title: Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain; Health in Code SL, A Coruña, Spain. Electronic address: martin.ortiz@healthincode.com.
authors.forename: Martín F
authors.initials: MF
authors.lastname: Ortiz-Genga
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Cuenca
authors.affiliation: Cardiovascular Department, Azienda Ospedaliero - Universitaria Ospedali Riuniti, Trieste, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Ferro
authors.affiliation: Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Zorio
authors.affiliation: Hospital Universitario de Burgos, Burgos, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Salgado-Aranda
authors.affiliation: Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Climent
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Padrón-Barthe
authors.affiliation: Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
authors.forename: Iria
authors.initials: I
authors.lastname: Duro-Aguado
authors.affiliation: Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Jiménez-Jáimez
authors.affiliation: Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Hidalgo-Olivares
authors.affiliation: Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: García-Campo
authors.affiliation: Policlinico Casilino, ASL Roma B, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzillo
authors.affiliation: Instituto Nacional de Toxicología y Ciencias Forenses, Madrid, Spain.
authors.forename: M Paz
authors.initials: MP
authors.lastname: Suárez-Mier
authors.affiliation: Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Hagith
authors.initials: H
authors.lastname: Yonath
authors.affiliation: Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Marcos-Alonso
authors.affiliation: Health in Code SL, A Coruña, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Ochoa
authors.affiliation: Health in Code SL, A Coruña, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Santomé
authors.affiliation: Health in Code SL, A Coruña, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: García-Giustiniani
authors.affiliation: Health in Code SL, A Coruña, Spain; Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Rodríguez-Garrido
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Domínguez
authors.affiliation: Cardiovascular Department, Azienda Ospedaliero - Universitaria Ospedali Riuniti, Trieste, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.affiliation: Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Palomino
authors.affiliation: Hospital Universitario Virgen del Rocio, Sevilla, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Peña
authors.affiliation: Health in Code SL, A Coruña, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Trujillo
authors.affiliation: Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martín-Vila
authors.affiliation: Cardiovascular Department, Azienda Ospedaliero - Universitaria Ospedali Riuniti, Trieste, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Stolfo
authors.affiliation: Servicio de Patología, Instituto de Medicina Legal, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Molina
authors.affiliation: Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
authors.affiliation: Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Calvo-Iglesias
authors.affiliation: Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Nof
authors.affiliation: Policlinico Casilino, ASL Roma B, Rome, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Calò
authors.affiliation: Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain; Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Barriales-Villa
authors.affiliation: Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Gimeno-Blanes
authors.affiliation: Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Francisco de Vitoria University, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: García-Pavía
authors.affiliation: Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain; Health in Code SL, A Coruña, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Monserrat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D064448:Filamins / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D017180:Tachycardia, Ventricular / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C578661:FLNC protein, human; D064448:Filamins; D004247:DNA
keywords: filamin C; filaminopathy; genotype; prognosis; sudden death; ventricular arrhythmia