|
|||||
|
|
Exome Sequencing as a Diagnostic Tool for Pediatric‐Onset Ataxia |
|
| Authors: | Sarah L. Sawyer Jeremy Schwartzentruber Chandree L. Beaulieu David Dyment Amanda Smith Jodi Warman Chardon Grace Yoon Guy A. Rouleau Oksana Suchowersky Victoria Siu Lisa Murphy Robert A. Hegele Christian R. Marshall FORGE Canada Consortium Dennis E. Bulman Jacek Majewski Mark Tarnopolsky Kym M. Boycott |
| Affiliation: | 1. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada;2. McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada;3. Divisions of Neurology and Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;4. Montreal Neurological Institute and Hospital, McGill University Montreal, Quebec, Canada;5. Departments of Medicine (Neurology) and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada;6. Department of Pediatrics, Division of Medical Genetics, Western University, London, Ontario, Canada;7. Robarts Research Institute, University of Western Ontario, London, Canada;8. Program in Genetics and Genome Biology, Hospital for Sick Children and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada;9. Department of Human Genetics, McGill University, Montréal, Quebec, Canada;10. Department of Pediatrics, McMaster Children's Hospital, Hamilton, Ontario, Canada |
| Abstract: | Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard‐of‐care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation‐wide project focused on identifying novel disease genes for rare pediatric diseases using whole‐exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative. |
| Keywords: | ataxia whole‐exome sequencing clinical diagnosis |