Author + information
- Received October 5, 2017
- Revision received November 20, 2017
- Accepted December 7, 2017
- Published online April 16, 2018.
- Rene L. Begay, MSa,
- Sharon L. Graw, PhDa,
- Gianfranco Sinagra, MDb,
- Angeliki Asimaki, PhDc,
- Teisha J. Rowland, PhDa,
- Dobromir B. Slavov, PhDa,
- Katherine Gowan, BSd,
- Kenneth L. Jones, PhDd,
- Francesca Brun, MDb,
- Marco Merlo, MDb,
- Daniela Miani, MDe,
- Mary Sweet, BAa,
- Kalpana Devaraj, MDf,
- Eric P. Wartchow, BSg,
- Marta Gigli, MDb,
- Ilaria Puggia, MDb,
- Ernesto E. Salcedo, MDa,
- Deborah M. Garrity, PhDh,
- Amrut V. Ambardekar, MDa,
- Peter Buttrick, MDa,
- T. Brett Reece, MDi,
- Michael R. Bristow, MD, PhDa,
- Jeffrey E. Saffitz, MD, PhDc,
- Luisa Mestroni, MDa and
- Matthew R.G. Taylor, MD, PhDa,∗ ()
- aCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, Aurora, Colorado
- bDepartment of Cardiology, Ospedali Riuniti and University of Trieste, Trieste, Italy
- cDepartment of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, Massachusetts
- dDepartment of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado Denver, Aurora, Colorado
- eDepartment of Cardiothoracic Science, University Hospital S. Maria della Misericordia, Udine, Italy
- fDepartment of Pathology, University of Colorado, University Hospital, Aurora, Colorado
- gDepartment of Pathology, Children's Hospital Colorado, Aurora, Colorado
- hCenter for Cardiovascular Research and Department of Biology, Colorado State University, Fort Collins, Colorado
- iDepartment of Surgery, University of Colorado Denver, Aurora, Colorado
- ↵∗Address for correspondence:
Dr. Matthew Taylor, Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, 12700 East 19th Avenue, Room P15-8022, Aurora, Colorado 80045.
Objectives The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype.
Background Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement.
Methods A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry.
Results A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell–cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa.
Conclusions We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.
- arrhythmogenic dilated cardiomyopathy
- cardiovascular genetics
- Filamin C
- familial dilated cardiomyopathy
- heart failure
This study was supported by National Institutes of Health grants R01 HL69071 and HL116906 (to Dr. Mestroni), R01 116906 (to Dr. Saffitz), and 1K23HI067915 and R01HL109209 (to Dr. Taylor); and by the CRTrieste Foundation and GENERALI Foundation (to Dr. Sinagra). This work is also supported in part by a Trans-Atlantic Network of Excellence grant from the Leducq Foundation (14-CVD 03) and by National Center for Advancing Translation Sciences at the National Institutes of Health Colorado CTSA Grant Number UL1 TR001082. Dr. Mestroni has served as a consultant for Array Biopharma. Dr. Taylor has served on the Speakers Bureau of GeneDx. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Received October 5, 2017.
- Revision received November 20, 2017.
- Accepted December 7, 2017.
- 2018 The Authors