Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1795-1803; doi:10.1093/hmg/ddi186
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Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis
1Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium, 2Human Genome Laboratory, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium and 3Microarray Facility, VIB, Leuven, Belgium
* To whom correspondence should be addressed at: Human Genome Laboratory, Department of Human Genetics, VIB, Gasthuisberg O&N6, Herestraat 49, PO Box 602, B-3000 Leuven, Belgium. Tel: +16-345948; Fax: +16-347166; Email: guy.froyen{at}med.kuleuven.ac.be
Received March 16, 2005; Accepted May 4, 2005
X-linked ichthyosis (XLI) is often associated with a recurrent microdeletion at Xp22.31 due to non-allelic homologous recombination between the CRI-S232 low-copy repeat regions flanking the STS gene. The clinical features of these patients may include mental retardation (MR) and the VCX-A gene has been proposed as the candidate MR gene. Analysis of DNA from four XLI patients with MR by array-comparative genomic hybridization (array-CGH) on a 150 kb resolution X chromosome-specific array revealed a 1.5 Mb interstitial microdeletion with breakpoints in the CRI-S232 repeat sequences, each of which harbors a VCX gene. We demonstrate that the recombination sites in all four cases are situated in the 1 kb repeat unit 2 region present at the 3' ends of the VCX-A and VCX-B genes thereby deleting VCX-A and VCX-B1 but not VCX-B and VCX-C. Array-CGH with DNA of an XLI patient with MR and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all four VCX genes and duplication of both VCY homologs. These data confirm the role of VCX-A in the occurrence of MR in XLI patients. Moreover, we propose a VCX/Y teamwork-dependent mechanism for the incidence of mental impairment in XLI patients.
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