Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Institut National de la Santé et de la Recherche Médicale U1130, 75005 Paris, France; Centre National de la Recherche Scientifique UMR 8246, 75005 Paris, France; Neuroscience Paris Seine, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, 75005 Paris, France.
Am J Hum Genet. 2014 May 1;94(5):677-94. doi: 10.1016/j.ajhg.2014.03.018. Epub 2014 Apr 24.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
罕见的拷贝数变异（CNV）是自闭症谱系障碍（ASD）的一个重要风险来源。我们分析了 2446 个 ASD 受影响的家庭，并证实了受影响组与对照组之间基因缺失和重复的过度（1.41 倍，p = 1.0×10(-5))，并且携带与显性或 X 连锁 ASD 和智力障碍相关的已知基因座重叠的外显子致病性 CNV 的受影响受试者增加（优势比=12.62，p = 2.7×10(-15)，约 3%的 ASD 受试者）。致病性 CNV 通常表现出可变的外显率，包括 36 个基因座的罕见新生和遗传事件，涉及与其他神经发育障碍相关的 ASD 相关基因（CHD2、HDAC4 和 GDI1），以及其他基因，如 SETD5、MIR137 和 HDAC9。与假设的性别特异性调节剂一致，患有 ASD 的女性更有可能具有高外显率的 CNV（p = 0.017），并且在脆性 X 综合征蛋白靶标患者中也过度存在（p = 0.02）。受新生 CNV 和/或功能丧失性单核苷酸变异影响的基因汇聚到与神经元信号转导和发育、突触功能和染色质调节相关的网络上。
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