Novel candidates for actionable genetic population screening

The Centers for Disease Control and Prevention, as well as the American College of Medical Genetics and Genomics (ACMG), provide guidelines for population screening of genetic conditions in US health programs. Although the ACMG has identified dozens of genes recommended for return of secondary finding results, most are not recommended for population screening because they are too rare or have not been assessed for their clinical or economic impact. In this issue, Schiabor Barrett and colleagues identified associations between rare variants and common diseases that are statistically significant at the population level. The researchers analyzed genetic disease associations from electronic health record and exome sequencing data from two large cohorts: the UK Biobank and the Healthy Nevada Project. The analysis uncovered 74 statistically significant associations between 27 genes and nearly 50 phecodes. To narrow in on associations relevant for population genetic screening, Schiabor Barrett and colleagues utilized a positive predictive value (PPV) cutoff of 30%. In addition to three established disease–gene relationships included in population screening programs (BRCA1 and BRCA2 with breast cancer and LDLR with atherosclerosis), the researchers identified four others with equally strong or stronger PPVs. The novel associations included loss-of-function (LoF) variants in HBB with hemoglobinopathies, LoF variants in PKD1 with polycystic kidney disease, coding variants in GCK with diabetes mellitus, and coding variants in MIP with cataracts. All of the associations have some level of actionability, where patients would benefit from earlier diagnosis. For example, although GCK heterozygotes are often misclassified as type 2 diabetics, they are known to be at increased risk for gestational diabetes, and monitoring during pregnancy is recommended. The authors conclude that adding HBB, GCK, PKD1, and MIP variants into genetic screening programs would reach another 0.2% of participants with actionable disease risk. —V. L. Dengler, News Editor

HeartCare changes management for heart disease patients

Cardiovascular disease (CVD) is responsible for nearly a quarter of deaths in the United States. Although the role of inherited susceptibility is well established, the perceived lack of clinical utility and availability of point-of-care genetic testing hinders widespread adoption of genetic screening. As such, including genetic screening as a standard component of CVD care is uncommon. To address these issues, Murdock and colleagues developed a next-generation sequence–based DNA capture panel called HeartCare. Composed of a 158-gene panel, HeartCare assesses actionable Mendelian conditions including cardiomyopathies, aortopathies, arrhythmias, and dyslipidemias; coronary artery disease (CAD) polygenic risk; LPA gene polymorphisms that are an independent risk factor for atherosclerotic CVD events; and pharmacogenetic variants relevant to simvastatin-induced myopathy and warfarin metabolism. The researchers tested the utility of the screen in a cohort of more than 700 adult patients at Baylor College of Medicine ambulatory cardiology outpatient clinics. The panel uncovered a genetic finding with clinical implications in 32% of participants. Yield was highest among those indicated for cardiomyopathy, with 13% harboring a relevant likely pathogenic or pathogenic variant. Overall, about 9% of participants were diagnosed with a cardiac-related Mendelian condition. A fifth of patients carried an LPA risk allele, and nearly 10% had high polygenic risk of CAD. About half of participants had a positive pharmacogenetic result. Clinicians reported that the HeartCare results were beneficial for patients and clinical care. Based on the results, clinicians recommended management changes for the vast majority (84%) of participants, including interventions such as medication changes, cascade testing, specialist referrals, and additional cardiac tests. Together, the authors conclude that the findings support routine use of comprehensive genetic testing in cardiovascular health management. —V. L. Dengler, News Editor