Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Key Points Question What are the diagnostic yield and clinical utility of genetic sequencing for patients with unexplained pediatric epilepsy? Findings This cohort study of 522 children with previously unexplained epilepsy used exome sequencing to identify and clinically confirm diagnostic results for 100 children, including 89 with single nucleotide variants and 11 with copy number variants. Individuals with earlier seizure onset, intellectual disability, and motor impairment were more likely to have diagnostic results, and at least 29 patients had changes in treatment, surveillance, or prognosis based on their genetic diagnoses. Meaning These findings suggest that for children with unexplained epilepsy, genetic evaluation yielded precise diagnoses with direct clinical implications. This cohort study examines the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. Importance Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling. Objective To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. Design, Setting, and Participants This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022. Exposures Phenotypic features associated with diagnostic genetic results. Main Outcomes and Measures Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported. Results A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses. Conclusions and Relevance These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.