FLNC truncating variants were identified in 2.2% of dilated cardiomyopathy families and were associated with ventricular arrhythmias or sudden cardiac death in 85% of carriers.
Observational (n=319)
Yes
What is the clinical and cellular phenotype associated with FLNC truncating variants in patients with dilated cardiomyopathy?
FLNC truncating variants are associated with a highly arrhythmogenic form of dilated cardiomyopathy, highlighting the importance of genetic screening for risk stratification.
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.
Begay et al. (2018) conducted an observational in Dilated cardiomyopathy (n=319). FLNC truncation variants was evaluated on Ventricular arrhythmias or sudden cardiac death. FLNC truncating variants were identified in 2.2% of dilated cardiomyopathy families and were associated with ventricular arrhythmias or sudden cardiac death in 85% of carriers.
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