Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation

Atrial Fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, responsible for considerable morbidity and mortality. The heterogenic and complex pathogenesis of AF remains poorly understood, which contributes to the current limitation in effective treatments. We aimed to identify rare...

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Bibliographic Details
Published in:	Frontiers in genetics Vol. 13; p. 806429
Main Authors:	Vad, Oliver Bundgaard, Yan, Yannan, Denti, Federico, Ahlberg, Gustav, Refsgaard, Lena, Bomholtz, Sofia Hammami, Santos, Joana Larupa, Rasmussen, Simon, Haunsø, Stig, Svendsen, Jesper Hastrup, Christophersen, Ingrid Elizabeth, Schmitt, Nicole, Olesen, Morten Salling, Bentzen, Bo Hjorth
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 28-01-2022
Subjects:	arrhythmias (cardiac) atrial fibrillation cardiology Genetics ion channels mechanisms of arrhythmia arrhythmias (cardiac) atrial fibrillation genetics mechanisms of arrhythmia cardiology ion channels
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Summary:	Atrial Fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, responsible for considerable morbidity and mortality. The heterogenic and complex pathogenesis of AF remains poorly understood, which contributes to the current limitation in effective treatments. We aimed to identify rare genetic variants associated with AF in patients with familial AF. We performed whole exome sequencing in a large family with familial AF and identified a rare variant in the gene c.5053G > A which co-segregated with AF. The gene encodes for the protein variants Ca 2.1-V1686M, and is important in neuronal function. Functional characterization of the CACNA1A, using patch-clamp recordings on transiently transfected mammalian cells, revealed a modest loss-of-function of Ca 2.1-V1686M. We identified a rare loss-of-function variant associated with AF in a gene previously linked with neuronal function. The results allude to a novel link between dysfunction of an ion channel previously associated with neuronal functions and increased risk of developing AF.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors share last authorship Edited by: Kelvin Yuen-Kwong Chan, Hong Kong Genome Institute (HKGI), Hong Kong SAR, China Reviewed by: Hongsheng Gui, Henry Ford Health System, United States This article was submitted to Human and Medical Genomics, a section of the journal Frontiers in Genetics These authors share first authorship Ping Liang, Zhejiang University, China
ISSN:	1664-8021 1664-8021
DOI:	10.3389/fgene.2022.806429