Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure

Item Type:	Article
Title:	Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure
Creators Name:	Waldmueller, S. and Erdmann, J. and Binner, P. and Gelbrich, G. and Pankuweit, S. and Geier, C. and Timmermann, B. and Haremza, J. and Perrot, A. and Scheer, S. and Wachter, R. and Schulze-Waltrup, N. and Dermintzoglou, A. and Schoenberger, J. and Zeh, W. and Jurmann, B. and Brodherr, T. and Boergel, J. and Farr, M. and Milting, H. and Blankenfeldt, W. and Reinhardt, R. and Oezcelik, C. and Osterziel, K.J. and Loeffler, M. and Maisch, B. and Regitz-Zagrosek, V. and Schunkert, H. and Scheffold, T.
Abstract:	Aims: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding {beta}-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations. Methods and Results: Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM. Conclusion: A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.
Keywords:	Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy, Mutation, Myosin-Binding Protein, Myosin Heavy Chain
Source:	European Journal of Heart Failure
ISSN:	1388-9842
Publisher:	Oxford University Press
Volume:	13
Number:	11
Page Range:	1185-1192
Date:	November 2011
Official Publication:	https://doi.org/10.1093/eurjhf/hfr074
PubMed:	View item in PubMed

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