Abstract
BackgroundThe breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.MethodsSeveral techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent in situ Hybridization).ResultsThe ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV).ConclusionsWe concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).
Highlights
The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients
We report here the mechanisms of ring chromosome formation and ring instability in 14 patients evaluated by cytogenetic and molecular techniques and we discuss their clinical consequences
In the patients reported here, different mechanisms of ring formation were found: breaks in both chromosome arms followed by end-to-end reunion, a break in one chromosome arm followed by fusion with the subtelomeric region of the other, a break in one chromosome arm followed by fusion with the opposite telomeric region, fusion of two subtelomeric regions, and telomere-telomere fusion
Summary
The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients. Ring chromosomes usually result from two terminal breaks in both chromosome arms, followed by fusion of the broken ends, or from the union of one broken chromosome end with the opposite telomere region, leading to the loss of genetic material [1] They can be formed by fusion of subtelomeric sequences or telomere-telomere fusion with no deletion, resulting in complete ring chromosomes [1,2,3,4,5]. In patients with ring chromosomes, sister chromatid exchanges occurring during mitosis usually result in secondary chromosomal abnormalities, such as dicentric rings, interlocked rings, and other structural conformations. These unstable chromosomes can lead to ring chromosome loss, producing monosomic cells, which may or may not be viable [16,17,18,19,20]. Apart from the deletions due to ring formation, ring instability can result in other genomic imbalances, with decrease or increase of genetic material and possible consequences on the phenotype
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