1. 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 (May 2019)
DOI: /j.mayocp
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2. 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).
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3. 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.
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4. 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_ ). 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.
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