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Functional impact of global rare copy number variation in autism spectrum disorders.

Dalila Pinto 1 Alistair Pagnamenta 2 Lambertus Klei 3 Richard Anney 4 Daniele Merico 5 Regina Regan 6 Judith Conroy 6 Tiago Magalhaes 7, 8 Catarina Correia 7, 8 Brett Abrahams 9 Joana Almeida 10 Elena Bacchelli 11 Gary Bader 5 Anthony Bailey 12 Gillian Baird 13 Agatino Battaglia 14 Tom Berney 15 Nadia Bolshakova 4 Sven Bölte 16 Patrick Bolton 17 Thomas Bourgeron 18 Sean Brennan 4 Jessica Brian 19 Susan Bryson 20 Andrew Carson 1 Guillermo Casallo 1 Jillian Casey 6 Brian Chung 1 Lynne Cochrane 4 Christina Corsello 21 Emily Crawford 22 Andrew Crossett 23 Cheryl Cytrynbaum 1 Geraldine Dawson 24, 25 Maretha de Jonge 26 Richard Delorme 27, 28 Irene Drmic 19 Eftichia Duketis 16 Frederico Duque 10 Annette Estes 29 Penny Farrar 2 Bridget Fernandez 30 Susan Folstein 31 Eric Fombonne 32 Christine Freitag 16 John Gilbert 31 Christopher Gillberg 33 Joseph Glessner 34 Jeremy Goldberg 35 Andrew Green 5 Jonathan Green 36 Stephen Guter 37 Hakon Hakonarson 34, 38 Elizabeth Heron 4 Matthew Hill 4 Richard Holt 2 Jennifer Howe 1 Gillian Hughes 4 Vanessa Hus 21 Roberta Igliozzi 14 Cecilia Kim 34 Sabine Klauck 39 Alexander Kolevzon 40, 3 Olena Korvatska 41 Vlad Kustanovich 42 Clara Lajonchere 42 Janine Lamb 43 Magdalena Laskawiec 12 Marion Leboyer 28, 44 Ann Le Couteur 15 Bennett Leventhal 45, 46 Anath Lionel 1 Xiao-Qing Liu 1 Catherine Lord 21 Linda Lotspeich 14 Sabata Lund 22 Elena Maestrini 11 William Mahoney 47 Carine Mantoulan 48 Christian Marshall 1 Helen Mcconachie 15 Christopher Mcdougle 49 Jane Mcgrath 4 William Mcmahon 50 Alison Merikangas 4 Ohsuke Migita 1 Nancy Minshew 51 Ghazala Mirza 2 Jeff Munson 52 Stanley Nelson 53 Carolyn Noakes 19 Abdul Noor 54, 55 Gudrun Nygren 33 Guiomar Oliveira 10 Katerina Papanikolaou 56 Jeremy Parr 57 Barbara Parrini 14 Tara Paton 1 Andrew Pickles 58 Marion Pilorge 59 Joseph Piven 60 Chris Ponting 61 David Posey 49 Annemarie Poustka 39 Fritz Poustka 16 Aparna Prasad 1 Jiannis Ragoussis 2 Katy Renshaw 12 Jessica Rickaby 1 Wendy Roberts 19 Kathryn Roeder 23 Bernadette Roge 48 Michael Rutter 62 Laura Bierut 63 John Rice 63 Jeff Salt 37 Katherine Sansom 1 Daisuke Sato 1 Ricardo Segurado 4 Ana Sequeira 7, 8 Lili Senman 19 Naisha Shah 5 Val Sheffield 64 Latha Soorya 3, 40 Inês Sousa 2 Olaf Stein 65 Nuala Sykes 2 Vera Stoppioni 66 Christina Strawbridge 35 Raffaella Tancredi 14 Katherine Tansey 4 Bhooma Thiruvahindrapduram 1 Ann Thompson 35 Susanne Thomson 22 Ana Tryfon 3, 40 John Tsiantis 56 Herman van Engeland 26 John Vincent 54, 55 Fred Volkmar 67 Simon Wallace 12 Kai Wang 34 Zhouzhi Wang 1 Thomas Wassink 68 Caleb Webber 61 Rosanna Weksberg 1 Kirsty Wing 2 Kerstin Wittemeyer 48 Shawn Wood 3 Jing Wu 23 Brian Yaspan 22 Danielle Zurawiecki 3, 40 Lonnie Zwaigenbaum 69 Joseph Buxbaum 3, 40 Rita Cantor 53 Edwin Cook 37 Hilary Coon 50 Michael Cuccaro 31 Bernie Devlin 3 Sean Ennis 6 Louise Gallagher 4 Daniel Geschwind 9 Michael Gill 4 Jonathan Haines 70 Joachim Hallmayer 14 Judith Miller 50 Anthony Monaco 2 John Nurnberger 49 Andrew Paterson 1 Margaret Pericak-Vance 31 Gerard Schellenberg 71 Peter Szatmari 35 Astrid Vicente 7, 8 Veronica Vieland 65 Ellen Wijsman 72 Stephen Scherer 1, 73, * James Sutcliffe 22 Catalina Betancur 59
* Corresponding author
Abstract : 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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Submitted on : Friday, December 10, 2010 - 9:28:11 AM
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Dalila Pinto, Alistair Pagnamenta, Lambertus Klei, Richard Anney, Daniele Merico, et al.. Functional impact of global rare copy number variation in autism spectrum disorders.. Nature, Nature Publishing Group, 2010, 466 (7304), pp.368-72. ⟨10.1038/nature09146⟩. ⟨inserm-00521387⟩

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