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Mutations in cis can confound genotype-phenotype correlations in hypertrophic cardiomyopathy
  1. Edward Blaira,
  2. Simon J Pricea,
  3. Catherine J Batya,
  4. Ingegerd Östman-Smithb,
  5. Hugh Watkinsa
  1. aDepartment of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK, bDepartment of Paediatric Cardiology, University of Oxford, John Radcliffe Hospital, Oxford, UK
  1. Dr Blair, Molecular Cardiology, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK,eblair{at}

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Editor—Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease with a wide range of clinical features; a “benign” condition in some families, it can cause a high incidence of sudden death in others. FHC is caused by mutations in at least nine genes encoding sarcomeric proteins.1 The gene most commonly implicated in causing FHC is that encoding the β-MHC protein. Over 60 missense mutations have been described in theβ-MHC gene.1 The mutations identified cluster in exons 3-27 of this 40 exon gene; these encode the functionally important ATP, actin, essential and regulatory light chain binding sites. Based on analysis of clinical features in genotyped families (grouped by mutation), broad genotype-phenotype correlations have been proposed for individual mutations. Such analyses have shown that certain mutations of β-MHC, for example Arg403Gln and Arg453Cys, produce a “malignant” phenotype associated with a high incidence of sudden death.2 Others, such as Val606Met2 and Leu908Val,3 tend to behave in a “benign” fashion. However, a minority of families harbouring previously reported “benign” mutations show a greater than expected incidence of adverse events.3 ,4

Classical genetic studies in model organisms have shown that “second hits” in a single gene can modify an abnormal phenotype.5 Double mutations incis, that is, in the same copy of a gene, have been postulated as a possible mechanism accounting for discrepancies in genotype-phenotype studies. For example, double mutations have been described in the enzyme cystathione beta-synthase causing particularly severe homocystinuria.6 It is also possible that double mutations of disease genes may not be as rare as one might expect. A comprehensive mutation screen of 44 patients with cystic fibrosis found four had inherited one double mutant allele.7 All evidence points to mutated β-MHC genes acting in a dominant …

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