Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy

European Journal of Human Genetics : EJHG
Ilse LuyckxAline Verstraeten

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 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 ...Continue Reading

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Citations

May 30, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Yongjia YangYimin Zhu
Mar 11, 2020·Molecular Genetics & Genomic Medicine·Bertrand ChesneauJulie Plaisancié
Feb 2, 2020·Journal of Medical Genetics·Christian BabbsVeronica J Buckle
Jun 10, 2020·Journal of Hypertension·Daan H H M VieringDetlef Bockenhauer
Jun 6, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Eduardo CalpenaAndrew O M Wilkie
Sep 6, 2020·Journal of Hypertension·Daan H H M VieringDetlef Bockenhauer
Jan 13, 2021·Journal of the American Heart Association·Lauren E Parker, Andrew P Landstrom
Jun 3, 2021·International Journal of Molecular Sciences·Alejandro Junco-VicenteIsabel Rodríguez
Jul 3, 2021·International Journal of Molecular Sciences·Ljuba C PonomarevAn Zwijsen

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Methods Mentioned

BETA
dissection
gene panel

Software Mentioned

Human Splicing Finder
PolyPhen
Combined Annotation Dependent Depletion ( CADD
Alamut Visual
HaloPlex Target Enrichment System
- 2
CADD
Alamut
gnomAD
SIFT

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