# 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

## TL;DR

This study identifies a new SCN1A gene variant linked to a type of epilepsy called GEFS+ in a Chinese family, showing how genetic analysis can help understand and manage inherited seizure disorders.

## Contribution

The study reports a novel SCN1A missense variant (c.4522T>A, p.Tyr1508Asn) associated with GEFS+ and provides detailed genetic and clinical analysis of a Chinese pedigree.

## Key findings

- The SCN1A variant c.4522T>A (p.Tyr1508Asn) was found in five affected family members and one asymptomatic carrier.
- The variant is classified as a Variant of Uncertain Significance (VUS) due to its absence in population and clinical databases.
- Structural analysis suggests the variant affects a critical domain of Nav1.1, potentially altering neuronal excitability.

## Abstract

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 SCN1A 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 SCN1A: 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 in silico 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 SCN1A 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.