Can genetic testing improve our aim in hypertrophic cardiomyopathy?

Hypertrophic cardiomyopathy (HCM) is a common inherited disorder with an estimated prevalence of 1 in 500 worldwide. The disease is inherited in families in an autosomal dominant fashion and is usually caused by mutations in genes encoding contractile proteins such as cardiac -myosin heavy chain (MYH7), cardiac troponin T (TNNT2), cardiac myosin binding protein-C (MYBPC3), cardiac troponin I, -myosin heavy chain, cardiac -actin, -tropomyosin, titin, myosin regulatory light chain, and myosin essential light chain. Several HCM disease genes remain to be identified. The most obvious clinical manifestation of HCM is left ventricular hypertrophy. Although such hypertrophy is classically asymmetrical with prominent involvement of the interventricular septum, both concentric and apical hypertrophy can also occur. In fact, affected individuals may not exhibit any hypertrophy. Other clinical features are similarly variable in their expression and include sudden cardiac death, heart failure, arrhythmias, stroke, heart block, and infective endocarditis. Some patients remain asymptomatic throughout their lifetime. Many HCM patients have no or only minor symptoms, and asymptomatic affected children and adolescents are often diagnosed during family screening after another family member comes to medical attention.1 The average annual risk of sudden cardiac death in a HCM patient is 1%,2 and in high risk patients, prophylactic defibrillator implantation can be lifesaving. Given marked variation in penetrance and expressivity, early diagnosis and reliable prognostic tools are crucial for primary prevention and proper followup of affected individuals and their family members. Current guidelines recommend that all firstdegree relatives of an individual affected by HCM should be clinically evaluated by history, physical examination, electrocardiography, and echocardiography. With increased understanding of the molecular genetic causes of HCM and advances in modern laboratory technology, clinical genetic testing for HCM has become increasingly feasible.3 The GeneTests database (http://www.ncbi.nlm.nih.gov/sites/GeneTests) currently lists 5 US clinical laboratories offering some form of HCM genetic testing, as well as 7 additional European clinical laboratories. However, a role of clinical genetic testing for HCM has not been well defined. The 2003 American College of Cardiology/European Society of Cardiology Task Force on HCM3 noted that obstacles to routine deployment of HCM genetic testing include the marked intergenic and intragenic heterogeneity of the disorder as well as expensive and complex technological barriers to efficient screening of at least 10 different causal genes in any given proband. Although costs of sequencing and mutational analyses have markedly decreased since then, the price of testing generally remains in the thousands of dollars, and genetic heterogeneity remains a persistent challenge. Thus, HCM genetic testing has remained a mainstay of evaluation of families with a previously identified gene mutation rather than a screening tool for the general population. Using genetic testing in HCM families acknowledges that first degree relatives generally have a 50% risk of sharing disease causing mutations, and all relatives found to carry such a mutation (even if they do not initially manifest any clinical signs or symptoms of HCM) should have annual surveillance evaluations including resting and ambulatory ECG, echocardiography, and exercise testing to assess progression of hypertrophy and sudden cardiac death risk. However, even when an HCM causing mutation has been identified, it is challenging to use the genotype to predict an individual patient’s clinical course. In some cases, unrelated families with the same sarcomeric gene mutation have been identified, but prognosis and severity has been dramatically different. Such seeming paradoxes are likely consequences of extensive modifying effects of as yet unidentified genetic factors as well as impact of poorly understood environmental factors such as diet.1 However, the greater challenge to establishing genotype/phenotype correlations has been the extensive frequency of “private” mutations. The Partners Healthcare Center for Personalized Genetic Medicine has found in their clinical testing program that approximately two-thirds of the HCM mutations identified among more than 2000 probands occur in only one family (H. Rheim, personal communication). However, some genetic variants do represent mutational “hotspots.” In this issue of Circulation Research, Saltzman et al4 provide intriguing findings regarding one relatively common recurring HCM mutation. They report about significance of the Arg502Trp MYBPC3 variant in 1414 unrelated white HCM patients. It is generally accepted that the most common genetic causes of HCM are mutations in MYH7, TNNT2, and MYBPC3, and, combined, mutations in these 3 genes account for approximately half of HCM. Up to one-fourth of patients have MYBPC3 mutations, and mutations in this gene account for 40% to 48% of HCM causing mutations that have been The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York. Correspondence to Craig T. Basson, MD, PhD, Director, Cardiovascular Research, Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065. E-mail [email protected] (Circ Res. 2010;106:1446-1448.) © 2010 American Heart Association, Inc.