Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders
Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders
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DOI：
10.1016/j.ajhg.2012.05.011
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发表时间：
2012-07-13
影响因子：
9.8
通讯作者：
Geschwind, Daniel H.
中科院分区：
文献类型：
--
作者：
Luo, Rui;Sanders, Stephan J.;Geschwind, Daniel H.
拷贝数变异（cnv）是自闭症谱系障碍（asd）病理生理的主要因素，但cnv的功能影响在很大程度上仍未被探索。由于大多数样本中没有脑组织，我们对Simons Simplex Collection中244个兄弟姐妹不一致的家族的淋巴母细胞的基因表达进行了研究，以确定潜在的致病变异。我们的研究结果显示，在先证者和未受影响的兄弟姐妹中发现的显著错误表达基因（我们在这里称之为异常值）的总体频率没有差异。然而，在先证者中，而不是其未受影响的兄弟姐妹中，异常基因组在神经相关通路中显着富集，包括神经肽信号，突触发生和细胞粘附。我们证明了异常基因聚集在大多数致病性CNVs （rare de novo CNVs）中，并且可以用于潜在未知意义的罕见CNVs的优先级排序。发现了几个具有显著基因表达改变的非复发性cnv（包括染色体区域3q27、3p13和3p26的缺失以及2p15的重复），表明这些是潜在的候选ASD位点。此外，我们在16p11.2微缺失、16p11.2微重复和7q11.23重复中发现了不同的表达变化，并表明16p CNV区间内的特定基因与头围差异相关，这是一种与自闭症相关的表型。这项研究提供了证据，证明致病性结构变异在全基因组水平上通过asd的转录组改变对功能产生影响，并证明了将基因表达与突变数据整合在一起，对被潜在致病性突变破坏的基因进行优先排序的实用性。
Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.