Homozygous mutation in cardiac troponin T - Implications for hypertrophic cardiomyopathy

Background-Mutations in the gene that encode cardiac troponin T (cTnT) acco unt for approximate to 15% of cases of familial hypertrophic cardiomyopathy (HCM). These mutations are associated with a particularly severe form of H CM characterized by a high incidence of sudden death and a poor overall pro gnosis, despite subclinical or mild left ventricular hypertrophy. Methods and Results-We evaluated a family with HCM and multiple occurrences of sudden death in children. DNA samples were isolated from peripheral blo od or paraffin-embedded tissue, and all protein-encoding exons of the cTnT gene were sequenced. A mutation was identified in exon 11 and is predicted to substitute a phenylalanine-for-serine mutation at residue 179 (Ser(179)P he) in cTnT. Both parents and 3 of 4 surviving and clinically unaffected ch ildren were heterozygous for this mutation; another clinically unaffected c hild did not carry the mutation. Genetic analysis of DNA from a child who d ied suddenly at age 17 years demonstrated he was homozygous for this mutati on. A review of his echocardiogram revealed profound left and right ventric ular hypertrophy. Conclusions-An homozygous Ser(179)Phe mutation in cTnT causes a severe form of HCM characterized by striking morphological abnormalities and juvenile lethality. In contrast, the natural history of the heterozygous mutation is benign. These studies emphasize the relevance of genetic diagnosis in hype rtrophic cardiomyopathy and provide a new perspective on the clinical conse quences of troponin T mutations.