Latest update: 17/03/2016

Scientific research

The CMG is involved in a large number of specialised studies in the field of genetics. For an overview see below.

You can find additional information on the various research projects on the EMGE website run by the VUB's Embryology and genetics department.



More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/martinederycke.php

Our aim in this study is to acquire more fundamental knowledge of the epigenetic rearrangements in gametes and in-vitro pre-implantation human embryos, particularly about overall DNA methylation patterns, chromatin organisation and the expression and intracellular trafficking of DNA methyltransferases. We also wish to find out whether abnormalities in these processes may be a possible cause of impaired development of some pre-implantation embryos in ART, and whether hormonal stimulation and culture media are implicated.

As well as the overall analysis, the number of specific genes are also studied in this project. Experiments on animal models in underfed conditions which are restricted to the pre-implantation period indicate impaired epigenetic regulation of cardiometabolic genes and DNMT1, the 'maintenance' DNA methyltransferase, which results in altered postnatal phenotypes and an increased risk of cardiovascular disorders. By analogy, assisted reproduction techniques could result in impaired expression of DNMT1 and cardiometabolic loci.

The study considers the extent to which differences arise in the epigenetic status of selected loci (DNMT1, imprinted genes and cardiometabolic genes) after intracytoplasmic sperm injection (ICSI) as compared with spontaneous pregnancy. The epigenetic status of the selected genes is determined on the basis of DNA methylation and expression patterns on DNA and RNA prepared from blood samples. The relative quantification of mRNA transcripts will be carried out using quantitative real-time RT-PCR. Pyrosequencing will be used to quantify DNA methylation. The research results can then be linked to the data from the follow-up study of IVF/ICSI children to study the correlation between expression/methylation patterns in the genes being researched and cardiometabolic markers.

This research will yield an answer to recent questions about the safety of ART and may help to optimise the ART protocols that are used on the basis of the epigenetic stability and safety.

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More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/saraseneca.php
 

Mitochondria are the energy powerhouses of the cell. They carry their own genetic material, which is separate from the nuclear genome in human cell nuclei. MtDNA is organised into double-stranded, circular molecules. It codes for individual subunits of the oxidative phosphorylation system or respiratory chain.
If energy delivery to cells does not function correctly, this may be either due to errors in nuclear DNA or errors in mtDNA. One typical feature of mitochondrial dysfunction is that patients suffer from multisystem disorders as a result.
By means of this research the Medical Genetics laboratory wishes to identify and study the mutations underlying dysfunction. The research is taking place in collaboration with laboratories from other hospitals, such as UZ Gent and UZ Leuven.

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More information about this project, the principal investigator and the research teamon http://emgerege.vub.ac.be/Follow_up.php

ART children are those born as a result of the use of artificial reproductive techniques (ART).

Why is this research necessary?

UZ Brussel plays an internationally pioneering role in fertility medicine. We have been involved on more than one occasion in developing new fertility techniques such as ICSI (injection of a single sperm into the oocyte) and PGD (genetic diagnosis of the embryo).
This progressive medical and scientific approach does, however, entail certain responsibilities. UZ Brussel has therefore always followed up all the children born using ART techniques, as a form of quality control. This follow-up is carried out by the CMG. This research, which has taken place over many years, allows us to give the scientific community and parents the fullest possible perspective on the implications of fertility treatment.
There is no legal obligation to maintain a follow-up database, either in Belgium or in most other countries. In Belgium, fertility and genetics centres are only obliged to record the number of children born as a result of fertility treatment, not details about their health.
There is no doubt, however, that research of this kind is very important. The CMG therefore carries out its research largely with the help of sponsorship. It applies for some of this from the FWO, while a proportion also comes from companies in the private sector.

What is it and how is it done?

Our centre systematically follows up the populations of IVF and ICSI children: there are now more than 15,000 of them (as of the end of July 2010). We do the same for children born using the latest techniques such as PGD and PGD-AS. A paediatrician carries out a physical examination at the age of two months, one year and two years. He or she also monitors the children's psychomotor development.
At about five years, eight years and ten years of age more detailed assessments of the child's continuing physical, mental and motor development are carried out. The way the child is functioning within the family is also assessed, in collaboration with the Psychology department at VUB. This is done for both IVF and ICSI children and also for children born after natural conception. At about 14 years of age the development of puberty is also studied in ICSI and control children, and the possible inherited nature of any fertility problems that were already present in the parents is studied.
A number of these studies are carried out in collaboration with universities abroad. This makes the results more statistically valuable and also allows us to identify possible differences between fertility centres.

