Ongoing projects

Development of an innovative hiPSC-derived cardiac-microtissue-based functional assay to determine the pathogenicity of genetic variants with uncertain significance identified in patients with inherited cardiac arrhythmia; 01/10/2021 - 30/09/2025

Abstract

Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal and potentially harmful heart rhythm. These episodes often go unnoticed, but can lead to sudden cardiac death. At present, over 60 ICA genes have been identified. Using novel next-generation sequencing technology it is possible to screen all ICA genes in a single molecular diagnostic test. This analysis allows the identification of clear disease-causing variants in patients, but also results in detection of a high number of genetic variants for which causality is unsure. These pose a major burden for the management of ICA patients. Therefore, the aim of this project is to develop a functional tool that allows to test the functional impact of these so-called 'variants of uncertain significance' (VUS). We will create an advanced model of 'human induced pluripotent stem cells (hiPSC)' with built-in special fluorescent proteins that report on calcium and voltage signals. Starting from these hiPSCs we will generate cardiomyocytes, cardiac fibroblasts and endothelial cells that we grow in a controlled mixture into cardiac microtissues (cMT). The electrical activity and calcium handling of these cMTs can then be monitored with a specialized confocal fluorescence microscope. To validate our tool, we will first introduce known disease-causing alterations into the genome of these transgenic hiPSCs and study the effect on the electrical activity of the derived cMTs. Next, we will apply this method to evaluate the functional effect of VUS identified in patients. This innovative approach will improve the molecular diagnostics of inherited cardiac arrhythmias and allow clinicians to deliver true personalized medicine.

Researcher(s)

Research team(s)

Converging mechanisms for thoracic aortic aneurysm and dissection: dissecting the transcriptomic landscape of the diseased aorta. 01/10/2021 - 30/09/2025

Abstract

Progressive dilatation of the aorta leads to the development of thoracic aortic aneurysms (TAAs), frequently resulting in aortic dissection or rupture. The latter events associate with an ultimate mortality rate of 50% and, hence, represent a prominent cause of morbidity and mortality in the Western population. Prophylactic surgery of TAA patients reduces the mortality rate down to about 5%, but comes with a relatively high risk of complications. Medical therapies capable of stopping or even reversing aneurysm formation are clearly highly needed, but are not available yet. Further deciphering of the mechanisms underlying TAA is essential to develop more efficient drugs. Owing to the advent of -omics technologies, it is now possible to dig into pan-TAA pathomechanisms in a hypothesis-free manner, opening new avenues to discover yet unexplored disease pathways and, hence, novel therapeutic targets. With this project, we want to be the first to take up the challenge of discovering convergent disease-linked pathways for TAA in a hypothesis-free manner using mouse and iPSC-derived cell models. The anticipated findings will advance the pathomechanistic TAA knowledge significantly beyond the current understanding and will greatly facilitate the development of novel therapeutic strategies.

Researcher(s)

Research team(s)

Unraveling the paradigm of opposing phenotypes due to pathogenic variants in the FBN1 gene. 01/10/2021 - 30/09/2024

Abstract

Marfan syndrome (MFS) and acromelic dysplasias (AD) are caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Remarkably, whereas MFS is characterized by thoracic aortic aneurysms (TAA), tall stature and arachnodactyly, AD patients present with short stature, brachydactyly, and no aortic involvement. Loss of structural integrity of the microfibrils is proposed as the cause of MFS, while altered protein interactions are thought to be at heart of the pathogenesis of AD. However, the alterations in protein interactions identified so far do not seem to fully explain the AD phenotype. Remarkably, increased transforming growth factor beta (TGF-?) signaling has been observed both in human and murine MFS aortic wall tissue and in fibroblasts of AD patients. As such, the exact functional consequences of AD and MFS mutations on cell signaling pathways remain a matter of debate. The main questions therefore remain: (1) which mechanisms explain why TAA is unique to MFS? And (2) why do heterozygous FBN1 mutations, both leading to increased TGF-? signaling, give rise to opposite skeletal phenotypes? In this project, I want to decipher the divergent pathomechanistic processes underlying these contrasting skeletal and aortic phenotypes by applying multi-omics approaches in murine and human (cellular) models of MFS and AD. The expected results may reveal novel therapeutic targets, which is especially important to treat the life-threatening TAA from which MFS patients are suffering.

Researcher(s)

Research team(s)

Molecular exploration of a new aortopathy syndrome with strong potential to inform the pathogenesis and treatment of heritable thoracic aortic aneurysm. 01/01/2021 - 31/12/2024

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. This dramatic event may leave family members of the deceased terrified and oblivious. To date, genetic defects in >30 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current pathomechanistic aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, we most recently identified recessive truncating mutations in IPO8 as a novel cause of syndromic TAA. This project builds on this exciting finding. More specifically, we aim to significantly improve our current TAA pathomechanistic insight and future TAA patient management by (1) aortic phenotyping and functional characterization of an Ipo8 null mouse line, (2) validation of the mouse findings in the human context using patient- and control-derived iPSC-VSMCs, and (3) identifying putative drug compounds for IPO8-related aortopathy using a cell-based matrix metalloproteinase inhibition assay.

Researcher(s)

Research team(s)

Genome-wide Epistasis for cardiovascular severity in Marfan Study. 01/01/2021 - 31/12/2024

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and interfamilial phenotypic variability, ranging from completely asymptomatic to sudden death at young age, is observed. The precise mechanisms underlying this variability remain elusive. In this project, we have selected an innovative strategy to fully understand the functional effects of the FBN1 mutation and discover genetic modifiers of MFS aortopathy with the following objectives: (1) CRISPR/Cas9 correction of the recurrent FBN1 p.Ile2585Thr in patient-derived iPSC-VSMCs and functional comparison to FBN1 mutant and control iPSC-VSMCs. (2) Whole genome and RNA-sequencing of patient iPSC-VSMCs at the extreme ends of the phenotypical spectrum for genetic modifier identification. (3) CRISPR-modification for validation of their modifying capacities. The understanding of the functional effects of the FBN1 mutation and the identification of genetic modifiers will advance the knowledge on aortopathy-mechanisms beyond current understanding, it will allow to individualize treatment protocols and will offer new leads to novel therapeutic targets.

Researcher(s)

Research team(s)

Infrastructure for zebrafish modeling of human disease 01/12/2020 - 30/11/2021

Abstract

Financial support from University of Antwerp needed for establishing zebrafish facility for the modeling of human genetic disease. This funding will be complemented with support of the Fund for Scientific Research Flanders.

Researcher(s)

Research team(s)

In search of genetic modifiers for aortopathy in Loeys-Dietz families with a SMAD3 mutation. 01/11/2020 - 31/10/2022

Abstract

Loeys-Dietz syndrome (LDS) is a genetic disorder presenting with thoracic aortic aneurysm (TAA), causing abnormal widening of the aorta, which leads to aortic rupture or dissection, a life-threatening complication that occurs unexpectedly. LDS is caused by genetic defects in six different genes of the TGF? pathway (TGFBR1/2, SMAD2/3, TGFB2/3), which is vital in the proper development of the body's connective tissue. Despite the progress in unraveling its genetic basis, there is a lack of understanding of the wide range of severity of cardiovascular involvement. In my project, I will focus on patients within families, carrying pathogenic SMAD3 variants, which show either no or early-onset aortic aneurysmal disease. I hypothesize that genetic modifiers of the primary SMAD3 mutation are the main contributors to the striking aortopathy variability in LDS-SMAD3 families. In this project, an innovative strategy will be used to identify genetic modifiers. I will perform genome-wide single nucleotide polymorphism-based linkage analysis on two large SMAD3 families and whole-genome sequencing on selected individuals, combined with SMAD3 iPSC-VSMC (induced pluripotent stem cell-derived vascular smooth muscle cells) model creation and characterization and subsequent CRISPR/Cas9-based validation of the identified modifier(s). The predicted outcomes will advance the LDS and TAA knowledge, contributing to the discovery and development of novel therapeutic targets and personalized medicine.

Researcher(s)

Research team(s)

Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish 01/11/2020 - 31/10/2022

Abstract

Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to prove their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiomyocyte cell model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging and electrophysiological techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving its contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.

Researcher(s)

Research team(s)

Cardiogenomics. 01/10/2020 - 30/09/2023

Abstract

My mission is to consolidate and expand my cardiogenetics research group of the University of Antwerp as a center of excellence that aims to identify the genetic causes and underlying pathogenetic mechanisms of both common and rare genetic disorders affecting the cardiovascular system, in particular aortic aneurysmal disorders and primary inheritable arrhythmias. It will be the ultimate goal to translate our genetic and pathomechanistic discoveries into an improvement of the quality of life of patients.

