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

Fecha de publicación: 06/12/2016

Autores de IIS La Fe

Esther Zorio Grima

Autor

Participantes ajenos a IIS La Fe

Ortiz-Genga, MF
Cuenca, S
Dal Ferro, M
Salgado-Aranda, R
Climent, V
Padron-Barthe, L
Duro-Aguado, I
Jimenez-Jaimez, J
Hidalgo-Olivares, VM
Garcia-Campo, E
Lanzillo, C
Suarez-Mier, MP
Yonath, H
Marcos-Alonso, S
Ochoa, JP
Santome, JL
Garcia-Giustiniani, D
Rodriguez-Garrido, JL
Dominguez, F
Merlo, M
Palomino, J
Pena, ML
Trujillo, JP
Martin-Vila, A
Stolfo, D
Molina, P
Lara-Pezzi, E
Calvo-Iglesias, FE
Nof, E
Calo, L
Barriales-Villa, R
Gimeno-Blanes, JR
Arad, M
Garcia-Pavia, P
Monserrat, L

Grupos

Cardiopatías familiares, muerte súbita y mecanismos de enfermedad (CAFAMUSME)

Investigador Principal

Aitana Braza Boils

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. (C) 2016 by the American College of Cardiology Foundation.

Datos de la publicación

ISSN/ISSNe:: 0735-1097, 1558-3597
Tipo:: Article
Páginas:: 2440-2451
DOI:: 10.1016/j.jacc.2016.09.927
Factor de Impacto:: 12,020 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

Keywords

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

Campos de estudio

Proyectos asociados

RED INVESTIGACION (RECAVA)

RD06/0014/0004 . INSTITUTO DE SALUD CARLOS III; FUNDACION PARA LA INV BIOMEDICA- HOSPITAL GREGORIO MARAÑON; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006