A comprehensive approach to evaluating the clinical utility of genome sequencing in rare disease: A large prospective Canadian cohort

Purpose We characterized dimensions of clinical utility in a prospective, observational cohort of patients with rare diseases undergoing genome sequencing (GS). Methods Clinical utility data (diagnostic, clinical management, and research recommended, avoided, or pursued for index cases and relatives) were collected from medical records and summarized using descriptive statistics. A multivariable regression model characterized factors associated with each type of utility, reported as odds ratios with 95% confidence intervals. Results Among 715 cases who underwent GS, results triggered diagnostic investigations in 17.5%, clinical management activities in 35.8%, research opportunities in 30.8%, and genetic counseling/testing for relatives in 19.0%. Results also limited diagnostic investigations in 87.9%. Regression analyses identified clinical, geographic, and ethnicity-related factors as significantly associated with utility. Diagnostic/potentially diagnostic results increased odds of changes in diagnostic investigations, management, and genetic testing recommendations for relatives. Patients from larger sites had higher odds of management or research recommendations and patients of non-European ethnicity were less likely to pursue recommendations. Conclusion Our findings provide evidence that GS has clinical utility beyond diagnostic care, including management, research, as well as familial care and preventing unnecessary medical activity. To determine which factors are associated with utility, multiple dimensions of care and broad sociodemographic factors warrant consideration.