RT Journal Article
T1 Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies
A1 Ortiz-Genga, Martin F.
A1 Cuenca, Sofia
A1 Dal Ferro, Matteo
A1 Zorio, Esther
A1 Salgado-Aranda, Ricardo
A1 Climent, Vicente
A1 Padron-Barthe, Laura
A1 Duro-Aguado, Iria
A1 Jimenez-Jaimez, Juan
A1 Hidalgo-Olivares, Victor M.
A1 Garcia-Campo, Enrique
A1 Lanzillo, Chiara
A1 Suarez-Mier, M. Paz
A1 Yonath, Hagith
A1 Marcos-Alonso, Sonia
A1 Ochoa, Juan P.
A1 Santome, Jose L.
A1 Garcia-Giustiniani, Diego
A1 Rodriguez-Garrido, Jorge L.
A1 Dominguez, Fernando
A1 Merlo, Marco
A1 Palomino, Julian
A1 Pena, Maria L.
A1 Trujillo, Juan P.
A1 Martin-Vila, Alicia
A1 Stolfo, Davide
A1 Molina, Pilar
A1 Lara-Pezzi, Enrique
A1 Calvo-Iglesias, Francisco E.
A1 Nof, Eyal
A1 Calo, Leonardo
A1 Barriales-Villa, Roberto
A1 Gimeno-Blanes, Juan R.
A1 Arad, Michael
A1 Garcia-Pavia, Pablo
A1 Monserrat, Lorenzo
K1 filamin C
K1 filaminopathy
K1 genotype
K1 prognosis
K1 sudden death
K1 ventricular arrhythmia
K1 Actin-binding protein
K1 Filamin c cause
K1 Muscle
K1 Myopathy
K1 Isoforms
K1 Domain
AB 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.
PB Elsevier science inc
SN 0735-1097
YR 2016
FD 2016-12-06
LK http://hdl.handle.net/10668/18807
UL http://hdl.handle.net/10668/18807
LA en
DS RISalud
RD Apr 7, 2025