Early onset or syndromic epilepsy

Gene: SCN1A

Green List (high evidence)

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.

Created: 2 Nov 2026, 5:17 p.m. | Last Modified: 2 Nov 2026, 5:18 p.m.

Panel Version: 9.94

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 25795284
• PMID: 33042244
• PMID: 34174751
• PMID: 34917021
• PMID: 33674996
• PMID: 39200163
• PMID: 40120363
• PMID: 37955180

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD Dravet syndrome, >80% of cases. Common cause of epilepsy (also assoc with AD generalised epilepsy with febrile seizures, AD febrile seizures and AD familial hemiplegic migraine).

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, generalized, with febrile seizures plus,604403; Epileptic encephalopathy, early infantile, (Dravet syndrome),607208; Febrile seizures, familial,604403; Migraine, familial hemiplegic,609634

Publications

• 12821740

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dravet syndrome; Epilepsy, generalized, with febrile seizures plus, type 2; Febrile seizures, familial, 3A

Publications

• Claes et al (2001) Am J Hum Genet 68: 1327_1332
• Escayg et al (2000) Nature Genet 24: 343-345

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dravet syndrome; Epilepsy, generalized, with febrile seizures plus, type 2; Febrile seizures, familial, 3A

Publications

• Claes et al (2001) Am J Hum Genet 68: 1327_1332
• Escayg et al (2000) Nature Genet 24: 343-345

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dravet syndrome; Epilepsy, generalized, with febrile seizures plus, type 2; Febrile seizures, familial, 3A

Publications

• Claes et al (2001) Am J Hum Genet 68: 1327_1332
• Escayg et al (2000) Nature Genet 24: 343-345

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dravet syndrome; Epilepsy, generalized, with febrile seizures plus, type 2; Febrile seizures, familial, 3A

Publications

• Claes et al (2001) Am J Hum Genet 68: 1327 1332
• Escayg et al (2000) Nature Genet 24: 343-345

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Variable phenotype, which can include focal epilepsy

Created: 1 Feb 2016, 11:39 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
607208

Publications

• 26188943

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: Confirmed DD gene and all 4 reviewers agree this should be green. Mode of inheritance and loss-of-function mechanism confirmed.

Created: 21 Jan 2016, 11:50 a.m.

Comment on mode of inheritance: Confirmed, and not on imprinted gene list.

Created: 21 Jan 2016, 11:49 a.m.