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 architectural features other 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 quantitative polymerase chain reaction (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 and conclusion: 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 the architectural features most likely to 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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Funding: This work was made possible by grants G.0200.03 from the FWO and GOA-grant 12051203 from Ghent University. Karen Buysse and An Crepel are Research Assistants of the Research Foundation - Flanders (FWO - Vlaanderen). Filip Pattyn is supported by the Vlaamse Liga tegen Kanker through a grant of the Stichting Emmanuel van der Schueren. This study is supported, in part, by the Fund for Scientific Research, Flanders, with a mandate fundamental clinical research to Geert R Mortier and Koen Devriendt. This text presents research results of the Belgian program of Interuniversity Poles of attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming (IUAP). Wilhelm Johannsen Centre for Functional Genome Research is established by the Danish National Research Foundation.
Competing interests: None declared.
Patient consent: Obtained.