Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures

JACC Clin Electrophysiol. 2018 Apr;4(4):504-514. doi: 10.1016/j.jacep.2017.12.003. Epub 2018 Feb 2.


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.

Keywords: Filamin C; arrhythmias; arrhythmogenic dilated cardiomyopathy; cardiovascular genetics; familial dilated cardiomyopathy; heart failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrhythmias, Cardiac
  • Cardiomyopathy, Dilated* / epidemiology
  • Cardiomyopathy, Dilated* / genetics
  • Cardiomyopathy, Dilated* / pathology
  • Cell Adhesion / genetics
  • DNA Mutational Analysis
  • Europe
  • Filamins / genetics*
  • Humans
  • Immunohistochemistry
  • Mutation / genetics*
  • Myocardium* / cytology
  • Myocardium* / pathology
  • Polymorphism, Single Nucleotide / genetics
  • Prospective Studies
  • United States


  • FLNC protein, human
  • Filamins

Supplementary concepts

  • Familial dilated cardiomyopathy