Research team

Expertise

My expertise is situated within cardiogenetics, more specifically within molecular cardiogenetics. Cardiogenetics include the following disorders: thoracic aortic aneurysm and dissection, primary electrical diseases, cardiomyopathy and familial hypercholesterolemia. Sudden cardiac death is an important cause of death with an annual incidence of one death per 1000 person-years. Above the age of 45 years sudden cardiac death is usually due to atherosclerotic coronary disease, however below the age of 45 years often hereditary heart diseases are responsible for the sudden death. The four most frequent causes within this age group are premature atherosclerosis (for example familial hypercholesterolemia), cardiomyopathy (for example hypertrophic cardiomyopathy), primary electrical diseases (for example long-QT or Brugada syndrome) and aortic dissection. The objective of our research is to recognize the cause of the sudden death in individuals younger than 45 years of age, to identify the role of hereditary causes and to define the best strategy for diagnostics and prevention. Our main focus lies on the genetic etiology of aortic aneurysms and primary electrical diseases. Aortic aneurysms and dissection/rupture is an important health problem in the Western world with an estimated mortality of 1-2%. The current knowledge on aortic aneurysms was generated mostly based on the study of rare monogenic forms of thoracic aortic aneurysms (TAA), such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Through the identification of the genetic basis of LDS and the study of mouse models for MFS, a key role for the dysregulation of the TGFβ signaling pathway in the pathogenesis of TAA was discovered. Subsequently, dysregulation of TGFβ signaling was also demonstrated for other syndromic and non-syndromic forms of TAA. With our research we try to identify new causal genes for TAA, to elucidate the related pathogenic mechanisms and to further explore the role of dysregulated TGFβ signaling in the development of TAA. Primary electrical diseases consist of a group of mostly autosomal dominant disorders that are characterized by disturbed action potentials in the heart that can lead to sudden cardiac death at a young age. Although more than 50 genes have been associated with these disorders, the exact causal gene remains elusive in approximately 70% of the patients. Moreover, these hereditary cardiac arrhythmias are genetically and phenotypically heterogeneous and, in addition, a lot of variants of uncertain significance are found within the molecular diagnostic setting. This hampers an exact risk assessment and as a consequence also an efficient preventive and therapeutic policy for the patient. We aim to tackle these problems through the identification of new causal genes and to develop new diagnostic tools that allow to characterize the functional and phenotypic effect of genetic variants.

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.

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    • Research Project

    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.

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      • Research Project

      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.

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        • Research Project

        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.

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          • Research Project

          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.

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            • Research Project

            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.

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              • Research Project

              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.

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                • Research Project

                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.

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                  • Research Project

                  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.

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                    • Research Project

                    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

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                      • Research Project

                      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.

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                        • Research Project

                        Elucidation of the pathofysiology of DFNA5 - associated hearing loss. 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.

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                          • Research Project

                          Identification and characterisation of genes responsible for age-related hearing impairment. 01/01/2009 - 31/12/2012

                          Abstract

                          The general aim of this project is to acquire better insights into the development of ARHI, a complex type of hearing loss. To achieve this we will firstly perform additional investigations on two recently identified ARHI susceptibility genes, GRHL2 and GRM7, using genetic and functional studies.

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                            • Research Project

                            Genetic and functional studies for GRHL2 and GRM7, two genes for Age-Related Hearing Impairment. 01/10/2008 - 30/09/2009

                            Abstract

                            Age-Related Hearing Impairment (ARHI), the most prevalent sensory impairment in the elderly, is a complex disease caused by environmental and genetic factors. Our laboratory recently identified two susceptibility genes for ARHI, GRHL2 and GRM7. The current project will elaborate the role of these two genes for the development of ARHI by genetic and functional studies.

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                              • Research Project

                              Elucidation of the pathofysiology of DFNA5 - associated hearing loss. 01/01/2008 - 31/12/2009

                              Abstract

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                                • Research Project

                                Elucidation of the pathofysiology of DFNA5 - associated hearing loss. 01/10/2007 - 31/12/2007

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                                  • Research Project

                                  Identification of susceptibility genes for complex types of hearing loss. 01/10/2006 - 31/03/2007

                                  Abstract

                                  The main objective of this project is to acquire insight into the development of complex types of hearing loss, more specifically of ARHI (Age-Related Hearing Impairment) and NIHL (Noise-Induced Hearing Loss), through the identification of the susceptibility genes that are involved.

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                                    • Research Project

                                    Identification of genes for noise-induced hearing loss. 01/01/2006 - 31/12/2008

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                                      • Research Project

                                      Identification of modifier genes for hearing loss caused by GJB2 mutations. 01/05/2005 - 31/12/2006

                                      Abstract

                                      GJB2 mutations are responsible for a major part of prelingual hearing loss. The hearing loss ranges from mild to profound.The phenotypic variation can partially be explained by the GJB2 genotype. In addition to this genotype-phenotype correlation, modifier genes undoubtedly play a role in this variation. This project aims at the identification of these modifier genes using genetic association studies in carefully selected candidate genes.

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                                        • Research Project

                                        Construction and characterization of a mouse model for hereditary hearing impairment caused by mutations in DNA5. 01/01/2005 - 31/12/2007

                                        Abstract

                                        DFNA5 is a gene for an autosomal dominant, progressive, sensorineural hearing loss, starting at the high frequencies at an age of 5 to 15 years. A first attempt to generate a mouse model by mimicking the human mutation through targeted recombination resulted in a knockout mouse. However, the knockout mouse did not show any hearing loss. In the mean time, a hypothesis was formulated posing that the hearing loss probably was due to a gain-of-function and not, as was assumed before, to haplo-insufficiency. In this project the gain-of-function hypothesis will be further investigated, by the generation of a mouse model through pronuclear injection of human mutant DFNA5 cDNA coupled to the DFNA5 promoter.