Researcher(s)

Research team(s)

Optical mapping of in vivo cardiac mechanics in zebrafish: exploring the pathogenesis and mode of inheritance in catecholaminergic polymorphic ventricular tachycardia. 01/10/2020 - 30/09/2022

Abstract

Sudden death in the young is primarily caused by inherited diseases of the heart. These conditions are frequently caused by mutations in genes responsible for maintaining a regular heartbeat. Many genes that can cause sudden death have already been identified. However, for an important portion of patients, the genetic test reveals a genetic variant with unknown significance. With my project, I intend to create a new model to study the effects of these mutations on the heart in vivo. For this purpose, I will generate a new zebrafish line, in which cardiac electrical and chemical calcium signals will be converted into fluorescent light signals. As zebrafish are translucent during the first days of development, this animal model lends itself perfectly to visualize these signals in vivo. I will use the new zebrafish line to improve our understanding of one specific cardiac disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT). This condition is characterized by abnormal calcium signaling in the heart, and as such my method will be highly suitable to study CPVT. Both in the literature and in our own cardiogenetics clinic, several CPVT families with an uncertain inheritance pattern have been discovered. With my assay I intend to expose the mechanisms of CPVT in these families and hereby clarify the results of the genetic tests and contribute to future diagnostic testing in CPVT.

Researcher(s)

Research team(s)

Multi-well microelectrode array (MEA): a bridge to highthroughput electrophysiology. 01/05/2020 - 30/04/2024

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

Researcher(s)

Research team(s)

BMP signalling in vascular biology and disease signalling 01/01/2020 - 31/12/2024

Abstract

Cardiovascular diseases are worldwide the leading cause of mortality (31% of all deaths, WHO) and disability. These diseases include heart failure, coronary artery disease, hypertension, cerebrovascular and peripheral vascular diseases. Dysfunction of endothelial cells (ECs) lining the inner wall of the vasculature is a major initiator that fuels the progression of cardiovascular disease. Mutations in genes encoding different components of the bone morphogenetic protein (BMP) pathway cause various severe vascular diseases such as hereditary hemorrhagic telangiectasia (HHT), bicuspid aortic valve with thoracic aortic aneurysms (BAV/TAA) and pulmonary arterial hypertension (PAH) (Goumans et al., Cold Spring Harbor Persp. Biol. 2018). BMPs are secreted factors that belong to the larger transforming growth factor (TGF)β family. Signaling by BMPs contributes to the morphological, functional and molecular differences ('heterogeneity') among ECs in different vessel types like arteries, veins, lymphatic vessels and in different organs. Understanding how BMP signaling co-regulates EC heterogeneity in homeostasis and how its deregulation can contribute to disease is key to obtain insights in the genesis of vessel-type restricted disorders and design improved disease-tailored therapies with reduced side effects. The BMP pathway is an important therapeutic target in vascular disease, with several BMP modulators being used already in clinic. The BMP signaling output critically depends on the cellular context in the vessel wall which includes flow hemodynamics, inflammation, interplay with other "vascular" signaling cascades and the interaction of ECs with peri-endothelial cells and surrounding matrix. The BMP community – which has long remained bone-centered – is joining forces relatively recently in vascular biology within Europe. We feel momentum to team-up with the present multidisciplinary network consortium consisting of 8 'Flemish' teams from 3 Universities (A. Zwijsen (KUL1), E.A. Jones (KUL2), B. Loeys/A. Verstraeten (UA), A. Luttun (KUL3), R. Quarck/M. Delcroix (KUL4), P. Segers (UGent) and H. Van Oosterwyck (KUL5),) and 6 external teams (M.J. Goumans (NL1), F. Itoh (JP), P. Knaus (DE), F. Lebrin (NL2/FR2), G. Valdimarsdottir (IS) and M. Vikkula (BE)) to jointly address how i) dysfunctional BMP pathways contribute to vessel (instability) diseases, ii) how impaired BMP signaling affects mechanobiology (interpretation of flow, cellular tractions, matrix stiffness) in the vessel wall and iii) validate promising BMP-based vessel repair strategies across our different models. The various partners of this WOG network study different aspects of BMP/TGFβ signaling and/or vascular (mechano)biology and disease (see further). Within this multidisciplinary consortium, we aim to accelerate the unraveling of BMP-mediated mechanisms of EC heterogeneity and mechanotransduction to refine and improve etiology-based vascular repair strategies, a major challenge in curing vessel-related diseases. Our objectives are to: i) increase critical mass in Flanders on BMP signaling and its interplay with mechanotransduction in vascular diseases and boost trans- and interdisciplinary collaborations within this consortium, to underscore faster commonalities and specificities of (impaired) BMP functions in different vascular beds and vessel (instability) diseases; ii) model and validate vessel normalization strategies in our various physiopathological systems and translate results to a clinical setting; iii) create an "incubator" environment and solid basis for future successful funding applications (leverage); iv) expose and challenge each other's work at an early stage to strengthen and increase research output and competitiveness; v) increase visibility of all the teams in Flanders and internationally, propel the junior talents in the teams and deliver high-quality trained PhDs/masters/bachelors.

Researcher(s)

Research team(s)

BMP signaling in vascular biology and disease. 01/01/2020 - 31/12/2024

Abstract

Cardiovascular diseases are worldwide the leading cause of mortality (31% of all deaths, WHO) and disability. These diseases include heart failure, coronary artery disease, heart disease, hypertension, cerebrovascular and peripheral vascular diseases. Dysfunction of endothelial cells (ECs) lining the inner wall of the vasculature is a major initiator that fuels the progression of cardiovascular disease. Mutations in genes encoding different components of the bone morphogenetic protein (BMP) pathway cause various severe vascular diseases such as hereditary hemorrhagic telangiectasia, bicuspid aortic valve with thoracic aortic aneurysms and pulmonary arterial hypertension. BMPs are secreted factors that belong to the larger transforming growth factor (TGF)β family. Signaling by BMPs contributes to the morphological, functional and molecular differences ('heterogeneity') among ECs in different vessel types like arteries, veins, lymphatic vessels and in different organs. Understanding how BMP signaling co-regulates EC heterogeneity in homeostasis and how its deregulation can contribute to disease is key to obtain insights in the genesis of vessel-type restricted disorders and design improved disease-tailored therapies with reduced side effects.

Researcher(s)

Research team(s)

Pathomechanistic study of biglycan mutations in aortopathy and skeletal dysplasia. 01/01/2020 - 31/12/2023

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, we identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with our observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

Research team(s)

Discovery of genetic modifiers of the phenotypical cardiovascular variability in Marfan syndrome to pave the road to individualized treatment protocols. 01/11/2019 - 31/10/2022

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and interfamilial phenotypic variability, ranging from completely asymptomatic to sudden death at young age, is observed. The precise mechanisms underlying this variability remain elusive. In this project, I have selected an innovative strategy to fully understand the functional effects of the FBN1 mutation and discover genetic modifiers of MFS aortopathy with the following objectives: (1) CRISPR/Cas9 correction of the recurrent FBN1 p.Ile2585Thr in patient-derived iPSC-VSMCs and functional comparison to FBN1 mutation and control iPSC-VSMCs. (2) Whole genome sequencing, and RNA-seq of patient iPSCVSMCs at the extreme ends of the phenotypical spectrum for genetic modifier identification. (3) CRISPR-modification for validation of their modifying capacities. The understanding of the functional effects of the FBN1 mutation and the identification of genetic modifiers will advance the knowledge on aortopathy-mechanisms beyond current understanding, it will allow to individualize treatment protocols and will offer new leads to novel therapeutic targets.

Researcher(s)

Research team(s)

Functional genomics. 01/10/2019 - 30/09/2024

Abstract

Connective tissue disease (CTD) refers to a large and diverse group of disorders affecting the protein-rich tissues that support our body's organ systems. Patients most typically present with skin, spinal cord, eye, heart, blood vessel and/or skeletal manifestations. CTDs can either be inherited or provoked by environmental factors. With respect to hereditary CTD, an increasing number of genetic causes has been discovered over the past ten years owing to the advent of high-throughput DNA sequencing technologies. In-depth investigation of these defects' molecular mode of action at the cellular and tissue level is now increasingly needed in order to complete the mechanistic CTD puzzles and to facilitate the development of novel drug therapies. I will establish a research group that aims to address these CTD needs, with a primary focus on thoracic aortic aneurysm and dissection (TAAD) and skeletal dysplasia. TAAD denotes an abnormal widening and/or rupture of the largest human artery, i.e. the aorta, and entails a high risk for sudden death due to severe internal bleeding. It is estimated to account for 1-2% of all deaths in the Western population. Skeletal dysplasias are a group of more than 200 disorders that affect bone and cartilage growth, resulting in abnormal skeleton shape and size. At first glance, these two conditions might seem oddly dissimilar. From a molecular point of view they have quite a lot in common though. Different defects in a set of genes have been shown to cause both TAAD and skeletal dysplasia. Moreover, significant overlap exists with regard to the yet described dysregulated subcellular processes. By comprehensively studying the entire disease continuum, I will contribute synergistically to a better understanding of the disease mechanisms and, hence, the treatment of both separate clinical entities. Three major strategic research pillars have been defined on which I desire to concentrate: (1) identification of the DNA variants that explain why some subjects carrying a certain disease-causing genetic defect are more severely affected than others with that identical defect (i.e. modifier variants); (2) elucidation of the molecular mode of action of disease-causing and disease-modifying genetic variants; and (3) discovery of novel disease-remedying drug compounds as well as the genetic determinants that explain variation in drug response between patients. The experimental set-up will be determined in a project-by-project manner, but will typically involve high-throughput DNA, RNA and/or protein analyses (-omics) as well as classical molecular biology strategies in relevant mouse and induced pluripotent stem cell (iPSC)-derived models. IPSCs are somatic cells (e.g. from skin or blood) that have been reprogrammed to pluripotent cells, and can be differentiated into virtually any cell type of interest. Patient- and control-derived iPSC-vascular smooth muscle cells and iPSC-chondrocytes will be used (i.e. relevant TAAD and skeletal dysplasia cell types, respectively) because of limited access to their native counterparts.

