Charlotte L Hall1, Mohammed M Akhtar1, Maria Sabater-Molina2, Marta Futema1, Angeliki Asimaki3, Alexandros Protonotarios1, Chrysoula Dalageorgou1, Alan M Pittman4, Mari Paz Suarez5, Beatriz Aguilera5, Pilar Molina6, Esther Zorio7, Juan Pedro Hernández8, Francisco Pastor9, Juan R Gimeno10, Petros Syrris11, William J McKenna1. 1. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK. 2. Laboratorio de Cardiogenética, Instituto Murciano de Investigación Biosanitaria and Universidad de Murcia, Murcia, Spain. 3. Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St Georges University of London, London, UK. 4. Molecular and Clinical Sciences Research Institute, St Georges University of London, London, UK. 5. Instituto Nacional de Toxicologia y Ciencias Forenses de Madrid (INTCF), Madrid, Spain. 6. Department of Pathology at the Instituto de Medicina Legal y Ciencias Forenses de Valencia (IMLCF-Valencia), Histology Unit at the Universitat de València, Research Group on Inherited Heart Diseases, Sudden Death and Mechanisms of Disease (CaFaMuSMe) from the Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain. 7. Cardiology Department at Hospital Universitario y Politécnico La Fe and Research Group on Inherited Heart Diseases, Sudden Death and Mechanisms of Disease (CaFaMuSMe) from the Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain. 8. Instituto de Medicina Legal de Murcia (IML-Murcia), Murcia, Spain. 9. Servicio de Cardiologia del Hospital Universitario Virgen de la Arrixaca and Departamento de Medicina Interna de la Universidad de Murcia, Murcia, Spain. 10. Hospital Universitario Virgen de la Arrixaca, Murcia, Spain. 11. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK. Electronic address: p.syrris@ucl.ac.uk.
Abstract
BACKGROUND: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. METHODS: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. RESULTS: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. CONCLUSIONS: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.
BACKGROUND: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. METHODS: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. RESULTS: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. CONCLUSIONS: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.
Authors: Charlotte L Hall; Priyatansh Gurha; Maria Sabater-Molina; Angeliki Asimaki; Marta Futema; Ruth C Lovering; Mari Paz Suárez; Beatriz Aguilera; Pilar Molina; Esther Zorio; Cristian Coarfa; Matthew J Robertson; Sirisha M Cheedipudi; Keat-Eng Ng; Paul Delaney; Juan Pedro Hernández; Francisco Pastor; Juan R Gimeno; William J McKenna; Ali J Marian; Petros Syrris Journal: Int J Cardiol Date: 2019-12-06 Impact factor: 4.164
Authors: Eric D Carruth; Maria Qureshi; Amro Alsaid; Melissa A Kelly; Hugh Calkins; Brittney Murray; Crystal Tichnell; Amy C Sturm; Aris Baras; H Lester Kirchner; Brandon K Fornwalt; Cynthia A James; Christopher M Haggerty Journal: Circ Genom Precis Med Date: 2022-06-14
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Authors: Marta Gigli; Davide Stolfo; Sharon L Graw; Marco Merlo; Caterina Gregorio; Suet Nee Chen; Matteo Dal Ferro; Alessia PaldinoMD; Giulia De Angelis; Francesca Brun; Jean Jirikowic; Ernesto E Salcedo; Sylvia Turja; Diane Fatkin; Renee Johnson; J Peter van Tintelen; Anneline S J M Te Riele; Arthur A M Wilde; Neal K Lakdawala; Kermshlise Picard; Daniela Miani; Daniele Muser; Giovanni Maria Severini; Hugh Calkins; Cynthia A James; Brittney Murray; Crystal Tichnell; Victoria N Parikh; Euan A Ashley; Chloe Reuter; Jiangping Song; Daniel P Judge; William J McKenna; Matthew R G Taylor; Gianfranco Sinagra; Luisa Mestroni Journal: Circulation Date: 2021-09-30 Impact factor: 29.690