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Multicenter Study
. 2016 Dec 6;68(22):2440-2451.
doi: 10.1016/j.jacc.2016.09.927.

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

Martín F Ortiz-Genga  1 , Sofía Cuenca  2 , Matteo Dal Ferro  3 , Esther Zorio  4 , Ricardo Salgado-Aranda  5 , Vicente Climent  6 , Laura Padrón-Barthe  7 , Iria Duro-Aguado  8 , Juan Jiménez-Jáimez  9 , Víctor M Hidalgo-Olivares  10 , Enrique García-Campo  11 , Chiara Lanzillo  12 , M Paz Suárez-Mier  13 , Hagith Yonath  14 , Sonia Marcos-Alonso  15 , Juan P Ochoa  16 , José L Santomé  16 , Diego García-Giustiniani  16 , Jorge L Rodríguez-Garrido  17 , Fernando Domínguez  2 , Marco Merlo  3 , Julián Palomino  11 , María L Peña  18 , Juan P Trujillo  16 , Alicia Martín-Vila  11 , Davide Stolfo  3 , Pilar Molina  19 , Enrique Lara-Pezzi  20 , Francisco E Calvo-Iglesias  11 , Eyal Nof  14 , Leonardo Calò  12 , Roberto Barriales-Villa  21 , Juan R Gimeno-Blanes  22 , Michael Arad  14 , Pablo García-Pavía  23 , Lorenzo Monserrat  24
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Free article
Multicenter Study

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

Martín F Ortiz-Genga et al. J Am Coll Cardiol. .
Free article

Abstract

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.

Keywords: filamin C; filaminopathy; genotype; prognosis; sudden death; ventricular arrhythmia.

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