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.

Keywords: ANK2; Wolff-Parkinson-White (WPW) syndrome; atrial fibrillation; exome sequencing.

Figure 1:. Schematic of methodology applied for prioritization of candidate genes

Figure 2.. Burden analysis of rare deleterious variants in AF genes in WPW affecteds.

(A) An increased proportion of WPW European cases have 1 or 2 rare (MAF<=0.005) and deleterious (CADD>=25) alleles in AF genes (N=66). The column plot shows the proportion of exomes in WPW European affecteds (n=83, depicted in green), WPW European unaffected first degree relatives (n=106, depicted in brown) and ARIC European unaffected controls (ARIC-controls) (n=3,137, depicted in purple) (y-axis) in terms of the number of rare (MAF <=0.005) and deleterious (CADD score >=25) alleles in AF genes carried in their personal genomes (x-axis). (B) The average rare and deleterious allele count in AF genes was compared between affecteds vs. ARIC-controls (top), unaffected first degree relatives vs. ARIC-controls (middle) and affecteds vs. unaffected first degree relatives (bottom) using Mann-Whitney U test. 10,000 permutations were applied by shuffling the allele counts between each pair of group of patients. Gray boxplots shows the distribution of Mann-Whitney U test P-values regarding each permutation. The observed P-value was examined in terms of its location the distribution of 10,000 P-values. This analysis revealed that the average allele rare and deleterious count of AF genes in affecteds was significantly greater (0.277) as compared to ARIC-controls (average allele count=0.18) (Permutation test one-tailed P-value =0.0023) and unaffected first-degree relatives (average allele count=0.207) (Permutation test one-tailed P-value =0.033). There was not a significant increase in rare and deleterious variant burden in AF genes in unaffected relatives [n=106] (average allele count=0.207) compared to ARIC- controls [N=3,064] (average allele count=0.18) (Permutation test one-tailed P-value =0.297). (C) The heatplot shows the AF genes, in which an affected carries a rare variant. Each row corresponds to a gene and each column corresponds to a patient. Red rectangles show that there is a rare and deleterious variant in the AF gene with its HUGO gene symbol presented in the corresponding row in the individual with ID presented in the corresponding column.