Nathan R Tucker1, Micheal A McLellan1, Dongjian Hu1, Jiangchuan Ye1, Victoria A Parsons1, Robert W Mills1, Sebastian Clauss1, Elena Dolmatova1, Marisa A Shea1, David J Milan1, Nandita S Scott1, Mark Lindsay1, Steven A Lubitz1, Ibrahim J Domian1, James R Stone1, Honghuang Lin1, Patrick T Ellinor2. 1. From the Cardiovascular Research Center, Massachusetts General Hospital, Charlestown (N.R.T., M.A.M., D.H., J.Y., V.A.P., R.W.M., S.C., E.D., D.J.M., M.L., S.A.L., I.J.D., P.T.E.); Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (N.R.T., J.Y., V.A.P., S.A.L., H.L., P.T.E.); Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Germany (S.C.); German Centre for Cardiovascular Research, Partner site Munich, Germany (S.C.); Division of Cardiology (M.A.S., D.J.M., N.S.S., M.L., S.A.L., I.J.D., P.T.E.) and Department of Pathology, Center for Systems Biology (J.R.S.), Massachusetts General Hospital, Boston; and Computational Biomedicine Section, Department of Medicine, Boston University School of Medicine, MA (H.L.). 2. From the Cardiovascular Research Center, Massachusetts General Hospital, Charlestown (N.R.T., M.A.M., D.H., J.Y., V.A.P., R.W.M., S.C., E.D., D.J.M., M.L., S.A.L., I.J.D., P.T.E.); Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (N.R.T., J.Y., V.A.P., S.A.L., H.L., P.T.E.); Department of Medicine I, Klinikum Grosshadern, University of Munich (LMU), Germany (S.C.); German Centre for Cardiovascular Research, Partner site Munich, Germany (S.C.); Division of Cardiology (M.A.S., D.J.M., N.S.S., M.L., S.A.L., I.J.D., P.T.E.) and Department of Pathology, Center for Systems Biology (J.R.S.), Massachusetts General Hospital, Boston; and Computational Biomedicine Section, Department of Medicine, Boston University School of Medicine, MA (H.L.). ellinor@mgh.harvard.edu.
Abstract
BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. METHODS AND RESULTS: We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls. CONCLUSION: We have identified a novel variant in FLNC as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.
BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. METHODS AND RESULTS: We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls. CONCLUSION: We have identified a novel variant in FLNC as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.
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