Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies.
Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies.
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全外显子组测序鉴定出癫痫性脑病 DYNC1H1 中的一种新的从头突变
DOI：
10.1038/s41598-017-00208-6
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发表时间：
2017-03-21
影响因子：
4.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Lin Z;Liu Z;Li X;Li F;Hu Y;Chen B;Wang Z;Liu Y
癫痫性脑病（epileptic encephalopathies，EE）是一组以难治性癫痫发作、认知障碍和神经功能缺损为特征的严重儿童癫痫疾病。最近的全外显子组测序（WES）的研究表明，从头突变EE的显着贡献。在这项研究中，我们利用WES确定因果从头突变的4个父母-后代三人组受西方综合征。结果，我们在两个三人组中发现了DYNC1H1和RTP1的两个有害的从头突变。表达谱分析表明，DYNC1H1和RTP1在几乎所有的大脑区域和发育阶段表达。有趣的是，共表达和遗传相互作用网络分析表明，DYNC1H1和RTP1与已知的癫痫基因密切相关。此外，我们观察到先前的研究在EE、自闭症谱系障碍和智力障碍等几种不同的神经精神疾病中发现了DYNC 1H1的从头突变，并且这些突变主要发生在该蛋白的功能域。综上所述，这些结果表明DYNC1H1作为一个强有力的候选人和RTP1作为一个潜在的候选人的发病EE。此外，这项工作也证明了WES作为一个强大的工具的分子遗传解剖的儿童受散发性EE。
Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that DYNC1H1 and RTP1 are tightly associated with known epilepsy genes. Furthermore, we observed that the de novo mutations of DYNC1H1 were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.