Language
English
Publication Date
8-1-2024
Journal
Circulation: Genomic and Precision Medicine
DOI
10.1161/CIRCGEN.124.004614
PMID
38953222
PMCID
PMC11335451
PubMedCentral® Posted Date
8-1-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.
Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice.
Results: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration.
Conclusions: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.
Keywords
Adult, Animals, Female, Humans, Male, Mice, Middle Aged, Electrocardiography, Exome Sequencing, Mutation, Missense, Pedigree, Tachycardia, Supraventricular, Wolff-Parkinson-White Syndrome, Receptors, Cell Surface, Membrane Glycoproteins, Accessory pathway, Arrhythmias, Fibrosis, Mannose receptor C-type 2, Supraventricular tachycardia, Wolff-Parkinson-White syndrome, Animal models, Carriac arrhythmias, Fibrosis
Published Open-Access
yes
Recommended Citation
Potter, Adam S; Miyake, Christina Y; Gonzaga-Jauregui, Claudia; et al., "A Rare Variant in MRC2 Associated with Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome" (2024). Faculty and Staff Publications. 4017.
https://digitalcommons.library.tmc.edu/baylor_docs/4017