Arising from: Awad MM et al. (2008) Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med 5: 258–267 doi: 10.1038/ncpcardio1182

We have read the Review article by Awad et al. on the genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)1 with great interest and believe that the article, and the subsequent communications,2 deserve further comment. We have sequenced the coding region of desmocollin-2 (DSC2) and desmoglein-2 (DSG2) in patients with familial dilated cardiomyopathy (FDCM).3 In our study we also identified the DSG2-E713K polymorphism in 16% of 73 patients with FDCM as well as in 13.9% of 180 control subjects. We, therefore, agree with Dr Millting's response, and with Awad et al.'s reply to these comments,2 that the E713K variant is unlikely to be pathogenic for familial cardiomyopathies. We further identified patients with FDCM harboring DSG2-V56M, DSG2-V158G, and DSG2-V920G. Surprisingly, these variations have been described as pathogenic mutations for ARVC/D,4 and are also displayed in Figure 2 of the Review article.1 However, we also found all three variations in healthy control subjects. The overall prevalence of V158G and V920G among control individuals was 2.2% and 0.8%, respectively. Therefore, in addition to E713K, the V158G and V920G variants are likely to be 'innocent' polymorphisms rather than mutations related to familial cardiomyopathies. We did, however, find V56M to be significantly overrepresented in patients with idiopoathic dilated cardiomyopathy (2.1% of 611) compared with control individuals (0.5% of 617) indicating that V56M might represent a susceptibility variation for idiopathic dilated cardiomyopathy.3 Nevertheless, this variant is also not exclusively present in patients with familial cardiomyopathies. We believe that caution should be exercised in the interpretation of rare sequence variations in cardiomyopathy-related genes. Genetic analysis of large control cohorts is an essential precondition for reliable identification of cardiomyopathy-related mutations, which is in turn the basis for proper genetic counselling of patients with familial heart diseases.