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Research topics

Unravelling new candidate genes associated with NDDs.

Neurodevelopmental disorders (NDDs) are a heterogenous group of early onset conditions that impact development of the central nervous system (CNS) affecting approximately 2-5% of children worldwide.

The clinical and genetic heterogeneity of NDDs, make it challenging to find a molecular diagnosis for individual cases. Although recent technological improvements have led to a significant increase in diagnostic yield and identification of several new NDD associated genes, many associated genes remain to be discovered.

Initiatives such as GeneMatcher have catalyzed this process allowing clinicians worldwide to indicate their interest in particular genes. In this research line, we aim to study and characterize the function of novel NDD candidate genes as well as assess the effect of specific variants affecting novel or known NDD genes.

For this purpose, we use a wide range of model systems such as 2D and 3D in vitro models, model organisms such as Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish). We aim to characterize the function of these novel NDD genes by using a multi-omics strategy consisting of a combination of functional genomics, transcriptomics and proteomics.

Unveiling the role of the noncoding genome in NDDs.

The emergence of novel sequencing technologies has greatly improved the identification of structural variation, revealing that a human genome harbors tens of thousands of structural variants (SVs).

Since these SVs primarily impact noncoding DNA sequences, the next challenge is one of interpretation, to improve our understanding of human disease etiology. However, this task is severely complicated by the complexity of the gene regulatory landscapes embedded within these noncoding regions, their incomplete annotation, and their dependence on the three-dimensional (3D) conformation of the genome.

In the last decade, new technologies arose to map 3D genome conformation, providing an ever finer view on regulatory interactions. Furthermore, large consortia have made tremendous progress in characterizing regulatory elements in a large range of human tissues and cell types. Nevertheless, there still is a large gap between the interpretation of coding variants, both SVs and single nucleotide variants (SNVs), and noncoding variation not only in the general population but certainly in view of rare diseases.

Since the development of the brain, the most complex human organ, is tightly regulated, the impact of noncoding SVs must also be carefully considered in the context of neurodevelopmental diseases. Therefore, this research line aims to shed more light on the importance of noncoding elements in neurodevelopment and thus in NDDs.

We study specific noncoding loci that appear to be enriched for SV breakpoints, e.g. the MEF2C and FOXG1 loci. We aim to characterize the 3D conformation of these loci and identify and validate important regulatory elements that regulate the NDD gene(s) in these loci.

To this end we use relevant 2D and 3D model systems, chromatin conformation capture technologies such as 4C and Hi-C as well as in vitro and in vivo enhancer assays.

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