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.

Prospero registration CRD42019094101.

外显子组测序和基因组测序有可能提高接受基因调查的患者的临床效用。然而，临床效用的证据仅限于儿科人群；我们旨在通过对有关外显子组/基因组测序在儿童和成人人群中的疾病适应症的临床效用进行系统审查来填补这一空白。2016 年至 2020 年期间检索了 MEDLINE、EMBASE 和 Cochrane 图书馆。包括评估诊断率的定量研究；如果报告了临床效用的其他测量，例如临床管理的变化，则记录在案。两名评价员筛选、提取数据并评估偏倚风险。50 项研究符合我们的纳入标准。所有研究都报告了诊断率，范围从 3% 到 70%，神经系统适应症和急性疾病的产量范围更高，分别为 22% 至 68% 和 37% 至 70%。诊断引发了一系列临床管理变化，包括监测、生殖风险咨询和确定 4% 至 100% 患者的高危亲属，报告的急性疾病发生频率更高，范围为 67% 至 95%。在所有研究中，不确定显着性变异的频率范围为 5% 至 85%，具有随时间推移频率降低的潜在趋势，并且在非欧洲血统的患者中发现了更高的发生率。这篇综述提供了与标准基因检测相比外显子组/基因组测序诊断率更高的证据，尤其是在神经和急性适应症方面。然而，我们发现研究程序和结果存在显着异质性，排除了可用于决策的证据的有意义的荟萃分析和确定性。未来的研究需要采用全面和一致的方法来捕捉更广泛祖先群体的外显子组/基因组测序的临床效用，以提高诊断准确性和产量，并允许随着时间的推移分析趋势。

Prospero 注册CRD42019094101。