Diagnostic Yield, Diagnostic Delay, and Clinical Utility of Genetic Testing in 930 Children with Suspected Genetic Epilepsy

Background: Next-generation sequencing (NGS) has transformed pediatric epilepsy care, but real-world data on diagnostic delay and clinical utility remain limited, particularly in Chinese populations. Methods: This retrospective cohort included 930 children with suspected genetic epilepsy. Diagnostic delay was defined as the interval from seizure onset to genetic testing. Monogenic cases were grouped by functional pathways. Drug resistance was defined per International League Against Epilepsy (ILAE) guidelines. Results: The overall diagnostic yield was 40.0% (373/930), encompassing 122 genes. The median diagnostic delay was 3.0 months (interquartile range (IQR), 0.0–18.0), with 30.1% of patients delayed >12 months. Drug resistance occurred in 25.5%. Developmental delay was the strongest independent predictor (adjusted odds ratio (aOR) = 3.00, p < 0.001). mTOR pathway variants had the highest observed resistance rate (54.2%). Among diagnosed patients, 31.1% had genotype-informed treatment recommendations; 59.5% led to changes in clinical management, with over 85% achieving favorable seizure outcomes. Conclusions: NGS demonstrates high diagnostic yield in Chinese pediatric epilepsy, but diagnostic delay remains substantial. Developmental delay is the strongest predictor of drug resistance, and mTOR pathway variants were associated with the highest observed drug-resistance rate. These findings support earlier genetic testing and pathway-stratified therapeutic strategies.