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

Zeynep H. Coban-Akdemir, Wu Lin Charng, Mahshid Azamian, Ingrid S. Paine, Jaya Punetha, Christopher M. Grochowski, Tomasz Gambin, Santiago O. Valdes, Bryan Cannon, Gladys Zapata, Patricia P. Hernandez, Shalini Jhangiani, Harsha Doddapaneni, Jianhong Hu, Fatima Boricha, Donna M. Muzny, Eric Boerwinkle, Yaping Yang, Richard A. Gibbs, Jennifer E. PoseyXander H.T. Wehrens, John W. Belmont, Jeffrey J. Kim, Christina Y. Miyake, James R. Lupski, Seema R. Lalani

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)1387-1399
Number of pages13
JournalAmerican Journal of Medical Genetics, Part A
Volume182
Issue number6
DOIs
StatePublished - 1 Jun 2020
Externally publishedYes

Keywords

  • ANK2
  • Wolff–Parkinson–White (WPW) syndrome
  • atrial fibrillation
  • exome sequencing

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