Utility of Whole-Genome Sequencing in Primary Care Uncertain

Adding whole-genome sequencing (WGS) to standardized family history assessment of healthy patients in the primary care setting uncovers new molecular findings, although the findings prompt additional clinical investigation and their clinical utility remains uncertain, according to a study published June 26 in the Annals of Internal Medicine. Additionally, the study found that the majority of primary care providers (PCPs) are able to manage WGS results appropriately without causing patients undue distress, both of which had been previous concerns about employing WGS technology in nonspecialist settings and among healthy patients.

The researchers retrospectively assessed affected AD severity based on As part of the MedSeq Project at Brigham and Women's Hospital, the researchers conducted a pilot in which 100 generally healthy patients (aged 40 to 65 years and free of cardiovascular disease or diabetes mellitus) were randomly assigned to receive a family history report alone (FH) or in combination with an interpreted WGS report (FH + WGS). The report included a summary of variant interpretation (monogenic disease risk [MDR] associated with Mendelian disorders, carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits), disease information, and familial risk, but did not include recommendations for clinical management.

Prior to patient enrollment nine PCP participants received an educational intervention (four hours of case-based online modules and two one-hour, inperson group classes, including an orientation to the genome report). During the study, PCPs could contact a genome resource center staffed by medical geneticists and genetic counselors to ask questions about test result interpretation. Patients received their results from their PCP. These sessions were recorded and a panel of clinician-geneticists rated the appropriateness of PCP management of MDR results. Additionally, downstream outcomes (health care utilization, cost, and outcomes) were assessed for 6 months following return of results.

The researchers found that 11 of 50 FH + WGS patients had new MDR results. However, only two had phenotypic evidence by the MDR result (one ophthalmic condition and one dermatologic condition). Two of the 12 MDR variants were in medically actionable genes (KCNQ1 and TNNT2), as defined by the American College of Medical Genetics and Genomics, but were classified as likely pathogenic and as a variant of uncertain significance favoring pathogenic in the report. Six variants in five patients prompted additional clinical evaluation, including electrocardiograms, referrals to specialists, or a laboratory test. The external panel of geneticists judged that eight of the 11 cases had been managed appropriately and two cases inappropriately (one due to underevaluation of a pathogenic variant and one because of miscommunication about inheritance).

Overall, 96 percent of patients received a pharmacogenomic result indicating atypical or nonstandard response to at least one medication and six of these patients were receiving at least one of these medications at baseline. However, no prescription change or adverse effect was seen during the 6-month observation period.

It should be noted that even in these established PCP–patient dyads, discussion of FH alone prompted additional actions, such as a specialist referral and laboratory testing.

Total costs for the immediately attributable recommended actions averaged $41 in the FH group and $68 in the FH + WGS group. Six-month costs averaged $1,142 in the FH group and $1,490 in the FH + WGS group, overall and $2,526 for 11 patients with new MDR results. No patients with a new molecular diagnoses showed clearly improved short-term health outcomes or harm from WGS.

"The results of this pilot study do not support the use of WGS in primary care but suggest that, if a healthy adult has WGS, some of the resulting increased health care use may be clinically appropriate, write the authors, led by Jason Vassy, M.D. "Furthermore, they challenge the common notion that PCPs are unprepared to make appropriate medical decisions about complex sequencing results."

Takeaway: The clinical utility of incorporating WGS results into routine primary care remains uncertain, although this study shows that with a little preparation, PCPs are able to appropriately manage clinical sequencing data.