Genetic screening for hypertrophic cardiomyopathy in large, asymptomatic military cohorts

Abstract

Sudden cardiac death (SCD) is one of the leading causes of mortality in the U.S. military and competitive athletes. In this study, we simulate how genetic screening may be implemented in the military to prevent an SCD endpoint resulting from hypertrophic cardiomyopathy (HCM). We created a logistic regression model to predict variant pathogenicity in the most common HCM associated genes MYH7 and MYBPC3. Model predictions were used in conjunction with the gnomAD database to identify frequencies of pathogenic variants. Extrapolating these variants to a military population, lives saved and cost benefit analyses were conducted for screening for HCM related to pathogenic variants in MYH7 and MYBPC3. Genetic screening for HCM followed by echocardiography in individuals with pathogenic variants is predicted to save an average of 2.9 lives per accession cohort, based on historical cohort sizes, and result in a break-even cost of ~$7 per test. The false positives, defined as disqualified individuals for military service who do not have HCM, are predicted to be 0 individuals per accession cohort. This study suggests that the main barriers for the implementation of genetic screening for the U.S. military are the low detection rate and variant interpretation.

Keywords: genetic screening; hypertrophic cardiomyopathy; population genetics; variant classification.