Abstract
Epilepsy is one of the most common neurological disorders in pediatric patients with other underlying neurological defects. Identifying the underlying etiology is crucial for better management of the disorder. We performed trio-whole exome sequencing in 221 pediatric patients with epilepsy. Probands were divided into seizures with developmental delay/intellectual disability (DD/ID) and seizures without DD/ID groups. Pathogenic (P) or likely pathogenic (LP) variants were identified in 71/110 (64.5%) patients in the seizures with DD/ID group and 21/111 (18.9%) patients in the seizures without DD/ID group (P < 0.001). Eighty-seven distinct P/LP single nucleotide variants (SNVs)/insertion deletions (Indels) were detected, with 55.2% (48/87) of them being novel. All aneuploidy and P/LP copy number variants (CNVs) larger than 100 Kb were identifiable by both whole-exome sequencing and copy number variation sequencing (CNVseq) in 123 of individuals (41 pedigrees). Ten of P/LP CNVs in nine patients and one aneuploidy variant in one patient (Patient #56, #47, XXY) were identified by CNVseq. Herein, we identified seven genes (NCL, SEPHS2, PA2G4, SLC35G2, MYO1C, GPR158, and POU3F1) with de novo variants but unknown pathogenicity that were not previously associated with epilepsy. Potential effective treatment options were available for 32 patients with a P/LP variant, based on the molecular diagnosis. Genetic testing may help identify the molecular etiology of early onset epilepsy and DD/ID and further aid to choose the appropriate treatment strategy for patients.
Highlights
Epilepsy is one of the most common neurological disorders with 50–100 million affected, and 2– 4 million new cases diagnosed each year worldwide (Pitkänen et al, 2016)
Patients were divided into two groups: the seizures with delay/intellectual disability (DD/intellectual disability (ID)) group and the seizures without developmental delay (DD)/ID group (Figure 1)
Recent cohort studies suggested that the diagnostic yield of Whole-exome sequencing (WES) varies from 23 to 42% in patients with epilepsy (Helbig et al, 2016; McTague et al, 2016; Costain et al, 2019; Snoeijen-Schouwenaars et al, 2019; Yang et al, 2019; Johannesen et al, 2020; Rochtus et al, 2020)
Summary
Epilepsy is one of the most common neurological disorders with 50–100 million affected, and 2– 4 million new cases diagnosed each year worldwide (Pitkänen et al, 2016). Epilepsy is a chronic disorder characterized by recurrent spontaneous seizures, and often begins in childhood. The genetic etiology of epilepsy may be monogenic, resulting from single-gene mutations. Mutations or variants in multiple genes are important to cause epilepsy (Møller et al, 2015). Epilepsy genetics can be broadly characterized into two categories: (i) genes and loci associated with primary epilepsy; and (ii) genes associated with neurological disorders where epilepsy may be one of the symptoms (Poduri and Lowenstein, 2011). Numerous pathogenic variants in several genes have been associated with epilepsy and seizures (Yang et al, 2019)
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