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

25OBJECTIVES: 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.openopenBegay, Rene L.; Graw, Sharon L.; Sinagra, Gianfranco; Asimaki, Angeliki; Rowland, Teisha J.; Slavov, Dobromir B.; Gowan, Katherine; Jones, Kenneth L.; Brun, Francesca; Merlo, Marco; Miani, Daniela; Sweet, Mary; Devaraj, Kalpana; Wartchow, Eric P.; Gigli, Marta; Puggia, Ilaria; Salcedo, Ernesto E.; Garrity, Deborah M.; Ambardekar, Amrut V.; Buttrick, Peter; Reece, T. Brett; Bristow, Michael R.; Saffitz, Jeffrey E.; Mestroni, Luisa; Taylor, Matthew R.G.*Begay, Rene L.; Graw, Sharon L.; Sinagra, Gianfranco; Asimaki, Angeliki; Rowland, Teisha J.; Slavov, Dobromir B.; Gowan, Katherine; Jones, Kenneth L.; Brun, Francesca; Merlo, Marco; Miani, Daniela; Sweet, Mary; Devaraj, Kalpana; Wartchow, Eric P.; Gigli, Marta; Puggia, Ilaria; Salcedo, Ernesto E.; Garrity, Deborah M.; Ambardekar, Amrut V.; Buttrick, Peter; Reece, T. Brett; Bristow, Michael R.; Saffitz, Jeffrey E.; Mestroni, Luisa; Taylor, Matthew R. G