期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 101, 期 5, 页码 664-685出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2017.09.008
关键词
-
资金
- Genome Canada
- Genome Quebec
- Jeanne and Jean-Louis Levesque Foundation
- Michael Bahen Chair in Epilepsy Research
- Ontario Brain Institute
- McLaughlin Foundation
- University of Toronto
- National Institute of Neurological Disorders and Stroke [RO1 NS069605]
- University of Toronto McLaughlin Accelerator Grant in Genomic Medicine [MC-2013-08]
- MRC [MC_PC_U127561093] Funding Source: UKRI
- Epilepsy Research UK [P1205] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561093] Funding Source: researchfish
Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据