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Identification of Rare Recurrent Copy Number Variants in High-Risk Autism Families and Their Prevalence in a Large ASD Population

机译：高风险自闭症家庭中罕见的经常性拷贝数变异及其在大量ASD人群中的流行

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Structural variation is thought to play a major etiological role in the development of autism spectrum disorders (ASDs), and numerous studies documenting the relevance of copy number variants (CNVs) in ASD have been published since 2006. To determine if large ASD families harbor high-impact CNVs that may have broader impact in the general ASD population, we used the Affymetrix genome-wide human SNP array 6.0 to identify 153 putative autism-specific CNVs present in 55 individuals with ASD from 9 multiplex ASD pedigrees. To evaluate the actual prevalence of these CNVs as well as 185 CNVs reportedly associated with ASD from published studies many of which are insufficiently powered, we designed a custom Illumina array and used it to interrogate these CNVs in 3,000 ASD cases and 6,000 controls. Additional single nucleotide variants (SNVs) on the array identified 25 CNVs that we did not detect in our family studies at the standard SNP array resolution. After molecular validation, our results demonstrated that 15 CNVs identified in high-risk ASD families also were found in two or more ASD cases with odds ratios greater than 2.0, strengthening their support as ASD risk variants. In addition, of the 25 CNVs identified using SNV probes on our custom array, 9 also had odds ratios greater than 2.0, suggesting that these CNVs also are ASD risk variants. Eighteen of the validated CNVs have not been reported previously in individuals with ASD and three have only been observed once. Finally, we confirmed the association of 31 of 185 published ASD-associated CNVs in our dataset with odds ratios greater than 2.0, suggesting they may be of clinical relevance in the evaluation of children with ASDs. Taken together, these data provide strong support for the existence and application of high-impact CNVs in the clinical genetic evaluation of children with ASD.
机译：人们认为结构变异在自闭症谱系障碍（ASD）的发展中起着主要的病因学作用，自2006年以来，发表了许多研究证明ASD中拷贝数变异（CNV）的相关性。 -可能对普通ASD人群具有更广泛影响的CNV，我们使用Affymetrix全基因组人类SNP阵列6.0从9个多重ASD谱系中鉴定了55名55名患有ASD的个体存在的153种自闭症特异性CNV。为了评估这些CNV的实际患病率，以及据报道来自已发表的研究中的185例与ASD相关的CNV的普遍性，其中许多动力不足，我们设计了一个定制的Illumina阵列，并用它来询问3,000例ASD病例和6,000个对照中的这些CNV。阵列上的其他单核苷酸变体（SNV）识别了我们在家庭研究中以标准SNP阵列分辨率未检测到的25种CNV。经过分子验证后，我们的结果表明，在两个或多个ASD病例中也发现了高风险ASD家族中鉴定出的15种CNV，其比值比大于2.0，从而加强了他们对ASD风险变体的支持。此外，在我们定制阵列上使用SNV探针鉴定出的25种CNV中，有9种的比值比也大于2.0，这表明这些CNV也是ASD风险变体。以前尚未在ASD患者中报告过18个经过验证的CNV，而仅观察到3次。最后，我们确认了我们数据集中185个已发布的与ASD相关的CNV之间的关联，其比值比大于2.0，这表明它们与ASD儿童的评估可能具有临床意义。综上所述，这些数据为高影响力CNV在ASD儿童临床遗传评估中的存在和应用提供了有力的支持。

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