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Wolff–Parkinson–White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation
Author(s) -
CobanAkdemir Zeynep H.,
Charng WuLin,
Azamian Mahshid,
Paine Ingrid S.,
Punetha Jaya,
Grochowski Christopher M.,
Gambin Tomasz,
Valdes Santiago O.,
Can Bryan,
Zapata Gladys,
Hernandez Patricia P.,
Jhangiani Shalini,
Doddapaneni Harsha,
Hu Jianhong,
Boricha Fatima,
Muzny Donna M.,
Boerwinkle Eric,
Yang Yaping,
Gibbs Richard A.,
Posey Jennifer E.,
Wehrens Xander H. T.,
Belmont John W.,
Kim Jeffrey J.,
Miyake Christina Y.,
Lupski James R.,
Lalani Seema R.
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61571
Subject(s) - atrial fibrillation , cardiomyopathy , medicine , candidate gene , exome sequencing , population , cardiology , genetics , genetic testing , gene , mutation , biology , heart failure , environmental health
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.