Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Sawyer
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Hartley
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Dyment
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Beaulieu
McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
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Schwartzentruber
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Smith
Genetics Program, North York General Hospital, Toronto, Canada.
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Bedford
Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montréal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Canada.
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Bernard
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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Bernier
Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
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Brais
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Bulman
Department of Neurology, The Ottawa Hospital, Ottawa, Canada.
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Warman Chardon
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.|The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
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Chitayat
Department of Medicine, Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Canada.
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Deladoëy
Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
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Fernandez
Departments of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
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Frosk
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Geraghty
Cardiac Sciences and Medical Genetics, University of Calgary, Calgary, Canada.
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Gerull
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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Gibson
Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
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Gow
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Graham
Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
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Green
Department of Ophthalmology and Vision Sciences, Program of Genetics and Genomic Biology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
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Heon
Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.
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Horvath
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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Innes
Departments of Pediatrics and Human Genetics, McGill University, Montreal, Canada.
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Jabado
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.|Department of Medicine, University of Toronto, Toronto, Canada.
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Kim
McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Canada.
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Koenekoop
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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Khan
Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Canada.
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Lehmann
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
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Mendoza-Londono
Department of Medicine, Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Canada.
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Michaud
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Nikkel
Medical Genetics, IWK Health Centre, Halifax, Canada.
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Penney
Departments of Pediatrics and Human Genetics, McGill University, Montreal, Canada.
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Polychronakos
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Richer
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
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Rouleau
Department of Medicine, Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Canada.
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Samuels
Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, Canada.
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Siu
Departments of Medicine, Medical Genetics, and Pediatrics, University of Alberta, Edmonton, Canada.
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Suchowersky
Department of Pediatrics, McMaster University, Hamilton, Canada.
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Tarnopolsky
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
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Yoon
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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Zahir
Departments of Pediatrics and Human Genetics, McGill University, Montreal, Canada.
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Majewski
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
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Boycott
D002170:Canada; D002648:Child; D059472:Exome; D005796:Genes; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D017422:Sequence Analysis, DNA
FORGE Canada Consortium; clinical exome; rare diseases; whole-exome sequencing