Abstract
ObjectiveTo elucidate the structure of terminal inverted duplications and to investigate potential mechanisms of formation in two cases where there was mosaicism with cells of apparently normal karyotype.ResultsA karyotype [46,XY,inv dup(4)(p16.3p15.1)/46,XY] performed on blood lymphocytes from a patient referred for developmental delay (case 1) demonstrated a normal karyotype in 60% of cells with a terminal inverted duplication 4p in the remainder. In case 2, referred for multiple fetal anomalies on an ultrasound scan, 33% of amniocyte colonies were karyotypically normal, with a terminal inv dup 10p in the remainder [46,XX,inv dup(10)(p15.3p11)/46,XX]. Duplicated FISH signals for GATA3 and NEBL loci (in case 2), and for the Wolf-Hirschhorn locus (case 1) confirmed the inverted structure of both duplications. In the GTL banded normal cells from both cases, there was a cryptic deletion detected by FISH of one copy of the subtelomere 4p (case 1, probe GS-36P21), and subtelomere 10p (case 2, probe GS-306F7). At pter on both inv dup chromosomes there was no FISH signal present for the specific subtelomere probe. However, a positive pantelomeric probe signal was detected at 4 pter and 10 pter in both the cryptically-deleted chromosomes and the inv dup chromosomes in the respective cell lines of both cases.ConclusionAn inv dup structure was evident for both cases on GTL bands, and confirmed by the various FISH studies. The presence of telomere (TTAGGG repeat) sequences at pter on the inv dup chromosomes (where more proximal chromosome specific subtelomeric probes were negative) was indicated by the pantelomeric probe signals in both cases. We conclude the most likely mechanism of origin in both cases was by sub-telomeric breakage in the zygote at pter, and delayed repair/rearrangement until after one or more subsequent mitotic divisions. In these divisions, at least one breakage-fusion-bridge cycle occurred, to produce inverted duplications. It is proposed then that two differently "repaired" daughter cells proliferated in parallel. In one daughter cell line (with an overtly normal karyotype) there was deletion of the subtelomere and presumed repair through capping by a neo-telomere (i.e. "healing", as initially proposed by McClintock). This occurred in both cases presented. In the other daughter cell of each case, it is proposed that chromosome stabilization was achieved (after replication) by sister chromatid reunion to form a dicentric, which broke at a subsequent anaphase, to form an inverted duplication (with loss of the reciprocal product, and the other daughter cell line). One inv dup was repaired without an interstitial specific subtelomere (case 1) and one was repaired with a duplicated specific interstitial subtelomere (case 2). After repair TTAGGG repeats were detected by FISH at each respective new pter.
Highlights
Of the various types of inverted duplications, most are non-mosaic, and one of the most frequently reported types involves an additional bisatellited inv dup(15) [1]
In the apparently normal cells of both cases (Figs 2B, 3B), there was a submicroscopic deletion of the subtelomere involved in the inv dup formation; each apparently "normal" cell line had a cryptic abnormality related to the inverted duplication event
The two terminal inv dup of the present cases most probably arose by the same mechanism. i.e. possibly according to the hypothesis of Chabchoub et al [6]
Summary
Of the various types of inverted duplications (inv dup), most are non-mosaic, and one of the most frequently reported types involves an additional bisatellited inv dup(15) [1]. The interstitial direct and inverted duplications are non-mosaic and have specific meiotic origins [3] unrelated to the present structures. The "mosaic inverted duplications", are a group derived by different mechanisms for which various postzygotic origins have been proposed by several authors [4,5,6]. The duplication in these cases often ends terminally on the chromosome arm with the former pter or qter region rearranged to an interstitial position. It has been proposed that a new chromosome telomere has to be formed, or "captured" to stabilize the chromosome [6]
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