Abstract

Background: Pathogenic variants in SCN1A, encoding the Nav1.1 sodium channel, underlie a spectrum of epilepsy syndromes ranging from genetic epilepsy with febrile seizures plus (GEFS+) to Dravet Syndrome (DS). Genotype-phenotype correlations, particularly between loss-and gain-of-function variants, have important therapeutic implications. Asian cohort data remain comparatively limited.
Methods: We conducted a retrospective review of 12 unrelated patients with SCN1A-related epilepsy managed at a Hong Kong tertiary center. Clinical, genetic, and treatment data were collected. Variants were classified as missense, truncating or 2q24 deletions. Outcomes including age at seizure onset, Drug- Resistant Epilepsy (DRE), and neurodevelopmental impairment were compared between groups.
Result: The cohort comprised 12 patients (75% female), with a median seizure onset of 8.8 months. Dravet syndrome was diagnosed in 83%. Median diagnostic interval was 1.89 years, with longest delays of 23 years in the pre-next-generation sequencing era after seizure onset. Variants included 8 missense (67%) and 2 intragenic truncating (16.7%) and 2 copy number variants (CNVs) (16.7%). DRE was observed in 67%, with a median of 4.5 anti-seizure medications trialed. CNVs were associated with earlier seizure onset and more severe learning disability compared intragenic variants. Sodium channel blockers were used prior to genetic diagnosis in four patients, with seizure exacerbation in most cases. Two cases were maternally inherited, and one demonstrated post-zygotic mosaicism.
Conclusion: In this Hong Kong cohort, CNV variants with continuous gene deletions with SCN1A involved were associated with earlier seizure onset and more severe neurodevelopmental outcomes compared to other variants. Early molecular diagnosis is critical to guide precision therapy, avoid contraindicated medications, and inform genetic counseling. Larger regional studies are warranted to refine genotypephenotype correlations.

Keywords:SCN1A protein; Dravet syndrome; Epilepsy; Genetic; Drug resistance; Epilepsy