Patients with familial hypertrophic cardiomyopathy caused by a Phe110Ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis.

BACKGROUND Mutations that cause familial hypertrophic cardiomyopathy have been identified in several genes that encode contractile proteins. Patients with mutations in the cardiac troponin T (cTnT) gene have particularly poor prognosis but only mild hypertrophy. To date, no benign mutation in the cTnT gene has been reported. The clinical characteristics and prognosis of patients with the Phe110Ile mutation in the cTnT gene is unclear because few affected individuals have been identified. METHODS AND RESULTS Forty-six probands with familial hypertrophic cardiomyopathy were screened for mutations in the cTnT gene. The Phe110Ile missense mutation was found in 6 probands. Individuals in the 6 families were analyzed genetically and clinically. Haplotype analysis was performed with markers encompassing the cTnT gene. Left ventricular hypertrophy was classified as type I, II, III, or IV according to the criteria of Maron et al. The Phe110Ile mutation in the cTnT gene was identified in 16 individuals. Two of the 6 families shared the same flanking haplotype, and 4 were different from each other. Affected individuals exhibited different cardiac morphologies: 4 had type II, 6 had type III, and 3 had type IV hypertrophy with apical involvement. Three individuals with the disease-causing mutation did not fulfill clinical criteria for the disease. The product-limit survival curve analysis demonstrated a favorable prognosis. CONCLUSIONS Multiple independent mutations of residue 340 in the cTnT gene have been described, suggesting that this may be a "hot spot" for such events. The Phe110Ile substitution causes hypertrophic cardiomyopathy with variable cardiac morphologies and a favorable prognosis.