Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes

J Mol Cell Cardiol. 2010 May;48(5):899-909. doi: 10.1016/j.yjmcc.2010.03.005. Epub 2010 Mar 16.


Cardiomyopathies, familial or sporadic, have become recognized as one of the leading cardiac threats. Hypertrophic cardiomyopathy (HCM) affects 0.2% of the population and is the leading cause of sudden death in young adults. Dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) are associated with sudden death as well as heart transplantations. Ventricular noncompaction cardiomyopathy (VNCM) is associated with heart failure and arrhythmias. Currently, more than 630 mutations in 10 sarcomeric genes associated with cardiomyopathy have been identified. HCM is associated with more than 550 mutations, whereas DCM, RCM and VNCM are associated with 52, 14 and 17 mutations, respectively. In many cases, the genes affected present a varying range of phenotypic and pathological severity. Recent data suggest that at least two main genetic determinants are involved in the pathogenesis and phenotypic variability within families afflicted by the same disease-linked gene. Individuals that are homozygous for a mutation or heterozygous for two or more mutations often show more severe phenotypes. Secondly, genetic modifiers are present in some cardiomyopathy patients and are associated with a poorer prognosis. At the protein level, changes in protein-protein interactions may also be important in determining the type of cardiomyopathy caused by different mutations. This review provides insight into the complex cardiovascular phenotypes and genetic variability associated with HCM, DCM, RCM and VNCM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / metabolism
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Hypertrophic / genetics
  • Cardiomyopathy, Hypertrophic / metabolism
  • Cardiomyopathy, Hypertrophic / pathology
  • Cardiomyopathy, Restrictive / genetics
  • Cardiomyopathy, Restrictive / metabolism
  • Cardiomyopathy, Restrictive / pathology
  • Humans
  • Mutation
  • Sarcomeres / metabolism