Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms

ABSTRACTObjectives Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis.Methods This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders.Results Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy.Conclusion Emerging advances of next-generation technologies and 'in silico' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.KEYWORDS: Epilepsy case seriesgenotypephenotypenovel variants Abbreviations TableDownload CSVDisplay TableAcknowledgmentsThe authors would like to thank all families and referring clinicians who collaborated in this study as well as the technician Mrs Efthalia Daniel for her technical assistance.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewers' disclosurePeer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.Data availability statementThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Ethical publication statementWe confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Approval number for this study is 12,160/23-05-16.Author contributionsDV performed exome sequencing data analysis, variant interpretation, segregation analysis, and drafted the article. F-NT and NMM performed part of the data analysis. MS helped with RNA analysis. AM performed a-CGH analysis. KK, IT, PM, VT, MK, PV, GN, GV, AD, AE, SM, AK, SM, and AP examined patients and provided clinical information, on phenotypic characteristics and neurological findings. MT performed a-CGH analysis and reviewed the article. RP examined patients and provided clinical informationon phenotypic characteristics and neurological findings and reviewed the article. JT-S supervised the study and reviewed the article. CS performed variant interpretation and findings evaluation, supervised the study, and critically reviewed the article.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/14737159.2023.2173578Additional informationFundingThis paper was not funded.