An assessment of the role of vinculin (VCL) loss of function variants in inherited cardiomyopathy.
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2020-08-26
Date Acceptance
2020-06-05
Citation
Human Mutation, 2020, 41 (9), pp.1577-1587
ISSN
1059-7794
Publisher
Wiley
Start Page
1577
End Page
1587
Journal / Book Title
Human Mutation
Volume
41
Issue
9
Copyright Statement
© 2020 Wiley Periodicals LLC. This is the accepted version of the following article: Hawley, MH, Almontashiri, N, Biesecker, LG, et al. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Human Mutation. 2020; 41: 1577– 1587, which has been published in final form at https://doi.org/10.1002/humu.24061
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32516855
Subjects
Cardiomyopathy Gene Panel Testing
Dilated Cardiomyopathy
Dilated Cardiomyopathy Genetics
Pediatric Cardiomyopathy
Risk Allele
VCL
Vinculin
Vinculin Loss of function
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-06-09