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. 2023 Jul 3;6(7):e2324380.
doi: 10.1001/jamanetworkopen.2023.24380.

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

Hyun Yong Koh  1   2   3   4 , Lacey Smith  1   2 , Kimberly N Wiltrout  1   2   5 , Archana Podury  6 , Nitish Chourasia  2   7 , Alissa M D'Gama  1   6   8 , Meredith Park  1 , Devon Knight  1 , Emma L Sexton  1 , Julia J Koh  1 , Brandon Oby  1 , Rebecca Pinsky  1 , Diane D Shao  1   2   5 , Courtney E French  9 , Wanqing Shao  9 , Shira Rockowitz  4   9 , Piotr Sliz  4   9   10 , Bo Zhang  2   11 , Sonal Mahida  1   2 , Christelle Moufawad El Achkar  1   2   5   11 , Christopher J Yuskaitis  1   2   3   5 , Heather E Olson  1   2   3   5 , Beth Rosen Sheidley  1   2 , Annapurna H Poduri  1   2   3   5   12 ; BCH Neurology Referral and Phenotyping Group
Collaborators, Affiliations

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

Hyun Yong Koh et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wiltrout reported receiving personal fees from Stoke Therapeutics outside the submitted work. Dr Sliz reported serving as a cofounder, scientific advisory board member, and equity holder of Redona Therapeutics. Dr Olson reported receiving personal fees from Takeda Pharmaceuticals, Zogenix, Ovid Therapeutics, Marinus Pharmaceuticals, FOXG1 Research Foundation, Efficient CME, and FamilieSCN2A and grants from the International Foundation for CDKL5 Research Centers of Excellence, LouLou Foundation, and National Institute of Neurological Disorders and Stroke (NINDS) outside the submitted work. Dr Poduri reported serving as on scientific advisory boards for TevardBio and SynGAP Research Fund outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Summary of Diagnostic Yield From Exome Sequencing (ES) Patients With Unexplained Epilepsy
A total of 522 patients with previously unexplained epilepsy were enrolled and underwent ES, with 1 or both parents as available. We identified diagnostic single nucleotide variants (SNVs) in 89 individuals. These pathogenic or likely pathogenic variants and diagnostic variants of uncertain significance (VUS) were clinically confirmed and returned to patients and families. Dedicated copy number variant (CNV) analysis of the ES data identified an additional 11 diagnostic CNVs, which were also returned to patients and families. Candidate gene findings and VUS in epilepsy-associated genes that were not determined to be diagnostic were not returned to families but will be reevaluated as additional data emerges or in the eventual emergence of functional data supporting pathogenesis.
Figure 2.
Figure 2.. Clinical Features in Patients With Diagnostic Variants
Multiple logistic regression analysis of 7 phenotypic variables found that developmental epileptic encephalopathy (DEE) or diagnosis of intellectual disability and history of motor impairment were the strongest factors associated with identifying a diagnostic Exome Sequencing (ES) finding. ADHD indicates attention deficit hyperactivity disorder; ASD, autism spectrum disorder; and OR, odds ratio. aP < .001. bP < .05.
See this image and copyright information in PMC

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