A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy

Abstract

Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.3q25 region identified by SNP array analysis. The size of the duplication is 26.7 Mb and contains 170 genes (OMIM). The duplication results in partial trisomy of the region in question with clinical consequences, including bilateral renal dysplasia, delayed development, and a heart defect. Moreover, the karyotype determined by R-banding and chromosome painting as well as by hybridization with specific sub-telomere probes revealed the presence of an unbalanced t(9;11)(p24;q22.3) translocation with a unique breakpoint involving the sub-telomere region of the short arm of chromosome 9. The karyotypes of the parents were normal. Telomere integrity in circulating lymphocytes from the child and from his parents was assessed using an automated high-throughput method based on fluorescence in situ hybridization (FISH) with telomere- and centromere-specific PNA probes followed by M-FISH multicolor karyotyping. Very short telomeres, as well as an increased frequency of telomere loss and formation of telomere doublets, were detected in the child’s cells. Interestingly, similar telomere profiles were found in the circulating lymphocytes of the father. Moreover, an assessment of clonal telomere aberrations identified chromosomes 9 and 11 with particularly high frequencies of such aberrations. These findings strongly suggest that telomere dysfunction plays a central role in the formation of this specific unbalanced chromosome rearrangement via chromosome end-to-end fusion and breakage–fusion–bridge cycles.

High Resolution and Automatable Cytogenetic Biodosimetry Using In Situ Telomere and Centromere Hybridization for the Accurate Detection of DNA Damage: An Overview

“…The fastest method at present is to ‘paint’ three pairs of chromosomes, each pair being the same or different in color from another pair [ 54 , 55 ]. However, some imprecision in the detection of the nature of aberrations cannot be completely avoided, such as an incomplete translocation or terminal translocation, and the distinction between translocation and a specific configuration of a dicentric chromosome with both centromeres in close proximity [ 17 , 18 ]. However, by combining telomere and centromere staining with chromosome painting, the scoring of chromosomal aberrations becomes considerably simpler and more reliable.…”

“…It is, in fact, applicable in the assessment of the effect of any genotoxic agent as well as that of inherent spontaneous genome instability in, e.g., cancer patients. The need to improve cytogenetic biodosimetry assays has been driven by the need to transfer technology to all cytogenetic laboratories to achieve high sample throughput for the processing of large cohorts of exposed populations as well as in medical settings [ 17 , 18 , 82 ].…”

“…However, M-FISH has not been used intensively due to the complexity of the analysis. Recently, some studies started to use this technique [ 83 , 84 , 85 , 86 , 87 , 88 ]; however, the resolution of chromosomes to identify complex rearrangements can be vastly improved when TC staining with M-FISH [ 17 , 18 , 89 ].…”

“…The TC+M-FISH approach permits the establishment of reliable and accurate karyotypes for cancer diagnosis [ 17 , 18 ]. Thus, the application of TC+M-FISH has revealed a much higher frequency of dicentric chromosomes with a specific configuration (two centromeres in close proximity) than has been observed previously by using conventional and molecular cytogenetics.…”

“…For instance, chromosomal instability is a prerequisite of ongoing cellular transformation and cancer development. These significantly improved cytogenetic techniques should constitute a valuable tool for the improved characterization of karyotypes in cancer patients, and hence, focused individual treatment and follow-up [ 17 , 18 ].…”