Whole genome and exome sequencing in clinical practice: a systematic review of economic evaluations

Abstract Introduction Whole genome and exome sequencing (WGS and WES) may improve significantly the early diagnosis of rare and inherited diseases and the development of personalized therapies. A key issue is whether these strategies are cost-effective investments, with cost linked to improved health outcome. Methods We conducted a systematic search of three databases for full economic evaluations assessing the cost-effectiveness of WGS and WES based on health outcomes (quality-adjusted life years -QALYs- and life-years gained -LYG) according to PRISMA Statement and CRD Guidance. Quality was evaluated using the Quality of Health Economic Studies instrument. We analyzed methodological aspects, including economic models, cost perspectives, and key assumptions. A narrative synthesis categorized studies by testing scope. (PROSPERO CRD42023430992) Results Of 39,477 identified articles, 12 met the inclusion criteria, evaluating WGS and WES for targeted therapies in cancer or major depression, and rare disease diagnosis in paediatric populations or during pregnancy. Findings suggest that sequencing is cost-effective for diagnosing rare diseases, resulting the dominant strategy in two studies. WGS/WES are currently not cost-effective to guide cancer treatment under a Willingness-to-Pay threshold of €80,000, and are less cost-effective compared to clinically guided treatment for depression. WGS/WES may become cost-effective for treatment guidance under conditions such as reduced test costs, increased diagnostic accuracy, and expanded treatment applications. However, the lack of long-term outcome data and the clinical heterogeneity of studied conditions pose significant challenges to EEs. Variability in perspectives, populations, and costs further limits comparability. Conclusions WGS/WES-based diagnosis of rare diseases proves cost-effective. Standardized methodologies and long-term studies are needed to improve the quality of health economic evidence on this topic. Key messages • WGS/WES are cost-effective for rare disease diagnosis - but not yet for cancer or depression - highlighting need for standardized, long-term economic studies to guide precision medicine integration. • The study underscores gaps: high test costs, lack of long-term outcome data, and clinical heterogeneity hinder cost-effectiveness of sequencing in cancer/depression, calling for unified methodologies.