Background Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase healthcare utilization without clinical value. Objective Describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design Pilot randomized trial. Setting Academic primary care practices. Participants Nine primary care physicians (PCPs) and 100 generally healthy patients aged 40–65. Interventions Patients were randomly assigned to receive a family history report alone (FH arm) or in combination with an interpreted WGS report including monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits (FH+WGS arm). Each patient met with his or her PCP to discuss the reports. Measurements Clinical outcomes and healthcare utilization through six months were obtained from audio-recorded PCP-patient discussions and medical records. Patients’ health behavior changes were surveyed six months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results. Results Mean age was 55 years; 58% were female. Eleven FH+WGS patients (22%, 12%–36%) had new MDR results. Only two (4%, 0.01%–14%) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). PCPs recommended new clinical actions for 16% (8%–30%) of FH patients and 34% (22%–49%) of FH+WGS patients. Thirty (17%–45%) and 41% (27%–56%) of FH and FH+WGS patients, respectively, reported making a health behavior change after six months. Geneticists rated PCP management of eight MDR results (73%, 39%–99%) as appropriate and two (18%, 3%–52%) as inappropriate. Limitations Limited sample size and ancestral and socioeconomic diversity. Conclusions Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Non-geneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value. Registration ClinicalTrials.gov identifier NCT01736566 Funding National Institutes of Health

National Human Genome Research Institute, Doris Duke Charitable Foundation, National Health Service Blood and Transplant, National Institute for Health Research, and Wellcome Trust.

Many expect genome sequencing (GS) to become routine in patient care and preventive medicine, but uncertainties remain about its ability to motivate participants to improve health behaviors and the psychological impact of disclosing results. In a pilot trial with exploratory analyses, we randomized 100 apparently healthy, primary-care participants and 100 cardiology participants to receive a review of their family histories of disease, either alone or in addition to GS analyses. GS results included polygenic risk information for eight cardiometabolic conditions. Overall, no differences were observed between the percentage of participants in the GS and control arms, who reported changes to health behaviors such as diet and exercise at 6 months post disclosure (48% vs. 36%, respectively, p = 0.104). In the GS arm, however, the odds of reporting a behavior change increased by 52% per high-risk polygenic prediction (p = 0.032). Mean anxiety and depression scores for GS and control arms had confidence intervals within equivalence margins of ±1.5. Mediation analyses suggested an indirect impact of GS on health behaviors by causing positive psychological responses (p ≤ 0.001). Findings suggest that GS did not distress participants. Future research on GS in more diverse populations is needed to confirm that it does not raise risks for psychological harms and to confirm the ability of polygenic risk predictions to motivate preventive behaviors.