Author + information
- Received January 26, 2016
- Revision received September 2, 2016
- Accepted September 6, 2016
- Published online December 6, 2016.
- Martín F. Ortiz-Genga, MDa,b,∗ (, )
- Sofía Cuenca, MD, PhDc,
- Matteo Dal Ferro, MDd,
- Esther Zorio, MD, PhDe,
- Ricardo Salgado-Aranda, MDf,
- Vicente Climent, MDg,
- Laura Padrón-Barthe, PhDh,
- Iria Duro-Aguado, MDi,
- Juan Jiménez-Jáimez, MD, PhDj,
- Víctor M. Hidalgo-Olivares, MDk,
- Enrique García-Campo, MDl,
- Chiara Lanzillo, MD, PhDm,
- M. Paz Suárez-Mier, MD, PhDn,
- Hagith Yonath, MDo,
- Sonia Marcos-Alonso, MD, PhDp,
- Juan P. Ochoa, MDb,
- José L. Santomé, BScb,
- Diego García-Giustiniani, MDb,
- Jorge L. Rodríguez-Garrido, MDb,p,
- Fernando Domínguez, MDc,
- Marco Merlo, MDd,
- Julián Palomino, MD, PhDl,
- María L. Peña, MDq,
- Juan P. Trujillo, MD, PhDb,
- Alicia Martín-Vila, PharmDl,
- Davide Stolfo, MDd,
- Pilar Molina, MD, PhDr,
- Enrique Lara-Pezzi, PhDh,s,
- Francisco E. Calvo-Iglesias, MD, PhDl,
- Eyal Nof, MDo,
- Leonardo Calò, MDm,
- Roberto Barriales-Villa, MD, PhDa,p,
- Juan R. Gimeno-Blanes, MD, PhDt,
- Michael Arad, MD, PhDo,
- Pablo García-Pavía, MD, PhDc,u and
- Lorenzo Monserrat, MD, PhDa,b
- aInstituto de Investigación Biomédica (INIBIC), A Coruña, Spain
- bHealth in Code SL, A Coruña, Spain
- cHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- dCardiovascular Department, Azienda Ospedaliero – Universitaria Ospedali Riuniti, Trieste, Italy
- eHospital Universitario y Politécnico La Fe, Valencia, Spain
- fHospital Universitario de Burgos, Burgos, Spain
- gHospital General Universitario de Alicante, Alicante, Spain
- hMyocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
- iHospital Clínico Universitario de Valladolid, Valladolid, Spain
- jHospital Universitario Virgen de las Nieves, Granada, Spain
- kComplejo Hospitalario Universitario de Albacete, Albacete, Spain
- lComplexo Hospitalario Universitario de Vigo, Vigo, Spain
- mPoliclinico Casilino, ASL Roma B, Rome, Italy
- nInstituto Nacional de Toxicología y Ciencias Forenses, Madrid, Spain
- oSheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel
- pComplexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain
- qHospital Universitario Virgen del Rocio, Sevilla, Spain
- rServicio de Patología, Instituto de Medicina Legal, Valencia, Spain
- sNational Heart and Lung Institute, Imperial College London, London, United Kingdom
- tHospital Universitario Virgen de la Arrixaca, Murcia, Spain
- uFrancisco de Vitoria University, Madrid, Spain
- ↵∗Reprint requests and correspondence:
Dr. Martín F. Ortiz-Genga, Health in Code SL, As Xubias s/n, Edificio O Fortín, Hospital Marítimo de Oza, 15006, A Coruña, Spain.
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.
This work was supported by Instituto de Salud Carlos III (grants PI11/0699, PI14/0967, PI14/01477, RD012/0042/0029, RD012/0042/0049, RD012/0042/0066, and RD12/0042/0069) and the Spanish Ministry of Economy and Competitiveness (grant SAF2015-71863-REDT). Grants are supported by Plan Nacional de I+D+I 2008-2011 and Plan Estatal de I+D+I 2013-2016, European Regional Development Fund (“A Way of Making Europe”). Drs. Ortiz-Genga, Rodríguez-Garrido, Palomino, Peña, and Barriales-Villa receive personal fees from Health in Code SL. Drs. Ochoa, Santomé, García-Giustiniani, and Trujillo are employees of Health in Code SL. Dr. Monserrat is the CEO and a stakeholder of Health in Code SL. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received January 26, 2016.
- Revision received September 2, 2016.
- Accepted September 6, 2016.
- American College of Cardiology Foundation