Abstract
Introduction:
Cardiovascular disease (CVD) is the leading cause of mortality in the United States, leading to one in four deaths. The role of inherited susceptibility to CVD is well established, from rare monogenic disorders to polygenic traits. For many of these conditions, guidelines exist for medical interventions and other preventative care that can improve outcomes and quality of life.
Methods:
We developed a comprehensive genetic screen, "HeartCare", consisting of a 158 gene panel evaluating 1) Mendelian conditions including cardiomyopathies, aortopathies, arrhythmias, and dyslipidemias, 2) a coronary artery disease polygenic risk score (PRS), 3) variants in the LPA gene encoding Lipoprotein(a) that are an independent risk factor for atherosclerotic CVD events, and 4) pharmacogenetic (PGx) variants contributing to simvastatin-induced myopathy and warfarin metabolism. After sequencing in a CAP/CLIA certified laboratory, results were returned to the ordering physician after a multi-disciplinary sign-out conference and uploaded to the EMR.
Results:
As of June 2020, 678 individuals had completed testing with a 31% overall positive rate for Mendelian genes, elevated polygenic risk, and LPA risk alleles (excluding PGx). Of these, 8.1% had a positive finding for a Mendelian condition, the majority (60%) being dyslipidemias (e.g., FH), followed by 25% cardiomyopathies (e.g., HCM, DCM, ARVC) and 6% aortopathies (e.g., Marfan, Loeys-Dietz). Approximately 20% of individuals carried an LPA risk allele, and 9.3% belonged to the high-risk group according to their PRS. Approximately half had a PGx finding related to simvastatin and/or warfarin metabolism. Nearly one in five individuals had a finding with direct clinical care impact, including referral to specialists, imaging, laboratory studies, therapies/procedures (e.g., PCSK9i, ICD).
Conclusions:
To our knowledge, this is the first test of its kind assaying four distinct categories of genetic variation related to cardiovascular health. Our results demonstrate that comprehensive testing can be routinely used to identify individuals who may benefit from interventions to improve survival, reduce morbidity, and enhance quality of life.