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oai:repisalud.isciii.es:20.500.12105/79792024-09-27T09:49:29Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ortiz-Genga, Martín F author Cuenca, Sofía author Dal Ferro, Matteo author Zorio, Esther author Salgado-Aranda, Ricardo author Climent, Vicente author Padron-Barthe, Laura author Duro-Aguado, Iria author Jiménez-Jáimez, Juan author Hidalgo-Olivares, Víctor M author García-Campo, Enrique author Lanzillo, Chiara author Suárez-Mier, M Paz author Yonath, Hagith author Marcos-Alonso, Sonia author Ochoa, Juan P author Santomé, José L author García-Giustiniani, Diego author Rodríguez-Garrido, Jorge L author Domínguez, Fernando author Merlo, Marco author Palomino, Julián author Peña, María L author Trujillo, Juan P author Martín-Vila, Alicia author Stolfo, Davide author Molina, Pilar author Lara-Pezzi, Enrique author Calvo-Iglesias, Francisco E author Nof, Eyal author Calò, Leonardo author Barriales-Villa, Roberto author Gimeno-Blanes, Juan R author Arad, Michael author García-Pavía, Pablo author Monserrat, Lorenzo author 2016-12 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. J Am Coll Cardiol. 2016; 68(22):2440-2451 10.1016/j.jacc.2016.09.927 1558-3597 0735-1097 Journal of the American College of Cardiology 27908349 http://hdl.handle.net/20.500.12105/7979 Filamin C Filaminopathy Genotype Prognosis Sudden death Ventricular arrhythmia Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies