Sturm, Amy C

Importance Completion of the Human Genome Project prompted predictions that genomics would transform medicine, including through genomic screening that identifies potentially medically actionable findings that could prevent disease, detect it earlier, or treat it better. However, genomic screening remains anchored in research and largely unavailable as part of routine care. Objective To summarize 11 years of experience with genomic screening and explore the landscape of genomic screening efforts. Design, Setting, and Participants This cohort study was based in Geisinger’s MyCode Community Health Initiative, a genomic screening program in a rural Pennsylvania health care system in which patient-participants exomes are analyzed. Main Outcomes and Measures Genomic screen-positive rates were evaluated and stratified by condition type (cancer, cardiovascular, other) and US Centers for Disease Control and Prevention (CDC) Tier 1 designation. The proportion of participants previously unaware of their genomic result was assessed. Other large-scale population-based genomic screening efforts with genomic results disclosure were compiled from public resources. Results A total of 354 957 patients participated in Geisinger’s genomic screening program (median [IQR] age, 54 [36-69] years; 194 037 [59.7%] assigned female sex at birth). As of June 2024, 175 500 participants had exome sequencing available for analysis, and 5934 participants (3.4%) had a pathogenic variant in 81 genes known to increase risk for disease. Between 2013 and July 2024, 5119 results were disclosed to 5052 eligible participants, with 2267 (44.2%) associated with risk for cardiovascular disease, 2031 (39.7%) with risk for cancer, and 821 (16.0%) with risk for other conditions. Most results (3040 [59.4%]) were in genes outside of those with a CDC Tier 1 designation. Nearly 90% of participants (4425 [87.6%]) were unaware of their genomic risk prior to disclosure. In a survey of large-scale biobanks with genomic and electronic health record (EHR) data, only 25.0% (6 of 24) disclosed potentially actionable genomic results. Conclusions and Relevance In this large, genomics-informed cohort study from a single health system, 1 in 30 participants had a potentially actionable genomic finding. However, nearly 90% were unaware of their risk prior to screening, demonstrating the utility of genomic screening in identifying at-risk individuals. Most large-scale biobanks with genomic and EHR data did not return genomic results with potential medical relevance, missing opportunities to significantly improve genomic risk ascertainment for these individuals and to perform longitudinal studies of clinical and implementation outcomes in diverse settings.

Background: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network. Methods: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review. Results: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00–4.53]) and premature CHD (odds ratio, 3.68 [2.34–5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results. Conclusions: In a multisite cohort of electronic health record–linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record–linked biobanks to detect FH.