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Publications

Journal Article Research Support, Non-U.S. Gov't Ppublish

PubMed: 37924259 DOI: 10.1016/j.gim.2023.101012

Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.

Genet Med 26(2):101012

Authors: Taila Hartley, Deborah Marshall, Meryl Acker, Katharine Fooks, Meredith K Gillespie, E Magda Price, Ian D Graham, Alexandre White-Brown, Layla MacKay, Stella K Macdonald, Lauren Brady, Angela Y Hui, Joseph D Andrews, Ashfia Chowdhury, Erika Wall, Élisabeth Soubry, Grace U Ediae, Samantha Rojas, Daniel Assamad, David Dyment, Mark Tarnopolsky, Sarah L Sawyer, Caitlin Chisholm, Gabrielle Lemire, Kimberly Amburgey, Joanna Lazier, Roberto Mendoza-Londono, James J Dowling, Tugce B Balci, Christine M Armour, Priya T Bhola, Gregory Costain, Lucie Dupuis, Melissa Carter, Lauren Badalato, Julie Richer, Christie Boswell-Patterson, Peter Kannu, Dawn Cordeiro, Jodi Warman-Chardon, Gail Graham, Victoria Mok Siu, Cheryl Cytrynbaum, Alison Rusnak, Ritu B Aul, Grace Yoon, Hernan Gonorazky, Vanda McNiven, Saadet Mercimek-Andrews, Andrea Guerin … and 16 other authors

Affiliations

  • Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; University of Ottawa, Ottawa, Canada.
  • University of Calgary, Calgary, Canada.
  • Hospital for Sick Children, Toronto, Canada.
  • Hospital for Sick Children, Toronto, Canada; University of Toronto, Toronto, Canada.
  • Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
  • University of Ottawa, Ottawa, Canada; Ottawa Hospital Research Institute, Ottawa, Canada.
  • McMaster Children's Hospital, McMaster University, Hamilton, Canada.
  • Kingston Health Sciences Center, Queen's University, Kingston, Canada.
  • London Health Sciences Centre, Western University, London, Canada.
  • University of Toronto, Toronto, Canada.
  • Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; University of Ottawa, Ottawa, Canada; Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • University of Ottawa, Ottawa, Canada; Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; University of Ottawa, Ottawa, Canada.
  • Hospital for Sick Children, Toronto, Canada; University of Toronto, Toronto, Canada; The Ottawa Hospital, Ottawa, Canada.
  • University of Ottawa, Ottawa, Canada; Children's Hospital of Eastern Ontario, Ottawa, Canada; Ottawa Hospital Research Institute, Ottawa, Canada; University of Alberta, Edmonton, Alberta, Canada.
  • University of Ottawa, Ottawa, Canada; Children's Hospital of Eastern Ontario, Ottawa, Canada; Kingston Health Sciences Center, Queen's University, Kingston, Canada.
  • University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada.

Abstract

PURPOSE

To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.

METHODS

We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.

RESULTS

Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses.

CONCLUSION

We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.

MeSH

Diagnosis, Laboratories, Cohort Studies, Rare Diseases, Genetics, Medical, Exome

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