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Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy
Akl C Fahed1,2, Georges Nemer3,4, Fadi F Bitar3,5
1Division of Cardiology, Department of Medicine, Center of Genomic Medicine, Massachusetts General Hospital (A.C.F.), Harvard Medical School, Boston.
Insights
The TNNI3 p.Arg21Cys mutation causes severe hypertrophic cardiomyopathy and sudden cardiac death (SCD) in South Lebanon. Early genetic diagnosis is crucial for risk stratification in affected families.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Cardiac troponin I (TNNI3) gene mutations are linked to hypertrophic cardiomyopathy (HCM) and sudden cardiac death (SCD).
- A specific TNNI3 mutation, p.Arg21Cys, found in the N-terminus, affects protein kinase A (PKA) phosphorylation and calcium sensitivity in model organisms.
- The clinical impact of the TNNI3 p.Arg21Cys mutation in human HCM patients was previously unknown.
Purpose of the Study:
- To investigate the clinical phenotype and outcomes of the TNNI3 p.Arg21Cys mutation in hypertrophic cardiomyopathy.
- To determine the risk of sudden cardiac death associated with this specific TNNI3 mutation.
Main Methods:
- Sequencing of 29 hypertrophic cardiomyopathy families identified five families with the TNNI3 p.Arg21Cys mutation.
- Cascade screening of 57 affected individuals to assess clinical phenotypes.
- Survival analysis was performed to evaluate the age of onset for sudden cardiac death in mutation carriers.
Main Results:
- The TNNI3 p.Arg21Cys mutation was found in five families from South Lebanon, indicating a founder effect.
- A malignant phenotype was observed, with 53% of affected individuals experiencing sudden cardiac death at a median age of 22.5 years.
- Sudden cardiac death occurred even in carriers without evident left ventricular hypertrophy, with subclinical disease features identified through advanced imaging and autopsy.
Conclusions:
- The TNNI3 p.Arg21Cys mutation has a founder effect in South Lebanon and is associated with malignant hypertrophic cardiomyopathy and early sudden cardiac death.
- This mutation can cause sudden cardiac death even in the absence of detectable left ventricular hypertrophy.
- Genetic testing for the TNNI3 p.Arg21Cys mutation may be sufficient for risk stratification of sudden cardiac death.
Background:
Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD). Only one mutation (p.Arg21Cys) has been reported in the N terminus of the protein. In model organisms, it impairs PKA (protein kinase A) phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction. The phenotype of this unique mutation in patients with hypertrophic cardiomyopathy remains unknown.
Methods:
We sequenced 29 families with hypertrophic cardiomyopathy enriched for pediatric-onset disease and identified 5 families with the TNNI3 p.Arg21Cys mutation. Using cascade screening, we studied the clinical phenotype of 57 individuals from the 5 families with TNNI3 p.Arg21Cys-related cardiomyopathy. We performed survival analysis investigating the age at first SCD in carriers of the mutation.
Results:
All 5 families with TNNI3 p.Arg21Cys were from South Lebanon. TNNI3 p.Arg21Cys-related cardiomyopathy manifested a malignant phenotype-SCD occurred in 30 (53%) of 57 affected individuals at a median age of 22.5 years. In select carriers without left ventricular hypertrophy on echocardiogram, SCD occurred, myocyte disarray was found on autopsy heart, and tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement.
Conclusions:
The TNNI3 p.Arg21Cys mutation has a founder effect in South Lebanon and causes malignant hypertrophic cardiomyopathy with early SCD even in the absence of hypertrophy. Genetic diagnosis with this mutation may be sufficient for risk stratification for SCD.
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