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, David J. Tester, Samuel J Asirvatham, Peter Noseworthy, Michael John Ackerman, John R. Giudicessi

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Abstract

A 51-year-old man with a long-standing history of bileaflet mitral valve prolapse accompanied by mitral annular disjunction and mild mitral regurgitation presented for evaluation of increasingly frequent palpitations. Ambulatory Holter monitoring, cardiac magnetic resonance imaging, serial transthoracic echocardiography, and diagnostic electrophysiology studies were consistent with a diagnosis of arrhythmogenic bileaflet mitral valve prolapse syndrome. Because of the presence of a similar phenotype in the proband's mother, brother, and maternal aunt, research-based whole exome sequencing was pursued and a novel truncating variant (p.Trp34*-FLNC) in the cardiomyopathy-causative FLNC-encoded filamin C unearthed that cosegregated with disease. Unexpectedly, these observations provide the first evidence that a heritable proarrhythmic genetic substrate (ie, FLNC haploinsufficiency–mediated weakening of cell-cell adhesion) may underlie, at least in part, some cases of arrhythmogenic mitral valve prolapse syndrome.

Original languageEnglish (US)
JournalMayo Clinic proceedings
DOIs
StatePublished - Jan 1 2019

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Filamins
Mitral Valve Prolapse
Mothers
Exome
Ambulatory Monitoring
Ambulatory Electrocardiography
Electrophysiology
Mitral Valve Insufficiency
Cardiomyopathies
Cell Adhesion
Echocardiography
Siblings
Magnetic Resonance Imaging
Phenotype
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "A Novel Truncating Variant in FLNC-Encoded Filamin C May Serve as a Proarrhythmic Genetic Substrate for Arrhythmogenic Bileaflet Mitral Valve Prolapse Syndrome",
abstract = "A 51-year-old man with a long-standing history of bileaflet mitral valve prolapse accompanied by mitral annular disjunction and mild mitral regurgitation presented for evaluation of increasingly frequent palpitations. Ambulatory Holter monitoring, cardiac magnetic resonance imaging, serial transthoracic echocardiography, and diagnostic electrophysiology studies were consistent with a diagnosis of arrhythmogenic bileaflet mitral valve prolapse syndrome. Because of the presence of a similar phenotype in the proband's mother, brother, and maternal aunt, research-based whole exome sequencing was pursued and a novel truncating variant (p.Trp34*-FLNC) in the cardiomyopathy-causative FLNC-encoded filamin C unearthed that cosegregated with disease. Unexpectedly, these observations provide the first evidence that a heritable proarrhythmic genetic substrate (ie, FLNC haploinsufficiency–mediated weakening of cell-cell adhesion) may underlie, at least in part, some cases of arrhythmogenic mitral valve prolapse syndrome.",
author = "Sahej Bains and Tester, {David J.} and Asirvatham, {Samuel J} and Peter Noseworthy and Ackerman, {Michael John} and Giudicessi, {John R.}",
year = "2019",
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language = "English (US)",
journal = "Mayo Clinic Proceedings",
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AU - Bains, Sahej

AU - Tester, David J.

AU - Asirvatham, Samuel J

AU - Noseworthy, Peter

AU - Ackerman, Michael John

AU - Giudicessi, John R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - A 51-year-old man with a long-standing history of bileaflet mitral valve prolapse accompanied by mitral annular disjunction and mild mitral regurgitation presented for evaluation of increasingly frequent palpitations. Ambulatory Holter monitoring, cardiac magnetic resonance imaging, serial transthoracic echocardiography, and diagnostic electrophysiology studies were consistent with a diagnosis of arrhythmogenic bileaflet mitral valve prolapse syndrome. Because of the presence of a similar phenotype in the proband's mother, brother, and maternal aunt, research-based whole exome sequencing was pursued and a novel truncating variant (p.Trp34*-FLNC) in the cardiomyopathy-causative FLNC-encoded filamin C unearthed that cosegregated with disease. Unexpectedly, these observations provide the first evidence that a heritable proarrhythmic genetic substrate (ie, FLNC haploinsufficiency–mediated weakening of cell-cell adhesion) may underlie, at least in part, some cases of arrhythmogenic mitral valve prolapse syndrome.

AB - A 51-year-old man with a long-standing history of bileaflet mitral valve prolapse accompanied by mitral annular disjunction and mild mitral regurgitation presented for evaluation of increasingly frequent palpitations. Ambulatory Holter monitoring, cardiac magnetic resonance imaging, serial transthoracic echocardiography, and diagnostic electrophysiology studies were consistent with a diagnosis of arrhythmogenic bileaflet mitral valve prolapse syndrome. Because of the presence of a similar phenotype in the proband's mother, brother, and maternal aunt, research-based whole exome sequencing was pursued and a novel truncating variant (p.Trp34*-FLNC) in the cardiomyopathy-causative FLNC-encoded filamin C unearthed that cosegregated with disease. Unexpectedly, these observations provide the first evidence that a heritable proarrhythmic genetic substrate (ie, FLNC haploinsufficiency–mediated weakening of cell-cell adhesion) may underlie, at least in part, some cases of arrhythmogenic mitral valve prolapse syndrome.

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