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.