A DE-NOVO MUTATION IN ALPHA-TROPOMYOSIN THAT CAUSES HYPERTROPHIC CARDIOMYOPATHY

Background Two missense mutations in the gene for alpha-tropomyosin ha ve been described that segregate with hypertrophic cardiomyopathy in s ingle families. To confirm that these mutations are the cause of the d isease, we have investigated the origins of one of these mutations, As p175Asn, in a third and unrelated family. Methods and Results The pres ence or absence of an alpha-tropomyosin mutation and the haplotypes of the flanking chromosomal regions were determined for members of a fam ily with hypertrophic cardiomyopathy. Haplotypes were constructed by u se of an intragenic polymorphism and 10 flanking polymorphisms spannin g a region of 35 centimorgans. The Asp175Asn missense mutation was pre sent in the proband and his two affected offspring but not in any of t he proband's three siblings. Although both parents were deceased, the haplotypes of the four parental chromosomes could be reconstructed. On e parental chromosome was transmitted to two offspring: one bearing th e Asp175Asn mutation (the affected proband) and one clinically unaffec ted sibling who lacked the alpha-tropomyosin mutation. Thus, the Asp17 5Asn mutation must have arisen de novo. Conclusions De novo mutations in the alpha-tropomyosin gene can result in hypertrophic cardiomyopath y that may appear to be sporadic but in subsequent generations gives r ise to familial disease. Individuals with sporadic hypertrophic cardio myopathy should be advised of the risk of transmission to offspring. I n addition, these findings provide the strongest genetic evidence that mutations in the alpha-tropomyosin gene are directly responsible for hypertrophic cardiomyopathy.