The Genetics of Cardiomyopathies: What Clinicians Should Know Rahul Deo, MD, PhD, and Calum A. MacRae, MBChB, PhD Corresponding author Calum A. MacRae, MBChB, PhD Cardiovascular Division and Cardiovascular Research Center, Massachusetts General Hospital, Yawkey 5-964, 55 Fruit Street, Boston, MA 02114, USA. E-mail: macrae@cvrc.mgh.harvard.edu Current Heart Failure Reports 2007, 4:229–235 Current Medicine Group LLC ISSN 1546-9530 Copyright © 2007 by Current Medicine Group LLC Primary myocardial diseases, or cardiomyopathies, affect millions of individuals worldwide. Although there are siz- able environmental contributors to the etiology of these diseases, many cardiomyopathies have a high degree of heritability and, thus, genetic aspects of diagnosis and therapy warrant special consideration. The past two decades have seen enormous progress in elucidating the epidemiology, genetic architecture, and pathophysiology of these diseases. In this review, we focus on translating advances in the genetics of cardiomyopathies to clinical care. We discuss the underlying genetic and phenotypic complexity of these disorders, highlighting the implica- tions for diagnosis, treatment, screening, and prognosis of patients and their family members. Introduction Primary myocardial diseases, so-called cardiomyopathies, contribute substantially to the morbidity and mortality from heart failure, arrhythmias, and sudden death [1]. Although the classiication of cardiomyopathies continues to evolve with elucidation of their pathophysiology [2•], traditional categorization is based on dividing morphologic and/or functional characteristics into three broad groups: dilated cardiomyopathy (DCM), hypertrophic cardiomy- opathy (HCM), and restrictive cardiomyopathy (RCM). DCM, HCM, and RCM have highly heritable forms, and pioneering genetic investigations in the past two decades have enabled the discovery of many of the genes implicated in the pathobiology of cardiomyopathy. This high heritability, combined with the potential for identify- ing the causal genetic variant, offers the physician treating the cardiomyopathy patient a number of opportunities that are not seen in the management of other cardiovascu- lar diseases. Importantly, it may create a situation in which clinical beneit can be extended to the patient’s family members. Physicians traditionally have had little training in some of the distinctive aspects of genetic diseases. This review focuses on management of the cardiomyopathies with known heritable contributions, emphasizing how our genetic understanding of these diseases can be translated to clinical care. DCM, HCM, arrhythmogenic right ven- tricular cardiomyopathy (ARVC) or dysplasia, and RCM are discussed. Important Considerations in Heritable Disease Before addressing speciic cardiomyopathies, we review some important considerations in the management of any disorder with a large heritable component. Since the completion of the Human Genome Project in 2001, con- siderable attention has been given to the promise of genetic information to transform clinical medicine by making it more “predictive, preventive, and personalized.” To achieve these ideals for a given patient, the physician must be able to identify disease early in its course, preferably before clinical manifestations. Furthermore, to make individual- ized management decisions to alter the natural history of a disease, we would need a rigorous understanding of the speciic etiology for a particular patient. Currently, the management of highly heritable diseases offers the greatest likelihood of realizing these lofty goals. We share half of our genetic material with any irst-degree relative. For an autosomal dominant mendelian trait with complete pene- trance (Table 1), there is a 50% chance that any irst-degree relative of an affected individual also will be affected. In the ideal case we can identify the underlying genetic variant causing the disease in the individual patient. Consequently, we would be able to screen unaffected family members and identify those who will develop the disease before clinical manifestations occur. If this genetic variant has a predict- able disease incidence and course, it would be feasible to implement monitoring and treatment measures with the aim of mitigating morbidity and mortality. In reality, for cardiomyopathies and most other heritable diseases, many hurdles still stand in the way of this ideal. Inheritance patterns may not be autosomal dominant, penetrance is usually incomplete, and disease manifestations vary con-