Next generation sequencing in children with unexplained epilepsy: A retrospective cohort study.

Objective: To evaluate the clinical utility of next-generation sequencing (NGS) in unexplained pediatric epilepsy, and to identify the potential predictors associated with Mendelian genetic causes.

Methods: Two hundred and ten children with unexplained epilepsy, who underwent NGS test were included. We analyzed the demographic, clinical and genetic characteristics, and executed a Logistic regression analysis for identifying predictors for Mendelian genetic causes. Patients were classified as either with isolated epilepsy or syndromic epilepsy with concurrent neurodevelopmental phenotypes.

Results: The overall diagnostic yield was 29.0% (61/210). A total of 68 variants spanning 39 genes were identified in 58 patients (27.6%, 58/210) from exome sequencing based testing. Of the 68 variants, 33 were novel ones. Besides, STAR and CNTN2 were identified to be a candidate gene for epilepsy. Patients with syndromic epilepsy had a much higher diagnostic yield than that of isolated epilepsy (53/135, 39.3% vs. 8/75, 10.7%, p = 0.000). The odds ratio of detecting genetic cause was 3.939 (95% CI 1.369-11.332) for syndromic epilepsy without epileptic encephalopathy (EE), 5.814 (95% CI 2.208-15.306) for EE, 2.958 (95% CI 1.093-8.000) for patients with seizure onset <12 months, and 2.932 (95%CI 1.414-6.080) for female. Of the 210 patients, 78.4% of patients (145/185) had at least a 50% reduction in seizure frequency and 58.9% (109/185) reached seizure freedom. There was no difference between seizure prognosis and diagnostic outcomes.

Significance: NGS is effective for Mendelian genetic etiological diagnosis for unexplained pediatric epilepsy. Female patients with syndromic epilepsy with onset within the first year of life are most likely to yield a positive test result.