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Diagnostics
Original research
Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study
  1. Salma Shickh1,2,
  2. Mariana Gutierrez Salazar3,
  3. Kathleen-Rose Zakoor3,
  4. Conxi Lázaro3,4,5,
  5. Jessica Gu3,6,
  6. Jamie Goltz7,
  7. Dakota Kleinman3,
  8. Abdul Noor3,
  9. Sam Khalouei3,
  10. Chloe Mighton1,2,
  11. Emma Reble1,
  12. Rita Kodida1,
  13. Yvonne Bombard1,2,
  14. Stephanie DiTroia8,
  15. Samantha Baxter8,
  16. Nicholas Watkins3,9,
  17. Melanie Care9,10,
  18. Arnon Adler11,12,
  19. Sheri Horsburgh10,
  20. Oana Morar10,13,
  21. Jillian Murphy9,10,
  22. Dayna-Lynn Nevay10,
  23. Marta Szybowska10,
  24. Melyssa Aronson14,
  25. Seema Panchal15,
  26. Ruth Godoy15,16,
  27. Spring Holter14,
  28. Susan Randall Armel17,
  29. Kara Semotiuk14,
  30. Christine Elser12,15,
  31. Raymond H Kim10,12,18,
  32. David Chitayat9,19,20,
  33. Joyce So10,12,
  34. Hanna Faghfoury10,12,
  35. Josh Silver9,10,
  36. Chantal F Morel10,12,
  37. Jordan Lerner-Ellis3,21,22
  1. 1 Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
  2. 2 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
  3. 3 Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  4. 4 Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Hospital Duran i Reynals, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet, Barcelona, Spain
  5. 5 Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
  6. 6 Genetics, Medcan Clinic, Toronto, Ontario, Canada
  7. 7 University of Guelph, Guelph, Ontario, Canada
  8. 8 Center for Mendelian Genomics, Broad Institute, Cambridge, Massachusetts, USA
  9. 9 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  10. 10 Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada
  11. 11 Department of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada
  12. 12 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  13. 13 Clinical Genetics, Trillium Health Partners, Mississauga, Ontario, Canada
  14. 14 Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  15. 15 Marvelle Koffler Breast Centre, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  16. 16 Lifelabs, Toronto, Ontario, Canada
  17. 17 Familial Breast and Ovarian Cancer Clinic, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  18. 18 Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada
  19. 19 Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  20. 20 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  21. 21 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  22. 22 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  1. Correspondence to Dr Jordan Lerner-Ellis, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; jordan.lerner-ellis{at}sinaihealth.ca

Abstract

Background Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.

Methods Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.

Results Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.

Conclusions This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

  • genetics
  • diagnostics tests
  • clinical genetics
  • molecular genetics

https://doi.org/10.1136/jmedgenet-2020-106936

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    Footnotes

    • Contributors JL-E conceived the study and participated in the design of the cohort. SS, MGS, JG, RK, NW, MC, ShH, OM, JM, D-LN, MS, MA, SP, RG, SH, SRA, KS, CE, RHK, DC, JoyS, HF, JS and CFM contributed to patient recruitment. RK, MC, ShH, OM, JM, D-LN, AA, MS, MA, SP, RG, SH, SRA, KS, CE, RHK, DC, JoyS, HF, JS and CFM contributed with clinical and phenotypic information. AN and SK assisted with development of the bioinformatics pipeline. K-RZ performed bioinformatics analysis. CL, JaG, JG, DK, MGS, RK, CM, SS, ER, MS, SD, SB and JL-E analysed exome and genome data. SS, MGS, K-RZ, JG and CL contributed to drafting of the manuscript with critical input from J-LE and YB authors provided feedback and contributed to the final version of the manuscript

    • Funding J-LE was funded by the McLaughlin Centre (grant #MC-2012–13, #MC-2014-11-1 and MC-2017–12) and CIHR- Champions of Genetics: Building the Next Generation Grant (FRN: 135730). CL was a visiting scientist at Pathology and Laboratory Medicine, Mount Sinai Hospital and Women’s College Hospital thanks to Salvador Madariaga (PRX18/00267) and M-BAE (BA18/00018) grants (Spanish Government). Analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This work was approved by the Mount Sinai Hospital Research Ethics Board (#12-

      0222-E)

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information.