Imperial College London
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ProfessorJamesWare

Faculty of Medicine, National Heart & Lung Institute

Professor of Cardiovascular and Genomic Medicine
 
 
 
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Contact

 

j.ware Website

 
 
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Assistant

 

Ms Lisa Quinn +44 (0)20 7594 1345

 
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Location

 

3 13GLMS BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Fahed:2020:10.1161/CIRCGEN.120.002991,
author = {Fahed, AC and Nemer, G and Bitar, FF and Arnaout, S and Abchee, AB and Batrawi, M and Khalil, A and Abou-Hassan, O and DePalma, SR and McDonough, B and Arabi, MT and Ware, JS and Seidman, JG and Seidman, CE},
doi = {10.1161/CIRCGEN.120.002991},
journal = {Circulation: Genomic and Precision Medicine},
pages = {444--452},
title = {Founder mutation in N-terminus of cardiac troponin I causes malignant hypertrophic cardiomyopathy},
url = {http://dx.doi.org/10.1161/CIRCGEN.120.002991},
volume = {13},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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. Only one mutation (p.Arg21Cys) has been reported in the N-terminus of the protein. In model organisms, it impairs protein kinase A phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction. The phenotype of this unique mutation in hypertrophic cardiomyopathy patients 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 sudden cardiac death in carriers of the mutation.Results - All five families with TNNI3 p.Arg21Cys were from south Lebanon. TNNI3 p.Arg21Cys-related cardiomyopathy manifested a malignant phenotype - sudden cardiac death occurred in 30 (53%) of 57 affected individuals at median age of 22.5 years. In select carriers without left ventricular hypertrophy on echocardiogram, sudden cardiac death 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 sudden cardiac death even in the absence of hypertrophy. Genetic diagnosis with this mutation may be sufficient for risk stratification for sudden cardiac death.
AU  - Fahed,AC
AU  - Nemer,G
AU  - Bitar,FF
AU  - Arnaout,S
AU  - Abchee,AB
AU  - Batrawi,M
AU  - Khalil,A
AU  - Abou-Hassan,O
AU  - DePalma,SR
AU  - McDonough,B
AU  - Arabi,MT
AU  - Ware,JS
AU  - Seidman,JG
AU  - Seidman,CE
DO  - 10.1161/CIRCGEN.120.002991
EP  - 452
PY  - 2020///
SN  - 2574-8300
SP  - 444
TI  - Founder mutation in N-terminus of cardiac troponin I causes malignant hypertrophic cardiomyopathy
T2  - Circulation: Genomic and Precision Medicine
UR  - http://dx.doi.org/10.1161/CIRCGEN.120.002991
UR  - https://www.ahajournals.org/doi/10.1161/CIRCGEN.120.002991
UR  - http://hdl.handle.net/10044/1/82743
VL  - 13
ER  -
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