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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 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
* Corresponding author
1 Program in Genetics and Genomic Biology
2 The Wellcome Trust Centre for Human Genetics [Oxford]
3 Department of Psychiatry [Pittsburgh]
4 Division of Mental Health and Addiction
5 Banting and Best Department of Medical Research
6 ACoRD - Academic Centre on Rare Diseases
7 Instituto Nacional de Saude Dr Ricardo Jorge
8 BioFIG
9 Department of Neurology
10 UNDA - Unidade de Neurodesenvolvimento e Autismo
11 Department of Pharmacy and Biotechnology
12 Department of Psychiatry
13 Newcomen Centre
14 Department of Psychiatry
15 Child and Adolescent Mental Health
16 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
17 Department of Child and Adolescent Psychiatry
18 Génétique Humaine et Fonctions Cognitives
19 Autism Research Unit
20 Department of Pediatrics and Psychology
21 Autism and Communicative Disorders Centre
22 Department of Molecular Physiology & Biophysics and Psychiatry
23 Department of Statistics
24 Scientific Affairs
25 Department of Psychiatry
26 Department of Psychiatry
27 Service de psychopathologie de l'enfant et de l'adolescent
28 IMRB - Institut Mondor de Recherche Biomédicale
29 Department of Speech and Hearing Sciences [Washington]
30 Disciplines of Genetics and Medicine
31 John P. Hussman Institute for Human Genomics
32 Department of Psychiatry [Montréal]
33 Department of Child and Adolescent Psychiatry
34 The Center for Applied Genomics
35 Department of Psychiatry and Behavioural Neurosciences
36 Academic Department of Child Psychiatry
37 Department of Psychiatry
38 Department of Pediatrics
39 Division of Molecular Genome Analysis
40 Human Genetics Center
41 Department of Medicine
42 Autism Genetic Resource Exchange
43 Centre for Integrated Genomic Medical Research, Manchester
44 IUH - Institut Universitaire d'Hématologie
45 NKI - Nathan Kline Institute for Psychiatric Research
46 Department of Child and Adolescent Psychiatry
47 Department of Psychiatry and Behavioral Sciences [Stanford]
48 Department of Pediatrics
49 Centre d'Etudes et de Recherches en PsychoPathologie
50 Department of Psychiatry
51 Department of Developmental Neuroscience
52 Departments of Psychiatry and Neurology
53 Department of Psychiatry and Behavioural Sciences
54 Department of Human Genetics, Los Angeles
55 Centre for Addiction and Mental Health
56 Department of Psychiatry
57 University Department of Child Psychiatry
58 Institutes of Neuroscience and Health and Society
59 Department of Medicine
60 Physiopathologie des Maladies du Système Nerveux Central
61 Carolina Institute for Developmental Disabilities
62 MRC Functional Genomics Unit
63 Social, Genetic and Developmental Psychiatry Centre
64 Department of Psychiatry
65 Department of Pediatrics
66 Battelle Center for Mathematical Medicine
67 Neuropsichiatria Infantile
68 Child Study Centre
69 Department of Psychiatry
70 Department of Pediatrics
71 Vanderbilt Brain Institute
72 Pathology and Laboratory Medicine
73 Departments of Biostatistics and Medicine
74 Department of Molecular Genetics [Toronto]
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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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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