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

Purpose: Clinical sequencing emerging in healthcare may result in secondary findings (SFs). Methods: Seventy-four of 6,240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original ACMG-recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near term healthcare costs; additional studies are needed to confirm these findings.

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

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

The eMERGE Consortium* , * The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.