Adding Protective Genetic Variants to Clinical Reporting of Genomic Screening Results: Restoring Balance

Most clinical genetic testing is limited to diagnostic testing for monogenic diseases, such as hereditary breast and ovarian cancer syndrome and hypertrophic cardiomyopathy, and focused on a limited number of genes among individuals with a high pretest probability for the genetic condition. The key clinical question has been whether a causal pathogenic variant is present, which has represented a pragmatic approach because DNA sequencing was expensive and interpretive knowledge limited. Medicine is now entering the era of sequencing-based screening of healthy populations like the MyCode Community Health Initiative cohort1 and the All of Us cohort.2 This means that assessment of a broader spectrum of genetic contribution to risk, including both pathogenic and protective variants,3 will be important to answer clinical questions about penetrance4 and prognosis.5 For example, loss-of-function alleles in the PCSK9 gene are known to be protective against coronary artery disease (CAD).4