Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA.
Neuron. 2011 Jun 9;70(5):863-85. doi: 10.1016/j.neuron.2011.05.002.
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
我们对 1124 个自闭症谱系障碍 (ASD) 家系进行了全基因组范围内罕见拷贝数变异 (CNV) 的分析，每个家系包括一个先证者、未受影响的父母，以及在大多数家系中，一个未受影响的兄弟姐妹。我们发现 ASD 与 7q11.23 的新生重复有关，其反向缺失导致威廉姆斯-贝伦综合征，其特征是高度社交的人格。我们在另外五个区域发现了罕见的新生重复 CNV，包括 16p13.2（包含 USP7 和 C16orf72 基因）和钙黏蛋白 13，并实施了严格的方法来评估这些观察结果的统计学意义。总体而言，大的新生 CNV，特别是那些包含多个基因的 CNV，会带来很大的风险（OR=5.6；CI=2.6-12.0，p=2.4×10(-7))。我们估计人类基因组中有 130-234 个与 ASD 相关的 CNV 区域，并基于累积数据提供了强有力的证据，证明 7q11.23、15q11.2-13.1、16p11.2 和神经连接蛋白 1 上的新生重复事件与 ASD 有关。
