Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy.

Genetic diagnosis of childhood epilepsy is crucial to provide disease-specific treatments. This report describes the genetic landscape of childhood epilepsy revealed by targeted next-generation sequencing panels for epilepsy (TNGSP-E) and whole exome sequencing (WES). In this retrospective cohort study, TNGSP-E and/or WES were applied to identify underlying genetic diagnoses in children seen in a single Pediatric Epilepsy Genetics Clinic. We reviewed electronic patient charts for phenotypes and biochemical, genetic, and neuroimaging investigations. Forty-four different genetic diagnoses were confirmed in 71 of 197 patients (36%; 95% CI 29.3%–43.2%). The diagnostic yield of WES (37%) was 1.9-fold greater than the diagnostic yield of TNGSP-E (19.0%; P =.0018). The number of genes included in TNGSP-E was not correlated with whether or not the test resulted in a diagnosis (Pearson's R = -0.02, P =.8). Inherited metabolic disorders accounted for 13% of the genetic diagnoses, despite abnormal metabolic investigations being an exclusion criteria. There was a direct treatment implication in 6% of patients with inherited metabolic disorders including pyridoxine dependent epilepsy, glucose transporter 1 deficiency and neuronal ceroid lipofuscinosis type 2. Additionally, there might be some treatment implications in 30% of patients with genetic diagnoses including SCN1A, SCN2A, SCN8A , and KCNQ2 associated epilepsies by application of effective anti-epileptic drugs or the ketogenic diet therapy. The high diagnostic yield of clinical molecular genetic investigations and their disease-specific treatment implications highlight the importance of genetic diagnosis in childhood epilepsy. We recommend a stepwise diagnostic algorithm including metabolic investigations for treatable disorders, chromosomal microarray analysis, TNGSP-E, and WES. • Forty-four different genetic diagnoses using targeted next-generation sequencing panels for epilepsy and whole exome sequencing. • The diagnostic yield of targeted next-generation sequencing panels for epilepsy was 19%. • The diagnostic yield of whole exome sequencing was 37%. • Inherited metabolic disorders were present in 13% of the patients with normal metabolic investigations. • Direct treatment implication of a genetic diagnosis in 6% of the patients with inherited metabolic disorders. [ABSTRACT FROM AUTHOR]