The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease. Our analysis showed that despite a higher average read depth in panels (3058 vs. 855), MedExome yielded full coverage of the enriched regions (>20X) and 99% variant concordance rate with panels. The discordance rate was associated with low-complexity regions, high-GC content, and low allele fractions, observed in both platforms. MedExome yielded full sensitivity in detecting clinically actionable variants, and the assessment of 138 patients with suspected genetic conditions resulted in 76 clinical reports (31 full [22.1%], 3 partial, and 42 uncertain/possible molecular diagnoses). MedExome sequencing has comparable performance in variant detection to gene panels. Added diagnostic yield justifies expanded implementation of broad genomic approaches in unresolved patients; however, cost-benefit and health systems impact warrants assessment.

与靶向遗传方法相比，广泛的基因组测序方法在临床环境中的适应伴随着对临床效用、技术性能和诊断产量的考虑。我们开发了 MedExome，这是一个用于测序、变异识别（SNV、Indel 和 CNV）以及约 4600 个医学相关基因的临床评估的集成框架。我们将 MedExome 与全外显子组和靶向基因组测序的技术性能进行了比较，评估了不一致的原因，并评估了 MedExome 在一组疑似遗传疾病的未解决受试者中增加的临床产量。我们的分析表明，尽管面板中的平均读取深度更高（3058 对 855），但 MedExome 产生了对富集区域的完全覆盖（> 20X) 和面板的 99% 变体一致性率。不一致率与在两个平台中观察到的低复杂性区域、高 GC 含量和低等位基因分数相关。MedExome 在检测临床上可行的变异方面产生了完全的敏感性，对 138 名疑似遗传病患者的评估产生了 76 份临床报告（31 份完整 [22.1%]、3 份部分和 42 份不确定/可能的分子诊断）。MedExome 测序在变异检测方面的性能与基因面板相当。增加的诊断率证明在未解决的患者中扩大实施广泛的基因组方法是合理的；然而，成本效益和卫生系统影响值得评估。MedExome 在检测临床上可行的变异方面产生了完全的敏感性，对 138 名疑似遗传病患者的评估产生了 76 份临床报告（31 份完整 [22.1%]、3 份部分和 42 份不确定/可能的分子诊断）。MedExome 测序在变异检测方面的性能与基因面板相当。增加的诊断率证明在未解决的患者中扩大实施广泛的基因组方法是合理的；然而，成本效益和卫生系统影响值得评估。MedExome 在检测临床上可行的变异方面产生了完全的敏感性，对 138 名疑似遗传病患者的评估产生了 76 份临床报告（31 份完整 [22.1%]、3 份部分和 42 份不确定/可能的分子诊断）。MedExome 测序在变异检测方面的性能与基因面板相当。增加的诊断率证明在未解决的患者中扩大实施广泛的基因组方法是合理的；然而，成本效益和卫生系统影响值得评估。增加的诊断率证明在未解决的患者中扩大实施广泛的基因组方法是合理的；然而，成本效益和卫生系统影响值得评估。增加的诊断率证明在未解决的患者中扩大实施广泛的基因组方法是合理的；然而，成本效益和卫生系统影响值得评估。