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

Author:

Koh Hyun Yong1234,Smith Lacey12,Wiltrout Kimberly N.125,Podury Archana6,Chourasia Nitish27,D’Gama Alissa M.168,Park Meredith1,Knight Devon1,Sexton Emma L.1,Koh Julia J.1,Oby Brandon1,Pinsky Rebecca1,Shao Diane D.125,French Courtney E.9,Shao Wanqing9,Rockowitz Shira49,Sliz Piotr4910,Zhang Bo211,Mahida Sonal12,Moufawad El Achkar Christelle12511,Yuskaitis Christopher J.1235,Olson Heather E.1235,Sheidley Beth Rosen12,Poduri Annapurna H.123512,Barkoudah Elizabeth13,Bergin Ann M.13,Bernson-Leung Miya13,Binney Elizabeth13,Bolton Jeffrey13,Donatelli Stephanie13,Ebrahimi-Fakhari Darius13,Gorman Mark P.13,Harini Chellamani13,Jayaraman Divya13,Kielian Agnieszka A.13,LaFortune Lauren13,Larovere Kerri13,Libenson Mark13,Lieberman David N.13,Loddenkemper Tobias13,Marti Candice E.13,Minster Anna13,Mysak Kate13,Paris Ann13,Patel Archana A.13,Pearl Phillip L.13,Peters Jurriaan M.13,Pinto Anna13,Raffalli Peter13,Rotenberg Alexander13,Salussolia Catherine13,Sarvendram Rebecca13,Shapiro Hannah13,Soul Janet13,Spence Sarah13,Spencer Karen13,Stowe Robert C.13,Stredny Coral M.13,Takeoka Masanori13,Tracy Molly13,Trowbridge Sara K.13,Tsuboyama Melissa13,Urion David K.13,

Affiliation:

1. Epilepsy Genetics Program, Boston Children’s Hospital, Boston, Massachusetts

2. Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts

3. F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts

4. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Massachusetts

5. Department of Neurology, Harvard Medical School, Boston, Massachusetts

6. Harvard Medical School, Boston, Massachusetts

7. Department of Pediatrics and Neurology, University of Tennessee Health Science Center, Memphis

8. Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts

9. Research Computing, Department of Information Technology, Boston Children’s Hospital, Boston, Massachusetts

10. Division of Molecular Medicine, Boston Children’s Hospital, Boston, Massachusetts

11. Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, Massachusetts

12. Broad Institute of MIT and Harvard, Cambridge, Massachusetts

13. for the BCH Neurology Referral and Phenotyping Group

Abstract

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.

Publisher

American Medical Association (AMA)

Subject

General Medicine

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