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

Dalila Pinto (1) , Alistair T. Pagnamenta (2) , Lambertus Klei (3) , Richard Anney (4) , Daniele Merico (5) , Regina Regan (6) , Judith Conroy (6) , Tiago R. Magalhaes (7, 8) , Catarina Correia (7, 8) , Brett S. Abrahams (9) , Joana Almeida (10) , Elena Bacchelli (11) , Gary D. Bader (5) , Anthony J. Bailey (12) , Gillian Baird (13) , Agatino Battaglia (14) , Tom Berney (15) , Nadia Bolshakova (4) , Sven Bölte (16) , Patrick F. Bolton (17) , Thomas Bourgeron (18) , Sean Brennan (4) , Jessica Brian (19) , Susan E. Bryson (20) , Andrew R. Carson (1) , Guillermo Casallo (1) , Jillian Casey (6) , Brian H. Y. Chung (1) , Lynne Cochrane (4) , Christina Corsello (21) , Emily L. 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 A. Fernandez (30) , Susan E. Folstein (31) , Eric Fombonne (32) , Christine M. Freitag (16) , John Gilbert (31) , Christopher Gillberg (33) , Joseph T. Glessner (34) , Jeremy Goldberg (35) , Andrew Green (5) , Jonathan Green (36) , Stephen J. Guter (37) , Hakon Hakonarson (34, 38) , Elizabeth A. Heron (4) , Matthew Hill (4) , Richard Holt (2) , Jennifer L. Howe (1) , Gillian Hughes (4) , Vanessa Hus (21) , Roberta Igliozzi (14) , Cecilia Kim (34) , Sabine M. Klauck (39) , Alexander Kolevzon (40, 3) , Olena Korvatska (41) , Vlad Kustanovich (42) , Clara M. Lajonchere (42) , Janine A. Lamb (43) , Magdalena Laskawiec (12) , Marion Leboyer (28, 44) , Ann Le Couteur (15) , Bennett L. Leventhal (45, 46) , Anath C. Lionel (1) , Xiao-Qing Liu (1) , Catherine Lord (21) , Linda Lotspeich (14) , Sabata C. Lund (22) , Elena Maestrini (11) , William Mahoney (47) , Carine Mantoulan (48) , Christian R. Marshall (1) , Helen Mcconachie (15) , Christopher J. Mcdougle (49) , Jane Mcgrath (4) , William M. Mcmahon (50) , Alison Merikangas (4) , Ohsuke Migita (1) , Nancy J. Minshew (51) , Ghazala K. Mirza (2) , Jeff Munson (52) , Stanley F. Nelson (53) , Carolyn Noakes (19) , Abdul Noor (54, 55) , Gudrun Nygren (33) , Guiomar Oliveira (10) , Katerina Papanikolaou (56) , Jeremy R. Parr (57) , Barbara Parrini (14) , Tara Paton (1) , Andrew Pickles (58) , Marion Pilorge (59) , Joseph Piven (60) , Chris P. Ponting (61) , David J. 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 L. Rutter (62) , Laura J. Bierut (63) , John P. Rice (63) , Jeff Salt (37) , Katherine Sansom (1) , Daisuke Sato (1) , Ricardo Segurado (4) , Ana F. Sequeira (7, 8) , Lili Senman (19) , Naisha Shah (5) , Val C. 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 P. Thompson (35) , Susanne Thomson (22) , Ana Tryfon (3, 40) , John Tsiantis (56) , Herman van Engeland (26) , John B. Vincent (54, 55) , Fred Volkmar (67) , Simon Wallace (12) , Kai Wang (34) , Zhouzhi Wang (1) , Thomas H. Wassink (68) , Caleb Webber (61) , Rosanna Weksberg (1) , Kirsty Wing (2) , Kerstin Wittemeyer (48) , Shawn Wood (3) , Jing Wu (23) , Brian L. Yaspan (22) , Danielle M. Zurawiecki (3, 40) , Lonnie Zwaigenbaum (69) , Joseph D. Buxbaum (3, 40) , Rita M. Cantor (53) , Edwin H. Cook (37) , Hilary Coon (50) , Michael L. Cuccaro (31) , Bernie Devlin (3) , Sean Ennis (6) , Louise Gallagher (4) , Daniel H. Geschwind (9) , Michael Gill (4) , Jonathan L. Haines (70) , Joachim Hallmayer (14) , Judith Miller (50) , Anthony P. Monaco (2) , John I. Nurnberger (49) , Andrew D. Paterson (1) , Margaret A. Pericak-Vance (31) , Gerard D. Schellenberg (71) , Peter Szatmari (35) , Astrid M. Vicente (7, 8) , Veronica J. Vieland (65) , Ellen M. Wijsman (72) , Stephen W. Scherer (1, 73) , James S. Sutcliffe (22) , Catalina Betancur (59)

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 INSA - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
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 and Behavioral Sciences [Stanford]
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 Pediatrics
48 Centre d'Etudes et de Recherches en PsychoPathologie
49 Department of Psychiatry
50 Department of Developmental Neuroscience
51 Departments of Psychiatry and Neurology
52 Department of Psychiatry and Behavioural Sciences
53 Department of Human Genetics, Los Angeles
54 Centre for Addiction and Mental Health
55 Department of Psychiatry
56 University Department of Child Psychiatry
57 Institutes of Neuroscience and Health and Society
58 Department of Medicine
59 Physiopathologie des Maladies du Système Nerveux Central
60 Carolina Institute for Developmental Disabilities
61 MRC Functional Genomics Unit
62 Social, Genetic and Developmental Psychiatry Centre
63 Department of Psychiatry
64 Department of Pediatrics
65 Battelle Center for Mathematical Medicine
66 Neuropsichiatria Infantile
67 Child Study Centre
68 Department of Psychiatry
69 Department of Pediatrics
70 Vanderbilt Brain Institute
71 Pathology and Laboratory Medicine
72 Departments of Biostatistics and Medicine
73 Department of Molecular Genetics [Toronto]

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.

Domaines: Génétique

Dalila Pinto, Alistair T. Pagnamenta, Lambertus Klei, Richard Anney, Daniele Merico, et al.. Functional impact of global rare copy number variation in autism spectrum disorders.. Nature, 2010, 466 (7304), pp.368-72. ⟨10.1038/nature09146⟩. ⟨inserm-00521387⟩