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SCN1A encodes the voltage-gated sodium channel alpha-1 subunit (NaV1.1) predominantly expressed in inhibitory interneurons. Heterozygous SCN1A variants are the most common genetic cause of Genetic Epilepsy with Febrile Seizures Plus (GEFS+). Patients present in infancy with febrile seizures followed by a spectrum of afebrile generalized and focal seizure types.
GEFS+ is inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. Familial aggregation in multiplex GEFS+ pedigrees demonstrates co-segregation of SCN1A variants, while de novo changes are occasionally reported in sporadic cases.
Clinical validity is categorized as Definitive given >53 unrelated index cases screened for SCN1A mutations (PMID:11254444), segregation in 19 affected relatives, and concordant functional studies. Experimental data from heterologous expression, neuronal models, and computational simulations consistently recapitulate the GEFS+ phenotype.
Genetic evidence (Strong): Autosomal dominant inheritance with >30 distinct missense and truncating variants reported across >50 probands, segregation in 19 affected family members, and occurrence of both inherited and de novo alleles. Representative variant: c.5224G>A (p.Asp1742Asn) identified in a large South American pedigree (PMID:15694566).
Functional evidence (Strong): Patch-clamp analyses show that GEFS+–associated missense mutations disrupt channel inactivation, alter persistent current, and shift voltage-dependence inactivation, leading to neuronal hyperexcitability (PMID:12086636). Computational models predict increased repetitive firing in neurons co-expressing mutant and wild-type NaV1.1.
No significant conflicting evidence undermines the association; SCN1A screening is negative in isolated febrile seizure cohorts without GEFS+ phenotypes.
In summary, SCN1A variants confer a definitive risk for GEFS+ via dominant-negative or loss-of-function mechanisms that impair inhibitory interneuron activity. SCN1A genetic testing informs diagnosis, guides antiepileptic therapy, and enables genetic counseling.
Key Take-home: SCN1A sequencing is clinically essential for early and accurate diagnosis of GEFS+, enabling personalized management and prognostication.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong53 unrelated index cases, segregation in 19 affected relatives, >30 distinct missense and truncating variants Functional EvidenceStrongElectrophysiological studies demonstrate gain- and loss-of-function defects across multiple SCN1A variants consistent with GEFS+ pathophysiology |