A Novel Truncating Variant in FLNC-Encoded Filamin C May Serve as a Proarrhythmic Genetic Substrate for Arrhythmogenic Bileaflet Mitral Valve Prolapse.

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Date of download: 7/7/2016 Copyright © The American College of Cardiology. All rights reserved. From: Frequency and clinical expression of cardiac troponin.

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A Novel Truncating Variant in FLNC-Encoded Filamin C May Serve as a Proarrhythmic Genetic Substrate for Arrhythmogenic Bileaflet Mitral Valve Prolapse Syndrome Sahej Bains, BS, David J. Tester, BS, Samuel J. Asirvatham, MD, Peter A. Noseworthy, MD, Michael J. Ackerman, MD, PhD, John R. Giudicessi, MD, PhD Mayo Clinic Proceedings Volume 94, Issue 5, Pages 906-913 (May 2019) DOI: 10.1016/j.mayocp.2018.11.028 Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 Imaging and electrocardiographic features of the p.Trp34*-FLNC–positive proband. A-C, Transthoracic echocardiograms displaying bileaflet mitral valve prolapse (panel A), marked mitral annular disjunction (MAD) (panel B), and moderate left ventricular enlargement (panel C). D, Cardiac magnetic resonance imaging short axis view displaying inferobasal delayed enhancement. E-F, Preablation 12-lead ambulatory Holter monitor displaying predominant premature ventricular contractions or runs of nonsustained ventricular tachycardia likely originating from the posteromedial papillary muscle (right bundle branch block pattern with a superior axis) (panel E) and anterolateral papillary muscle (right bundle branch block pattern with an inferior axis) (panel F). Mayo Clinic Proceedings 2019 94, 906-913DOI: (10.1016/j.mayocp.2018.11.028) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Exome sequencing and in silico gene prioritization identify a potential genetic substrate for familial arrhythmogenic bileaflet mitral valve prolapse syndrome. A, Multigenerational pedigree with mitral valve prolapse, mitral annular disjunction, left ventricular enlargement, frequent multifocal PVCs, and NSVT (green circles indicate patients who underwent whole exome sequencing). B, Schematic representation of the variant filtering strategy. C, Sanger sequencing confirmation of the p.Trp34*-FLNC variant in the proband. D, Wild-type FLNC sequence. 1KG = 1000 genomes; ExAC = Exome Aggregation Consortium; gnomAD = Genome Aggregation Database; LV = left ventricular; LVEDD = left ventricular end-diastolic dimension; MAF = minor allele frequency; NSVT = nonsustained ventricular tachycardia; PVC = premature ventricular contraction. Mayo Clinic Proceedings 2019 94, 906-913DOI: (10.1016/j.mayocp.2018.11.028) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 3 Role of FLNC genetic variation in cardiac disease. A, Distribution of nonsynonymous variants associated with a cardiac-restricted phenotype within the FLNC-encoded filamin C linear protein topology (actin-binding domain plus 24 immunoglobulin-like repeats; transcript NP_001449.3). The familial ABiMVPS-associated truncating variant reported in this study is depicted in red; DCM-associated truncating variants are depicted in blue; HCM-associated missense variants are depicted in maroon; and RCM-associated missense variants are depicted in orange. B, Hypothesized mechanism by which missense variants in FLNC likely contribute to the pathogenesis of DCM and RCM via the accumulation of cytotoxic protein aggregates. C, Hypothesized mechanism by which protein-truncating variants (frameshift, stop-gain, etc) in FLNC contribute to the pathogenesis of DCM, LDACM, and ABiMVPS with MAD via haploinsufficiency. ABiMVPS = arrhythmogenic bileaflet mitral valve prolapse syndrome; BiMVP = bileaflet mitral valve prolapse; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LA = left atrium; LDACM = left-dominant arrhythmogenic cardiomyopathy; LV = left ventricle; MAD = mitral annular disjunction; RCM = restricted cardiomyopathy. Representative immunohistochemistry and electron microscopy images adapted from JACC Clin Electrophysiol12 and Nat Commun14 with permission from Elsevier and Springer Nature, respectively. Mayo Clinic Proceedings 2019 94, 906-913DOI: (10.1016/j.mayocp.2018.11.028) Copyright © 2018 Mayo Foundation for Medical Education and Research Terms and Conditions