Article Text

Expression of HCM causing mutations: lessons learnt from genotype-phenotype studies of the South African founder MYH7A797T mutation
  1. *US/MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, University of Stellenbosch Medical School, PO Box 19063, Tygerberg 7505, South Africa
  2. †Department of Internal Medicine, University of Stellenbosch Medical School and Tygerberg Hospital, Tygerberg, South Africa
  1. Dr Corfield, VCl{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Editor—Genotype-phenotype correlations provide another perspective in studies seeking to identify the factors that underlie the clinical variability that is a feature of several inherited diseases. This approach has been particularly revealing in investigations into the molecular causes and phenotypic heterogeneity associated with hypertrophic cardiomyopathy (HCM), a common inherited primary cardiac disorder.1 2 Although, as its name suggests, hypertrophy may be a noticeable feature of the disease, it is not invariant, nor does the degree of hypertrophy necessarily correlate with the risk of sudden cardiac death (SCD), which is the most feared consequence of HCM.3 4

Molecular genetic investigations have shown that HCM is caused by more than 100 distinct mutations in at least seven different sarcomeric protein encoding genes.5 When the clinical features of HCM are correlated in a family context with the specific disease causing gene and its associated mutation, a recognisable pattern emerges. Essentially, mutations in the cardiac β myosin heavy chain gene (MYH7) are more often associated with echocardiographically detectable to marked hypertrophy and a variable risk of SCD, usually before the age of 35 years, which generally relates to the specific causative mutation.6 In striking contrast, mutations in the cardiac troponin T gene (TNNT2) are most frequently accompanied by subtle, or even undetectable, hypertrophy, yet confer a high risk of SCD in adolescence or young adulthood.3 4 Between these extremes lie the myosin binding protein C gene mutations, which are responsible for a considerably later age of onset of a steadily progressive form of hypertrophy, which may result in death from congestive heart failure later in life, more often than SCD.7 8 Further studies are needed before conclusive genotype-phenotype profiles can be defined for mutations in other HCM causing genes.9-11

This stratification of HCM into distinguishable subclasses …

View Full Text