Researcher(s)

Research team(s)

In search for chaperone-agonizing drugs for skeletal dysplasias attributed to dominant-negative COL2A1 mutations. 01/10/2019 - 30/09/2023

Abstract

Heterozygous missense mutations in the collagen type II-encoding gene COL2A1 explain about 95% and 70% of the hypochondrogenesis and spondyloepiphyseal dysplasia congenita patients, respectively, as well as a smaller fraction of patients with closely related phenotypes. Prior functional characterization of iPSC-derived and transdifferentiated chondrocytes of carriers of COL2A1 missense mutations revealed increased expression of endoplasmatic reticulum (ER) stress and apoptosis markers in addition to reduced levels of cartilage matrix proteins. Abnormal procollagen folding is considered a key pathogenic skeletal dysplasia mechanism, rendering chaperone-oriented therapy an interesting pharmacological avenue. Subjecting iPSC-chondrocytes of a COL2A1 glycine substitution carrier to a drug library comprising roughly 2,400 chaperone agonists and antagonists, we aim to identify a highly potent novel drug for skeletal dysplasias attributed to COL2A1 missense mutations. To evaluate the compounds' efficiency in restoring the cellular phenotype, integrated high content quantification of collagen type II as well as apoptosis and ER stress markers will be done. The most interesting compounds will be tested in knock-in COL2A1 mice to establish in vivo performance.

Researcher(s)

Research team(s)

Unravelling the discriminative pathomechanisms for biglycan-related aortopathy and spondylo-epi-metaphyseal dysplasia. 01/10/2019 - 30/09/2022

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, I identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with my observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

Research team(s)

GENOmics in MEDicine: From whole genome sequencing towards personalized medicine (GENOMED). 03/07/2019 - 31/12/2025

Abstract

GENOMED is an interfaculty consortium of four research groups and Center of Excellence at the University of Antwerp. The general aim of GENOMED is to enhance genetic research in biomedical sciences by application of state-of-the-art technologies such as next generation sequencing (NGS), induced pluripotent stem cells (iPSC) and gene editing (CRISPR/Cas). In the past few years, GENOMED has focused on exome sequencing which has led to new gene discoveries but now anticipates that whole genome sequencing (WGS) will become the next standard genetic analysis and an essential step towards personalized medicine. The future research within GENOMED will focus on two major challenges: first, the development of technologies that allow better understanding of the biological meaning of both coding and noncoding genetic variants in the human genome, and second, the translation of these new genetic findings into better diagnostics and treatment. At present, the major bottleneck with NGS is the ability to distinguish causal mutations from benign variants. The study of the functional effect of these variants will be key in the understanding of the disease biology but also necessary for the translation into personalized medicine. It will require robust and efficient systems to explore the functional consequences of these variants by using in vitro cell cultures (especially iPSC) and/or animal models (mouse, zebrafish) that are representative for the human disorder. To address the second challenge, the consortium will establish collaborations with clinicians and industry to transfer genetic knowledge into biomarkers and to translate the new genetic insights into innovative therapies.

Researcher(s)

Research team(s)

Functional assessment and therapeutic targeting of a novel aortapathy syndrome with the strong potential to inform the pathogenesis and treatment of Marfan syndrome. 01/07/2019 - 30/06/2022

Abstract

Thoracic aortic aneurysm (TAA) entails a high risk for aortic dissection and rupture. The latter events are a prominent cause of morbidity and mortality in the Western population. Over the past 25 years, extensive gene discovery efforts have identified over 30 genes in which variants impinge on TAA risk. Although collectively explaining less than 30% of all familial patients, their identification and functional characterization have been key in acquiring the vast majority of our current knowledge on aortopathy pathomechanisms. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering further identification of predictive markers for aneurysm development and progression as well as novel therapies capable of stopping or even reversing the disease process. In search for novel entry points in the etiology of TAA, I most recently identified recessive truncating mutations in IPO8 as a novel cause of a TAA syndrome clinically resembling TGF-β-related syndromes such as Marfan syndrome, Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome. More precisely, patients present with childhood-onset aneurysms at the level of the aortic root and/or aorta ascendens, global developmental delay, facial dysmorphism, joint laxity, neonatal hypotonia, pectus deformity and hernia. Not much is known about IPO8, except that it encodes a protein involved in cytosol-to-nucleus cargo shuttling (including pSMAD2, pSMAD3 and SMAD4) as well as miRNA processing. My project proposal builds further on this novel genetic finding. More specifically, I aim (1) to unravel the IPO8-related pathomechanisms using patient- and control-derived skin fibroblasts and induced pluripotent stem cell-derived vascular smooth muscle cells (iPSC-VSMCs), and (2) to discover FDA-approved drug compounds for aortopathy using a matrix metalloproteinase inhibition assay in iPSC-VSMCs of an IPO8 mutation-positive patient. The project's anticipated outcomes will advance TAA knowledge significantly beyond the current understanding and improve patient management.

Researcher(s)

Research team(s)

Genomic Modifiers of Inherited Aortapathy (Genomia). 01/01/2019 - 31/12/2023

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature's own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.

Researcher(s)

Research team(s)

Functional assessment and therapeutic targeting of a novel aortopathy syndrome caused by resessive IPO8 mutations. 01/01/2019 - 31/12/2022

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. This dramatic event may leave family members of the deceased terrified and oblivious. To date, genetic defects in >30 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, the Antwerp Cardiogenetics research group most recently identified recessive truncating mutations in IPO8 as a novel cause of syndromic TAA. My PhD project builds on this exciting finding. More specifically, I aim to significantly improve our current TAA pathomechanistic insight and future TAA patient management by (1) investigating IPO8 as a novel syndromic TAA gene through characterization of an Ipo8 null mouse line, (2) elucidating the IPO8-related pathomechanisms using patient- and control-derived cell lines, and (3) identifying putative drug compounds for IPO8-related aortopathy using a cell-based matrix metalloproteinase inhibition assay.

Researcher(s)

Research team(s)

Development of a functional model to determine the pathogenicity of COL4A1- and COL4A2-variants of unknown significance in cerebrovascular disorders and aortic aneurysms. 01/01/2019 - 31/12/2021

Abstract

COL4A1- and COL4A2-related disorders cause a broad spectrum of problems comprising abnormal brain development, brain hemorrhage at any age, aneurysms (local dilatations) of the brain arteries, but also eye or renal problems. In clinical practice, both genes are studied in disorders of brain vasculature or development and are included in gene panels to study individuals with intellectual disability. These investigations sometimes identify variants of unknown significance (VUS). Because of the important consequences of truly disease-causing mutations, it is of great importance to interpret these variants correctly. In addition, in research setting it was found that COL4A1- and COL4A2-mutations may influence the occurrence of aortic aneurysms. However, further studies are needed. We will develop a zebrafish model to study the effect of variants of unknown significance. No zebrafish model currently exists to study COL4A1- and COL4A2-related disorders. We will start with introducing known disease-causing mutations and study their effect on zebrafish development using a fish that has fluorescent blood vessels in order to easily pick up abnormal vessels. We will study the occurrence of brain haemorrhage, changes in movement patterns and the basement membrane, a structure that stabilizes the wall of blood vessels and measure the aortic diameter. After identifying the abnormalities in true disease-causing mutations, it is possible to study whether VUS contribute to disease.

Researcher(s)

Research team(s)

Identification of novel therapeutic targets of Brugada Syndrome through discovery and characterization of genetic modifiers. 01/01/2018 - 30/06/2022

Abstract

Brugada syndrome (BrS) is an inherited electrical disorder of the heart, presenting in patients with an irregular heart rhythm. This can go unnoticed throughout life, but also lead to sudden cardiac death, typically in patients between age 25-55. At present, more than 25 genes have been identified that can explain about 30% of BrS cases. The question remains why in the same family individuals with the identical genetic alteration can live without symptoms, have few or many arrhythmia episodes or even experience sudden death. I will look for an answer to this question in a group of families with a known error in the SCN5A gene causing BrS. I will study the exact effect of this genetic error and I will compare the difference in genetic signals between a selection of patients without symptoms and patients with severe symptoms, using whole genome and RNA sequencing techniques. Since it is important to work with heart cells in this study, I will use an advanced method that allows me to create heart cells from the patient's own skin or blood cells. Analysis of the genetic signals will lead us to the 'modifier genes' responsible for the differences in BrS disease severity. Identification of these modifiers will lead to a better insight into the mechanisms causing BrS, drive the development of novel therapies and result in more accurate risk prediction and personalized management of BrS patients.

