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.
- diagnostics tests
- clinical genetics
- molecular genetics
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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-
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.
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