Begay, RL;
Graw, SL;
Sinagra, G;
Asimaki, A;
Rowland, TJ;
Slavov, DB;
Gowan, K;
Jones, KL;
Brun, F;
Merlo, M;
et al.
Begay, RL; Graw, SL; Sinagra, G; Asimaki, A; Rowland, TJ; Slavov, DB; Gowan, K; Jones, KL; Brun, F; Merlo, M; Miani, D; Sweet, M; Devaraj, K; Wartchow, EP; Gigli, M; Puggia, I; Salcedo, EE; Garrity, DM; Ambardekar, AV; Buttrick, P; Reece, TB; Bristow, MR; Saffitz, JE; Mestroni, L; Taylor, MRG
(2018)
Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.
JACC Clin Electrophysiol, 4 (4).
pp. 504-514.
ISSN 2405-5018
https://doi.org/10.1016/j.jacep.2017.12.003
SGUL Authors: Asimaki, Angeliki
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Abstract
OBJECTIVES: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.
Item Type: | Article | |||||||||||||||||||||
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Additional Information: | © 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | |||||||||||||||||||||
Keywords: | Filamin C, arrhythmias, arrhythmogenic dilated cardiomyopathy, cardiovascular genetics, familial dilated cardiomyopathy, heart failure | |||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | |||||||||||||||||||||
Journal or Publication Title: | JACC Clin Electrophysiol | |||||||||||||||||||||
ISSN: | 2405-5018 | |||||||||||||||||||||
Language: | eng | |||||||||||||||||||||
Publisher License: | Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 | |||||||||||||||||||||
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PubMed ID: | 30067491 | |||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/110422 | |||||||||||||||||||||
Publisher's version: | https://doi.org/10.1016/j.jacep.2017.12.003 |
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