2019-02-28
Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene
Publication
Publication
European Journal of Human Genetics , Volume 27 - Issue 7 p. 1033- 1043
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
Additional Metadata | |
---|---|
doi.org/10.1038/s41431-019-0364-y, hdl.handle.net/1765/117853 | |
European Journal of Human Genetics | |
Organisation | Department of Clinical Genetics |
Luyckx, I., Kumar, A.A., Reyniers, E., Dekeyser, E., Vanderstraeten, K., Vandeweyer, G, … Krebsova, A. (2019). Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene. European Journal of Human Genetics, 27(7), 1033–1043. doi:10.1038/s41431-019-0364-y |