Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene

Eur J Hum Genet. 2019 Jul;27(7):1033-1043. doi: 10.1038/s41431-019-0364-y. Epub 2019 Feb 28.


Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Valve / abnormalities*
  • Bicuspid Aortic Valve Disease
  • DNA Copy Number Variations*
  • Databases, Genetic*
  • Female
  • Genome-Wide Association Study
  • Heart Defects, Congenital / genetics*
  • Heart Valve Diseases / genetics*
  • Humans
  • Male
  • Middle Aged
  • T-Box Domain Proteins / genetics*


  • T-Box Domain Proteins
  • TBX20 protein, human