Researcher(s)

Research team(s)

Past projects

Identification of key patho-mechanisms underlying bicuspid aortic valve-related aortopathy using primary endothelial cells isolated from embryonic Madh6 pups. 01/04/2020 - 31/01/2021

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart malformation affecting 1-2% of the population. This aortic valve defect is characterized by two leaflets instead of the normal three. While most BAV patients remain asymptomatic, approximately 35% of patients develop cardiovascular complications including dangerous thoracic aortic aneurysms (TAAs) and lethal dissections. To date, BAV/TAA remains a serious health problem due to the high heritability of BAV and no curative pharmacological therapies for (BAV-related) TAA are currently available. In 2017, we demonstrated a significant enrichment of deleterious SMAD6 variants in BAV/TAA patients compared to the general population. SMAD6 is highly expressed in the cardiovascular system, particularly in endothelial cells. It encode an inhibitory SMAD protein which negatively regulates BMP and TGF-β signaling. Both pathways have been previously and independently described to associate with defects of the aortic valve and thoracic aortic wall including aneurysms. Furthermore, endothelial cell dysfunction is gaining momentum as potential disease contributor, or even disease driver in both valve and aortic aneurysmal disease. Our knowledge on genetic SMAD6 data will serve as the perfect starting point to significantly expand our understanding on the mechanistic insights on BAV/TAA disease. Hence, this projects aims to relate SMAD6 deficiency to abnormalities of the aortic valve and wall by interrogating distinctive cellular and molecular processes in embryonic endothelial cells isolated from a Madh6 mouse model. The anticipated results will aid to elucidate the pathogenesis as well as initiate the identification of novel therapeutic targets for (BAV-related) TAA.

Researcher(s)

Research team(s)

Subsidy for Center Medical Genetics 01/01/2020 - 31/12/2020

Abstract

This is funding from the Flemish Government to support the genetic centers in Flanders in their key tasks such as research, teaching and patient care. The funding is renewable every year after positive evaluation of the annual activity report

Researcher(s)

Research team(s)

Price of Research Council 2019 - Price Vandendriessche: Medicine and Biomedical sciences 01/12/2019 - 31/12/2020

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, I identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with my observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

Research team(s)

In search of genetic modifiers for aortopathy in Loeys-Dietz families with a SMAD3 mutation. 01/11/2019 - 31/10/2020

Abstract

Loeys-Dietz syndrome (LDS) is a genetic disorder presenting with thoracic aortic aneurysm (TAA), causing abnormal widening of the aorta, which leads to aortic rupture or dissection, a life-threatening complication that occurs unexpectedly. LDS is caused by genetic defects in six different genes of the TGF? pathway (TGFBR1/2, SMAD2/3, TGFB2/3), which is vital in the proper development of the body's connective tissue. Despite the progress in unravelling its genetic basis, there is a lack of understanding of the wide range of severity of cardiovascular involvement. In my project, I will focus on patients within families, carrying pathogenic SMAD3 variants, which show either no or early onset aortic aneurysmal disease. I hypothesize that genetic modifiers of the primary SMAD3 mutation are the main contributors to the striking aortopathy variability in LDS-SMAD3 families. In this project, an innovative strategy will be used to identify genetic modifiers. I will perform genome-wide single nucleotide polymorphism-based linkage analysis on two large SMAD3 families and whole genome sequencing on selected individuals, combined with SMAD3 iPSC-VSMC (induced pluripotent stem cell-derived vascular smooth muscle cells) model creation and characterization and subsequent CRISPR/Cas9-based validation of the identified modifier(s). The predicted outcomes will advance the LDS and TAA knowledge, contributing to the discovery and development of novel therapeutic targets and personalized medicine.

Researcher(s)

Research team(s)

Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish. 01/11/2019 - 31/10/2020

Abstract

Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to proof their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiac muscle cell-model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving it's contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.

Researcher(s)

Research team(s)

Unravelling the discriminative pathomechanisms for biglycan-related aortopathy and spondylo-epi-metaphyseal dysplasia. 01/04/2019 - 30/03/2020

Abstract

Progressive dilatation of the aorta leads to the development of thoracic aortic aneurysms, which are often asymptomatic but predispose to aortic dissection and rupture. The latter are associated with high mortality rates. In 2016, I identified loss-of-function (LOF) mutations in BGN, an X-linked gene, as a novel cause of a severe syndromic form of thoracic aortic aneurysms and dissections (TAAD) and is now designated as Meester-Loeys syndrome (MLS). In parallel with my observations in aneurysmal phenotypes, missense mutations in BGN were described as the cause of an X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD). The general aim of this proposal is to unravel the underlying mechanisms of different BGN mutations in the development of two very distinctive phenotypes: syndromic TAAD (MLS) and X-SEMD. We aim to further unravel these pathomechanisms using detailed phenotypical characterisation and transcriptomics in BALB/cA Bgn male knock-out (LOF) and knock-in (gain-of-function?) mouse models, respectively.

Researcher(s)

Research team(s)

Brugada syndrome research to the next level: identification of genetic modifiers. 01/04/2019 - 30/03/2020

Abstract

Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac electrical disorder, characterized by ventricular arrhythmias and a significant risk for sudden cardiac death (SCD). It accounts for up to 20% of SCD cases in young individuals (<45 years) with structurally normal hearts. At present over 25 genes, including SCN5A, have been associated with BrS, but mutations in these genes explain only 30% of the cases. One other major unresolved aspect of BrS concerns the significant variability in disease expression, from completely asymptomatic over mild arrhythmia to SCD, observed even within families with an established disease-causative mutation. Genetic modifiers must play an important role in this phenomenon, and the identification of such modifiers is the aim of this project. Hereto, I will use a unique collection of BrS families recruited through our cardiogenetics clinic, sharing a Belgian SCN5A founder mutation and displaying remarkable variable expressivity. I will perform whole genome sequencing and RNA-sequencing on the advanced model of induced pluripotent stem cell (iPSC)-derived cardiomyocytes from eight carefully selected mutation carriers, four at each end of the disease severity spectrum. An in-depth combined analysis of the resulting genome and transcriptome data will certainly reveal the modifier gene(s) underlying intra-familial phenotypic variability in BrS. This will lead to a significantly improved insight into the mechanisms causing BrS, drive the development of novel therapies and result in more accurate risk prediction and personalized management of BrS patients.

Researcher(s)

Research team(s)

Research agreement for funding PhD thesis Marinus Verbeek 01/04/2019 - 30/09/2019

Abstract

This project is focused on the identification of the causal gene in two families with an autosomal dominant form of spondylocostal dysostosis. In these two families, prior investigations have already excluded a mutation in any of the known genes for this condition

Researcher(s)

Research team(s)

Optical mapping of in vivo cardiac mechanics in zebrafish: exploring the pathogenesis and mode of inheritance in catecholaminergic polymorphic ventricular tachycardia. 01/10/2018 - 30/09/2020

Abstract

Sudden death in the young is primarily caused by inherited diseases of the heart. These conditions are frequently caused by mutations in genes responsible for maintaining a regular heartbeat. Many genes that can cause sudden death have already been identified. However, for an important portion of patients, the genetic test reveals a genetic variant with unknown significance. With my project, I intend to create a new model to study the effects of these mutations on the heart in vivo. For this purpose, I will generate a new zebrafish line, in which cardiac electrical and chemical calcium signals will be converted into fluorescent light signals. As zebrafish are translucent during the first days of development, this animal model lends itself perfectly to visualize these signals in vivo. I will use the new zebrafish line to improve our understanding of one specific cardiac disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT). This condition is characterized by abnormal calcium signaling in the heart, and as such my method will be highly suitable to study CPVT. Both in the literature and in our own cardiogenetics clinic, several CPVT families with an uncertain inheritance pattern have been discovered. With my assay I intend to expose the mechanisms of CPVT in these families and hereby clarify the results of the genetic tests and contribute to future diagnostic testing in CPVT.

Researcher(s)

Research team(s)

Unravelling the discriminative pathomechanisms for biglycan-related aortopathy and spondylo-epi-metaphyseal dysplasia. 01/10/2018 - 30/09/2019

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, I identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester- Loeys syndrome (MLS). In parallel with my observations, different mutations in BGN were described as the cause of spondylo-epi-metaphyseal dysplasia (SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with a BGN deletion also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

Research team(s)

Unravelling the pathophysiology of SMAD6-associated bicuspid aortic valve and thoracic aortic aneurysm. 01/04/2018 - 31/03/2019

Abstract

Bicuspid aortic valve (BAV) is characterized by an aortic valve with only two valve leaflets instead of the normal three. With an estimated prevalence of about 1-2% in the general population, BAV represents the most common human congenital heart malformation. Although most BAV individuals remain asymptomatic, up to 30% of patients develop severe cardiovascular complications throughout their life, including thoracic aortic aneurysms (TAA) and dissections. The latter manifestations associate with significant morbidity and mortality. In view of the prevalent nature of BAV and the current lack of efficient pharmacological therapies for (BAV-related) TAA, BAV/TAA puts a substantial burden on our health care system. In search of new genetic entry points in the etiology of BAV/TAA, we most recently observed an enrichment of damaging SMAD6 variants in BAV/TAA patients compared to the general population. SMAD6 is highly expressed in the cardiovascular system and encodes an inhibitory SMAD protein that negatively regulates BMP and TGF-β signalling, which both have been linked to aortic valve development and aneurysm formation before. This project proposal builds on our genetic SMAD6 data and aims at advancing the knowledge on the pathomechanisms underlying BAV/TAA significantly beyond the current understanding by extensively investigating the key molecular elements and processes that relate SMAD6 deficiency to aortic valve and wall abnormalities. For this purpose, we will use aortic valve and wall tissue dissected from the Madh6-/- mouse model. The project's outcomes are expected to instigate the discovery of novel therapeutic targets for BAV-related TAA and prompt drug compound testing in Madh6-/- mice.

Researcher(s)

Research team(s)

Cutting-edge exploration of the genetic modifiers underlying variable aortopathy expressivity. 01/10/2017 - 30/09/2021

Abstract

Thoracic aortic aneurysms (TAAs) result from progressive dilatation of the aorta and entail a high risk for aortic dissection and rupture. The latter events associate with a mortality rate of 50%, representing a prominent cause of morbidity and sudden death in the Western population. Over the past 25 years, extensive gene identification efforts have pinpointed more than 25 genes associated with familial TAA risk, explaining about 30% of all familial TAA cases. Functional characterization of these genes has revealed perturbed extracellular matrix homeostasis, transforming growth factor‑β signaling, and vascular smooth muscle cell contractility as important TAA processes. To expedite the development of novel therapeutic strategies, acquisition of even more extensive insights into the genetic and mechanistic TAA picture is mandatory. Owing to the recent advent and fast evolution of next-generation sequencing technologies, we anticipate that the identification of additional genetic TAA causes will remain quite straightforward in the upcoming years. Given that TAA is characterized by greatly reduced penetrance and variable expressivity, modifier studies now represent a challenging, yet important, new avenue in the field of TAA genetics. In this project, we pursue the genetic modifiers that determine phenotypical variability in selected families with an autosomal dominantly inherited syndromic TAA form, namely Loeys-Dietz syndrome. State-of-the-art technologies, such as genome sequencing and creation of induced pluripotent stem cells, will be used. The anticipated outcomes will advance TAA knowledge significantly beyond the current understanding, aid genetic counseling, and offer unprecedented opportunities to find leads to novel therapeutic strategies.

Researcher(s)

Research team(s)

Connecting genes to rare diseases through New Generation Sequencing (NGS) technology and advances teaching methods (NGeneS). 01/09/2017 - 31/08/2020

Abstract

With this international project we aim to develop training materials using blended and e-learning approaches to educate young scientists on the benefits and new possibilities of next generation sequencing technology with focus on rare and genetic disorders of the skeleton. We also want to advance the knowledge on rare bone disorders and to improve the diagnosis of unknown cases by making use of facilities available through BOND, an European Reference Network for rare bone disorders.

Researcher(s)

Research team(s)

Development of a novel transgenic zebrafish model to determine the pathogenicity of genetic variants for cardiac arrhythmia. 01/04/2017 - 31/03/2018

Abstract

Inherited Cardiac Arrhythmia (ICA), such as long QT syndrome (LQTS) and Brugada syndrome (BrS), refers to a group of hereditary disorders in which patients present with irregular heart rhythm, caused by altered cardiac electrical dynamics. These episodes can remain asymptomatic, but also lead to sudden syncope and sudden death of the individual. Up to date, over 50 different genes have been identified that can cause ICA. Thanks to the advent of next generation sequencing it is possible to test all these genes simultaneously in multiple ICA patients in a single experiment, allowing the identification of pathogenic genetic alterations. However, we are also confronted with a high number of genetic alterations for which it is unsure whether they are causally involved in the disease or not, so-called variants of unknown significance. Therefore, there is a high need for a physiologically relevant functional tool to test the pathogenicity of these variants. By combining two state-of-the-art techniques, genetically encoded voltage indicators (GEVI) and selective plane illumination microscopy (SPIM), I will develop such a novel tool to study the cardiac conduction system and characterize its anatomical connectivity in zebrafish at an unprecedented resolution. By converting electrical dynamics of the zebrafish heart into fluorescent signals, this tool will enable me to optically map action potentials in the complete heart at single cell level. This will allow me to determine cardiac conduction speed and observe conduction delays, making it a novel and ideal tool to investigate the electro- and pathophysiological mechanisms underlying two arrhythmia syndromes, LQTS and especially BrS. Finally, using this functional assay, I will be able to evaluate the pathogenicity of genetic variants with an unknown clinical significance.

Researcher(s)

Research team(s)

Towards a better understanding of the molecular mechanisms underlying thoracic aortic aneurysms and dissections. 01/01/2017 - 31/12/2020

Abstract

Expansion of a weakened region of the thoracic aorta (aneurysm; TAA) entails a high risk for aortic dissection/rupture. The latter events associate with severe internal bleedings, often resulting in sudden death. Over time, defects in more than 20 genes have been found to influence TAA predisposition. Yet, the disease's genetic and mechanistic picture is still far from complete, hampering development of amended diagnostic tools and therapies. We will further resolve the TAA puzzle by identifying novel protective and risk-inferring variants/genes and by examining their mode of action. Multiple lines of evidence suggest that some to be identified TAA genes locate to the X-chromosome. Recently, we indeed discovered TAA-causing defects in an X-linked gene, biglycan (BGN). Interestingly, in certain mouse strains protection from BGN-related TAA has been documented. We aim at mapping the protective factor and at translating its protective effect to men. A second genetic approach builds on the observation that in Turner syndrome (TS) girls lacking either the short X-arm (Xp) or the entire X-chromosome, TAA is strikingly frequent. The known X-linked TAA genes, however, locate to the long X-arm. Hence, we also aim at identifying novel Xp-located TAA genes in TS girls. Finally, to further delineate existing disease pathways or to discover novel ones, we will functionally characterize the identified protective and risk-inferring defects in patient samples and transgenic model systems.

Researcher(s)

Research team(s)

Inherited cardiac arrhythmias: identification of novel genes and development of a new diagnostic tool for translating genetic diagnosis into precision medicine. 01/01/2017 - 31/12/2020

Abstract

Inherited cardiac arrhythmias (ICA) are a group of predominantly autosomal dominant disorders characterized by a disturbed cardiac action potential that can lead to sudden cardiac death at a young age. Although currently more than 50 genes have been associated with ICA, in roughly 70% of the patients the precise genetic cause is still unknown. Moreover, this group of diseases is genetically and phenotypically heterogeneous and in a molecular diagnostic setting many variants of unknown pathogenic significance are detected, hampering proper risk stratification and efficient patient management. In a unique interfaculty collaboration between the Centre of Medical Genetics, the Cardiology department, the Laboratory of Experimental Hematology and Laboratory for Molecular Biophysics, Physiology and Pharmacology, we envision to address these needs in a project with two major aims: the identification of novel genes implicated in ICA and the development of a new diagnostic tool that allows functional phenotypic evaluation of the effect of genetic variants detected in ICA patients and family members. The first aim will be achieved using linkage analysis and state-of-the-art whole-genome sequencing in phenotypically well-characterized but genetically unresolved families, followed by functional characterization of the identified candidate variants. The second aim will be accomplished by the construction and electrophysiological characterization of patient-specific induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs). Focusing on the Brugada syndrome (BrS) as a proof-of-principle, iPSC-CMs will be created from fibroblasts of family members carrying an identical BrS-causing mutation but with different phenotypic expression of disease severity, and of BrS patients with a variant of unknown significance in the SCN5A gen. These powerful approaches in combination with the existing expertise in the different collaborating teams, will definitely allow accomplishing the envisioned ultimate goals of the project. As a result, a genetic diagnosis in a larger proportion of ICA families will be reached and can be translated into a personalized functional interpretation of the genetic result in patients and relatives. This will introduce the concept of precision medicine, tailoring proper risk stratification and efficient use of preventive and therapeutic measures for the individual patient.

Researcher(s)

Research team(s)

Genomics and innovative induced pluripotent stem cell (iPSC) modeling to improve understanding of pathomechanisms underlying Brugada syndrome (BrS). 01/01/2017 - 31/12/2020

Abstract

Brugada syndrome (BrS) is an inherited cardiac electrical disorder, presented in patients by irregular heart rhythm. It is often asymptomatic, therefore it can be unnoticed. However it can also cause sudden cardiac death, typically in patients between age 25-55. First degree relatives have a 50% chance to develop BrS, putting a high burden on a family. Although some genes have been causally involved, for roughly 75% of the patients the genetic background is unknown. This project aims to fill this knowledge gap, by searching for novel genetic alterations implicated in BrS. We have gathered DNA samples from individuals from 10 genetically unresolved BrS families. We will sequence the whole genome of 3 selected patients per family. For the 3 largest families, we will combine sequencing with a dedicated linkage approach to identify genomic regions shared by patients. After genetic identification of new disease-causing mutations, their effects will be investigated in an advanced cell model, consisting of heart cells created from the patient's own skin cells. This allows us to mimic the environment of the heart in vitro and study what is happening at the molecular level. This will lead to better insight into mechanisms causing BrS, driving the development of novel therapies and ultimately resulting in more accurate risk prediction and personalized management of the BrS patients.

