TY - JOUR
T1 - Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy
AU - Luyckx, Ilse
AU - MacCarrick, Gretchen
AU - Kempers, Marlies
AU - Meester, Josephina
AU - Geryl, Céline
AU - Rombouts, Olivier
AU - Peeters, Nils
AU - Claes, Charlotte
AU - Boeckx, Nele
AU - Sakalihasan, Natzi
AU - Jacquinet, Adeline
AU - Hoischen, Alexander
AU - Vandeweyer, Geert
AU - Van Lent, Sarah
AU - Saenen, Johan
AU - Van Craenenbroeck, Emeline
AU - Timmermans, Janneke
AU - Duijnhouwer, Anthonie
AU - Dietz, Harry
AU - Van Laer, Lut
AU - Loeys, Bart
AU - Verstraeten, Aline
N1 - Funding Information:
Funding This research was supported by funding from the University of Antwerp (Lanceringsproject), the Fund for Scientific Research, Flanders (FWO, Belgium, G.0356.17), The Dutch Heart Foundation (2013T093) and the Foundation Leducq (MIBAVA-Leducq 12CVD03). LB is senior clinical investigator of the Fund for Scientific Research, Flanders and holds a starting grant from the European Research Council (ERC-StG-2012-30972-BRAVE). VG and VA are postdoc researchers and supported by the Fund for Scientific Research Flanders. MJ is supported by the Fund for Scientific Research Flanders. LI is supported by a PhD grant from the Agency for Innovation by Science and Technology (IWT).
Publisher Copyright:
© 2019, European Society of Human Genetics.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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 loss-of-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.
AB - 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 loss-of-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.
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U2 - 10.1038/s41431-019-0363-z
DO - 10.1038/s41431-019-0363-z
M3 - Article
C2 - 30796334
AN - SCOPUS:85062011098
SN - 1018-4813
VL - 27
SP - 1044
EP - 1053
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -