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