Researcher(s)

Research team(s)

Disentangling the role of the X-chromosome in the pathogenesis of thoracic aortic aneurysms and dissections. 01/10/2016 - 30/09/2019

Abstract

The aorta serves as the responsible artery for blood distribution from the heart towards the distal parts of the human body. Expansion of weakened regions of the thoracic aorta (aneuysms; TAA) entails a high risk for aortic dissection/rupture. The latter events associate with severe internal bleedings, often resulting in sudden death. As relatives of TAA patients are at high risk, genetic defects are certainly involved in disease development. Multiple lines of evidence suggest that at least one TAA-causing gene locates to a sex (i.e. the X-) chromosome: firstly, TAA is much more frequent in males and secondly, Turner syndrome (TS) girls, in whom one X-chromosome is partially or completely deleted, strikingly often present with TAA. Most recently, our research group identified genetic defects in the biglycan (BGN) gene, which is located on the long arm of the X-chromosome (Xq), causing syndromic TAA. This project partially builds on this finding. We aim at (1) elucidating the role of BGN promoter defects in non-syndromic TAA, (2) determining the downstream consequences of BGN loss and (3) identifying a genetic factor influencing manifestation of BGN-related TAA in mice. As TS patients missing the short X-arm (Xp) are more frequently affected with TAA, it is likely that an Xp-located TAA gene remains to be identified. Therefore, goal (4) encompasses identification of an Xp aortopathy gene using X-chromosome sequencing in TS patients.

Researcher(s)

Research team(s)

Improving care for cohenisopathies: from heart phenotypes to novel therapies (CoHEART). 01/05/2016 - 30/04/2019

Abstract

When cells in the body grow and take decisions such as how fast they divide or which fate they choose for their development, they need to read and interpret the genetic code. This process is facilitated by proteins that are called the cohesin complex. When these proteins are mutated, several rare diseases can ensue; these diseases are now often referred to as cohesinopathies. Several of them can cause cardiac malformations or other forms of heart disease, in addition to other features such as delayed growth, developmental delay, and others. In this project, we will study in particular two rare cohesinopathies that affect the heart, namely Cornelia de Lange (CdLS) and CAID syndrome. The goal of our study is to better understand at molecular level what these two diseases have in common, and what distinguishes them. Specifically, we are planning to pursue the following aims: 1.) We will create models of disease 'in a dish' from cells obtained in patients and controls. This will help us to find out which parts of the genetic circuitry do not function correctly in single cells. 2.) We will study animals engineered to carry the same disease-causing mutations as those found in patients. This will allow us to find out whether identical parts of the genetic circuitry are disturbed in the whole organism. 3.) We will test all known genes in cell culture to find interactors that worsen or alleviate disease in cell-based and animal models. These results will help us to better understand a group of rare, devastating disease, and permit a more rational way to identify promising drugs for clinical use

Researcher(s)

Research team(s)

In pursuit of X-linked aortopathy genes in patients with Turner syndrome 01/04/2016 - 31/03/2017

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart disorder. Although BAV is intrinsically asymptomatic, it associates with thoracic aortic aneurysms (TAA) and ruptures that are highly mortal. BAV and TAA are strikingly frequent in Turner syndrome (TS), which affects approximately 1 in 2,500 live-born females and is caused by either partial or complete absence of one X-chromosome. One possible mechanistic hypothesis (a 2-hit hypothesis) states that increased BAV/TAA prevalence in TS is caused by mutations in a "cardiovascular" gene on the residual X-chromosome. To identify such X-linked aortopathy genes, all protein coding sequences of the X-chromosome will be sequenced in 22 TS patients with BAV as well as in 10 tricuspid TS patients. Supporting genetic evidence for the identified aortopathy candidate genes will be acquired by sequence analysis of their coding regions in additional TS/BAV samples as well as in a small non-syndromic male BAV/TAA discovery cohort. The expected experimental findings will prove beneficial for molecular diagnostic applications, genetic counselling or clinical follow-up of BAV/TAA families and, through acquisition of novel pathomechanical insights, development of preventive and more personalized therapies.

Researcher(s)

Research team(s)

Identification of novel genetic variants implicated in Brugada syndrome 01/04/2016 - 31/03/2017

Abstract

Brugada syndrome (BrS) is an autosomal dominant heart rhythm disorder associated with a high risk for sudden cardiac death. It has a prevalence of 1:2000 in the general population. Since clinical diagnosis is imperfect, genetic testing has an important added value, but for roughly 70% of the patients the genetic causality is still unknown. Therefore, the objective of this project is to identify novel genetic variants implicated in BrS. Eleven BrS patients and 15 unaffected relatives from two well-characterized family that are negative for all currently known arrhythmia genes will be subjected to SNP-array genotyping followed by linkage analysis. We will apply whole-genome sequencing to DNA of five of the patients to allow a comprehensive interrogation of coding, non-coding and structural DNA variation, focusing on shared variants in the linked candidate regions. This powerful approach in combination with the best suitable bioinformatics pipelines will enable us to identify novel causal variants related to BrS within the timeframe of this project. The novel BrS genes or variants will immediately be incorporated into our existing diagnostic arrhythmia gene panel, allowing direct translation into clinical care and improved risk prediction, genetic counselling and prevention of sudden cardiac death. Investigation of the function of the gene at pathway and cellular level will provide new insights into the pathogenesis of BrS and likely other arrhythmogenic disorders and ultimately drive the development of novel therapies.

Researcher(s)

Research team(s)

Exploration of the genetic basis of thoracic aortic aneurysm with focus on bicuspid aortic valve related aortopathy. 01/10/2015 - 30/09/2020

Abstract

Bicuspid aortic valve, a heart valve with only two leaflets instead of three, is the most common congenital heart defect with a prevalence of 1-2%. The heart defect often remains asymptomatic but at least 10% of the bicuspid aortic valve patients develop an ascending aortic aneurysm. If not detected in a timely fashion, this can lead to an aortic dissection with high mortality. In view of the prevalent nature of this heart defect, this implies an important health care problem. Historically, it was always hypothesized that abnormal blood flow across the bicuspid valve led to aneurysm formation. However in recent years, the importance of a genetic contribution has been suggested based on the high heritability and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Until now, the latter have significantly hampered the causal gene identification but the era of next generation sequencing is now offering unprecedented opportunities for a major breakthrough in this area. Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver new therapeutic targets.

Researcher(s)

Research team(s)

Support maintenance scientific equipment (Medical Genetics). 01/01/2015 - 31/12/2020

Abstract

The maintenance contracts for our NGS devices (MiSeq and HiSeq1500) are partly covered by BOF funding. These devices were gained by Hercules funding. They make next generation sequencing for research purposes possible.

Researcher(s)

Research team(s)

GENOMED - Genomics in Medicine. 01/01/2015 - 31/12/2019

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

Research team(s)

Identification and characterisation of genes involved in bicuspid aortic valve associated aortopathy. 01/01/2015 - 31/12/2018

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation with a population prevalence of 1 to 2%. Ten to twenty percent of the BAV patients develop thoracic aortic aneurysms (TAA). Untreated TAA will lead to life-threatening aortic dissections and ruptures. Therefore, it is important to identify TAA in BAV patients, to monitor continuously the progression of TAA and to treat TAA. The general aim of this project is to unravel the underlying genetic basis of BAV/TAA, to characterise the identified genes and to gain insights into the pathogenic mechanisms.

Researcher(s)

Research team(s)

Ma.Tr.OC - Identification of molecular therapeutic targets and diagnostic/prognostic biomarkers of malignant transformation of osteochondromas. 01/04/2014 - 31/03/2017

Abstract

This is a fundamental research project financed by the Research Foundation – Flanders (FWO). The project was subsidized after selection by the FWO-expert panel. The molecular basis of peripheral chondrosarcoma development is are currently unknown. This leads to the lack of prognostic markers and, most importantly, the absence of a therapeutic approach alternative to the surgery. This project aims the identification of pathways underlying peripheral chondrosarcoma development and identify prognostic markers in patients with mutiple osteochondroma (MO), who are at increased risk of developing peripheral chondrosarcoma.

Researcher(s)

Research team(s)

Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL). 01/10/2013 - 30/09/2018

Abstract

The aim of SYBIL is to carry out extensive functional validation of the genetic determinants of rare and common skeletal diseases and the age related factors contributing to these painful conditions. To achieve this goal SYBIL will gather complementary translational and transnational scientists, systems biologists, disease modellers, leading SMEs and industrialists that will perform in-depth characterisation (complete molecular phenotyping) of pre-clinical models (cellular and animal) for a variety of common and rare skeletal diseases.

Researcher(s)

Research team(s)

The (patho)genetic study of bicuspid aortic valve and associated aortic aneurysm 01/10/2013 - 30/09/2016

Abstract

Bicuspid aortic valve (BAV), a heart valve with only two leaflets instead of three, is the most common congenital heart defect with an estimated prevalence of approximately 1-2%. The heart defect often remains asymptomatic but ascending aortic aneurysms develop in 10-20% of the bicuspid aortic valve patients. If not detected in a timely fashion, this can lead to aortic dissection with an important mortality. Due to the prevalent nature of this heart defect, bicuspid aortic valve disease presents an important health problem. Historically, it was hypothesized that abnormal blood flow across the bicuspid aortic valve led to aneurysm formation. However in recent years, an important genetic contribution has been suggested and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most nsistent with an autosomal dominant disorder with variable penetrance and expressivity. Within this project, two specific aims will be pursued. Firstly, we will investigate the potential contribution of canonical and non-canonical TGFβ signaling cascades in BAV that have been firmly implicated in Marfan-related aneurysms. Secondly, we will identify the genetic basis using a state-of-the-art technique: whole exome sequencing.

