Insight into the mechanisms and consequences of recurrent telomere capture associated with a sub-telomeric deletion

Abstract

A complex mosaicism of the short arm of chromosome 1 detected by SNP microarray analysis is described in a patient presenting a 4-Mb 1p36 terminal deletion and associated phenotypic features. The array pattern of chromosome 1p displayed an intriguing increase in divergence of the SNP heterozygote frequency from the expected 50% from the centromere towards the 1p36 breakpoint. This suggests that various overlapping segments of UPD were derived by somatic recombination between the 1p homologues. The most likely explanation was the occurrence of a series of events initiated in either a gamete or an early embryonic cell division involving a 1pter deletion rapidly followed by multiple telomere captures, resulting in additive, stepped increases in frequency of homozygosity towards the telomere. The largest segment involved the entire 1p, and at least four other capture events were observed, indicating that at least five independent telomere captures occurred in separate cell lineages. The determination of breakpoint position by detection of abrupt changes in B-allele frequency using a moving window analysis demonstrated that they were identical in blood and saliva, the tissues available for analysis. We developed a model to explain the interaction of parameters determining the mosaic clones and concluded that, while number, size, and position of telomere captures were important initiating determinants, variation in individual clone frequencies was the main contributor to mosaic differences between tissues. All previous reports of telomere capture have been restricted to single events. Other cases involving multiple telomere capture probably exist but require investigation by SNP microarrays for their detection.

Mosaicism for copy number variations in the placenta is even more difficult to interpret than mosaicism for whole chromosome aneuploidy

“…Repair mechanisms in the following cell divisions may explain the occurrence of different CNVs or loss of heterozygosity in a specific chromosomal region. In the literature, a commonly accepted explanation of the mechanisms behind the origin of CNVs (mosaic or nonmosaic) has no definite evidence 29–31 . All three cases with mosaicism for smaller CNVs (<6 Mb) in CVS had full (Case 7, 7q11 duplication) or related mosaicism (Cases 11 and 13) distributed in all their individual ppCVSs.…”

Clinical significance and mechanisms associated with segmental UPD

“…The fourth NIPT case had a non-mosaic terminal 1p36 deletion and mosaic terminal 18q gain that was corrected in blood, but not in the placenta, consistent with two different somatic mechanisms. The absence of the 18q gain in the blood CMA strongly suggests that it was acquired in a population of placental cells because of the need for a 1p telomere via telomere capture [ 26 ]. However, there was subsequent selection for a euploid cell line with segUPD-related correction, rather than the telomere capture cell line with the deletion and partial trisomy.…”

Placental studies elucidate discrepancies between NIPT showing a structural chromosome aberration and a differently abnormal fetal karyotype

“…However, it is possible that the 4q was “captured” by the 2q terminal deletion for telomere stabilization, at least in one of the early embryonic cells that was allocated to the CTB. It was recently shown that distinct stabilizing events, telomere healing (eg, de novo telomere addition mediated by telomerase) and telomere capture from a different chromosome, resulting in a derivative chromosome, of the same terminal deletion can occur in different early embryonic cells . The mosaic karyotype observed in case 2 with terminal deletions of different lengths of chromosome 13q and with a segmental UPD of the distal 25 Mb on 13q is another example of postzygotic telomere stabilization through telomere capture as well as telomere healing in different embryonic cells .…”