SMAD4  gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia

Vorselaars, Veronique M.M.; Diederik, Arjen L.; Prabhudesai, Vikramaditya; Velthuis, Sebastiaan; Vos, Jan Albert; Snijder, Repke J.; Westermann, C. J. J.; Mulder, Barbara J.M.; Amstel, Hans Kristian Ploos van; Mager, Johannes J.; Faughnan, Marie E.; Post, Marco C.

doi:10.1016/j.ijcard.2017.06.059

Cited by 27 publications

(19 citation statements)

References 31 publications

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“…Another noteworthy gene is SMAD4, which also plays a role in angiogenesis and vascular remodeling as a member of the TGF-β signaling pathway [77]. Studies have demonstrated that mutations in SMAD4 may result in HHT, but also thoracic aortopathy and autosomal dominant cancer predisposition syndrome (juvenile polyposis syndrome -JPS) [78].…”

Section: Hereditary Hemorrhagic Telangiectasiamentioning

confidence: 99%

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

et al. 2021

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Vascular malformations are present in a great variety of congenital syndromes, either as the predominant or additional feature. They pose a major challenge to the clinician: due to significant phenotype overlap, a precise diagnosis is often difficult to obtain, some of the malformations carry a risk of life threatening complications and, for many entities, treatment is not well established. To facilitate their recognition and aid in differentiation, we present a selection of notable congenital disorders of vascular system development, distinguishing between the heritable germinal and sporadic somatic mutations as their causes. Clinical features, genetic background and comprehensible description of molecular mechanisms is provided for each entity.

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Section: Hereditary Hemorrhagic Telangiectasiamentioning

confidence: 99%

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

et al. 2021

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“…In addition, mutations in SMAD4 and in SKI, an inhibitor of the TGF-β pathway, cause hemorrhagic telangiectasia and Shprintzen-Goldberg syndrome respectively. Both conditions are associated with thoracic aortic pathology, although this is less common than in MFS and LDS [77][78][79]. Besides, mutations in SMAD6, another inhibitor of TGF-β signaling, are associated with bicuspid aortic valve and TAA [80].…”

Section: Tgf-β Pathway Genes Associated With Aneurysm Formationmentioning

confidence: 99%

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

Dorst

Wagenaar

Pluijm

et al. 2020

Cardiovasc Drugs Ther

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Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

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“…Molecular diagnostics to identify the single allele that is responsible for HHT in any given family offer the clearest route to date for the tailoring of care pathways best suited to the individual, by both ascertaining the presence of HHT, with attendant screening requirements, and subcategorizing according to emerging gene-specific risk profiles. [16][17][18][19][20][21][22][23][24][25][26] However, despite earlier recommendations, 14 serial data from international surveys indicate that between 2011 and 2018, the proportion of affected families undergoing genetic testing for HHT had only risen from 23.4% 27 to 49.4%, 28 with threefold differences between countries. 28 The majority of HHT patients with a molecular diagnosis have a pathogenic DNA sequence variant in ENG, encoding endoglin (ENG; HHT1), 29 or ACVRL1, encoding activin receptor-like kinase (ALK1; HHT2).…”

Section: Introductionmentioning

confidence: 97%

“…30 A smaller proportion harbor a pathogenic variant in SMAD4, which can also cause other pathologies, including juvenile polyposis and aortopathy. [23][24][25][26] Essentially all known HHT pathogenic variants are null alleles. Separate pathophysiological considerations apply to why individual vascular abnormalities then develop at particular sites (eg, specific local triggers in the setting of germ line haploinsufficiency, 31 potentially including somatic mosaic loss of the second allele), 32 but these considerations are not the focus of the current report.…”

Section: Introductionmentioning

confidence: 99%

Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

Shovlin

Simeoni

Downes

et al. 2020

Blood

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Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait. Care delivery is impeded by requirements for laborious, repeated phenotyping, and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address, we analysed DNA samples from 183 previously uncharacterised, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 168 heterozygous variants, 127 unique. Applying modified ACMG Guidelines, 106 were classified as pathogenic/likely pathogenic, 21 as non-pathogenic (variants of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using two approaches: subjective clinical predictions and statistical predictions based on eight Human Phenotype Ontology (HPO) terms. Both approaches had some predictive power but they were insufficiently accurate to be used clinically in isolation from genetic testing. The distributions of red cell indices from larger HHT and control populations differed by causal gene but not sufficiently for clinical use in isolation of genetic data. We conclude that parallel sequencing of the four known HHT genes, MDT review of variant calls sequencing results in the context of detailed clinical information, and statistical and structural modelling are all required to provide a framework to better prognosticate and treat HHT.

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SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia

Cited by 27 publications

References 31 publications

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

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