Chromosome Rearrangements and Disease Group

	Chromosome rearrangements and disease group
	Disease-associated balanced chromosome rearrangements
	X-linked intellectual disability
	Team
	Publications

Disease-associated balanced chromosome rearrangements

Intellectual disability (ID) is present in 2 to 3 percent of the population, either as an isolated finding or as part of a syndrome or broader disorder. Causes of ID are numerous and include genetic and environmental factors. Identification of families with affected males has led to the mapping and cloning of a number of X-linked recessive loci and relevant genes for ID. However, there has been little progress in the identification of autosomal genes for ID.

In collaboration with many national and international clinicians and cytogeneticists, we systematically investigate autosomal and X;autosomal chromosome rearrangements. Molecular cytogenetic analysis of the breakpoints is a prerequisite for the identification of disrupted genes and disturbed gene regulation. Examples for disrupted X-chromosomal genes are SHROOM4/KIAA1202, ZNF41, CDKL5/STK9, and ARHGEF9. Autosomal genes found disrupted in patients with cognitive deficits include c-Jun N-terminal Kinase 3 (JNK3), Forkhead Box G1B (FOXG1B), Netrin G1 (NTNG1), ephrin receptor EphA5 (EPHA5), Dual-specificity Tyrosine-(Y)-phosphorylation Regulated Kinase 1A (DYRK1A), and transcription factor 4 (TCF4).

In collaboration with the Molecular Cytogenetics group from our department we have established breakpoint mapping by array painting, i.e. flow sorting of the derivative translocated chromosomes and hybridisation onto a genomic array, which allows to map the breakpoints to a region of about 100 kb in a single hybridisation step, which is schematically shown in this figure.

Fig.1 Flow-sorted derivative chromosomes are labelled and hybridised to a genomic array. Results are shown for each derivative chromosome with Cy3:Cy5 ratios for each BAC clone indicated (by clone location on the horizontal axis) at the corresponding chromosome position along the chromosome ideogram. The translocation leads to an abrupt ratio shift. The arrow drawn in the zoom-in to the right points to the breakpoint-spanning clone.

One example can be found in our recent publication on the disrupted Autism Susceptibility Candidate 2 (AUTS2) gene.

Following hybridisation of the same flow-sorted chromosomes to a subarray, junction fragments can be amplified by PCR and subsequently sequenced.

More recently, in collaboration with the Applied Bioinformatics group from our department we have established breakpoint mapping using Solexa sequencing technology (Chen et al., Genome Res., 2008).

The projects are supported by NGFN2 and Deutsche Forschungsgemeinschaft SFB577.