Genetics and Clinical Destiny: Improving Care in Hypertrophic Cardiomyopathy
Authors: Carolyn Y. Ho
Journal: Circulation (2010)

T he greatest opportunity afforded by discovering the genetic basis of human heart disease is accurate prediction and prevention of illness.Hypertrophic cardiomyopathy (HCM) provides a paradigm to fulfill this opportunity.Human genetics research has identified many gene mutations that result in cardiac hypertrophy, of which HCM is the most common and well-characterized.Sarcomere gene mutations in HCM result in left ventricular hypertrophy (LVH), myocardial fibrosis and disarray, diastolic dysfunction, and increased risk for arrhythmias, sudden death, and heart failure.Making the clinical diagnosis of HCM currently hinges on identifying unexplained hypertrophy, but LVH is a sign of established disease only.This finding cannot identify at-risk mutation carriers and cannot discriminate HCM from other forms of cardiac hypertrophy, either genetic or acquired. Response by Landstrom on p 2440In contrast, gene-based diagnosis is not constrained in this manner.Defining the mutation that causes LVH in an individual provides an accurate diagnosis for that patient and, therefore, considerable information about their prognosis.Moreover, unlike clinical diagnosis which only identifies overt disease, genetic diagnosis can also identify patients at risk for developing disease.There are certainly many challenges to realizing the full potential of genetics, but such information provides unprecedented promise.Continued efforts to refine and clinically implement genetic testing in HCM will bring important payoffs in the future, and will serve as a model for other genetic cardiovascular diseases.By identifying at-risk individuals prior to clinical diagnosis, characterizing disease pathogenesis, and fostering development of novel therapies to delay or prevent phenotypic expression, genetic discoveries will improve the lives of our patients with HCM. Genetics of HCMThe familial, autosomal-dominant nature of HCM has long been recognized, but the precise genetic etiology was discovered through genome-wide linkage studies in the 1980s.This seminal work identified pathogenic mutations in genes encoding contractile proteins and established the paradigm that HCM is a disease of the sarcomere. 1,2Over the past 20 years, more than 900 individual mutations have been identified, the majority (Ϸ75% to 80%) involving cardiac ␤-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3).Other sarcomere genes, including cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), ␣-tropomyosin (TPM1), the myosin light chains (MYL2, MYL3) and actin (ACTC) have also been established as causing HCM.Genetic testing for HCM was initially available only in research laboratories and performed primarily to further basic understanding of disease.Clinical genetic testing can now be obtained through a variety of commercial laboratories, making diagnostic use feasible.Current testing is based on a candidate-gene approach, typically analyzing the 8 sarcomere genes most commonly implicated in HCM, listed above, and a small number of genes associated with metabolic/storage cardiomyopathies that may mimic HCM, including PRKAG2, LAMP2, and GLA, as discussed below.