Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
School of Medicine, Stanford University, Palo Alto, California.
Am J Med Genet C Semin Med Genet. 2020 Mar;184(1):124-128. doi: 10.1002/ajmg.c.31772. Epub 2020 Feb 6.
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.
心脏性猝死 (SCD) 是美国军人和竞技运动员死亡的主要原因之一。在这项研究中，我们模拟了如何在军队中实施基因筛查，以预防肥厚型心肌病 (HCM) 导致的 SCD 终点。我们创建了一个逻辑回归模型来预测最常见的与 HCM 相关的基因 MYH7 和 MYBPC3 中的变异致病性。模型预测与 gnomAD 数据库结合使用，以确定致病性变异的频率。将这些变体外推到军队人群中，对 MYH7 和 MYBPC3 中与致病性变体相关的 HCM 进行筛查，进行了生存和成本效益分析。根据历史队列规模，对 HCM 进行基因筛查，然后对致病性变体进行超声心动图检查，预计每个入队队列平均可挽救 2.9 条生命，且每个测试的盈亏平衡成本约为 7 美元。假阳性，定义为不符合军队服务条件但没有 HCM 的被淘汰者，预计每个入队队列为 0 人。本研究表明，美国军队实施基因筛查的主要障碍是检测率低和变异解读。