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                                          • Research Project

                                          The study of KCNQ4, a hearing impairment gene. 01/01/2005 - 31/12/2006

                                          Abstract

                                          This project comprises the functional study of KCNQ4, one of the genes responsible for progressive hearing impairment. The main goals are: the identification of the promotor elements and the construction and characterisation of a knock-out mouse. We will also investigate whether KCNQ4 plays a role within complex hearing impairment disorders.

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                                            • Research Project

                                            The identification of the DFNA5 gene and the first steps towards the elucidation of the function of the gene product. 27/11/2003 - 31/12/2004

                                            Abstract

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                                              • Research Project

                                              Study of monogenic and of complex forms of hearing impairment and vestibular dysfunction. 01/10/2003 - 30/09/2006

                                              Abstract

                                              Hearing loss is the most frequent sensory disability. Age-related hearing impairment (ARHI) is a problem for approximately 50% of the elderly. In addition, vestibular dysfunction is frequent: 3 to 5% of the population is faced with vertigo or dizziness during his lifetime. This project studies a complex type of hearing impairment (ARHI) through the identification of ARHI susceptibility genes as well as a monogenic type of hearing impairment through functional studies on the DFNA5 gene. Finally, the vestibular aspect will be studied through the identification and characterization of the gene responsible for the head bobbing phenotype of an ENU mutant mouse.

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                                                • Research Project

                                                Identification and characterisation of genes for hearing impairment and vestibular dysfunction in ENU mouse mutants. 01/01/2002 - 31/12/2004

                                                Abstract

                                                To study the molecular mechanisms acting in the inner ear, extensive pedigrees with monogenic hearing loss and naturally occurring mouse mutants are used. Although a large number of genes have been localised and identified up to now, the overlap between human and murine genes is very small. Therefore, many additional gene localisations are being expected. To achieve this, ENU (ethylnitrosurea) mouse mutants will be studied. Mice with a cirkling behaviour show vestibular dysfunction, which frequently is associated with hearing loss. As a consequence, cirkling mice are an obvious choice for the study of hearing impairment.This project aims at the localisation, identification and characterisation of the genes responsible for the cirkling behaviour in 2 ENU mouse mutants using positional cloning techniques. In addition, morphological studies on the mice inner ears will be performed and the hearing loss/vestibular dysfunction will be thoroughly characterised

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                                                  • Research Project

                                                  Functional analysis of a gene for progressive sensorineural hearing impairment. 01/01/2002 - 31/12/2004

                                                  Abstract

                                                  DFNA5 is a gene for an autosomal dominant form of hearing impairment. Up to now, no function could be assigned to the DFNA5 gene product. This project aims to contribute to the elucidation of the DFNA5 function using a combination of immunohistochemical and in-situ hybridization studies on inner ear, the subcellular localization of the protein, the identification of interacting proteins, a thorough study of a DFNA5 knockout mouse, and the evaluation of DFNA5 function from organ of Corti primary cell cultures.

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                                                    • Research Project

                                                    Functional analysis of a gene for autosomal dominant progressive sensorineural hearing impairment. 01/01/2002 - 31/12/2003

                                                    Abstract

                                                    DFNA5 is a gene for an autosomal dominant form of hearing impairment. Up to now, no function could be assigned to the DFNA5 gene product. This project aims to contribute to the elucidation of the DFNA5 function using a combination of immunohistochemical studies on inner ear, the subcellular localization of the protein, the identification of interacting proteins and a thorough study of a DFNA5 knock-out mouse.

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                                                      • Research Project

                                                      Functional characterization of a gene of non-syndromic progressive hearing impairment (DFNA5). 01/10/1999 - 30/09/2003

                                                      Abstract

                                                      Hearing impairment is one of the most frequent sensory handicaps. Until the beginning of the 9O's 1itt1e was known about the molecular mechanisms responsible for the complex process of hearing and the pathology of hearing loss. However, the last few years fast progression has been made due to molecular genetics. Up to now, 48 genes for non- syndromic hearing loss have been localized, confirming the predicted genetic heterogeneity .Only 11 genes have been identified so far . Recently, the DFNAS genewas identified in our research group (Van Laer et al., Nature Genet. 20,194-197,1998). DFNAS segregates according to an autosomal dominant inheritance pattem in an extended Dutch family with more than 100 affected family members. The family has been clinicaIly studied since the 60's. The hearing intpairment is non-syndromic, there were never any additional symptoms reported in the family. The progressive sensorineural hearing loss starts at an age between S and 15 years at the high frequencies. Only at older ages the lower frequencies become affected as weIl. The disease-causing mutation in the Dutch family is a complex intronic mutation in the DFNAS gene resulting in exon 8 skipping and leading to a frame shift and a premature protein truncation. Low expression levels of the DFNA5 gene were found in aIl the tissues that were investigated. Furthermore, DFNAS expression could be demonstrated in the cochlea. It remains unclear how mutations in a ubiquitously expressed gene can lead to hearing intpairment as the only phenotype. In spite of extensive computational analysis, no putative physiological function could be assigned to DFNA5.

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                                                        • Research Project