A SCN1A missense variant (c.4522T>A, p.(Tyr1508Asn) associated with genetic epilepsy with febrile seizures plus: clinical phenotype and genetic analysis of a Chinese pedigree

Genetic epilepsy with febrile seizures plus (GEFS+, OMIM 604403) is a clinically and genetically heterogeneous epilepsy spectrum disorder characterized by phenotypic variability and complex inheritance patterns. The <i>SCN1A</i> gene (encoding the α1 subunit of the voltage-gated sodium channel Nav1.1) is the most frequently implicated driver, although variants in other sodium channel genes and synaptic pathway regulators have also been reported. Herein, we describe a GEFS + pedigree identified in clinical practice, with comprehensive genetic and phenotypic characterization. It should be noted that this family has been previously reported in a Chinese publication, and the present study provides further in-depth genetic and clinical analysis based on the original cohort. High-throughput sequencing of the proband followed by Sanger sequencing validation in family members identified a heterozygous missense variant in <i>SCN1A</i>: c.4522T>A p. (Tyr1508Asn). This variant was detected in five affected family members and one asymptomatic carrier. In accordance with the ACMG/AMP guidelines (2015) and ClinGen Epilepsy Sodium Channel Expert Panel specifications (Version 2.0.0), the variant was classified as a Variant of Uncertain Significance (VUS), given its absence from population databases (1000 Genomes, gnomAD, ESP6500) and clinical variant repositories (ClinVar, HGMD), as well as lack of prior literature reports. Co-segregation analysis confirmed consistent association between the variant and GEFS + spectrum phenotypes, and <i>in silico</i> predictions (PolyPhen-2, SIFT, VariantTaster) supported a deleterious effect on protein function. The inheritance pattern was consistent with autosomal dominant inheritance with incomplete penetrance. Structural analysis localized the variant to the intracellular D3-D4 linker of Nav1.1, a domain critical for fast channel inactivation, providing a plausible mechanistic basis for altered neuronal excitability. Our findings expand the spectrum of <i>SCN1A</i> variants associated with GEFS+ and highlight the importance of comprehensive pedigree analysis in deciphering the genetic basis of heterogeneous epilepsy syndromes. These data also provide clinically actionable insights for genetic counseling and precision medicine in affected families once the variant is proven to be pathogenic.