title: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.
abstract: 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.
authors.affiliation: Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA.
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authors.lastname: Grice
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authors.initials: CL
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mesh_terms: D000293:Adolescent; D015820:Cadherins / Q000235:genetics; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005192:Family Health; D005260:Female; D020440:Gene Duplication / Q000235:genetics; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D019006:Neural Cell Adhesion Molecules; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D035781:Siblings; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D000076084:Ubiquitin-Specific Peptidase 7; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: C553664:CEP20 protein, human; D015820:Cadherins; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C099972:H-cadherin; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D011506:Proteins; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7