Wolff–Parkinson–White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation

Abstract

Background: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals.Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. Methods:We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.Results: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023).Conclusions: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients. K E Y W O R D SANK2, atrial fibrillation, exome sequencing, Wolff-Parkinson-White (WPW) syndrome

Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

“…Genes enriched only in AVC include trpm4 encoding a Ca 2+ -activated nonselective cation channel [66], which is implicated in human progressive familial heart block type I characterized by cardiac conduction blockage downstream of the AV node [67]. Another notable example is cacna1c, whose human ortholog is associated with the Wolff-Parkinson-White syndrome, a condition affecting the AV conduction system [68,69]. Other genes, including kcnq1.1, kcne4, and atp1b1a, possess human orthologs associated with the maintenance of QT interval [70][71][72].…”

Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes

“…Relevant to the cardiac conduction system, loss of ankyrin-B leads to aberrant SAN myocyte excitability and pacemaking, displayed by severe bradycardia and rate variability, secondary to defects in Ca 2+ cycling and loss of Ca v 1.3 membrane targeting [ 31 ]. Ankyrin-B dysfunction also induces inappropriate afterdepolarizations, structural remodeling and arrhythmia in the atria with increased susceptibility to atrial fibrillation, ventricular fibrillation, [ 34 , 35 ] and has even been associated with WPW syndrome [ 36 ]. More recently, a loss-of-function mutation in ankyrin-B was identified in a patient with severe arrhythmogenic cardiomyopathy and sudden death [ 37 ].…”

Transcriptome profile of the zebrafish atrioventricular canal reveals molecular signatures of pacemaker and valve mesenchyme

“…TRPM4 is implicated in human progressive familial heart block type I characterized by cardiac conduction blockage downstream of the AV node [74]. Another notable example is cacna1c, whose human ortholog is associated with the Wolff-Parkinson-White syndrome [75], a condition affecting the AV conduction system [76]. Other genes, including kcnq1.1, kcne4, and atp1b1a, possess human orthologs associated with the maintenance of QT interval [77][78][79].…”