Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular diseases, with a prevalence of at least 1 in 500 in the general population.1,2 HCM is characterized by left ventricular hypertrophy, in the absence of other loading conditions, such as hypertension.3 The hallmark feature of HCM is significant clinical heterogeneity in presentation, ranging from asymptomatic patients to those who have the most serious outcomes of heart failure and sudden cardiac death. Over 1500 mutations in at least 15 sarcomere-encoding genes have been identified.4–7 The significance of cardiac genetic testing in clinical practice is 2-fold. For the proband, identification of the underlying genetic cause in some cases can clarify the cause of hypertrophy, for example, clarifying phenocopies, such as PRKAG2-glycogen storage disease and Fabry disease. The greatest utility, however, is in cascade genetic testing of asymptomatic relatives, with clear benefits either for confirming a borderline clinical diagnosis, or suspicious clinical changes suggestive of early disease, or most importantly ruling out the disease in those who test gene-negative. Identification of a silent gene carrier will guide cascade testing of additional family members, in effect clarifying their risk status. Of most benefit, a negative genetic result can reassure offspring that they are not at risk of HCM. The escalation in our understanding of the genetic basis of HCM has been catalyzed by the implementation of next generation sequencing technologies. In response to faster and more affordable testing, commercial genetic testing for HCM now often comprises vast cardiac gene chips (ie, 50–200 or more genes). This approach, although comprehensive, also draws into sharp focus the limitations of our current knowledge. The challenges of cardiac genetic testing are increasingly documented, such as identification of variants of uncertain significance (VUS), incidental genetic findings,8 reclassification of variants,9 increased need …