Mechanisms of ring chromosome formation, ring instability and clinical consequences

Author(s)

Guilherme, Roberta S. ^[1] ; Meloni, Vera F. Ayres ^[1] ; Kim, Chong A. ^[2] ; Pellegrino, Renata ^[3] ; Takeno, Sylvia S. ^[1] ; Spinner, Nancy B. ^[4] ; Conlin, Laura K. ^[4] ; Christofolini, Denise M. ^[5] ; Kulikowski, Leslie D. ^[6] ; Melaragno, Maria I. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Div Genet, Dept Morphol & Genet, BR-04023900 Botucatu, SP - Brazil

^[2] Univ Sao Paulo, Genet Unit, Inst Crianca, BR-05403000 Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Dept Psychobiol, BR-04023900 Sao Paulo - Brazil

^[4] Childrens Hosp Philadelphia, Div Genet & Mol Biol, Philadelphia, PA - USA

^[5] Sch Med ABC, Gynecol & Obstet Div, BR-09060650 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Dept Pathol, BR-05403000 Sao Paulo - Brazil

• Document type: Journal article
• Source: BMC MEDICAL GENETICS; v. 12, DEC 21 2011.
• Web of Science Citations: 56

Abstract

Background: The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients. Methods: Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent in situ Hybridization). Results: The 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). Conclusions: We 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). (AU)