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
Schwartz MLB, Williams MS, Murray MF. Adding Protective Genetic Variants to Clinical Reporting of Genomic Screening Results: Restoring Balance. JAMA. 2017;317(15):1527–1528. doi:10.1001/jama.2017.1533
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