Researcher(s)

Research team(s)

Bicuspid Related Aortopathy, a Vibrant Exploration (BRAVE). 01/05/2013 - 30/04/2018

Abstract

Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver a mouse model for future therapeutical trials.

Researcher(s)

Research team(s)

Mechanistic interrogation of Bicuspid Aortic Valve associated aortapathy. 01/01/2013 - 31/12/2018

Abstract

This project represents a formal research agreement between UA and on the other Fondation LEDUCQ. UA provides Fondation LEDUCQ research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Investigation of the genetic basis and the pathogenic mechanisms involved in bicuspid aortic valve associated thoracic aortic aneurysm. 01/10/2012 - 30/09/2016

Abstract

Bicuspid aortic valve is the most common congenital heart defect and is often associated with ascending aortic aneurysms. As such it presents an important health problem. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Within this project, we will identify the genetic basis using copy number variation analysis and whole exome sequencing and we will investigate the potential contribution of TGFβ signaling cascades.

Researcher(s)

Research team(s)

The (patho)genetic study of bicuspid aortic valve and associated aortic aneurysm. 01/10/2012 - 30/09/2013

Abstract

The general aim of this project is to unravel the underlying genetic basis and to gain insight into the pathogenic mechanisms leading to BAV-associated aneurysm formation in order to advance the knowledge significantly beyond the current understanding. We will take advantage of the era of next generation sequencing, which is now offering unprecedented opportunities for a major breakthrough in the field of BAV/TAA.

Researcher(s)

Research team(s)

Sudden cardiac death: translating genetic technology into improved clinical care. 01/09/2012 - 31/08/2014

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Next generation sequencing technology opening new frontiers in biological and medical research. 28/06/2012 - 31/12/2017

Abstract

The aim of this project is to develop a next generation sequencing (NGS) platform to advance in a collaborative way biological and medical research within the Antwerp research community. The consortium involves more than 16 research groups in various disciplines of medicine, biology and biomedical informatics. The goals are to identify new genes and mutations in various rare Mendelian disorders, to achieve more insights in the genetic causes of cancer and to unravel more precisely the genetic determinants of infectious diseases. This new knowledge will improve both the diagnosis and management of these human diseases. The project will also focus on the interaction between environment and genes. More specifically, the effect of environmental stressors on genetic variation in aquatic organisms, the effect of teratogenic factors on embryonic development in vertebrates and the effects of environmental conditions on growth in maize and Arabidopsis lines will be studied. The analysis of the large amount of genomic and transcriptomic data, generated by the various research groups, will be coordinated by the recently founded UZA/UA bioinformatics group Biomina

Researcher(s)

Research team(s)

Pathogenetic study of the intersection of two frequent monogenic diseases: the Marfan syndrome and autosomal dominant polycystic kidney disease. 01/01/2012 - 31/12/2015

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Clinical and (patho)genetic study of bicuspid aortic valve and associated aortic aneurysm. 01/01/2012 - 31/12/2015

Abstract

The general aim of this project is to gain insight into the clinical course of BAV-associated TAA, into the pathogenic mechanisms leading to aneurysm formation and to unravel the underlying genetic basis. In this project we will correlate a specific subclassification of bicuspid aortic valves (Sievers classification) with cardiovascular characteristics including co-morbidity, arterial stiffness and eccentric flow patterns. In addition, we will investigate the contribution of different developmental pathways and identify the genetic basis using state-of-the-art techniques including microRNA profiling, Copy Number Variant analysis and exome sequencing.

Researcher(s)

Research team(s)

Physiopathological and genetic study of the intersection of two frequent monogenic disorders: the Marfan syndrome and autosomal dominant polycystic kidney disease. 30/08/2011 - 29/08/2012

Abstract

This project represents a formal research agreement between UA and on the other hand KAGB. UA provides KAGB research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Gene and microRNA discovery in the pathogenesis of aortic aneurysms. 26/07/2011 - 25/07/2012

Abstract

Aims of the project The project employs state-of-the art methodologies to explore the (patho)genetic mechanisms underlying aortic aneurysms, including their relation with ADPKD, and involves three major aims: 1. Identification of new genomic regions involved in the etiology of aortic aneurysms 2. Application of traditional positional cloning approaches using highly advanced technologies for gene discovery

Researcher(s)

Research team(s)

Application of whole exome sequencing to identify the genetic defect in hereditary connective tissue disorders 01/07/2011 - 31/12/2015

Abstract

With the completion of the human genome project in 2003 and its ambitious goal of sequencing the entire human genome, the field of genetic medicine has benefited from the development of resources and technology that has accelerated genetic analysis tremendously. In addition, the better understanding of the structure and the function of the human genome has lead to the development of new tools and findings that can be applied to human health and disease. This genetic revolution has opened opportunities for a personalized genomic medicine in which genetic information is used for better diagnosis, treatment and prevention of disease. In the past, the identification of disease genes was a time- and money-consuming and labor-intensive process that often took advantage of the study of large families with multiple affected individuals. By a process called positional cloning, genomic regions were identified through the analysis of the linkage of genetic markers and the disease phenotype within families. Subsequently, it often took years to identify the causal genetic variant (called mutation) in those genomic regions. Only after the identification of mutations, research of the mechanism by which mutations lead to disease could be started with the ultimate hope to find new therapeutic options. Over the last couple of years, the development of new innovative sequencing technologies, has significantly reduced the cost and increased the speed of DNA sequencing. With these next generation sequencing technologies, it has become feasible to sequence the whole genome of single individuals. In this project, we want to apply next generation sequencing technology to perform whole exome sequencing (WES). By applying the latter technique we focus the sequencing effort on the coding part of the genome (the exome) which represents approximately 1% of the human genome but is estimated to harbor about 85% of all disease causing mutations. We plan to apply this new powerful technology to accelerate the process of disease gene/mutation identification in order to enable further pathogenetic studies and to fasten the translation to clinical care. In the initial phase, we will use this strategy to study two disease groups for which the (co)promoters have a strong research record, namely aneurysmal disease and skeletal dysplasias. The strategies that we develop for these disease groups serve as a paradigm for the study of other cardiovascular diseases (such as rhythm disorders and cardiomyopathies) or more common disorders such as osteo-arthrosis and osteoporosis. Moreover, the workflow and the bio-informatics tools developed during the course of this project can be extrapolated to any human condition with a (partly) genetic basis. We will focus on three objectives. One objective aims to combine traditional linkage analysis with WES in order to identify new disease genes. Secondly, we will apply WES to facilitate the molecular screening process to identify mutations in conditions that can be caused by multiple genes. This will significantly decrease the time required for molecular confirmation of a clinical diagnosis. Thirdly, we will use WES to search the genetic cause in sporadic patients with disorders for which no obvious causal genes exist or in patients in whom all known genes were excluded. Ultimately, this project will generate the basis for further functional studies allowing a better understanding of the disease causing mechanism and will deliver a platform that can be used by other researchers to unravel the genetic basis of other diseases.

Researcher(s)

Research team(s)

Study of the role of genetic variation in the phenotypic variability and response in patients with Marfan syndrome. 01/02/2011 - 31/12/2013

Abstract

This project represents a formal research agreement between UA and on the other hand NMF. UA provides NMF research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Study of TGFbeta signaling pathway in hereditary connective tissue disorders. 01/12/2010 - 30/09/2015

Abstract

Aortic dissection is an important cause of death in the western world with an estimated prevalence of 1-2% of total mortality. Although most dissections occur abdominal, the study of thoracic aortic aneurysms (TAA) has provided major new insights into the pathogenesis of this disease. The genetic contribution to thoracic aortic aneurysms is demonstrated to be very important as about 20% of all affected individuals have a positive family history for aneurysms. For many years, the study of a monogenic syndromic cause of thoracic aortic aneurysm, Marfan syndrome (MFS), has served as a paradigm for the study of TAA. Detailed pathogenetic studies of humans and mouse models with MFS have lead to the identification of transforming growth factor beta signaling as a key pathway in the pathogenesis of aortic aneurysms. Through the detailed clinical description and the use of state-of-the-art molecular technologies (microarray, next generation sequencing, microRNA profiling, proteomics), this project aims at the further delineation and unraveling of the pathogenesis of TAA. A better understanding of this disease will ultimately lead to better diagnostic tools, improved counseling and development of new therapeutic strategies.

Researcher(s)

Research team(s)

GABAergic therapy for the fragile X syndrome 01/07/2010 - 31/12/2014

Abstract

We want to test the hypothesis whether the GABAergic system might be a target for treatment of fragile X syndrome. We will construct a genetic rescue mouse model to verify whether correction of deficient GABA synthesis rescues the fragile X phenotype in knockout mice. In addition, we will test novel gabaergic drugs in the fragile X knockout mouse.

