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).

ABSTRACT. Ring chromosomes are often associated with abnormal phenotypes due to loss of genomic material and also because of ring instability at mitosis after sister chromatid exchange events. We investigated ring chromosome instability in six patients with ring chromosomes 4, 14, 15, and 18 by examining 48-and 72-h lymphocyte cultures at the first, second and subsequent cell divisions after bromodeoxyuridine incorporation. Although most cells from all patients showed only one monocentric ring chromosome, ring chromosome loss and secondary aberrations were observed both in 48-and 72-h lymphocyte cultures and in 135©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 9 (1): 134-143 (2010) Ring chromosome instability metaphase cells of the different cell generations. We found no clear-cut correlation between ring size and ring instability; we also did not find differences between apparently complete rings and rings with genetic material loss. The cytogenetic findings revealed secondary aberrations in all ring chromosome patients. We concluded that cells with ring chromosome instability can multiply and survive in vivo, and that they can influence the patient's phenotype.