Belmont, John W.

Introduction: Bicuspid Aortic Valve (BAV), the most common adult congenital heart defect, is a major cause of aortic insufficiency or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications to sporadic late onset disease. We determined the frequency and gene content of rare genomic copy number variants (CNVs) in isolated BAV cases. Methods: We performed genome-wide SNP microarray analysis of familial BAV cases with early onset complications in the UTHealth BAV Research Registry (EBAV, n=394) and elderly probands from the International BAV Consortium (BAVCON, n=4216). CNVs were detected in Illumina genotypes using the PennCNV, QuantiSNP and cnvPartition algorithms. BAV cases were compared to 16,576 controls without known cardiovascular disease from the Database of Genotypes and Phenotypes. Only CNV calls with >6 consecutive variants, >20 kb in length, identified by at least two algorithms and intersected with known genes were included. For comparison, we assessed a cohort with left ventricular outflow tract obstructive lesions including BAV (LVOTO, n=1561) using identical methods. CNV burden and associations were tested using PLINK. Results: We identified 84 large recurrent CNVs in BAV cases that are absent or rare (<0.1%) in controls. 34 rare CNVs overlap between BAV and LVOTO cases and involve candidate genes that interact with each other during heart development. The largest and most prevalent of the recurrent CNVs are 8p23 duplications involving GATA4 (OR 340, CI: 42-2700). CNVs of genes that cause BAV when mutated were significantly enriched in cases (n=135, P =1x10 -27 ). The overall burden of rare genic CNVs, specifically large deletions, was also increased in BAV cases (empiric P < 1x10 -5 ) and was higher in younger EBAV cases than in older BAVCON cases. Conclusion: We identified likely pathogenic CNVs in more than 10% of BAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

AbstractBackgroundWolff–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.MethodsWe 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.ResultsA 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).ConclusionsOur 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.