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Mapping of 5q35 chromosomal rearrangements within a genomically unstable region
  1. Karen Buysse (karen.buysse{at}ugent.be)
  1. Center for Medical Genetics, Ghent University Hospital, Belgium
    1. An Crepel (an.crepel{at}uz.kuleuven.ac.be)
    1. Center for Human Genetics, University Hospital Gasthuisberg, Belgium
      1. Björn Menten (bjorn.menten{at}ugent.be)
      1. Center for Medical Genetics, Ghent University Hospital, Belgium
        1. Filip Pattyn (filip.pattyn{at}ugent.be)
        1. Center for Medical Genetics, Ghent University Hospital, Belgium
          1. Francesca Antonacci (francesca.antonacci{at}biologia.uniba.it)
          1. Department of Genetics and Microbiology, University of Bari, Italy
            1. Joris Veltman (j.veltman{at}antrg.umcn.nl)
            1. UMC Nijmegen, Netherlands
              1. Lars Allan Larsen (lal{at}imbg.ku.dk)
              1. Wilhelm Johannsen Centre for Functional Genome Research, Denmark
                1. Zeynep Tumer (zeynep{at}imbg.ku.dk)
                1. Centre for Functional Genome Research, Denmark
                  1. Annelies de Klein (a.deklein{at}erasmusmc.nl)
                  1. Erasmus MC, Netherlands
                    1. Ingrid van de Laar (i.vandelaar{at}erasmusmc.nl)
                    1. Erasmus MC, Netherlands
                      1. Koen Devriendt (koen.devriendt{at}med.kuleuven.be)
                      1. Center for Human Genetics, University Hospital Gasthuisberg, Belgium
                        1. Geert Mortier (geert.mortier{at}ugent.be)
                        1. Center for Medical Genetics, Ghent University Hospital, Belgium
                          1. Frank Speleman (franki.speleman{at}ugent.be)
                          1. Center for Medical Genetics, Ghent University Hospital, Belgium

                            Abstract

                            Background: Recent molecular studies of breakpoints of recurrent chromosome rearrangements revealed the role of genomic architecture in their formation. In particular, segmental duplications representing blocks of >1 kb with >90% sequence homology were shown to mediate non-allelic homologous recombination (NAHR). However, the occurrence of the majority of newly detected submicroscopic imbalances cannot be explained by the presence of segmental duplications. Therefore further studies are needed to investigate whether other architectural features than segmental duplications mediate these rearrangements.

                            Methods: We analysed a series of patients with breakpoints clustering within chromosome band 5q35. Using high density arrays and subsequent qPCR, we characterised the breakpoints of four interstitial deletions (including one associated with an unbalanced paracentric inversion), a duplication and a familial reciprocal t(5;18)(q35;q22) translocation.

                            Results: Five of the breakpoints were located within an interval of ~265 kb encompassing the RANBP17 and TLX3 genes. This region is also targeted by the recurrent cryptic t(5;14)(q35;q32) translocation, which occurs in ~20% of childhood T-cell acute lymphoblastic leukaemia (T-ALL). In silico analysis indicated that architectural features most likely contribute to the genomic instability of this region, which was supported by our molecular data. Of further interest, in two patients and the familial translocation, the delineated breakpoint regions encompassed highly homologous LINEs (long interspersed nuclear elements), suggesting that NAHR between these LINEs may have mediated these rearrangements.

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