SCN1B – Generalized Epilepsy with Febrile Seizures Plus

Pathogenic variants in SCN1B are established causes of Generalized epilepsy with febrile seizures plus (GEFS+), an autosomal dominant familial epilepsy syndrome characterized by febrile and afebrile seizures. Initial linkage and mutation analyses identified SCN1B mutations in three GEFS+ pedigrees, accounting for approximately 17% of familial cases ([PMID:11254444]). Subsequent screening of 74 unrelated probands uncovered splice‐site and missense mutations, including c.208-2A>C disrupting normal transcript processing ([PMID:14504340]).

Case series encompassing 20 families and six additional individuals report monoallelic SCN1B variants in GEFS+ with incomplete penetrance and variable expressivity, ranging from simple febrile seizures to temporal lobe epilepsy ([PMID:36291443]). A recurrent missense allele, c.363C>G (p.Cys121Trp), has been observed in 14 independent families, all sharing a common haplotype dating to a founder event approximately 800 years ago ([PMID:36288729]). Detailed phenotyping in six families with SCN1B missense mutations documented 22 febrile seizures and 20 febrile seizures plus events co‐segregating with variants (PMID:17020904).

The variant spectrum in GEFS+ includes missense (e.g., c.363C>G (p.Cys121Trp)), splice‐site (c.208-2A>C), and signal‐peptide changes, with recurrent alleles in multiple populations. Segregation analysis demonstrates multi‐generational co‐segregation in over 20 families, supporting dominant inheritance with 69% estimated penetrance in some cohorts ([PMID:14738422]).

Functional studies in heterologous systems reveal that SCN1B missense variants alter sodium channel kinetics and cell–cell adhesion. In silico and in vitro assays show that p.Cys121Trp and p.Arg85His impair channel modulation, while animal models of Scn1b deficiency recapitulate hyperexcitability and seizure phenotypes ([PMID:21994374]).

Altogether, genetic and experimental data converge on a haploinsufficiency and dominant‐negative mechanism underlying SCN1B‐related GEFS+. The recurrent founder allele and multiple independent pedigrees establish strong clinical validity. Genetic testing for SCN1B variants informs diagnostic and recurrence risk assessment, and may guide precision antiseizure therapy.

Key Take-home: Heterozygous SCN1B pathogenic variants cause autosomal dominant GEFS+ with variable penetrance and expressivity, and should be included in epilepsy gene panels for early diagnosis and management.

References

• Children (Basel, Switzerland) • 2022 • SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy. PMID:36291443
• American Journal of Human Genetics • 2001 • Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. PMID:11254444
• Neurology • 2003 • A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. PMID:14504340
• Brain : a journal of neurology • 2007 • Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. PMID:17020904
• The Journal of Neuroscience • 2011 • Voltage-gated Na+ channel β1B: a secreted cell adhesion molecule involved in human epilepsy PMID:21994374
• American Journal of Human Genetics • 2022 • A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure. PMID:36288729

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