Center for Medical Genetics Center for Medical Genetics

Aortic Aneurysm

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Thoracic aortic aneurysms and dissections (TAAD) are associated with high morbidity and account for 1-2% of mortality in Western countries. Accumulating evidence indicates a significant role for genetics in the etiology of TAAD. Currently, over a dozen causal genes have been identified in (rare) monogenetic aortic diseases and these offer very interesting models for the study of the underlying pathophysiology. In addition, improved genetic screening techniques now offer better opportunities for the identification of underlying mutations, which is important both for the management of individual patients and their families.

The clinical cardiovascular spectrum of TAAD disease extends beyond the aortic root and knowledge of associated abnormalities is essential to guide proper management of these patients.

Our research has several objectives:

In depth study of the underlying pathophysiology of TAAD and associated cardiovascular features

Marfan syndrome (MFS) is a pleiotropic autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1). It is considered as the textbook example for the study of the pathogenesis and treatment of TAAD. In addition, MFS patients are also characterized by cardiac involvement.

Our research group studies several Fbn1 mouse models to gain further insights into the mechanisms underlying the cardiovascular features associated with MFS. Abnormal activation of the TGFβ signaling pathway has been thought to be the major contributor to aortic disease. However, recent studies suggest that other signaling pathways and processes may play an important role. These signaling pathways and processes may act in concert with the TGFβ signaling pathway to result in the development and/or progression of thoracic aortic aneurysms and cardiomyopathy.

Improved strategies for mutation detection

The genetic background of TAAD is heterogeneous with overlapping clinical features, turning targeted and sequential genetic screening expensive and time-consuming. Strategies for molecular genetic testing have reached a hinge point with the introduction of high-throughput, next generation sequencing based techniques, which proved time- and cost-effective in daily diagnostic TAAD screening.

We recently published on the mutation detection rate using NGS-based panel sequencing of seven of the most frequent TAAD genes (FBN1, TGFBR1, TGFBR2, TGFB2, SMAD3, ACTA2, COL31A1) in a representative sample of patients referred to our genetic center. In the meanwhile, our diagnostic panel has been expanded now to include MYH11, TGFB3, PRKG1 and MYLK. With the introduction of NGS, large numbers of variants are generated, which will only increase with the evolution towards whole exome and whole genome sequencing. At the CMGG a zebrafish facility has been deployed to study in vivo the functional effects of variants of unknown significance.

Unraveling the molecular basis of congenital heart defects (CHD)

Congenital heart defects (CHD) affect 1% of all life-born children and are a leading inborn cause of morbidity and mortality. CHD can be part of a syndromal constellation, but the vast majority occurs isolated and sporadically with low recurrence risk in sibs. Over the last decade, important progress was made in the molecular etiology of syndromal CHD, while the isolated forms remained largely unexplained. With next-generation sequencing techniques the whole coding region of a patient’s genome (exome) can be analysed. Comparing the exome of a patient’s diseased cardiac tissue, harvested during surgery, with that of the patient’s blood or skin cells will reveal mutations only present in the former. In addition, comparison with the exomes of both parents may detect de novo mutations in the child. Bioinformatics can prioritize candidate genes based on their relationship with genes and pathways known to be involved in CHD.

Study of the natural evolution and cardiovascular risk stratification of patients with the Marfan syndrome

The CMGG has built up extensive experience in both clinical and molecular assessment of patients and families with (Thoracic) Aortic Aneurysms and Dissections. The unique interplay between the clinic and the laboratory and our extensive collaboration with researchers from over the world has resulted in numerous publications and research projects.

The CMGG is part of a multidisciplinary clinic for the diagnosis and management of patients with inheritable connective tissue disorders, including cardiovascular diseases. Thanks to a close collaboration between the medical department of Cardiology (Prof. Dr. J. De Backer) Pediatric cardiology (Prof. Dr. D. De Wolf), Congenital Cardiac surgery (Prof. Dr. K. François) and vascular surgery (Prof. Dr. F. Vermassen) the centre offers expert multidisciplinary diagnostics and management of patients with aortic aneurysms and has gathered extensive clinical data and collected aortic specimens of patients with inherited and congenital heart disease.

In addition to and in conjunction with these clinical collaborations, we also have close collaborations with the team of Prof. Dr. P. Segers (Biofluid Dynamics). Their expertise in modelling of aortic diseases from a biomechanical perspective along with our experience on the molecular level provides a unique setting to study the concepts of mechanosensing/mechanotransduction as mechanisms of disease in TAAD.

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The need for transparency and good practices in the qPCR literature

Two surveys of over 1,700 publications whose authors use quantitative real-time PCR (qPCR) reveal a lack of transparent and comprehensive reporting of essential technical information. Reporting standards are significantly improved in publications that cite the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, although such publications are still vastly outnumbered by those that do not.

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Nasal speech in patients with 12q15 microdeletions

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Study of the natural evolution and cardiovascular risk stratification in patients with the Marfan syndrome.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in de fibrilline 1 (FBN-1) gene. It is usually referred as the prototype for the syndromic heritable thoracic aneurysm disorders (H-TAD) and most of the knowledge we have on MFS is extrapolated to other H-TAD in terms of management and follow-up.

MFS is a pleiotropic disease affecting the ocular, skeletal and cardiovascular systems. The most known cardiovascular diseases affecting MFS patients are TAAD and mitral valve prolapse. At this moment an aortic diameter of 50mm is used as cut-off for prophylactic surgical aortic replacement. However some patients will experience dissection at lower diameters urging the necessity of finding new biomarkers for better predicting the risk of dissection in patients with MFS.

Next to the TAAD and mitral valve prolapse there is increasing evidence that patients with MFS can develop cardiomyopathy, independently of valve disease, and arrhythmia. Which patients are at risk of these cardiovascular complications still needs to be elucidated. We are studying different biomarkers and known cardiovascular risk factors such as sleep apnea to better stratify patients at risk. Furthermore we are prospectively looking at the effect of prophylactic aortic replacement on the cardiac function.

Unraveling the molecular basis of congenital heart defects (CHD)

The overall goal of this research project aims at a comprehensive exome-wide molecular screening in different types of ICHD. Understanding the molecular basis of ICHD is important for several reasons. Firstly, a comprehensive assessment of molecular causes will add to the understanding of the genetic complexity and the biological processes underlying cardiac organogenesis both in physiological and diseased states. The dissection of these processes may even have broader relevance and increase our knowledge about developmental biology in general. Secondly, and evenly important, this results will will aid the genetic counseling of patients. Indeed, the survival of an increasing number of patients without major incapacities raises the question of recurrence risk in their offspring. Acquiring this information may therefore not only be an explanation of the patient’s disease, but may actually have relevance for family planning. Investigated phenotypes are selected on the basis of prevalence and whether sufficient material can be obtained during surgery and include

septal defects of the heart (atrial septal defect; ventricular septal defect) and outflow tract abnormalities (Tetralogy of Fallot (right outflow tract, Thoracic aortic aneurysms with or without bicuspid aortic valves (left outflow tract abnormalities))

The goals are the identification in CHD of somatic mutations, de novo germline mutations, mutations with reduced penetrance or mutations underlying recessive ICHD phenotypes using a genome-wide approach and to evaluate putative mutations in an embryonic zebrafish model.

Last updated: 16 March 2016 - 16:14
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