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Am J Hum Genet. 2014 Jun 5;94(6):809-17. doi: 10.1016/j.ajhg.2014.05.003.

FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.

Author information

1
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
2
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
3
McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
4
Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Department of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
5
Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada.
6
Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
7
Department of Computer Science, Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto and Centre for Computational Medicine, Hospital for Sick Children, Toronto, ON M5S 3G4, Canada; The Centre for Applied Genomics and Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
8
McGill University and Centre of Genomics and Policy, Montreal, QC H3A 1A4, Canada.
9
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
10
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z4S6, Canada.
11
Centre de Recherche du Centre Hospitalier Universitaire de Québec, Department of Molecular Biology, Medical Biochemistry, and Pathology, Université Laval, Quebec City, QC G1L 3L5, Canada.
12
The Centre for Applied Genomics and Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
13
The Centre for Applied Genomics and Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 0A4, Canada.
14
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada. Electronic address: kboycott@cheo.on.ca.

Abstract

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.

PMID:
24906018
PMCID:
PMC4121481
DOI:
10.1016/j.ajhg.2014.05.003
[Indexed for MEDLINE]
Free PMC Article

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