Copy number variations in children with brain malformations and refractory epilepsy

Abstract

Brain malformations are a major cause of therapy-refractory epilepsy as well as neurological and developmental disabilities in children. This study examined the frequency and the nature of copy number variations among children with structural brain malformations and refractory epilepsy. The medical records of all children born between 1990 and 2009 in the epilepsy registry at the Astrid Lindgren's Children's Hospital were reviewed and 86 patients with refractory epilepsy and various brain malformations were identified. Array-CGH analysis was performed in 76 of the patients. Pathogenic copy number variations were detected in seven children (9.2%). In addition, rearrangements of unclear significance, but possibly pathogenic, were detected in 11 (14.5%) individuals. In 37 (48.7%) patients likely benign, but previously unreported, copy number variants were detected. Thus, a large proportion of our patients had at least one rare copy number variant. Our results suggest that array-CGH should be considered as a first line genetic test for children with cerebral malformations and refractory epilepsy unless there is a strong evidence for a specific monogenic syndrome.

Detection of copy number variations in epilepsy using exome data

“…In this study, we performed WES CNV analyses on 168 “unsolved” families with epilepsy and identified pathogenic CNVs in 18 patients (10.7%) (Table ). Our detection rates of pathogenic CNVs by WES‐based CNV analysis are similar to a previous report using microarray (3.2%‐10.9%) and WES‐based (2.9%) analyses in epilepsy. Different diagnostic yields of WES‐based CNV detection may arise from different phenotypes, numbers of patients with/without microarray prescreening, WES data quality, or different detection tools.…”

“…However, an “exome‐first approach,” WES for evaluating both SNVs and CNVs, could be an alternative to avoid a “diagnostic odyssey,” as in our Case 738, and may save time and cost . It has been reported that SNVs and CNVs involving epilepsy genes account for 10.0% to 48.5% and 3.2% to 10.9% of genetic causes, respectively. In our study using WES, pathogenic SNVs were identified in 126 (42.9%) and CNVs in 18 (6.1%) out of 294 families (Figure A), being compatible with these previous data.…”

“…Microarray technologies play important roles in CNV detection and have acquired higher resolution. Applying microarray analysis to samples from epileptic patients, pathogenic CNVs have been detected in 3.2% to 10.9% of patients in previous reports …”

“…Applying microarray analysis to samples from epileptic patients, pathogenic CNVs have been detected in 3.2% to 10.9% of patients in previous reports. [4][5][6][7][8][9] Whole-exome sequencing (WES) is a powerful tool for detecting pathogenic mutations, especially single nucleotide variants (SNVs) and small indels, and widely used to find highly heterogeneous genetic alterations. Recently, WES data has been also used for detecting CNVs.…”

“…2%-10.9%)[4][5][6][7][8][9] and WES-based (2.9%) 10 analyses in epilepsy. Different diagnostic yields of WES-based CNV detection may arise from…”