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

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.

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