Functional impact of global rare copy number variation in autism spectrum disorders by Pinto Dalila, Pagnamenta Alistair T, Klei Lambertus, Anney Richard, Merico Daniele, Regan Regina, Conroy Judith, Magalhaes Tiago R, Correia Catarina, Abrahams Brett S, Almeida Joana, Bacchelli Elena, Bader Gary D, Bailey Anthony J, Baird Gillian, Battaglia Agatino, Berney Tom, Bolshakova Nadia, Bölte Sven, Bolton Patrick F, Bourgeron Thomas, Brennan Sean, Brian Jessica, Bryson Susan E, Carson Andrew R, Casallo Guillermo, Casey Jillian, Chung Brian H Y, Cochrane Lynne, Corsello Christina, Crawford Emily L, Crossett Andrew, Cytrynbaum Cheryl, Dawson Geraldine, de Jonge Maretha, Delorme Richard, Drmic Irene, Duketis Eftichia, Duque Frederico, Estes Annette, Farrar Penny, Fernandez Bridget A, Folstein Susan E, Fombonne Eric, Freitag Christine M, Gilbert John, Gillberg Christopher, Glessner Joseph T, Goldberg Jeremy, Green Andrew, Green Jonathan, Guter Stephen J, Hakonarson Hakon, Heron Elizabeth A, Hill Matthew, Holt Richard, Howe Jennifer L, Hughes Gillian, Hus Vanessa, Igliozzi Roberta, Kim Cecilia, Klauck Sabine M, Kolevzon Alexander, Korvatska Olena, Kustanovich Vlad, Lajonchere Clara M, Lamb Janine A, Laskawiec Magdalena, Leboyer Marion, Le Couteur Ann, Leventhal Bennett L, Lionel Anath C, Liu Xiao-Qing, Lord Catherine, Lotspeich Linda, Lund Sabata C, Maestrini Elena, Mahoney William, Mantoulan Carine, Marshall Christian R, McConachie Helen, McDougle Christopher J, McGrath Jane, McMahon William M, Merikangas Alison, Migita Ohsuke, Minshew Nancy J, Mirza Ghazala K, Munson Jeff, Nelson Stanley F, Noakes Carolyn, Noor Abdul, Nygren Gudrun, Oliveira Guiomar, Papanikolaou Katerina, Parr Jeremy R, Parrini Barbara, Paton Tara, Pickles Andrew, Pilorge Marion, Piven Joseph, Ponting Chris P, Posey David J, Poustka Annemarie, Poustka Fritz, Prasad Aparna, Ragoussis Jiannis, Renshaw Katy, Rickaby Jessica, Roberts Wendy, Roeder Kathryn, Roge Bernadette, Rutter Michael L, Bierut Laura J, Rice John P, Salt Jeff, Sansom Katherine, Sato Daisuke, Segurado Ricardo, Sequeira Ana F, Senman Lili, Shah Naisha, Sheffield Val C, Soorya Latha, Sousa Inês, Stein Olaf, Sykes Nuala, Stoppioni Vera, Strawbridge Christina, Tancredi Raffaella, Tansey Katherine, Thiruvahindrapduram Bhooma, Thompson Ann P, Thomson Susanne, Tryfon Ana, Tsiantis John, Van Engeland Herman, Vincent John B, Volkmar Fred, Wallace Simon, Wang Kai, Wang Zhouzhi, Wassink Thomas H, Webber Caleb, Weksberg Rosanna, Wing Kirsty, Wittemeyer Kerstin, Wood Shawn, Wu Jing, Yaspan Brian L, Zurawiecki Danielle, Zwaigenbaum Lonnie, Buxbaum Joseph D, Cantor Rita M, Cook Edwin H, Coon Hilary, Cuccaro Michael L, Devlin Bernie, Ennis Sean, Gallagher Louise, Geschwind Daniel H, Gill Michael, Haines Jonathan L, Hallmayer Joachim, Miller Judith, Monaco Anthony P, Nurnberger John I, Paterson Andrew D, Pericak-Vance Margaret A, Schellenberg Gerard D, Szatmari Peter, Vicente Astrid M, Vieland Veronica J, Wijsman Ellen M, Scherer Stephen W, Sutcliffe James S, Betancur Catalina in Nature (2010).

[PMID: 20531469] PubMed


The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

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