Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
PLoS One. 2013;8(1):e52239. doi: 10.1371/journal.pone.0052239. Epub 2013 Jan 14.
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.
结构变异被认为在自闭症谱系障碍（ASD）的发展中起主要的病因作用，自 2006 年以来，已有大量记录拷贝数变异（CNVs）与 ASD 相关性的研究发表。为了确定大型 ASD 家系是否存在可能对一般 ASD 人群有更广泛影响的高影响力 CNVs，我们使用 Affymetrix 全基因组人类 SNP 阵列 6.0 来鉴定 9 个 ASD 家系中 55 名 ASD 个体中存在的 153 个假定的自闭症特异性 CNVs。为了评估这些 CNVs 的实际患病率以及从已发表的研究中报道的 185 个与 ASD 相关的 CNVs，其中许多研究的效力不足，我们设计了一个定制的 Illumina 阵列，并使用它在 3000 个 ASD 病例和 6000 个对照中检测这些 CNVs。该阵列上的额外单核苷酸变体（SNVs）鉴定出 25 个我们在标准 SNP 阵列分辨率的家族研究中未检测到的 CNVs。经过分子验证，我们的结果表明，在高风险 ASD 家系中鉴定出的 15 个 CNVs也在两个或更多 ASD 病例中发现，其优势比大于 2.0，这加强了它们作为 ASD 风险变体的支持。此外，在我们的定制阵列上使用 SNV 探针鉴定出的 25 个 CNVs 中，有 9 个的优势比也大于 2.0，这表明这些 CNVs 也是 ASD 风险变体。18 个经过验证的 CNVs 以前在 ASD 个体中没有报道过，其中 3 个仅观察到一次。最后，我们在我们的数据集证实了 185 个已发表的与 ASD 相关的 CNVs 中的 31 个与优势比大于 2.0 的关联，这表明它们在评估 ASD 儿童时可能具有临床相关性。总之，这些数据为高影响力 CNVs 在 ASD 儿童的临床遗传评估中的存在和应用提供了强有力的支持。
