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Structural variation of chromosomes in autism spectrum disorder |
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| Authors: | Marshall Christian R Noor Abdul Vincent John B Lionel Anath C Feuk Lars Skaug Jennifer Shago Mary Moessner Rainald Pinto Dalila Ren Yan Thiruvahindrapduram Bhooma Fiebig Andreas Schreiber Stefan Friedman Jan Ketelaars Cees E J Vos Yvonne J Ficicioglu Can Kirkpatrick Susan Nicolson Rob Sloman Leon Summers Anne Gibbons Clare A Teebi Ahmad Chitayat David Weksberg Rosanna Thompson Ann Vardy Cathy Crosbie Vicki Luscombe Sandra Baatjes Rebecca Zwaigenbaum Lonnie Roberts Wendy Fernandez Bridget Szatmari Peter Scherer Stephen W |
| Institution: | 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 |
| 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 approximately 7% and approximately 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 approximately 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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