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

Oliver Tim 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

*Corresponding author af dette arbejde


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.

TidsskriftFrontiers in genetics
StatusUdgivet - 2022


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