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<p>Bicuspid aortic valve, a prevalent congenital malformation, predisposes individuals to severe complications. Although the condition exhibits substantial heritability, known protein-coding and common regulatory mutations explain a minority of cases. To assess the contribution of rare regulatory variants, here we integrate high-resolution three-dimensional genome organization profiling with matched whole-genome sequencing from eight individuals with bicuspid aortic valves and eight with standard tricuspid aortic valves. In bicuspid aortic valve patients, mutation-driven chromatin rewiring affected 1.8-fold more valve development genes than in healthy individuals. Genome-wide in silico analyses show that rare regulatory mutations disrupt the transcriptomes of mesenchymal cell populations necessary for endocardial cushion formation. We identify 198 candidate genes associated with bicuspid aortic valve, revealing pronounced heterogeneity and complex interplay between coding and regulatory mutations. Collectively, our findings establish rare regulatory mutations as contributors to the heritability of bicuspid aortic valve and underscore the need to elucidate their mechanistic roles in disease pathogenesis.</p>

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Rare regulatory mutations disrupt mesenchymal molecular programs driving endocardial cushion formation in bicuspid aortic valve

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月18日

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  • Artemy Zhigulev,
  • Andrey Buyan,
  • Enikő Lázár,
  • Nikita Gryzunov,
  • Karin Lång,
  • Raphaël Mauron,
  • Vladimir Nozdrin,
  • Rapolas Spalinskas,
  • Sailendra Pradhananga,
  • Madeleine Petersson Sjögren,
  • Doreen Schwochow,
  • Anders Franco-Cereceda,
  • Joakim Lundeberg,
  • Ivan V. Kulakovskiy,
  • Per Eriksson,
  • Hanna M. Björck,
  • Pelin Sahlén

摘要

Bicuspid aortic valve, a prevalent congenital malformation, predisposes individuals to severe complications. Although the condition exhibits substantial heritability, known protein-coding and common regulatory mutations explain a minority of cases. To assess the contribution of rare regulatory variants, here we integrate high-resolution three-dimensional genome organization profiling with matched whole-genome sequencing from eight individuals with bicuspid aortic valves and eight with standard tricuspid aortic valves. In bicuspid aortic valve patients, mutation-driven chromatin rewiring affected 1.8-fold more valve development genes than in healthy individuals. Genome-wide in silico analyses show that rare regulatory mutations disrupt the transcriptomes of mesenchymal cell populations necessary for endocardial cushion formation. We identify 198 candidate genes associated with bicuspid aortic valve, revealing pronounced heterogeneity and complex interplay between coding and regulatory mutations. Collectively, our findings establish rare regulatory mutations as contributors to the heritability of bicuspid aortic valve and underscore the need to elucidate their mechanistic roles in disease pathogenesis.