A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy

Abstract

Background: Two missense mutations in the gene for alpha-tropomyosin have been described that segregate with hypertrophic cardiomyopathy in single families. To confirm that these mutations are the cause of the disease, we have investigated the origins of one of these mutations, Asp175Asn, in a third and unrelated family.

Methods and results: The presence or absence of an alpha-tropomyosin mutation and the haplotypes of the flanking chromosomal regions were determined for members of a family with hypertrophic cardiomyopathy. Haplotypes were constructed by use of an intragenic polymorphism and 10 flanking polymorphisms spanning a region of 35 centimorgans. The Asp175Asn missense mutation was present in the proband and his two affected offspring but not in any of the proband's three siblings. Although both parents were deceased, the haplotypes of the four parental chromosomes could be reconstructed. One parental chromosome was transmitted to two offspring: one bearing the Asp175Asn mutation (the affected proband) and one clinically unaffected sibling who lacked the alpha-tropomyosin mutation. Thus, the Asp175Asn mutation must have arisen de novo.

Conclusions: De novo mutations in the alpha-tropomyosin gene can result in hypertrophic cardiomyopathy that may appear to be sporadic but in subsequent generations gives rise to familial disease. Individuals with sporadic hypertrophic cardiomyopathy should be advised of the risk of transmission to offspring. In addition, these findings provide the strongest genetic evidence that mutations in the alpha-tropomyosin gene are directly responsible for hypertrophic cardiomyopathy.