures and ID. Variant tested in parents and siblings and detected in het state but no mention if they had seizures.
PMID: 34174751 - two additional families with homozygous SCN1A variants - c.2768T>G p.(Ile923Ser) and c.824A>G p.(Asn275Ser). Phenotype – seizures and cognitive impairment, parents were unaffected.
PMID: 34917021 - one homozygous variant in two siblings from a consanguineous family, c.4513A > C (p.Lys1505Gln). Phenotype: genetic epilepsy with febrile seizures plus. Parents unaffected.
PMID: 33674996 - described a homozygous de novo variant c.4319C>T (p.Ala1440Val), likely caused by gene conversion in a proband with epilespsy and profound dev delay. Parents and unaffected sister did not have the variant and were unaffected.
PMID: 39200163 - two siblings with comp het variants in this gene c.2770A>T, p.(Asn935Tyr) and c.4146T>A p.(His1393Gln), parents were unaffected and functional work proved that the combined action of those two variants were causing the pathogenic effect but not the variants separately. Phenotype: drug-responsive developmental and epileptic encephalopathy.
PMID: 40120363 - two consanguineous family with one affected proband each with SCN1A-related disorder. Phenotype: epilepsy and developmental delay. All parents were unaffected, variants were c. 1676T>A, (p. Ile559Asn) and c. 4970G>A, (p. Arg1657His).
PMID: 37955180 described a consanguineous family with two affected siblings with dravet syndrome, parents had seizures, variant is c.473A>G (p.Glu158Gly).
Multiple patients in CVA with phenotype consistent with SCN1A-related seizure disorder and homozygous or comp het SCN1A variants.
MOI should be changed from monoallelic to monoallelic and biallelic for this gene in the R59 panel.
Early onset or syndromic epilepsy v9.94 SCN1A Benito Banos Pinero reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25795284, PMID: 33042244, PMID: 34174751, PMID: 34917021, PMID: 33674996, PMID: 39200163, PMID: 40120363, PMID: 37955180; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.163 CACNB4 Helen Lord edited their review of gene: CACNB4: Added comment: PMID 35813387 - Naseer et al, 2022: WES i one family and targeted sequencing of SCN1A and CACNB4 in 25 sporadic epilepsy patients. 3 different unrelated patients found to have the c.78_79insG variant in CACNB4. Do mention that tecently het CACNB4 mutations are not linked with epilepsy [Heyne et al 2019] and that het mutated animal model did not show any tyoe of deformities [Coba et al, 2012].

Also PMID32176688 - see previous occurence where identifed homozygously.; Changed rating: AMBER; Changed publications to: 35813387
Early onset or syndromic epilepsy v2.435 UNC13B Zornitza Stark gene: UNC13B was added
gene: UNC13B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UNC13B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13B were set to 33876820
Phenotypes for gene: UNC13B were set to Epilepsy
Review for gene: UNC13B was set to RED
Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex).

Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified:
x1 de novo nonsense variant, absent in gnomad, damaging in silicos
x1 de novo splice site, absent in gnomad, damaging in silicos
x1 splice site variant present in unaffected mother (low frequency in gnomad)
x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad)
x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad
x1 missense variant - highly conserved residue, not in gnomad
x2 other missense variant - highly conserved residue, low frequency in gnomad
Latter 4 missense variants cosegregated with affected individuals in the families

In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila

De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder
Sources: Literature
Early onset or syndromic epilepsy v1.191 SCN1A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN1A.
Early onset or syndromic epilepsy v1.190 SCN1A Rebecca Foulger Source NHS GMS was added to SCN1A.
Early onset or syndromic epilepsy v1.189 SCN1A Rebecca Foulger reviewed gene: SCN1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
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 v1.44 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 SCN1A Sarah Leigh Added gene to panel