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Updated: Sep 22, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a
Robin Z Hayeems1, Christian R Marshall2, Meredith K Gillespie2
1Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont. robin.hayeems@sickkids.ca.
Background:
Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada.
Methods:
The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected).
Interpretation:
Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.
