Abstract
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.
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Acknowledgements
We would like to thank the patients, families and our collaborating partners for their participation and contribution to this work. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by Wellcome.
Members of MIBAVA Leducq consortium
Rustam Zhurayev12, Dmytro Zerbino12, Seema Mital13, Luc Mertens13, Anders Franco-Cereceda14, Judith M.A. Verhagen15, Ingrid M.B.H. van de Laar15, Marja W. Wessels15, Michaela Nemcikova16 and Alice Krebsova17
Funding
This work is supported by the Fund for Scientific Research Flanders [G.0221.12]; the Foundation Leducq [12 CVD 03] and the European Research Council [ERC-StG-2012–30972]. BL.L. is a senior clinical investigator of the Fund for Scientific Research Flanders. G.A. is a Senior Research Scholar of the Fonds de Recherche Québec—Santé. A.V. and G.V. are postdoc researchers and supported by the Fund for Scientific Research Flanders. I.L. is supported by a PhD grant from the Agency for Innovation by Science and Technology (IWT).
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Luyckx, I., Kumar, A.A., Reyniers, E. et al. Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene. Eur J Hum Genet 27, 1033–1043 (2019). https://doi.org/10.1038/s41431-019-0364-y
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DOI: https://doi.org/10.1038/s41431-019-0364-y
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