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{Hawley:2020:10.1002/humu.24061,
author = {Hawley, MH and Almontashiri, N and Biesecker, LG and Berger, N and Chung, WK and Garcia, J and Grebe, TA and Kelly, MA and Lebo, MS and Macaya, D and Mei, H and Platt, J and Richard, G and Ryan, A and Thomson, KL and Vatta, M and Walsh, R and Ware, JS and Wheeler, M and Zouk, H and Mason-Suares, H and Funke, B},
doi = {10.1002/humu.24061},
journal = {Human Mutation},
pages = {1577--1587},
title = {An assessment of the role of vinculin (VCL) loss of function variants in inherited cardiomyopathy.},
url = {http://dx.doi.org/10.1002/humu.24061},
volume = {41},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin gene (VCL) illustrates these challenges. Model organism data provides evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (OR= 9.01; CI=4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.
AU  - Hawley,MH
AU  - Almontashiri,N
AU  - Biesecker,LG
AU  - Berger,N
AU  - Chung,WK
AU  - Garcia,J
AU  - Grebe,TA
AU  - Kelly,MA
AU  - Lebo,MS
AU  - Macaya,D
AU  - Mei,H
AU  - Platt,J
AU  - Richard,G
AU  - Ryan,A
AU  - Thomson,KL
AU  - Vatta,M
AU  - Walsh,R
AU  - Ware,JS
AU  - Wheeler,M
AU  - Zouk,H
AU  - Mason-Suares,H
AU  - Funke,B
DO  - 10.1002/humu.24061
EP  - 1587
PY  - 2020///
SN  - 1059-7794
SP  - 1577
TI  - An assessment of the role of vinculin (VCL) loss of function variants in inherited cardiomyopathy.
T2  - Human Mutation
UR  - http://dx.doi.org/10.1002/humu.24061
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32516855
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.24061
UR  - http://hdl.handle.net/10044/1/79966
VL  - 41
ER  -
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