Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
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DOI：
10.1038/ng.3789
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发表时间：
2017-04
期刊：
影响因子：
30.8
通讯作者：
Daly MJ
中科院分区：
文献类型：
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作者：
Kosmicki JA;Samocha KE;Howrigan DP;Sanders SJ;Slowikowski K;Lek M;Karczewski KJ;Cutler DJ;Devlin B;Roeder K;Buxbaum JD;Neale BM;MacArthur DG;Wall DP;Robinson EB;Daly MJ
最近的研究发现，在神经发育障碍的从头变异的重要作用。使用来自9246个自闭症谱系障碍、智力残疾或发育迟缓家庭的汇总数据，我们发现，在外显子组聚集联盟的60,706名成年人队列中，约1/3的新生变异被独立观察到为常设变异，这些新生变异不会导致神经发育风险。我们进一步使用功能丧失（LoF）的不耐受性度量，pLI，以确定一个子集的LoF不耐受基因，包含相关的从头蛋白质截短变异体（PTVs）在神经发育障碍中观察到的信号。LoF不耐受基因也携带适度过量的遗传PTV;尽管最强的从头影响基因对此贡献不大，这表明遗传风险的过量存在于低渗透基因。这些发现说明了基于人群的参考队列对于解释候选致病变异的重要性，甚至对于复杂疾病和从头变异的分析也是如此。
Recent research has uncovered a significant role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium’s cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain the observed signal of associated de novo protein truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.