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 47 Sabata Lund 22 Elena Maestrini 11 William Mahoney 48 Carine Mantoulan 49 Christian Marshall 1 Helen Mcconachie 15 Christopher Mcdougle 50 Jane Mcgrath 4 William Mcmahon 51 Alison Merikangas 4 Ohsuke Migita 1 Nancy Minshew 52 Ghazala Mirza 2 Jeff Munson 53 Stanley Nelson 54 Carolyn Noakes 19 Abdul Noor 55, 56 Gudrun Nygren 33 Guiomar Oliveira 10 Katerina Papanikolaou 57 Jeremy Parr 58 Barbara Parrini 14 Tara Paton 1 Andrew Pickles 59 Marion Pilorge 60 Joseph Piven 61 Chris Ponting 62 David Posey 50 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 49 Michael Rutter 63 Laura Bierut 64 John Rice 64 Jeff Salt 37 Katherine Sansom 1 Daisuke Sato 1 Ricardo Segurado 4 Ana Sequeira 7, 8 Lili Senman 19 Naisha Shah 5 Val Sheffield 65 Latha Soorya 3, 40 Inês Sousa 2 Olaf Stein 66 Nuala Sykes 2 Vera Stoppioni 67 Christina Strawbridge 35 Raffaella Tancredi 14 Katherine Tansey 4 Bhooma Thiruvahindrapduram 1 Ann Thompson 35 Susanne Thomson 22 Ana Tryfon 3, 40 John Tsiantis 57 Herman Van Engeland 26 John Vincent 55, 56 Fred Volkmar 68 Simon Wallace 12 Kai Wang 34 Zhouzhi Wang 1 Thomas Wassink 69 Caleb Webber 62 Rosanna Weksberg 1 Kirsty Wing 2 Kerstin Wittemeyer 49 Shawn Wood 3 Jing Wu 23 Brian Yaspan 22 Danielle Zurawiecki 3, 40 Lonnie Zwaigenbaum 70 Joseph Buxbaum 3, 40 Rita Cantor 54 Edwin Cook 37 Hilary Coon 51 Michael Cuccaro 31 Bernie Devlin 3 Sean Ennis 6 Louise Gallagher 4 Daniel Geschwind 9 Michael Gill 4 Jonathan Haines 71 Joachim Hallmayer 47 Judith Miller 51 Anthony Monaco 2 John Nurnberger 50 Andrew Paterson 1 Margaret Pericak-Vance 31 Gerard Schellenberg 72 Peter Szatmari 35 Astrid Vicente 7, 8 Veronica Vieland 66 Ellen Wijsman 73 Stephen Scherer 1, 74, * James Sutcliffe 22 Catalina Betancur 60
* Auteur correspondant
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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Article dans une revue
Nature, Nature Publishing Group, 2010, 466 (7304), pp.368-72. 〈10.1038/nature09146〉
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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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