Dilated cardiomyopathy: more genes means more phenotypes.

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure after coronary artery disease and hypertension. DCM is the most frequent form of primary myocardial disease. Clinically, DCM is characterized by a progressive course of ventricular dilatation and systolic dysfunction. The different stages of DCM are reflected by the presentation of asymptomatic patients with left ventricular dilatation or impaired systolic function, patients with exercise-induced symptoms of heart failure, or overt congestive heart failure. The life expectancy is limited and varies according to the underlying aetiology. Myocarditis, immunological abnormalities, toxic myocardial damage, and genetic factors are all assumed to be causes. The familial occurrence of DCM, mostly as an autosomal dominant trait, is more common than generally believed. As a matter of fact, 20–30% of all cases of DCM are caused by genetic mutations. In the past decade, major progress has been achieved by investigating families with inherited DCM. The analysis of candidate genes led to the discovery of cardiac a-actin, the first DCM-causing gene. Additional candidate gene screening and linkage analyses in large families were successful in identifying 19 additional diseasecausing genes (Figure 1, Table 1 ). The interesting report by Villard et al. sheds new light on the frequency of mutations in the b-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes. The group examined 96 patients with DCM and most of their first-degree relatives. This important study design feature enabled the investigators to differentiate between sporadic and familial cases. Villard et al. identified 54 patients with inherited DCM. This proportion of inherited cases in a cohort of patients with ‘idiopathic’ DCM is higher than in previous reports and may be related to the function of the Pitié-Salpetrière hospital as a tertiary referral centre. In contrast, the investigators in most other studies did not differentiate between genetic and sporadic DCM patients or they reported solely on selected patients with idiopathic DCM. Because of the unknown number of inherited cases, the mutation frequency observed in many studies is prone to referral bias and must therefore be interpreted with caution. Villard et al. found seven missense mutations in the MYH7 gene and two mutations in the TNNT2 gene. They found no mutations in cardiac a-actin, desmin, d-sarcoglycan, phospholamban, or the metavinculin gene in this group of patients or in a similar population of DCM patients. The screening methods employed have a sensitivity of 80–90% in mutation detection. Bearing this fact in mind, these genes and probably many other DCM disease genes are rare causes of familial or sporadic DCM cases. Some mutations, the so-called private mutations, may be so rare as to be regarded a characteristic of only a single family. In the first report on MYH7 mutations as cause of familial DCM, two different missense mutations were identified in 2 out of 21 families with heritable pure DCM without other organ manifestations. This report was followed by two additional studies identifying two novel mutations in 46 unrelated German DCM patients and one novel mutation in one of the 52 Finnish DCM patients. In addition, several groups have described patients who exhibit a conversion from a hypertrophic cardiomyopathy (HCM) to a DCM phenotype. In such instances, mutations of the MYH7 gene seem to be