Detection of copy number variations in epilepsy using exome data

Abstract

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

The etiology of VACTERL association: Current knowledge and hypotheses

“…For example, approximately 8% of reported results from GeneDx exomes (over 100,000 exome have been run in total, including currently >1,500 cases/month) are CNVs. Studies of cohorts affected by other conditions have identified significant rates of causative CNVs by next‐generation sequencing (NGS; Bergant et al, ; Overwater et al, ; Tsuchida et al, ). The detection of other structural variants as well as mosaicism by NGS, including from exome, genome, and targeted panels, is also improving (Stosser et al, ).…”

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

“…Its efficiency at identifying single-nucleotide variants (SNVs) and small indels has been proven countless times. It also has recently been used for detecting CNVs, 16,17 but its performance and limitations for detecting CNVs are still undefined. We reanalyzed the WES data from our previously described cohort of 78 sequenced individuals 6 by focusing on CNV detection using ExomeDepth software 18 and identified a homozygous 8.4 kb intragenic deletion encompassing WDR66 (also known as CFAP251 [cilia-and flagella-associated protein 251 (MIM: 612573)]) exons 20 and 21 (out of 22) in seven individuals.…”

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study

“…A retrospective, single-center cohort study evidenced that clinical signs, MRI, and targeted metabolic tests lead to an etiological diagnosis in about 13% of patients with “epileptic encephalopathy” [4]. In patients with a clinically unrecognized etiology (likely) causative de novo copy number variants (CNVs) accounted for about 3–10% of patients in several studies [4–8]. A large whole-exome sequencing study in “epileptic encephalopathy” patients established de novo variants, as disease cause in 12% [9].…”