Rare gene deletions in genetic generalized and Rolandic epilepsies.

Kamel Jabbari,Jeroen Van Rooij,Roland Krause,Holger Lerche,Fritz Zimprich,Mohammad Reza Toliat,Vishal Sinha,André G Uitterlinden,Susanne Motameny,Federico Zara,Patrick May,Stefan Wolking,Robert Kraaij,M Arfan Ikram,Julian Schubert,Amit Kawalia,Peter Nürnberg,Eva M Reinthaler,Dennis Lal,Janine Altmüller,Bernd A Neubauer,Thomas Sander,Holger Thiele,Dheeraj Reddy Bobbili ,Anna‐Elina Lehesjoki

doi:10.1371/journal.pone.0202022

Abstract

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

Highlights

Epilepsies are among the most widespread neurological disorders with a lifetime incidence of ~3% [1]
Exomes of 390 epilepsy cases (196 Genetic generalized epilepsies (GGE), 194 Rolandic epilepsy (RE)) and 572 controls were used for downstream analyses (Fig 1)
75 out of 390 epilepsy patients (~19%) carried a total of 104 case-only deletions spanning 260 genes, which covered a wide size range between 915 bp and 3.11 Mbp. 43 out of 194 RE patients carried deletions compared to 32 out of 196 patients with GGE, we did not observe any significant difference in the total number of deletions between the two disease entities (p-value = 0.68)

Summary

Introduction

Epilepsies are among the most widespread neurological disorders with a lifetime incidence of ~3% [1] They represent a heterogeneous group of different disease entities that, with regard to aetiology, can be roughly divided in epilepsies with an exogeneous/symptomatic cause and those with a genetic cause. Genetic generalized epilepsies (GGE; formerly idiopathic generalized epilepsies) are the most common genetic epilepsies accounting for 30% of all epilepsies. They comprise syndromes such as juvenile myoclonic epilepsy, childhood absence epilepsy and juvenile absence epilepsy. They tend to take a benign course and show a good response to pharmacotherapy. RE has its onset in childhood or early adolescence and usually tapers off around the age of 15

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Conclusion