Martín F Ortiz-Genga1, Sofía Cuenca2, Matteo Dal Ferro3, Esther Zorio4, Ricardo Salgado-Aranda5, Vicente Climent6, Laura Padrón-Barthe7, Iria Duro-Aguado8, Juan Jiménez-Jáimez9, Víctor M Hidalgo-Olivares10, Enrique García-Campo11, Chiara Lanzillo12, M Paz Suárez-Mier13, Hagith Yonath14, Sonia Marcos-Alonso15, Juan P Ochoa16, José L Santomé16, Diego García-Giustiniani16, Jorge L Rodríguez-Garrido17, Fernando Domínguez2, Marco Merlo3, Julián Palomino11, María L Peña18, Juan P Trujillo16, Alicia Martín-Vila11, Davide Stolfo3, Pilar Molina19, Enrique Lara-Pezzi20, Francisco E Calvo-Iglesias11, Eyal Nof14, Leonardo Calò12, Roberto Barriales-Villa21, Juan R Gimeno-Blanes22, Michael Arad14, Pablo García-Pavía23, Lorenzo Monserrat24. 1. Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain; Health in Code SL, A Coruña, Spain. Electronic address: martin.ortiz@healthincode.com. 2. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 3. Cardiovascular Department, Azienda Ospedaliero - Universitaria Ospedali Riuniti, Trieste, Italy. 4. Hospital Universitario y Politécnico La Fe, Valencia, Spain. 5. Hospital Universitario de Burgos, Burgos, Spain. 6. Hospital General Universitario de Alicante, Alicante, Spain. 7. Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. 8. Hospital Clínico Universitario de Valladolid, Valladolid, Spain. 9. Hospital Universitario Virgen de las Nieves, Granada, Spain. 10. Complejo Hospitalario Universitario de Albacete, Albacete, Spain. 11. Complexo Hospitalario Universitario de Vigo, Vigo, Spain. 12. Policlinico Casilino, ASL Roma B, Rome, Italy. 13. Instituto Nacional de Toxicología y Ciencias Forenses, Madrid, Spain. 14. Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel. 15. Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain. 16. Health in Code SL, A Coruña, Spain. 17. Health in Code SL, A Coruña, Spain; Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain. 18. Hospital Universitario Virgen del Rocio, Sevilla, Spain. 19. Servicio de Patología, Instituto de Medicina Legal, Valencia, Spain. 20. Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; National Heart and Lung Institute, Imperial College London, London, United Kingdom. 21. 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. 22. Hospital Universitario Virgen de la Arrixaca, Murcia, Spain. 23. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Francisco de Vitoria University, Madrid, Spain. 24. Instituto de Investigación Biomédica (INIBIC), A Coruña, Spain; Health in Code SL, A Coruña, Spain.
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.
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.
Authors: Ana Morales; Daniel D Kinnamon; Elizabeth Jordan; Julia Platt; Matteo Vatta; Michael O Dorschner; Carl A Starkey; Jonathan O Mead; Tomohiko Ai; Wylie Burke; Julie Gastier-Foster; Gail P Jarvik; Heidi L Rehm; Deborah A Nickerson; Ray E Hershberger Journal: Circ Genom Precis Med Date: 2020-03-11
Authors: Fernando Domínguez; Sofía Cuenca; Zofia Bilińska; Rocío Toro; Eric Villard; Roberto Barriales-Villa; Juan Pablo Ochoa; Folkert Asselbergs; Arjan Sammani; Maria Franaszczyk; Mohammed Akhtar; Maria José Coronado-Albi; Diego Rangel-Sousa; Jose F Rodriguez-Palomares; Juan Jiménez-Jáimez; José Manuel Garcia-Pinilla; Tomás Ripoll-Vera; Maria Victoria Mogollón-Jiménez; Ana Fontalba-Romero; Dolores Garcia-Medina; Julian Palomino-Doza; David de Gonzalo-Calvo; Marcos Cicerchia; Joel Salazar-Mendiguchia; Clara Salas; Sabine Pankuweit; Thomas Morris Hey; Jens Mogensen; Paul J Barton; Philippe Charron; Perry Elliott; Pablo Garcia-Pavia Journal: J Am Coll Cardiol Date: 2018-11-13 Impact factor: 24.094
Authors: Nathan R Tucker; Micheal A McLellan; Dongjian Hu; Jiangchuan Ye; Victoria A Parsons; Robert W Mills; Sebastian Clauss; Elena Dolmatova; Marisa A Shea; David J Milan; Nandita S Scott; Mark Lindsay; Steven A Lubitz; Ibrahim J Domian; James R Stone; Honghuang Lin; Patrick T Ellinor Journal: Circ Cardiovasc Genet Date: 2017-12