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Originally published in Science Express on 15 March 2007
Science 20 April 2007:
Vol. 316. no. 5823, pp. 445 - 449
DOI: 10.1126/science.1138659
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Reports

Strong Association of De Novo Copy Number Mutations with Autism

Jonathan Sebat,1* B. Lakshmi,1 Dheeraj Malhotra,1* Jennifer Troge,1* Christa Lese-Martin,2 Tom Walsh,3 Boris Yamrom,1 Seungtai Yoon,1 Alex Krasnitz,1 Jude Kendall,1 Anthony Leotta,1 Deepa Pai,1 Ray Zhang,1 Yoon-Ha Lee,1 James Hicks,1 Sarah J. Spence,4 Annette T. Lee,5 Kaija Puura,6 Terho Lehtimäki,7 David Ledbetter,2 Peter K. Gregersen,5 Joel Bregman,8 James S. Sutcliffe,9 Vaidehi Jobanputra,10 Wendy Chung,10 Dorothy Warburton,10 Mary-Claire King,3 David Skuse,11 Daniel H. Geschwind,12 T. Conrad Gilliam,13 Kenny Ye,14 Michael Wigler1{dagger}

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

1 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
3 Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195–7720, USA.
4 Pediatrics and Neurodevelopmental Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892–1255, USA.
5 Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, NY 11030, USA.
6 Department of Child Psychiatry, University of Tampere, Medical School, Tampere, Finland.
7 Department of Clinical Chemistry, University Hospital of Tampere and University of Tampere, Medical School, Tampere, Finland.
8 Fay J. Lindner Center for Autism and Developmental Disorders, North Shore–Long Island Jewish Health System, 4300 Hempstead Turnpike, Bethpage, NY 11714, USA.
9 Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232–8548, USA.
10 Departments of Genetics and Development, and Pediatrics, Columbia University, New York, NY 10027, USA.
11 Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN 1EH, UK.
12 Interdepartmental Program in the Neurosciences, Program in Neurogenetics, Neurology Department, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095–1769, USA.
13 Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
14 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: sebat{at}cshl.edu (J.S.); wigler{at}cshl.edu (M.W.)

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Med. Genet. 46, 242-248
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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E B Caronna, J M Milunsky, and H Tager-Flusberg (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. Walsh, J. M. McClellan, S. E. McCarthy, A. M. Addington, S. B. Pierce, G. M. Cooper, A. S. Nord, M. Kusenda, D. Malhotra, A. Bhandari, et al. (2008)
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   Abstract »    Full Text »    PDF »
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P. Cahan, L. E. Godfrey, P. S. Eis, T. A. Richmond, R. R. Selzer, M. Brent, H. L. McLeod, T. J. Ley, and T. A. Graubert (2008)
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   Abstract »    Full Text »    PDF »
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Arch Neurol 65, 550-553
   Abstract »    Full Text »    PDF »
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(2008)
Journal Watch Neurology 2008, 2
   Full Text »
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R. A. Kumar, S. KaraMohamed, J. Sudi, D. F. Conrad, C. Brune, J. A. Badner, T. C. Gilliam, N. J. Nowak, E. H. Cook Jr, W. B. Dobyns, et al. (2008)
Hum. Mol. Genet. 17, 628-638
   Abstract »    Full Text »    PDF »
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E. E. Eichler and A. W. Zimmerman (2008)
N. Engl. J. Med. 358, 737-739
   Full Text »    PDF »
Association between Microdeletion and Microduplication at 16p11.2 and Autism.
L. A. Weiss, Y. Shen, J. M. Korn, D. E. Arking, D. T. Miller, R. Fossdal, E. Saemundsen, H. Stefansson, M. A.R. Ferreira, T. Green, et al. (2008)
N. Engl. J. Med. 358, 667-675
   Abstract »    Full Text »    PDF »
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
S. Jamain, K. Radyushkin, K. Hammerschmidt, S. Granon, S. Boretius, F. Varoqueaux, N. Ramanantsoa, J. Gallego, A. Ronnenberg, D. Winter, et al. (2008)
PNAS 105, 1710-1715
   Abstract »    Full Text »    PDF »
Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.
G. Kirov, D. Gumus, W. Chen, N. Norton, L. Georgieva, M. Sari, M. C O'Donovan, F. Erdogan, M. J Owen, H.-H. Ropers, et al. (2008)
Hum. Mol. Genet. 17, 458-465
   Abstract »    Full Text »    PDF »
Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases.
A. J. de Smith, A. Tsalenko, N. Sampas, A. Scheffer, N. A. Yamada, P. Tsang, A. Ben-Dor, Z. Yakhini, R. J. Ellis, L. Bruhn, et al. (2007)
Hum. Mol. Genet. 16, 2783-2794
   Abstract »    Full Text »    PDF »
Accelerated Rate of Gene Gain and Loss in Primates.
M. W. Hahn, J. P. Demuth, and S.-G. Han (2007)
Genetics 177, 1941-1949
   Abstract »    Full Text »    PDF »
The Neutral Coalescent Process for Recent Gene Duplications and Copy-Number Variants.
K. R. Thornton (2007)
Genetics 177, 987-1000
   Abstract »    Full Text »    PDF »
Authors' reply:.
J. McClellan, E. Susser, and M.-C. King (2007)
The British Journal of Psychiatry 191, 180-181
   Full Text »    PDF »
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X. Zhao, A. Leotta, V. Kustanovich, C. Lajonchere, D. H. Geschwind, K. Law, P. Law, S. Qiu, C. Lord, J. Sebat, et al. (2007)
PNAS 104, 12831-12836
   Abstract »    Full Text »    PDF »
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T. Bourgeron (2007)
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   Abstract »    PDF »


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