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January 17, 2008

Canadian scientists find frequent structural changes of chromosomes in autism

Copy number alterations of genes contribute to autism in seven per cent of cases

TORONTO – A Canadian team led by scientists at The Hospital for Sick Children (SickKids) has discovered numerous chromosomal regions containing autism spectrum disorder (ASD)-susceptibility genes. Gains or losses of genes (referred to as copy number variation or CNV) were found in seven per cent of the 400 autistic individuals examined. Additionally, a new region was identified on chromosome 16 which conferred risk of ASD in one per cent of families. These findings are published online today in the American Journal of Human Genetics .

This study builds on results the group co-published in February of last year in which genome-scanning methods were used to examine the genetic architecture underlying autism susceptibility. “In this phase of our work we applied even newer microarrays allowing us to better scrutinize DNA for CNV changes in autism, and we focused on Canadian families because of the detailed clinical information we've collected over the years," says Dr. Stephen Scherer, the senior corresponding author of the study, senior scientist in Genetics & Genomic Biology at SickKids and professor of Molecular Genetics at the University of Toronto. It was Scherer who discovered with others the existence of CNVs as the most common form of genetic variation, including that in some instances CNVs are involved in disease.

Autism is a complex developmental disorder found in roughly one in 165 children. ASD individuals exhibit impairments in reciprocal social interaction and communication, and show a preference for repetitive, stereotyped activities. Structural changes (CNV as well as translocation and inversion of genes) along chromosomes have been identified in some individuals with ASD, but the full etiologic role of these changes is unknown.

“Our finding that in seven per cent of families we find chromosome changes in ASD children not seen in their parents has important clinical implications,” says co-author Dr. Peter Szatmari, director of the Offord Centre for Child Studies, McMaster Children's Hospital, and head of Child Psychiatry at McMaster University. "Our experience through this study indicates that application of these new microarray-based genome scanning tests may serve to focus clinical examination in a search for undetected syndromes leading to ASD."

Dr. Wendy Roberts, head of the Autism Research Unit at SickKids and developmental pediatrician at Bloorview Kids Rehab adds, "The new CNVs we discovered on chromosome 16 in one per cent of our Canadian cohort are also now described in two American studies in the New England Journal of Medicine and Human Molecular Genetics by teams from Boston and Chicago, respectively." According to Roberts, the Canadian team also found other families with chromosome changes that overlap with some genes involved in other medical genetic conditions such as velocardiofacial syndrome (chromosome 22q) and mental retardation (chromosome 15q24 and 16p11.2), which in many cases led to an identification or refinement of the diagnoses. "It will be important to prepare for a demand for the new chromosome 16 and other tests, to understand what the data really means, and to realize that the significance could be quite different for each family requesting testing," adds Scherer.

Dr. Christian Marshall the lead author from SickKids notes, "Our genetic data held many complexities reminiscent of ASD itself. But in a subset of ASD cases we found at least six genes known to have a role in neuron function that were not present in the typical two-copies found in the general population." In addition to having potential clinical diagnostic importance these results also help to further unlock the biological mysteries of why autism comes about and what parts of the brain are involved.

The Canadian team partnered with scientists in Germany, The Netherlands, and the U. S. on this study, and also works as part of an international autism genetics consortium called the Autism Genome Project (AGP). The AGP began in 2002 when researchers from around the world decided to come together and share their samples, data, and expertise to facilitate the identification of autism susceptibility genes.

This research was supported by Genome Canada, The Centre for Applied Genomics, Autism Speaks, Bloorview Kids Rehab, the Canada Foundation of Innovation, the Canadian Institutes of Health Research (CIHR), the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto, the Canadian Institutes for Advance Research (CIFAR), The Catherine and Maxwell Meighen Foundation, Ontario Genomics Institute, the McLaughlin Centre for Molecular Medicine, the Lee K. and Margaret Lau Genetics Research Endowment Fund, the McMaster Children's Hospital Foundation, the Netherlands Organization for Scientific Research and the Royal Netherlands Academy of Arts and Sciences, Ontario Innovation Trust, Ontario Ministry of Research and Innovation, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the William Rosenberg Family Foundation, and the SickKids Foundation.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit http://www.sickkids.ca/ . SickKids is committed to healthier children for a better world.

For more information, please contact:

Janice Nicholson
Public Affairs
The Hospital for Sick Children
Phone: 416-813-6684
Fax: 416-813-5328
email: janice.nicholson@sickkids.ca