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

Oliver Bundgaard Vad,Jesper Hastrup Svendsen,Bo Hjorth Bentzen,Lena Refsgaard,Sofia Hammami Bomholtz,Stig Haunsø,Joana Larupa Santos,Morten Salling Olesen,Ingrid Elizabeth Christophersen,Nicole Schmitt,Federico Denti,Gustav Ahlberg,Simon Rasmussen,Yannan Yan

doi:10.3389/fgene.2022.806429

Abstract

Background: 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. Methods and results: We performed whole exome sequencing in a large family with familial AF and identified a rare variant in the gene CACNA1A c.5053G > A which co-segregated with AF. The gene encodes for the protein variants CaV2.1-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 CaV2.1-V1686M. Conclusion: 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.

Highlights

Atrial fibrillation (AF) is a supraventricular arrhythmia associated with increased morbidity and mortality, mainly through the increased risk of stroke and heart failure
Large genome wide association studies (GWAS) have so far identified 134 independent genetic loci associated with AF (Nielsen et al, 2018; Roselli et al, 2018), many of which are located near genes that are important for electro-physiological function (Roselli et al, 2018)
After bioinformatics processing of whole exome sequencing (WES) data, we focused on rare deleterious variants that co-segregated with AF within the pedigree

Summary

Introduction

Atrial fibrillation (AF) is a supraventricular arrhythmia associated with increased morbidity and mortality, mainly through the increased risk of stroke and heart failure. Variants in genes encoding cytoskeletal proteins, such as TTN and MYL4 have been associated with early-onset AF Large genome wide association studies (GWAS) have so far identified 134 independent genetic loci associated with AF (Nielsen et al, 2018; Roselli et al, 2018), many of which are located near genes that are important for electro-physiological function (Roselli et al, 2018). Atrial Fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, responsible for considerable morbidity and mortality. We aimed to identify rare genetic variants associated with AF in patients with familial AF

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Results

Conclusion