Results

A number of results have already become known.
Overall, the differences between ICSI and IVF children are minimal. There is no increased risk of malformations.
There may be an increased risk of multiple pregnancy if more than one embryo is returned to the uterus.
In singleton births there is a slightly increased risk of prematurity and low birth weight within both groups.
Karyograms of ICSI children indicate a slightly increased risk of disorders. We are able to identify this at an early stage in pregnancy, however, using chorionic villus biopsy or amniocentesis. These disorders are mainly due to the often poor quality of sperm cells from men for whom an ICSI procedure is the only way of becoming the biological father of a child.
PGD children from whom one or two cells have been removed at the eight-cell embryo stage are of course closely followed up as a group. Although only a few thousand PGD children have been born throughout the world, the results have been reassuring so far. Some 1000 children have been born in the PGD clinic at UZ Brussel (a collaboration between the CMG and the CRG), and no increased risk of abnormalities has been identified within this group.

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More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/katrienstouffs.php

In many cases the factors that cause infertility in men are unknown. We now know, however, that in about 10% of men who produce few or no sperm cells, specific parts of the Y chromosome are missing. When DNA is missing this is called a deletion. Deletions occur on the long arm of the Y chromosome and can be divided into three different regions. In each region there are a number of genes that are important for sperm cell development.

In collaboration with the CRG at UZ Brussel, the CMG is carrying out research into genetic causes of infertility in a population of infertile men who have consulted the CRG for fertility treatment. One of the studies incorporates an analysis of the whole genome to identify the presence of abnormalities that may possibly be related to male infertility. A second part of the study then looks at genes whose function is not yet known. This is intended both to determine the normal function of these gene products and also to ascertain whether they are actually important in fertility.

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More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/Cardiogenetics.php

Cardiac arrhythmias are among the major causes of morbidity and mortality throughout the world. Although environmental factors play an important part in the development of cardiac arrhythmias, family and population studies have shown that there is also a genetic component. Congenital primary cardiac arrhythmias are caused by defects in the electrical properties of the – structurally normal – heart. This disturbs the coordinated process of opening and closing ion channels and consequently affects the action potentials in the chambers of the heart.
Brugada syndrome is one of the most common cardiac arrhythmias and is inherited in an autosomal dominant pattern with variable penetrance and expression. Using functional analyses we have been able to partly account for the precise mechanism underlying the syndrome. So far, however, genetic studies have not been able to unravel it any further. On the contrary, the handful of genes that have been identified as being implicated offer an explanation for only about 20 to 30% of patients with Brugada syndrome. This means that it is now time to look for other possible causal genes. Thanks to recent revolutionary technological developments in molecular genetics, this is now possible. Not long ago we had to carry out analyses on a gene-by-gene basis, but 'Next-generation sequencing' now allows us to study the many candidate genes simultaneously and in parallel, and we can even include all the coding regions of the entire genome, which are known collectively as the exome.

The impact of the mutations and/or polymorphisms that are found will be correlated with phenotypes. There will also be further in-vitro study of the way in which these are transcribed and expressed as well as their electrophysiological characteristics.
The main benefit to the hospital will come from extrapolating our mutation analysis and in-vitro studies to patient management. We expect the main impacts to be seen in prevention, risk stratification, presymptomatic, prenatal and pre-implantation genetic diagnosis, and also in treatment and stratification of specific groups of patients.

This cardiogenetic study is being conducted in close collaboration with the CHVZ (Centre for Cardiovascular Diseases)

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More information about this project, the principal investigator and the research team on http://rgrg.vub.ac.be/NEGE.php

The development of the cerebral cortex is extremely complex but can nevertheless be divided into different, partly overlapping stages. Interference with one or more of these processes by genetic or external factors may result in malformations of cortical development (MCD). The most prevalent MCDs include lissencephaly/subcortical band heterotopia, polymicrogyria, periventricular heterotopia and focal cortical dysplasia. MCDs are an important cause of mental and motor impairment, severe epilepsy, learning disorders, and autism. Patients require a lifelong multidisciplinary follow-up and treatment is restricted to symptom relief. Most MCD have a genetic etiology but there is extensive heterogeneity both with respect to genotypes and phenotypes. For the large majority of patients with MCDs, the exact etiology of their disorder is still unknown, leaving a considerable number of families not having access to counseling or prenatal diagnosis in order to prevent recurrence.

This project aims at the further identification of genes involved in the regulation of neuronal migration and the study of the functional consequences of mutations in these genes by combining patient-driven molecular genetic studies and comparative genetic research in zebrafish models. This will result in mapping of major pathways involved in cortical development and function.

The project is performed in collaboration with the research groups of Prof. Peter De Witte (Laboratory for Pharmaceutical Biology, KUL - zebrafish models), Peter De Jonghe (VIB Department of Molecular Genetics, UA - NGS), and Ilse Smolders (Center for Neurosciences, VUB - mouse models).

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