Dataset Information

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

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 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.

SUBMITTER: Luyckx I

PROVIDER: S-EPMC6777625 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Luyckx Ilse I MacCarrick Gretchen G Kempers Marlies M Meester Josephina J Geryl Céline C Rombouts Olivier O Peeters Nils N Claes Charlotte C Boeckx Nele N Sakalihasan Natzi N Jacquinet Adeline A Hoischen Alexander A Vandeweyer Geert G Van Lent Sarah S Saenen Johan J Van Craenenbroeck Emeline E Timmermans Janneke J Duijnhouwer Anthonie A Dietz Harry H Van Laer Lut L Loeys Bart B Verstraeten Aline A

European journal of human genetics : EJHG 20190222 7

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 SMAD ...[more]

PMID: 30796334

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Project description:ObjectivesA bicuspid aortic valve (BAV) is characterized by variable phenotypic manifestations, as well as longitudinal evolution of valve dysfunction and ascending aorta dilatation. The present study investigated the impact of severe aortic stenosis (AS) on the flow patterns and wall shear stress (WSS) distribution in BAV patients with right-left (RL) and right-non-coronary (RN) cusp fusion types, and the study aimed to reveal whether aortic dysfunction could further alter intrinsic aortic haemodynamic aberrations generated by abnormal BAV cusp fusion patterns.MethodsFour-dimensional flow magnetic resonance imaging was performed in 120 BAV subjects and 20 tricuspid aortic valve controls. BAV patients were evenly categorized into 4 cohorts, including RL and RN BAV with no more than mild aortic dysfunction as well as RL and RN BAV-AS with isolated severe AS.ResultsBAV subjects exhibited eccentric outflow jets resulting in regional WSS elevation at the right-anterior position of the ascending aorta in the RL group and the right-posterior location in the RN group (P < 0.005). The presence of severe AS resulted in accelerated outflow jets and more prominent flow and WSS eccentricity (P < 0.005) by marked helical (P = 0.014) and vortical flow formation (P < 0.005), as well as increased prevalence of tubular and transverse arch dilatation. The changes to the flow jet in BAV-AS subjects blurred the differences in peak flow velocity and WSS distribution between RL and RN BAV. Differences in the phenotypes of aortopathy were associated with changes in functional haemodynamic parameters such as flow displacement and WSS eccentricity.ConclusionsSevere AS markedly exacerbated aortic flow aberrations in BAV patients and masked the existing distinct flow features deriving from RL and RN fusion types. Longitudinal studies are needed to investigate the evolution of ascending aortic dilatation relative to the interaction between intrinsic cusp fusion types and acquired severe valve dysfunction.

Dataset Information

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

Publications

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

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