|
Title
|
|
|
|
Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar lossof-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
European journal of human genetics / European Society of Human Genetics. - Leiden
| |
|
Publication
|
|
|
|
Leiden
:
2019
| |
|
ISSN
|
|
|
|
1018-4813
| |
|
DOI
|
|
|
|
10.1038/S41431-019-0363-Z
| |
|
Volume/pages
|
|
|
|
27
:7
(2019)
, p. 1044-1053
| |
|
ISI
|
|
|
|
000471871000006
| |
|
Pubmed ID
|
|
|
|
30796334
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (publisher's version - intranet only)
|
|
|
|
| |
|