Molecular Diagnosis in Children With Febrile Seizures: Beyond the Conventional Clinical Classification

ABSTRACT Objective Febrile seizures (FS) are currently classified as simple or complex primarily to describe seizure characteristics, with limited ability to identify the underlying etiology. We evaluated whether molecular diagnosis could complement conventional classification and improve the diagnosis and management of FS. Methods This nationwide, multi‐center, prospective cohort study, conducted from January 2019 to February 2023, enrolled patients who were clinically diagnosed with FS. The panel targeted 189 genes associated with fever‐induced seizures. Initially, children were categorized into simple febrile seizures (SFS) and complex febrile seizures (CFS) groups based on medical history and clinical evaluation. Variant classification followed the ACMG guidelines. We analyzed the cohort demographic characteristics, potential genetic etiologies across different clinical phenotypes, and clinical utility of genetic diagnosis. Results Our study included 3300 children with FS, and ultimately analyzed sequencing data from 2552 children, of whom 273 received a positive diagnosis. The molecular diagnostic yield was 11% (273 out of 2552 patients), with the top 10 genes accounting for 70.4% of all confirmed genetic diagnoses. No significant difference in molecular diagnostic yield was observed between the SFS (9.5%, 111/1163) and CFS (11.7%, 162/1389) groups ( p = 0.085). Molecular diagnostics had immediate clinical utility, influencing management (76.2%) and informing prognosis (72.6%). The cost of a single panel sequencing for a three‐person family was $240, with a turnaround time of 14 days. Interpretation Molecular diagnosis may improve the diagnosis of FS by identifying genetic fever‐sensitive epilepsies that may be missed by phenotype‐based classification, with implications for risk stratification and individualized management.