Wolff–Parkinson–White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation
- 31 March 2020
- journal article
- research article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 182 (6), 1387-1399
- https://doi.org/10.1002/ajmg.a.61571
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.Funding Information
- American Heart Association (17SDG33410183)
- National Heart, Lung, and Blood Institute (K23 HL1386932, UM1 HG006542)
- National Human Genome Research Institute (K08 HG008986, U54 HG003273, UM1 HG006542)
- National Institute of Neurological Disorders and Stroke (R01 NS058529, R35NS105078)
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