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The clinical utility of exome and genome sequencing across clinical indications: a systematic review


Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time.

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We would like to thank Mark Dobrow and Lusine Abrahamyan for their feedback on the research question and the first version of the manuscript and Agnes Sebastian for her assistance retrieving articles for the full text review.


SS received support from the Canadian Institutes of Health Research (CIHR, GSD-425969) and the Research Training Centre at St. Michael’s Hospital. CM received support from the Research Training Centre at St. Michael’s Hospital, a doctoral award from the Canadian Institutes of Health Research (CIHR, GSD-164222) and a studentship funded by the Canadian Centre for Applied Research in Cancer Control (ARCC); ARCC receives core funding from the Canadian Cancer Society (Grant #2015-703549). YB was supported by a CIHR New Investigator Award. Funding agencies did not play any role in design of the study, data collection, analysis, and interpretation of data.

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Design, conception of the study and development of search strategy: SS, YB, EU. Literature search: EU. Data collection: SS, CM. Data analysis and interpretation: SS, YB, PP. Drafted manuscript: SS, YB. Critical review and approval of final manuscript: all authors.

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Correspondence to Yvonne Bombard.

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Shickh, S., Mighton, C., Uleryk, E. et al. The clinical utility of exome and genome sequencing across clinical indications: a systematic review. Hum Genet 140, 1403–1416 (2021).

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