De novo variants in neurodevelopmental disorders with epilepsy
De novo variants in neurodevelopmental disorders with epilepsy
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DOI：
10.1038/s41588-018-0143-7
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发表时间：
2018-07-01
期刊：
影响因子：
30.8
通讯作者：
Lemke, Johannes R.
中科院分区：
文献类型：
--
作者：
Heyne, Henrike O.;Singh, Tarjinder;Lemke, Johannes R.
癫痫是神经发育障碍（NDD）的常见特征，但很少有人知道NDD与癫痫之间的遗传差异。我们分析了6,753个确定具有不同NDD的亲子三人组中的从头变异（DNV）。在1，942名患有NDD癫痫的患者中，我们确定了33个具有显著过量DNV的基因，其中SNAP 25和GABRB 2以前只有有限的疾病相关证据。对所有NDD患者的联合分析也表明CACNA 1 E是一种新的疾病相关基因。比较NDD伴或不伴癫痫，我们发现错义DNV、特定基因中的DNV、招募年龄和智力残疾的严重程度与癫痫相关。我们进一步证明了我们的研究结果在多大程度上影响了目前的基因检测和治疗，强调了准确的基因诊断在NDD癫痫中的益处。
Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.