Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

Martín F. Ortiz-Genga*, Sofía Cuenca, Matteo Dal Ferro, Esther Zorio, Ricardo Salgado-Aranda, Vicente Climent, Laura Padrón-Barthe, Iria Duro-Aguado, Juan Jiménez-Jáimez, Víctor M. Hidalgo-Olivares, Enrique García-Campo, Chiara Lanzillo, M. Paz Suárez-Mier, Hagith Yonath, Sonia Marcos-Alonso, Juan P. Ochoa, José L. Santomé, Diego García-Giustiniani, Jorge L. Rodríguez-Garrido, Fernando DomínguezMarco Merlo, Julián Palomino, María L. Peña, Juan P. Trujillo, Alicia Martín-Vila, Davide Stolfo, Pilar Molina, Enrique Lara-Pezzi, Francisco E. Calvo-Iglesias, Eyal Nof, Leonardo Calò, Roberto Barriales-Villa, Juan R. Gimeno-Blanes, Michael Arad, Pablo García-Pavía, Lorenzo Monserrat

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. Objectives The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. Methods FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. Results Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. Conclusions Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

Original languageEnglish
Pages (from-to)2440-2451
Number of pages12
JournalJournal of the American College of Cardiology
Issue number22
StatePublished - 6 Dec 2016


FundersFunder number
Plan Nacional de I+D+I
Ministerio de Economía y CompetitividadSAF2015-71863-REDT
Plan Estatal de I+D+I
European Regional Development Fund
Instituto de Salud Carlos IIIRD012/0042/0029, PI14/01477, PI11/0699, RD12/0042/0069, RD012/0042/0066, RD012/0042/0049, PI14/0967


    • filamin C
    • filaminopathy
    • genotype
    • prognosis
    • sudden death
    • ventricular arrhythmia


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