Center for Medical Genetics Center for Medical Genetics


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Intellectual disability (ID) is a major health issue, affecting up to 3% of the general population. ID can be caused by any condition that impairs the development of the human brain. Not only is ID a lifelong problem, it has a strong socio-economic impact on both patients and their families.

Both genetic and environmental factors play an important role in human cognition and hitherto, in approximately 30% of patients, a genetic aberration can be identified. Although the diagnostic yield has increased significantly over the years -mainly through the implementation of genomic microarrays- the emergence of next-generation sequencing (NGS) and in particular exome sequencing in a clinical setting, has provided new opportunities to elucidate genes associated with ID. Recently it was shown that in 10-16% of patients with ID a causal mutation can be detected with NGS thus adding significant power to our current diagnostic repertoire. Notwithstanding this progress, for many patients the underlying cause of ID remains undetermined, indicating further research is needed.

Our research group is trying to unravel the molecular basis of the many genetic mutations underlying intellectual disability in several ways.

First of all we try to implement novel innovating research tools in diagnostics. Examples of these are microarrays and more recently, next generation sequencing.

Furtermore we investigate candidate coding and non-coding ID genes in more detail by making use of several modelsystems. By combining in vitro (induced pluripotent stem cells) with in vivo (zebrafish and mouse) models we try to unravel a veil of the complex puzzle underlying intellectual disability.

Principal investigator

Senior researchers

Postdoctoral researchers

PhD students

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Different research topics:


Unraveling the role of MYT1L in intellectual disability: an integrated functional genetic approach

By the advent of genomic microarrays, several new microdeletion and microduplication syndromes responsible for intellectual disability (ID) have been identified. The underlying pathogenomic pathways resulting in cognitive impairment however remain elusive in most cases. Recently, we identified a new microdeletion syndrome on the short arm of chromosome 2 in nineteen patients with ID. The shortest region of overlap contains only one single gene: the myeline transcription factor 1-like (MYT1L). MYT1L expression is restricted to neuronal tissue with highest expression during neurogenesis. Moreover, common SNPs in MYT1L have been described to be associated with major depressive disorder and schizophrenia indicating this gene is a very strong candidate gene for proper neuronal functioning.

In this project we are using an integrated functional approach to unravel the function of MYT1L in human neuronal development. Both in vitro as well as in vivo model systems will be used to study the molecular pathways targeted by MYT1L through transcriptome analysis and ChIP-sequencing. The in vivo models will result in both a better understanding of the spatiotemporal expression of this gene as well as behavioral and morphological changes upon MYT1L knockout/knockdown. This research will not only elucidate the underlying pathogenic mechanisms of intellectual disability and mental disorders, but will also open new possibilities for the treatment of intellectual disability and psychiatric problems.

Long non-coding

The the expressed non-coding part of the human genome which recently emerged, remains largely unexplored as a target for genetic alterations leading to ID. Recent evidence shows that such long non-coding RNAs (lncRNAs; defined as transcripts longer than 200 bp in length without protein coding potential) are implicated in normal development and disease. Moreover, a significant percentage of disease association signals of genome wide association studies (GWAS) performed for many central nervous system (CNS) disorders, map to such expressed non-coding regions in the human genome. From several studies, it has become apparent that these CNS disorders (e.g. schizophrenia & bipolar disorder) have a fundamental overlap in biological pathways with ID. These pathways affect synapse formation and maintenance, as well as neurotransmission. The dysfunction of specific neuronal networks underlying the particular symptoms of each clinical condition most likely depends on additional genetic, epigenetic, and environmental factors that remain to be characterized.

Recent studies have assigned important and diverse functions to long non-coding RNAs in gene regulation and protein interactions, impacting on a multitude of cellular processes. Of particular importance, these lncRNAs have recently emerged during vertebrate and primate evolution, many of which have crucial importance in the most highly evolved and sophisticated organ, the human brain. Non-coding RNAs have indeed been linked to brain complexity with an important role in brain cellular diversity, amongst others.

Given the recent genomic annotation of most lncRNAs, the vast majority remains to be functionally assigned to specific cellular functions and developmental processes. There is no doubt that investigation of the mechanistic role of lncRNAs in the CNS will open a new and exciting direction in studying CNS development and function.

In this project we make use of embryonic and induced pluripotent stem cell (iPSC) derived neuronal cells to explore the role of lncRNAs in neuronal processes. The discovery of the induced pluripotent stem cell technology was crucial for the research towards the complex genetic regulation in the brain due to the difficulty of brain sampling. Not only can iPSCs be used for disease modeling in neuropsychiatric disorders, they can also be used to study developing neurons.

The aim of this project is two-fold: (1) to identify and investigate the role of lncRNAs that play an important role in ID and (2) to identify genetic networks involved in human cognition regulated by these lncRNAs. This will eventually lead to a better understanding of both the role of lncRNAs in the brain as well as the regulation of gene expression in the brain; opening possibilities for the development of new therapeutic targets.

Last updated: 21 January 2016 - 21:10
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