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

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

doi:10.3389/fgene.2022.806429

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

Front Genet. 2022 Jan 28:13:806429. doi: 10.3389/fgene.2022.806429. eCollection 2022.

Authors

Oliver Bundgaard Vad^{1

2}, Yannan Yan¹, Federico Denti¹, Gustav Ahlberg^{1

2}, Lena Refsgaard², Sofia Hammami Bomholtz¹, Joana Larupa Santos¹, Simon Rasmussen³, Stig Haunsø², Jesper Hastrup Svendsen^{2

4}, Ingrid Elizabeth Christophersen^{5

6}, Nicole Schmitt¹, Morten Salling Olesen^{1

2}, Bo Hjorth Bentzen¹

Affiliations

¹ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Laboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular-, Pulmonary and Infectious Diseases, Righospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³ Disease Systems Biology Program, University of Copenhagen, Copenhagen, Denmark.
⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ The Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁶ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway.

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 Ca_V2.1-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_V2.1-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.

Keywords: arrhythmias (cardiac); atrial fibrillation; cardiology; genetics; ion channels; mechanisms of arrhythmia.