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Canadian Project Uses Exome Sequencing to ID Cause of 146 Rare Disorders

NEW YORK (GenomeWeb) -- Researchers involved in the Finding of Rare Disease Genes (FORGE) research project have analyzed 264 rare disorders using exome sequencing and identified the causal mutations to 146 of them and identified 67 novel genes, the team reported today in a commentary in the American Journal of Human Genetics.

Whole-exome sequencing for the project was carried out by researchers at the McGill University and Genome Quebec Innovation Centre in Montreal, The Centre for Applied Genomics in Toronto, and The Genome Sciences Centre in Vancouver. They used Agilent's SureSelect technology for exome target enrichment, and the majority of sequencing was performed on the Illumina HiSeq 2000.

The authors, led by Kym Boycott, lead investigator of FORGE and clinician scientist at the Children's Hospital of Eastern Ontario, said that they were surprised by the "large proportion of causative variants identified in genes already known to be associated with human disease despite standard-of-care investigations by our clinical network; these mutations were often associated with the broadening of the known disease phenotype."

The FORGE project has now combined with an international research program called CARE for RARE, led by the CHEO. The project will continue to use exome sequencing to identify rare disease genes and will also design and test therapies in the lab to treat rare diseases.

"When we launched this project, we predicted we might explain, or solve, 50 disorders; we've almost tripled that goal," Boycott said in a statement.

The Canadian government funded the project in 2011 with a C$4.5 million (US$4.6 million) grant that supported both FORGE and the Canadian Pediatric Cancer Genome Consortium. Aside from identifying the cause of rare disorders, the project also aims to create national ethical guidelines for analyzing sequence data and sharing the results with families, as well as to set up a national data coordination center to streamline and improve sequence analysis tools.

"The rewarding part of this project for all involved has been the many lives we've impacted," Chandree Beaulieu, project manager of FORGE and first author of the report, said in a statement. "Every result was reported back to the families who participated in the research. The information never stayed in a lab or database. This was highly motivating for the entire team."