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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

机译：散发性自闭症外显子组揭示了从头突变的高度互连的蛋白质网络

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It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19)4, for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected p-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
机译：众所周知，自闭症谱系障碍（ASD）具有很强的遗传成分。但是，至少有70％的病例的潜在遗传原因未知。在没有从前有ASD或相关表型病史的家族（所谓的散发或单纯形家族）的假设中，从头突变是形成ASD风险的很大一部分，我们对基因组的所有编码区（外显子组）进行了测序。表现出偶发性ASD的亲子三重奏，包括189个新三重奏和20个先前报告的三重奏。此外，我们还对50个未受影响兄弟姐妹的外显子组进行了测序，这些兄弟姐妹对应于这些新的（n = 31）和先前报告的三重奏（n = 19）4，总共来自209个家庭的677个外显子组。在这里，我们显示从头突变是绝大多数的父系起源（4：1偏倚），并且与父系年龄呈正相关，这与年龄较大的父亲患ASD的风险适度增加相一致。此外，39％（126个中的49个）最严重或破坏性的从头突变映射到高度互连的p-catenin /染色质重塑蛋白网络，对自闭症候选基因的排名显着。在先证者外显子组中，在两个基因CHD8和NTNG1中观察到了反复发生的改变蛋白质的突变。对1,703个ASD先证者中的六个候选基因进行了突变筛选，确定了GRIN2B，LAMC3和SCN1A中其他从头改变蛋白质的突变。结合拷贝数变异（CNV）数据，这些结果表明极端的基因座异质性，但也为将来的发现，诊断和治疗提供了目标。

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  • 来源
    《Nature》 |2012年第7397期|p.246-250|共5页
  • 作者

    Brian J. ORoak; Laura Vives; Santhosh Girirajan; Emre Karakoc; Niklas Krumm; BradleyP. Coe; Roie Levy; Arthur Ko; CholiLee; Joshua D. Smith; Emily H. Turner; Ian B. Stanaway; Benjamin Vernot; Maika Malig; Carl Baker; Beau Reilly; Joshua M. Akey; Elhanan Borenstein; Mark J. Rieder; Deborah A. Nickerson; Raphael Bernier; Jay Shendure; Evan E. Eichler;

  • 作者单位

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle,Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA,Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA,Santa Fe Institute, Santa Fe, New Mexico 87501, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle,Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA,Howard Hughes Medical Institute, Seattle, Washington 98195, USA;

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