Utility of Genome Sequencing After Nondiagnostic Exome Sequencing in Unexplained Pediatric Epilepsy

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Abstract Importance Epilepsy is the most common neurological disorder of childhood. Identifying genetic diagnoses underlying epilepsy is critical to developing effective therapies and improving outcomes. Most children with non-acquired (unexplained) epilepsy remain genetically unsolved, and the utility of genome sequencing after nondiagnostic exome sequencing is unknown. Objective To determine the diagnostic (primary) and clinical (secondary) utility of genome sequencing after nondiagnostic exome sequencing in individuals with unexplained pediatric epilepsy. Design This cohort study performed genome sequencing and comprehensive analyses for 125 participants and available biological parents enrolled from August 2018 to May 2023, with data analysis through April 2024 and clinical return of diagnostic and likely diagnostic genetic findings. Clinical utility was evaluated. Setting Pediatric referral center Participants Participants with unexplained pediatric epilepsy and previous nondiagnostic exome sequencing; biological parents when available Exposure(s) Short-read genome sequencing and analysis Main Outcome(s) and Measure(s) Primary outcome measures were the diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding, and the unique diagnostic yield of genome sequencing, defined as the percentage of participants receiving a diagnostic or likely diagnostic genetic finding that required genome sequencing. The secondary outcome measure was clinical utility of genome sequencing, defined as impact on evaluation, treatment, or prognosis for the participant or their family. Results 125 participants (58 [46%] female) were enrolled with median age at seizure onset 3 [IQR 1.25, 8] years, including 44 (35%) with developmental and epileptic encephalopathies. The diagnostic yield of genome sequencing was 7.2% (9/125), with diagnostic genetic findings in five cases and likely diagnostic genetic findings in four cases. Among the solved cases, 7/9 (78%) required genome sequencing for variant detection (small copy number variant, three noncoding variants, and three difficult to sequence small coding variants), for a unique diagnostic yield of genome sequencing of 5.6% (7/125). Clinical utility was documented for 4/9 solved cases (44%). Conclusions and Relevance These findings suggest that genome sequencing can have diagnostic and clinical utility after nondiagnostic exome sequencing and should be considered for patients with unexplained pediatric epilepsy. Key Points Question What is the utility of genome sequencing after nondiagnostic exome sequencing in individuals with unexplained pediatric epilepsy? Findings In this cohort study of 125 individuals with unexplained pediatric epilepsy and nondiagnostic exome sequencing, genome sequencing identified diagnostic genetic findings in five cases and likely diagnostic genetic findings in four cases. Of the nine solved cases, seven required genome sequencing to solve, and four had documented clinical utility. Meaning Genome sequencing can identify genetic diagnoses not detectable by exome sequencing and should be considered for participants with unexplained pediatric epilepsy, as first-line testing or after nondiagnostic exome sequencing.

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