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Heritable Thoracic Aortic Disease

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“Understanding heritable thoracic aortic disease for better and personalized patient management”


In heritable thoracic aortic disease, research is driven by the need for an etiologically directed management and better risk stratification for potentially lethal complications. Though identification of causative variants is suboptimal and hampered by inter- and intragenic variability, recent progress in the knowledge of the underlying mechanisms of disease and the ensuing identification of potential treatment targets and additional risk factors have opened perspectives for more personalized management. By translating fundamental and clinical research in a more precise patient management we aim to gain more insights, which could function as a blueprint for future studies of other heritable (cardiovascular) diseases.


Heritable Thoracic Aortic Disorders (HTAD), including Marfan syndrome

MFS-related cardiomyopathy and arrhythmia


Clinical and genetic studies

Zebrafish models

Mouse models



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Sex, pregnancy and aortic disease in Marfan syndrome

Background : Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown. Objectives : In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17 beta-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts. Results : Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17 beta-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells. Conclusions : Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.

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Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for the interpretation of sequenced variants in the FBN1 gene for Marfan syndrome : proposal for a disease- and gene-specific guideline

Background: The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology proposed new variant interpretation guidelines. Gene-specific characteristics were, however, not considered, sometimes leading to inconsistent variant interpretation. Methods: To allow a more uniform interpretation of variants in the FBN1 (fibrillin-1) gene, causing Marfan syndrome, we tailored these guidelines to this gene and disease. We adapted 15 of the 28 general criteria and classified 713 FBN1 variants previously identified in our laboratory as causal mutation or variant of uncertain significance according to these adapted guidelines. We then compared the agreement between previous methods and the adapted American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Results: Agreement between the methods was 86.4% (K-alpha, 0.6). Application of the tailored guidelines resulted in an increased number of variants of uncertain significance (14.5% to 24.2%). Of the 85 variants that were downscaled to likely benign or variant of uncertain significance, 59.7% were missense variants outside a well-established functional site. Available clinical- or segregation data, necessary to further classify these types of variants, were in many cases insufficient to aid the classification. Conclusions: Our study shows that classification of variants remains challenging and may change over time. Currently, a higher level of evidence is necessary to classify a variant as pathogenic. Gene-specific guidelines may be useful to allow a more precise and uniform interpretation of the variants to accurately support clinical decision-making.

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Intrinsic cardiomyopathy in Marfan syndrome: results from in- and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

BACKGROUND: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. METHODS:To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. RESULTS: Fbn1(C1039G/+) mice demonstrated LV contractile dys-function. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGF beta-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. CONCLUSION: In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.

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Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients

Background: Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported. Methods: We performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative. Results: A mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS. Conclusion: NGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.

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“Integration of more detailed cardiovascular parameters in humans with data derived from the study of dedicated animal models”


In-depth cardiovascular phenotyping and genotyping of Marfan and other HTAD cohorts. The main goals are to better define clinical evolution and find tools to better risk stratify patients at risk of aortic dissection, arrhythmias and /or cardiomyopathy.


The zebrafish has emerged as a very useful animal model for the study of human disease. It is particularly well suited for modeling genetic disease since the development of new gene editing technologies allows us to quickly and efficiently make genetic modifications in the zebrafish genome. Another benefit of the zebrafish model is the high fecundity, which ensures a steady supply of embryos which can be used for drug discovery efforts by screening large libraries of pharmacological compounds.

We are currently generating new zebrafish models of Marfan syndrome and related disorders. On one hand we intend to use these new tools to identify potential new treatment options via unbiased pharmacological screens. On the other hand, we also plan to take advantage of the genetic tractability of zebrafish to test the in vivo effects of specific genetic variants identified in the clinic.


We study different mouse models of MFS in order to gain more insights into the mechanisms leading to aortic disease and MFS-related cardiomyopathy and arrhythmia. With this approach we aim to discover (new) pathways involved in the disease, which may open novel therapeutic perspectives. Moreover, these mouse models can also be used to validate treatment targets identified in our zebrafish studies.


European Reference Network for Vascular Disease

Aorta Team University Hospital Ghent

Last updated: 30 July 2018 - 11:29
Copyright 2018 Center for Medical Genetics, Gent.