Global characterization of copy number variants in epilepsy patients from whole genome sequencing

Abstract

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from 5 limited sensitivity and specificity. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. We found an enrichment 10 of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 15 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive profiling of CNVs could help explain a larger fraction of epilepsy cases.

Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

“…The diagnostic yield of CMA of 8% is similar to that reported from other published data of approximately 10%, 18,19 and the majority (77%) of patients in whom CMA was requested had developmental delay in addition to epilepsy. Among the pathogenic CNVs identified in our study, there were well-known epilepsy hotspots, 20 as well as previously unreported findings (such as the 8q21.13q22.1 duplication). In keeping with published literature, significant CNVs were detected among our patients with epilepsy accompanying a multisystem syndrome, most often in the setting of developmental delay and dysmorphic features.…”

From Genetic Testing to Precision Medicine in Epilepsy

“…Traditional Sanger sequencing, which allow direct determination of the nucleotide sequence of the exons of a single gene, has been replaced by next generation sequencing (NGS), a microchip-based technology allowing simultaneous sequencing of many genes at relatively low costs [20]. The advent of NGS has made feasible the simultaneous sequencing of hundreds of genes, up to all exons (coding sequences, approximately 1% of the whole genome) of all human genes through whole-exome sequencing (WES) [21,22]. Therefore, both gene panel sequencing and WES are being increasingly used in the clinical diagnosis of epileptic disorders with a presumed genetic basis [23,24].…”

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

“…12 Next-generation sequencing (NGS) using exome sequencing (ES), copy number variation sequencing (CNVseq), and whole-genome sequencing (WGS) has been greatly used in the clinic over the past decade and obtained satisfactory diagnostic results. 12,13 ES is further divided into targeted NGS panels (Panel), clinical exome sequencing (CES), and whole-exome sequencing (WES) according to the analytical genes included.…”