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Sudden death due to troponin T mutations
J C Moolman1, V A Corfield, B Posen
1University of Stellenbosch, Tygerberg, Republic of South Africa.
Insights
Cardiac troponin T gene mutations cause hypertrophic cardiomyopathy with mild hypertrophy but a poor prognosis, including sudden cardiac death in young individuals. Genetic screening for these mutations is crucial for patient management.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy is a leading cause of sudden cardiac death in young individuals, often with a familial inheritance pattern.
- Mutations in contractile protein genes are implicated in familial hypertrophic cardiomyopathy, suggesting potential for genetic screening.
- Previous findings indicated cardiac troponin T gene mutations are linked to poor prognosis and mild hypertrophy, necessitating further investigation due to genotype-phenotype variability.
Purpose of the Study:
- To validate initial findings on the clinical and prognostic characteristics of hypertrophic cardiomyopathy associated with cardiac troponin T gene mutations.
- To further analyze cardiac troponin T mutations given the variability observed in genotype-phenotype correlations.
Main Methods:
- Screening of deoxyribonucleic acid from hypertrophic cardiomyopathy patients for cardiac troponin T mutations using a ribonuclease protection assay.
- Utilizing polymerase chain reaction-based detection to genotype members of two pedigrees carrying a novel mutation.
- Conducting echocardiography, electrocardiology, and obtaining family histories for gene carriers.
Main Results:
- Identification of a novel cardiac troponin T gene mutation (arginine 92 tryptophan) in 19 out of 48 members across two pedigrees.
- The clinical phenotype exhibited minimal hypertrophy (mean maximal ventricular wall thickness 11.3 +/- 5.4 mm) and low clinical penetrance (40% by echocardiography).
- A high incidence of sudden cardiac death was observed, with a mean age of 17 +/- 9 years.
Conclusions:
- Diverse cardiac troponin T gene mutations consistently result in a specific disease phenotype.
- This phenotype is associated with a poor prognosis, despite mild or undetectable hypertrophy.
- Genotyping for cardiac troponin T mutations is highly informative for patient management and genetic counseling.
Objectives:
This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac tropnin T gene mutations.
Background:
The most common cause of sudden cardiac death in the young is hypertrophic cardiomyopathy, which is usually familial. Mutations causing familial hypertrophic cardiomyopathy have been identified in a number of contractile protein genes, raising the possibility of genetic screening for subjects at risk. A previous report suggested that mutations in the cardiac troponin T gene were notable because they were associated with a particularly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac troponin T mutations has been a priority.
Methods:
Deoxyribonucleic acid from 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 genotype members of two affected pedigrees. Gene carriers were examined by echocardiography and electrocardiology, and a family history was obtained.
Results:
A novel cardiac troponin T gene mutation, arginine 92 tryptophan, 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 disease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 +/- 9 years).
Conclusions:
These data support the observation that apparently diverse cardiac troponin T gene mutations produce a consistent disease phenotype. 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 counselling.