The genotypic spectrum of complex febrile seizures: insights from high-risk population genetic screening in a pediatric cohort

BackgroundComplex febrile seizures (CFS) confer an elevated risk of epilepsy progression; however, the underlying genetic architecture remains insufficiently characterized in Chinese pediatric populations. This study aimed to delineate the mutational landscape and genotype, phenotype associations in a clinically stratified high-risk febrile seizure cohort.MethodsThis retrospective, single-center study enrolled 233 children (aged 6 months, 6 years) who were consecutively screened at the Wuhan Children’s Hospital (July 2019, January 2025) and fulfilled ≥ 1 predefined high-risk criterion. Targeted epilepsy gene panel sequencing was performed, and variant pathogenicity was adjudicated according to ACMG/AMP guidelines. Between-group comparisons were made using the Mann, Whitney U test, Pearson’s χ2 test with continuity correction, or Fisher’s exact test; effect sizes are reported as odds ratios (OR) with 95% confidence intervals (CI).ResultsSixty-seven patients (28.8%) harbored pathogenic/likely pathogenic (P/LP) variants in 18 genes. Voltage-gated sodium channel genes (SCN1A, SCN1B, SCN2A, SCN8A) accounted for 44.8% of positive cases, with SCN1A being most prevalent (25.4%). Patients fulfilling ≥ 2 high-risk criteria demonstrated a higher diagnostic yield than those with a single criterion (35.4% vs. 20.8%; OR = 2.10; 95% CI: 1.16, 3.79; p = 0.020). P/LP-positive patients exhibited significantly elevated rates of status epilepticus (OR = 4.96), developmental delay (OR = 3.70), and abnormal interictal EEG (OR = 3.03). Among SCN1A-positive patients, 70.6% progressed to Dravet syndrome. Genetic findings modified antiseizure medication management in 62.7% of positive cases.ConclusionTargeted genetic screening in high-risk CFS populations yields a clinically significant diagnostic rate dominated by ion channel genes, facilitating early epilepsy risk identification and precise therapeutic intervention.