Familial Hypertrophic Cardiomyopathy-Related Troponin Mutations and Sudden Cardiac Death

Hypertrophic cardiomyopathy (HCM) is a common structural anomaly of the myocardium that is unexplained by an underlying condition such as hypertension. The main findings in HCM are varying degrees of ventricular and/or septal hypertrophy, myocyte disarray and increased myocardial fibrosis (Maron et al., 1995). There is significant variation in the clinical manifestation among patients, from asymptomatic, to mild dyspnea upon exertion, to substantive heart failure. While many individuals will present with clinical symptoms, including a cardiac murmur related to outflow tract obstruction, in some families, diagnosis is not established until the sudden death of, or incidental finding of hypertrophy within, a family member. Transthoracic echocardiography has traditionally been the clinician’s primary tool for determination of asymmetric hypertrophy of the left interventricular septum, with or without left ventricular outflow tract obstruction. Given the heterogeneity in severity of disease and penetrance within HCM-affected families, it is important to rule out other secondary causes of hypertrophy, such as hypertension or aortic stenosis. Diagnosis can be difficult, especially in elite athletes who may present with physiological left ventricular hypertrophy (Maron, 2009). Clinically identifiable HCM has a prevalence of 1:500 in young adults in the general population, making it the most common genetic cardiovascular disease in many countries (Maron et al., 1995). Although familial hypertrophic cardiomyopathy (FHC) was first described clinically more than half a century ago (Teare, 1958), it was only about 20 years ago that the underlying molecular causes of FHC began to be established, with the finding of a mutation in the betamyosin heavy chain (MYH7) gene (Geisterfer-Lowrance et al., 1990). Since this seminal discovery, there have been more than 900 different mutations identified in over 20 FHC candidate genes (Tester & Ackerman, 2009). Historically, attempts to establish the link between genotype and phenotype were based on studying FHC cohorts with severe, well established disease with cardiac remodelling and in some patients, progression to end-stage cardiac dilatation and failure. It is increasingly apparent that focussing on the end phenotype as a link to genotype is problematic; families are highly heterogeneous in their disease presentation with, in many cases, low penetrance (at least on echocardiography diagnoses) and with novel mutations not seen in other families. There are few large FHCaffected families, leading to linkage analysis difficulties. When a pathogenic FHC mutation is uncovered in the proband, genetic testing of all first degree relatives is highly

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