title: FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.
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.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Department of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.affiliation: Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Brudno
authors.affiliation: McGill University and Centre of Genomics and Policy, Montreal, QC H3A 1A4, Canada.
authors.forename: Bartha
authors.initials: B
authors.lastname: Knoppers
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Marcadier
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Dyment
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Shelin
authors.initials: S
authors.lastname: Adam
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z4S6, Canada.
authors.forename: Steve J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: McGill University and Centre of Genomics and Policy, Montreal, QC H3A 1A4, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Avard
authors.affiliation: McGill University and Centre of Genomics and Policy, Montreal, QC H3A 1A4, Canada.
authors.forename: Minh Thu
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: 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.
authors.forename: Francois
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: The Centre for Applied Genomics and Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics and Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Wintle
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z4S6, Canada.
authors.forename: Yaoqing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Friedman
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Department of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada. Electronic address: kboycott@cheo.on.ca.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D002170:Canada; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D035583:Rare Diseases / Q000175:diagnosis* / Q000235:genetics*; D012958:Societies, Scientific / Q000458:organization & administration*