Background: Familial hypertrophic cardiomyopathy can be caused by mutations in the genes for beta cardiac myosin heavy chain, alpha-tropomyosin, or cardiac troponin T. It is not known how often the disease is caused by mutations in the tropomyosin and troponin genes, and the associated clinical phenotypes have not been carefully studied.

Methods: Linkage between polymorphisms of the alpha-tropomyosin gene or the cardiac troponin T gene and hypertrophic cardiomyopathy was assessed in 27 families. In addition, 100 probands were screened for mutations in the alpha-tropomyosin gene, and 26 were screened for mutations in the cardiac troponin T gene. Life expectancy, the incidence of sudden death, and the extent of left ventricular hypertrophy were compared in patients with different mutations.

Results: Genetic analyses identified only one alpha-tropomyosin mutation, identical to one previously described. Five novel mutations in cardiac troponin were identified, as well as a further example of a previously described mutation. The clinical phenotype of four troponin T mutations in seven unrelated families was similar and was characterized by a poor prognosis (life expectancy, approximately 35 years) and a high incidence of sudden death. The mean (+/- SD) maximal thickness of the left ventricular wall in subjects with cardiac troponin T mutations (16.7 +/- 5.5 mm) was significantly less than that in subjects with beta cardiac myosin heavy-chain mutations (23.7 +/- 7.7 mm, P < 0.001).

Conclusions: Mutations in alpha-tropomyosin are a rare cause of familial hypertrophic cardiomyopathy, accounting for approximately 3 percent of cases. Mutations in cardiac troponin T account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy in this referral-center population. These mutations are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group.

• 600/TI_/Telethon/Italy