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Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 2, 477-488, 17 January 2008

doi:10.1016/j.ajhg.2007.12.009

Article

Structural Variation of Chromosomes in Autism Spectrum Disorder

Christian R. Marshall¹, Abdul Noor², John B. Vincent², Anath C. Lionel¹, Lars Feuk¹, Jennifer Skaug¹, Mary Shago³, Rainald Moessner¹, Dalila Pinto¹, Yan Ren¹, Bhooma Thiruvahindrapduram¹, Andreas Fiebig⁶, Stefan Schreiber⁶, Jan Friedman⁷, Cees E.J. Ketelaars⁸, Yvonne J. Vos⁸, Can Ficicioglu⁹, Susan Kirkpatrick¹⁰, Rob Nicolson¹¹, Leon Sloman², Anne Summers¹², Clare A. Gibbons¹², Ahmad Teebi⁴, David Chitayat⁴, Rosanna Weksberg⁴, Ann Thompson¹³, Cathy Vardy¹⁴, Vicki Crosbie¹⁴, Sandra Luscombe¹⁴, Rebecca Baatjes¹, Lonnie Zwaigenbaum¹⁵, Wendy Roberts^5, 16, Bridget Fernandez¹⁴, Peter Szatmari¹³ and Stephen W. Scherer^1, ,  

¹ The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
² Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada
³ Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
⁴ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
⁵ Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
⁶ Institute for Clinical Molecular Biology, Christian-Albrechts-University, 24105 Keil, Germany
⁷ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
⁸ Department of Child Psychiatry, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
⁹ Division of Metabolism, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
¹⁰ Department of Medical Genetics, University of Wisconsin, Madison, WI 53706-1580, USA
¹¹ Department of Psychiatry, University of Western Ontario, London, Ontario N6A 4G5, Canada
¹² Department of Genetics, North York General Hospital, Toronto, Ontario M2K 1E1, Canada
¹³ Offord Centre for Child Studies, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8P 3B6, Canada
¹⁴ Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3V6, Canada
¹⁵ Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2J3, Canada
¹⁶ Bloorview Kids Rehab, University of Toronto, Toronto, Ontario M4G 1R8, Canada

Corresponding author

Abstract

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in ∼7% and ∼2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at ∼1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

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• Articles by Christian R. Marshall
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