Transmission Disequilibrium of Small CNVs in Simplex Autism
Transmission Disequilibrium of Small CNVs in Simplex Autism
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DOI：
10.1016/j.ajhg.2013.07.024
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发表时间：
2013-10-03
影响因子：
9.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
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作者：
Krumm, Niklas;O'Roak, Brian J.;Eichler, Evan E.
我们通过使用可用的外显子组序列数据和CoNIFER（外显子组读数的拷贝数推断），在Simons Simplex Collection的411个受散发性自闭症谱系障碍（ASD）影响的家庭中搜索破坏性的基因罕见拷贝数变异（CNV）。与高密度SNP微阵列相比，我们的方法产生了相似的2倍更小的基因罕见CNVs。我们发现，受影响的先证者比他们的兄弟姐妹继承了更多的CNVs（453对394，p = 0.004;比值比[OR] = 1.19），先证者的CNVs影响了更多的基因（921对726，p = 0.02; OR = 1.30）。这些较小的CNV（中位大小为18 kb）优先从母亲（136母亲对100父亲，p = 0.02），虽然这种偏见发生的影响状态无关。先证者中遗传性CNVs的过度负担主要是由具有不一致社会行为表型的兄弟姐妹对驱动的（p < 0.0002，通过社会反应量表[SRS]评分测量），这与表型更接近匹配或不那么极端的家庭形成对比（p > 0.5）。最后，我们发现富集的大脑表达的基因独特的先证者，特别是在SRS不一致组（p = 0.0035）。在一个组合模型中，我们的遗传性CNVs、新生CNVs和新生单核苷酸变异都独立地导致了自闭症的风险（p < 0.05）。总之，这些结果表明，小的传播罕见的CNVs在单纯性自闭症的病因学中发挥作用。重要的是，这些变异体的小尺寸有助于识别特定基因作为与ASD相关的额外风险因素。
We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded similar to 2x more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.