Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Cologne Biocenter, Institute for Genetics, University of Cologne, Cologne, Germany.
PLoS One. 2018 Aug 27;13(8):e0202022. doi: 10.1371/journal.pone.0202022. eCollection 2018.
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.
遗传性全面性癫痫（GGE）和良性癫痫伴中央颞区棘波或罗兰多癫痫（RE）是常见的遗传性癫痫形式。罕见的拷贝数变异已被认为是脑疾病的重要风险因素。我们对影响蛋白编码基因的罕见缺失进行了系统调查，这些基因来自患有常见遗传性癫痫形式的患者的外显子数据。我们分析了 390 名欧洲患者（196 名 GGE 和 194 名 RE）和 572 名对照人群的外显子组，以识别低频基因缺失。我们发现 390 名患者中有 75 名（32 名 GGE 和 43 名 RE）携带罕见的基因缺失，即约 19%。特别是，与对照组相比，GGE 和 RE 综合征中较大的缺失（>400kb）更为常见。检测到的低频缺失（1）与大脑表达外显子共享受负选择影响的基因，（2）与已知的自闭症和癫痫相关候选基因重叠，（3）富含 Exome Aggregation Consortium（ExAC）记录的不耐受 CNV 的基因，以及（4）与来自 NPdenovo 数据库的可能破坏性新生突变一致。我们利用多个知识库讨论了 GGE 和 RE 的最显著的癫痫候选基因及其蛋白-蛋白网络。
