SUDDEN-DEATH DUE TO TROPONIN-T MUTATIONS

Objectives. This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy ca used by cardiac troponin T gene mutations. Background. The most common cause of sudden cardiac death in the young is hypertrophic cardiomyop athy, which is usually familial. Mutations causing familial hypertroph ic cardiomyopathy have been identified in a number of contractile prot ein genes, raising the possibility of genetic screening for subjects a t risk A previous report suggested that mutations in the cardiac tropo nin T gene were notable because they were associated with a particular ly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac trop onin T mutations has been a priority.Methods. Deoxyribonucleic acid fr om subjects with hypertrophic cardiomyopathy was screened for cardiac troponin T mutations using a ribonuclease protection assay. Polymerase chain reaction-based detection of a novel mutation was used to genoty pe members of two affected pedigrees. Gene carriers were examined by e chocardiography and electrocardiology, and a family history was obtain ed. Results. A novel cardiac troponin T gene mutation, arginine 92 try ptophan, was identified in 19 of 48 members of two affected pedigrees. The clinical phenotype was characterized by minimal hypertrophy (mean [+/-SD] maximal ventricular wall thickness 11.3 +/- 5.4 mm) and low d isease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 +/- 9 years). Con clusions. These data support the observation that apparently diverse c ardiac troponin T gene mutations produce a consistent disease phenotyp e. Because this is one of poor prognosis, despite deceptively mild or undetectable hypertrophy, genotyping at this locus may be particularly informative in patient management and counseling. (C) 1997 by the Ame rican College of Cardiology.