Researcher(s)

Research team(s)

Clinically molecular and functional study of multiple osteochondromes and related disorders. 01/01/2010 - 31/12/2011

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Detection of copy number changes in epilepsy patients using SNP arrays. 01/02/2009 - 30/04/2009

Abstract

Copy number vatiations are responsible for up to 20% of all mental retardation cases. Recently it has been postulated that these microdeletions might also be found in epilepsy patients. Therefore we want to test 30 epilepsy patients with mental retardation for the occurrence of microdeletions using Illumina Infinium SNP assays in this pilot project.

Researcher(s)

Research team(s)

Subsidy to the Human Heredity Centers. 01/01/2008 - 31/12/2011

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

Research team(s)

Development of array-based MLPA to detect microdeletions and duplications in the mentally retarded. 01/01/2007 - 31/12/2008

Abstract

Microdeletions and duplications are responsible for more than 10% of all mental retardation cases. Only a few of these aberrations result in a clinically recognizable phenotype. This implies that most patients need to be screened for all loci. Therefore we plan to develop array-based MLPA that allows the simultaneous testing for all loci on a large patient population.

Researcher(s)

Research team(s)

Development of a multiplex-PCR detection method for the identification of deletions causing Maturity-Onset-Diabetes-of-the Young (MODY). 01/01/2007 - 31/12/2008

Abstract

Maturity-Onset-Diabetes-of-the Young (MODY) is a monogenic, genetic heterogeneous form of diabetes which is characterized by autosomal dominant inheritance and early onset. This project aims the development of a fast detection method for the detection of deletions in the most frequently mutated MODY genes; the glucokinase (MODY2) and HNF1a (MODY3) genes. This should lead to a better, more sensitive molecular diagnostics for MODY patients.

Researcher(s)

Research team(s)

European network to promote research into uncommon cancers in adults and children: Pathology, Biology and Genetics of Bone Tumors. (EuroBoNet) 01/02/2006 - 31/07/2011

Abstract

European network to promote research into uncommon cancers in adults and children: Pathology, Biology and Genetics of Bone Tumors. (EuroBoNet) Primary bone tumours are rare, accounting ~0.2% of the cancer burden. Children and young adolescents are frequently affected. Their aggressiveness has major impact on morbidity and mortality. Though progress has been made in pathological and genetic typing, the aetiology is largely unknown. Though advances in therapeutic approaches increased survival, significant numbers of patients (~40%) still die. Within the EuroBoNeT integration will be achieved by staff exchange and website-based discussion forums to increase and disseminate knowledge of primary bone tumours at the molecular level for development of new tools for patient care and cure and technology. With this integration exchange of material (virtual BioBank), Standard Operating Protocols and the use of technology platforms will enable us to obtain statistical significant datasets, otherwise not achievable due to the rareness and large number of sub entities. A joint programme will contribute in obtaining molecular portraits of tumours, separated in 4 research lines (RL). In each RL the biology of the separate group (RL1: cartilaginous tumours; RL2: osteogenic tumours and related sarcomas; RL3: osteoclastogenesis and Giant cell tumours of bone; and RL4: Ewing family of tumours) will be examined by genome wide expression and genomic aberration studies. More specific hypothesis driven approaches will be investigated by RNA/protein expression and mutation analysis. Knowledge on normal growth and differentiation will be gathered through in vitro studies. This would lead to further understanding and identification of markers for malignant transformation and/or progression, as well as identification of therapeutic targets. Next to research, dissemination of knowledge will be achieved by training courses on bone and soft tissue pathology for all interested. The last is required since patients usually do not present themselves at centres, which necessitates spreading of knowledge.

Researcher(s)

Research team(s)

Identification and characterization of genes and molecular mechanisms causing the MHO (MHE) phenotype. 01/01/2006 - 30/06/2006

Abstract

Previous studies have shown that the majority of patients suffering from Multiple hereditary osteochondroma (MHO/MHE) harbor an EXT1 or EXT2 mutation. However, a significant fraction of patients does not show a mutation due to the different mutation detection techniques used in the various studies and because most labs do not invest in laborious and expensive techniques to identify mutations which are not found by standard mutation analysis of EXT1 and EXT2. To identify a potential EXT1 or EXT2 mutation, these negative patients will be analyzed with the most sensitive techniques, including RNA and promotor analysis to identify intronic or regulatory mutations. The identification of mutations in regulatory regions may point to sequences crucial for proper EXT regulation and these sequences can be used as targets for the identification of proteins regulating EXT expression. In addition, linkage analysis will be performed in large families without an EXT1 or EXT2 mutation to investigate whether additional MHO causing genes do exist. At present it is not clear whether a phenotype-genotype correlation exist in MHO. This is mainly due to the low number of available samples in previous studies and to the lack of a uniform phenotype scoring system. With the construction of a large MHO network these two problems have been addressed and by pooling the samples of MHO patients which are contributed by the different partners of this collaboration, a significant number of patients is now available. Moreover all these patients will be genotyped according to the same mutation analysis SOP which guaranties optimal molecular analysis and they will be phenotypically scored by a uniform scoring system. This will result in a statistical power allowing to address the question whether and/or which genotype/phenotype correlation exists. MHO shows great clinical variability, even intrafamilial. This suggest that other genes influence the severity of this disease. To identify such potential modifiers, SNPs of various candidate genes, selected based upon their functional relevance in bone and cartilage development, will be analyzed in a large set of MHO patients to investigate association with certain genotypes and severity. Large MHO families will greatly increase the power of this analysis.

Researcher(s)

Research team(s)

Identification an characterization of susceptibility genes for bipolar affective disorder. 01/01/2003 - 31/12/2006

Abstract

Our project builds on findings from four independent genome-wide linkage scans for bipolar affective disorder that have identified several chromosomal loci that may harbour genes for this disorder. The availability of large patient samples and the use of high-throughput genotyping methods will allow searching for linkage disequilibrium in the most promising regions and finally the identification of disease-associated genes.

Researcher(s)

Research team(s)

Identification of a gene for bipolar affective disorder in chromosomal region 8q24. 01/01/2003 - 31/03/2004

Abstract

Researcher(s)

  • Promotor: Nöthen Markus
  • Co-promotor: Cichon Sven

Research team(s)

Formal and molecular genetic studies of biplolar affective disorder. 01/01/2003 - 31/03/2004

Abstract

Researcher(s)

  • Promotor: Nöthen Markus
  • Co-promotor: Cichon Sven

Research team(s)

Identification and characterisation of heritable monogenic and polygenic disorders. 01/01/2002 - 31/12/2006

Abstract

This project clusters four research teams of the Center of Medical Genetics at the University of Antwerp in the field of bone disorders, hereditary deafness, mental retardation and psychiatric genetics. The general aims, shared over the different research topics are localisation of disease causing genes, identification of disease causing genes, functional analysis of newly identified genes, and exploring therapeutic possibilities in animal models, based on the results of the functional analysis.

Researcher(s)

Research team(s)

Molecular genetic investigation of schizophrenia. 01/01/2002 - 31/03/2004

Abstract

Researcher(s)

  • Promotor: Nöthen Markus

Research team(s)

Identification of a gene for bipolar affective disorder in chromosomal region 8q24. 01/01/2002 - 31/12/2003

Abstract

Bipolar affective disorder (BPAD), also known as manic depressive illness, is characterized by severe aberrant mood swings in alternating periods of mania and depression. The disorder is common with a lifetime prevalence of about 1% in all human populations and results in high costs in terms of morbidity as well as mortality. BPAD is substantially responsive to drug treatment, but episodes tend to recur throughout life. Although the etiology and pathophysiology is widely unknown, family, twin and adoption studies argue for a strong genetic determination of the disease. Theories concerning the possible involvement of multiple genes of small effect and/or the occurrence of major allelic effects in epistasis have been advanced. In order to identify chromosomal loci harbouring genes that predispose to BPAD, in the absence of substantial molecular pathophysiological knowledge, linkage analysis is one of the best available methods. However, despite encouraging linkage findings by several research groups worldwide, no gene has yet been identified in BPAD. The linked regions usually cover large genetic distances (>10cM) that are prohibitive to systematic investigation of candidate genes. Nevertheless, gene identification has been shown to be possible in other diseases with complex inheritance (Diabetes mellitus type 2; Morbus Crohn) via the detection of linkage diseqiulibrium (LD) which exists over short genetic distances (<1cM). Until very recently, the search for LD in candidate regions was severely hampered by the lack of densely spaced markers (SNPs and microsatellites), physical maps, large patient samples, and sufficiently rapid, cheap, and accurate methods of genotyping SNPs. Many of these problems have been substantially reduced by the data provided by the Human Genome Project as well as development of high-throughput genotyping technologies. Our project builds on findings from a genome scan for linkage to BPAD that we recently finished. It will focus on the search for LD in a linked chromosomal region on 8q24 and finally the identification of the gene involved in the development of BPAD. The identification of a disease-related gene should allow to understand the nature of the corresponding gene products and their disease-related deviations. The obtained insights into the etiology of BPAD will open a corridor for new diagnostic and therapeutic options.

Researcher(s)

  • Promotor: Nöthen Markus
  • Co-promotor: Cichon Sven
  • Fellow: Van Den Bogaert Ann

Research team(s)

Cloning and characterization of genes for hypotrochosis simplex. 01/10/2001 - 31/05/2004

Abstract

Researcher(s)

  • Promotor: Nöthen Markus
  • Fellow: Betz Regina

Research team(s)