Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy

Abstract

Rolandic epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio >1 was detected for loss-of-function variants.

Fig. 1

Burden analysis. Typical Rolandic epilepsy is represented as RE, atypical rolandic epilepsy as ARE and RE plus ARE as ROLANDIC. On the x axis, the odds ratios in cases vs controls are given. The names of the variant classes are given on the y axis. Each panel represents a different dataset. The dashed vertical line represents the expected odds ratio of 1. The horizontal lines indicate 95% confidence intervals. a Assessment of risk for deleterious variants in GRIN2A against two control groups (ExAC and In-house). The values on top of each point represent multiple-testing corrected p-values, the ones in red are significant p-values and the ones in black are the p-values that are not significant after multiple-testing correction. The odds ratios are restricted to a maximum value of 50. b Exome-wide burden analysis by different variant classes. The values on top of each point represent the p-value. Synonymous variants serve as a control functional group (colour figure online)

Fig. 2

Gene-set burden across different variant classes. Each panel represent a different variant class. The synonymous variants serve as a control variant class. GRIN2A was removed from all gene-sets to identify other contributing genes. On the x axis, the odds ratios in cases vs controls are given. On the y axis, the names of different gene-sets are given. The red vertical line represents the expected odds ratio of 1. The horizontal lines indicate 95% confidence intervals and are restricted to the maximum of odds ratios over all gene-sets. In that case, points are represented as the points without error bars to their right. The uncorrected p-values are shown on top of each point. CADD15 = deleterious predicted missense variants. LOF = Loss-of-function variants (colour figure online)