Balkan Journal of Medical Genetics

EVIDENCE FOR CORRELATION OF FRAGILE SITES AND CHROMOSOMAL BREAKPOINTS IN CARRIERS OF CONSTITUTIONAL BALANCED CHROMOSOMAL REARRANGEMENTS
Liehr T*, Kosayakova N, Schröder J, Ziegler M, Kreskowski K, Pohle B, Bhatt S, Theuss L, Wilhelm K, Weise A, Mrasek K
*Corresponding Author: Thomas Liehr, Universitätsklinikum Jena, Institut für Humangenetik, Postfach, D-07740 Jena, Germany; Tel.: +49-3641-935533; Fax. +49-3641-935582; E-mail: i8lith@mti.uni-jena.de
page: 13

RESULTS AND DISCUSSION

For 251 patients with different constitutional chromosomal aberrations, MCB and/or subcenM-FISH [6-8] exactly characterized the involved breakpoints; the corresponding results are summarized in the Supplementary Table 1. Overall, 529 break-events were characterized by molecular cytogenetics. It turned out that only 150 of these were unique break-events, the remainder have been observed between two and 10 times within the same chromosomal sub-bands (see Supplementary Table 2). Based on the FS published in [5] there was (molecular) cytogenetic co-localization in ~71% of the studied break-events, i.e., in 318 of 529 (Supplementary Table 2). As summarized in Figure 2, the breakpoints detected in the 251 studied cases were not distributed according to the size of the chromosomes, as one might expect. On the contrary, the chromosomes most frequently hit by chromosomal breaks where #9, #2 and #3, followed by #1, #4, #11, #10 and #5. The rarest involved chromosomes were the X-chromosome and chromosomes #17, #19-22 and #13. This supports the hypothesis that there are mechanisms preferably producing chromosomal breaks at special regions, such as those recently shown for low-copy repeats [4], and for FS in this study and also a previous one [1]. Thus, in Figure 3 (molecular) cytogenetic co-localization of FS and the 529 observed breakpoints are visualized per chromosome. For chromosomes #1, #9 and #10, which are in the group with high involvement in constitutional chromosomal rearrangements, there are also high percentages of cases with a correlation of breakpoint- and FS-co-localization. The same holds true, in reverse, for chromosomes #21 and #22, which are not often involved in the studied chromosomal break-events, and having below 25% of association with FS in the break-prone regions (Figure 3). The finding that FS play a role in formation of constitutional chromosomal rearrangements was further supported by the following experimental setup: nine selected cases with evidence for breakpoints within or near FS were additionally analyzed by FS-specific BAC probes (example in Figure 1), and strikingly, only one (case T-100), did not show a co-localization with the corresponding FS in chromosome 11. All other eight cases showed either a complete overlap (breakpoint spanning the BAC probe) or a tight co-localization of FS-BAC and studied breakpoint (Table 1). Further detailed molecular analysis is necessary to characterize the mechanisms and genetic basis for the phenomenon described here. Pathways such as those discussed by Mani and Chinnaiyan [9] must be involved, however, these models still lack proteins/enzymes involved FS-formation.

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