Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.
Sanders SJ., Ercan-Sencicek AG., Hus V., Luo R., Murtha MT., Moreno-De-Luca D., Chu SH., Moreau MP., Gupta AR., Thomson SA., Mason CE., Bilguvar K., Celestino-Soper PBS., Choi M., Crawford EL., Davis L., Wright NRD., Dhodapkar RM., DiCola M., DiLullo NM., Fernandez TV., Fielding-Singh V., Fishman DO., Frahm S., Garagaloyan R., Goh GS., Kammela S., Klei L., Lowe JK., Lund SC., McGrew AD., Meyer KA., Moffat WJ., Murdoch JD., O'Roak BJ., Ober GT., Pottenger RS., Raubeson MJ., Song Y., Wang Q., Yaspan BL., Yu TW., Yurkiewicz IR., Beaudet AL., Cantor RM., Curland M., Grice DE., Günel M., Lifton RP., Mane SM., Martin DM., Shaw CA., Sheldon M., Tischfield JA., Walsh CA., Morrow EM., Ledbetter DH., Fombonne E., Lord C., Martin CL., Brooks AI., Sutcliffe JS., Cook EH., Geschwind D., Roeder K., Devlin B., State MW.
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.