De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
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DOI：
10.1016/j.ajhg.2014.08.013
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发表时间：
2014-10-02
影响因子：
9.8
通讯作者：
Sherr, Elliott
中科院分区：
文献类型：
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作者：
Appenzeller, Silke;Balling, Rudi;Sherr, Elliott
新出现的证据表明，癫痫脑病在遗传上具有高度的异质性，这突显了需要大量特征良好的个人来进一步定义遗传格局。通过两个联合体(EuroEPINOMICS和Epi4K/EPGP)的合作，我们分析了356个患有典型癫痫脑病、婴儿痉挛和Lennox Gastaut综合征的三联体的外显子测序数据，其中包括之前由Epi4K/EPGP联合体分析的264个三联体。在这个扩大的队列中，我们发现了429个de nova突变，包括5个人的DNM1的de nova突变和两个人的GABBR2、FASN和RYR3的de nova突变。与以前的研究不同，这个队列足够大，通过似然分析(p=8.2x10(-4))显示癫痫脑病先证者中的De-nova突变显著多于普通人群(p=8.2x10(-4))，支持De-novo突变在癫痫脑病中的突出作用。我们带来了DNM1突变导致癫痫脑病的统计证据，找到了另外三个基因作用的提示性证据，并显示至少12%的被分析个体具有可识别的因果从头突变。引人注目的是，这些先驱基因中75%的突变被预测会扰乱参与调节突触传递的蛋白质，而且在整个队列中，这一途径中的基因新星突变也有显著的丰富。这些发现强调了突触失调在癫痫脑病中的重要作用，而不仅仅是离子通道功能障碍造成的。
Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de nova mutations, including de novo mutations in DNM1 in five individuals and de nova mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de nova mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 x 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de nova mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.