De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
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DOI：
10.1038/nature10945
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发表时间：
2012-04-04
期刊：
影响因子：
64.8
通讯作者：
State, Matthew W.
中科院分区：
文献类型：
--
作者：
Sanders, Stephan J.;Murtha, Michael T.;Gupta, Abha R.;Murdoch, John D.;Raubeson, Melanie J.;Willsey, A. Jeremy;Ercan-Sencicek, A. Gulhan;DiLullo, Nicholas M.;Parikshak, Neelroop N.;Stein, Jason L.;Walker, Michael F.;Ober, Gordon T.;Teran, Nicole A.;Song, Youeun;El-Fishawy, Paul;Murtha, Ryan C.;Choi, Murim;Overton, John D.;Bjornson, Robert D.;Carriero, Nicholas J.;Meyer, Kyle A.;Bilguvar, Kaya;Mane, Shrikant M.;Sestan, Nenad;Lifton, Richard P.;Guenel, Murat;Roeder, Kathryn;Geschwind, Daniel H.;Devlin, Bernie;State, Matthew W.
多项研究已经证实了罕见的从头拷贝数变异（CNV）对自闭症谱系障碍（ASD）风险的贡献。虽然已经在受影响的个体中发现了从头单核苷酸变异（SNV），但其对风险的贡献尚未得到澄清。具体而言，这些突变的频率和分布尚未在匹配的未受影响的对照中得到很好的表征，这些数据对于解释先证者中观察到的从头编码突变至关重要。在这里，我们通过对928个个体（包括200个表型不一致的兄弟姐妹对）进行全外显子组测序，发现脑表达基因中的高度破坏性（无义和剪接位点）从头突变与ASD相关，并具有很大的影响（OR=5.65; CI：1.44-22.2; p=0.01渐近检验）。基于未受影响个体的突变率，我们证明了在无关先证者中同一基因中的多个独立的从头SNV可靠地识别风险等位基因，为基因发现提供了明确的前进道路。在总共279个识别的从头编码突变中，有一个例子在先证者中，没有兄弟姐妹，其中两个独立的无义变体破坏相同的基因，SCN 2A（钠通道，电压门控，II型，α亚基），结果是极不可能的机会（p=0.005）。
Multiple studies have confirmed the contribution of rare de novo copy number variations (CNVs) to the risk for Autism Spectrum Disorders (ASD). While de novo single nucleotide variants (SNVs) have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations has not been well characterized in matched unaffected controls, data that are vital to the interpretation of de novo coding mutations observed in probands. Here we show, via whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with ASD and carry large effects (OR=5.65; CI: 1.44-22.2; p=0.01 asymptotic test). Based on mutation rates in unaffected individuals, we demonstrate that multiple independent de novo SNVs in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (Sodium Channel, Voltage-Gated, Type II, Alpha Subunit), a result that is highly unlikely by chance (p=0.005).
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影响因子：
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作者：
Rossin EJ;Lage K;Raychaudhuri S;Xavier RJ;Tatar D;Benita Y;International Inflammatory Bowel Disease Genetics Constortium;Cotsapas C;Daly MJ
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Daly MJ
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通讯作者：
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作者：
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通讯作者：
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