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Patterns and rates of exonic de novo mutations in autism spectrum disorders

机译：自闭症谱系障碍外显子从头突变的模式和发生率

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Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1'2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
机译：自闭症谱系障碍（ASD）被认为具有遗传和环境起源，但是只有极少数的个体可以识别出具体原因1'2。为了确定进一步的遗传危险因素，在这里我们通过对ASD病例及其父母的外显子组进行测序（n = 175三重奏）来评估从头突变在ASD中的作用。仅有不到一半的病例（46.3％）携带有错义或无义从头变异，并且总突变率仅略高于预期率。相比之下，由具有新错义或无义突变的基因编码的蛋白质在它们之间以及与以前的ASD基因3之间显示出更高程度的连通性，这是通过蛋白质-蛋白质相互作用筛选确定的。与蛋白质相互作用结果一起，从头事件发生率的小幅增加与ASD中从头点突变的重要但有限的作用是一致的，类似于从头拷贝数变体的文献报道。整合了这些数据的遗传模型表明，大多数观察到的从头事件与ASD无关。那些确实具有风险的基因分布在许多基因中，并且不完全渗透（也就是说，不一定足以治疗疾病）。我们的结果支持多基因模型，其中大量基因中任何一个的自发编码突变都会使风险增加5到20倍。尽管此类模型提出了挑战，但从头事件获得的结果和大量平行病例对照研究提供了有力证据，支持CHD8和KATNAL2作为真正的自闭症危险因素。

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  • 来源
    《Nature》 |2012年第7397期|p.242-245|共4页
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    Benjamin M. Neale; Yan Kou; Li Liu; Avi Maayan; Kaitlin E. Samocha et al;

  • 作者单位

    Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA,Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Departmentof Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA,Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York 10029, USA;

    Department of Statistics, Carnegie Mellon University,Pittsburgh, Pennsylvania 15232, USA;

    Departmentof Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA;

    Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA,Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

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