Project Leaders:   
Jan Friedman, Marco Marra

Involved Institutions:   
University of British Columbia, BC Cancer Agency

Technology Applications:   
Clinical diagnostics for mental retardation

Research Funding Program:   
Applied Health

GE³LS Activity:   
Genomics Research in Pediatric Populations

Mental retardation, which is usually defined as an IQ score below 70, occurs in approximately 1% of the population. It is the most frequent cause of severe life-long disability in Canada and its burden on affected families and society is considerable.

Genomic imbalances, such as the extra chromosome in Down Syndrome, are a major cause of mental retardation. “For more than 40 years, we have used a process called karyotyping to detect chromosomal abnormalities,” explains Dr. J. M. Friedman of UBC. “Unfortunately, karyotyping is a technically demanding microscopic technique that requires highly skilled interpretation. In addition, some children with mental retardation have loss or gain of chromosomal material that is too small to see with karyotyping.”

The goal of this project is to evaluate microarray genomic hybridization (AGH) to detect chromosome abnormalities in people with mental retardation as an alternative to karyotyping. Both methods detect differences in copy number but mA-CGH can identify chromosomal abnormalities 100 times smaller than those seen by karyotyping. However, smaller copy number changes are also seen in normal individuals and these normal variants must be distinguished from the pathological variants causing mental retardation. The initial phase of the project will validate mA-CGH with 200 people with known chromosomal abnormalities and 1000 ethnically-diverse Canadians to determine the frequency and nature of variants detectable by mA-CGH.

This array covers 99% of the 2002/06 Human Genome Sequence Assembly with a clone set of 32,433 BACs, selected from the human fingerprint map to optimize size and coverage plus reduce overlap between clones. In the project’s initial phase, bioinformatics and statistical assessment will characterize the range of responses for normal cells and identify clones that are too variable to be used clinically.

Once the mA-CGH is fully validated, it will be used to test children with mental retardation where standard karyotyping is normal. All genomic imbalances detected by mA-CGH will be confirmed by a separate technique. The general strategy is to compare copy number variants in trios comprised of a child with mental retardation and both clinically normal parents. Copy number variants found in the child and a parent are presumed to represent normal polymorphisms. Genomic imbalances found only in the affected child are presumed to be new mutations and may be related to the mental retardation.

No other research effort with similar goals and scope exists anywhere else in the world. This is a cross-Canada study, including more than 50 clinical geneticists and cytogeneticists from 18 genetic centres in 7 provinces. An ethics component will assure that the nationwide exchange of data and specimens is done appropriately and reflects Canadian and international norms. A Health Technology Assessment facility will provide the expertise to determine whether replacing karyotyping with mA-CGH benefits patients, their families, and the Canadian health care system. This work is of particular interest to groups developing cost-effective genomic diagnostic technologies that can be integrated into public health care systems.