Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy
Authors: Koh Hyun Yong , Smith Lacey , Wiltrout Kimberly N. , Podury Archana , Chourasia Nitish , D’Gama Alissa M. , Park Meredith , Knight Devon , Sexton Emma L. , Koh Julia J. , Oby Brandon , Pinsky Rebecca , Shao Diane D. , French Courtney E. , Shao Wanqing , Rockowitz Shira , Sliz Piotr , Zhang Bo , Mahida Sonal , Moufawad El Achkar Christelle , Yuskaitis Christopher J. , Olson Heather E. , Sheidley Beth Rosen , Poduri Annapurna H. ,   BCH Neurology Referral and Phenotyping Group, Barkoudah Elizabeth , Bergin Ann M. , Bernson-Leung Miya , Binney Elizabeth , Bolton Jeffrey , Donatelli Stephanie , Ebrahimi-Fakhari Darius , Gorman Mark P. , Harini Chellamani , Jayaraman Divya , Kielian Agnieszka A. , LaFortune Lauren , Larovere Kerri , Libenson Mark , Lieberman David N. , Loddenkemper Tobias , Marti Candice E. , Minster Anna , Mysak Kate , Paris Ann , Patel Archana A. , Pearl Phillip L. , Peters Jurriaan M. , Pinto Anna , Raffalli Peter , Rotenberg Alexander , Salussolia Catherine , Sarvendram Rebecca , Shapiro Hannah , Soul Janet , Spence Sarah , Spencer Karen , Stowe Robert C. , Stredny Coral M. , Takeoka Masanori , Tracy Molly , Trowbridge Sara K. , Tsuboyama Melissa , Urion David K. 
Published: July 2023

ImportanceGenomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling.ObjectiveTo delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy.Design, Setting, and ParticipantsThis 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.ExposuresPhenotypic features associated with diagnostic genetic results.Main Outcomes and MeasuresMain 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.ResultsA 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 RelevanceThese 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.