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Mechanisms of ring chromosome formation, ring instability and clinical consequences

Roberta S Guilherme1*, Vera F Ayres Meloni1, Chong A Kim2, Renata Pellegrino3, Sylvia S Takeno1, Nancy B Spinner4, Laura K Conlin4, Denise M Christofolini5, Leslie D Kulikowski6 and Maria I Melaragno1

Author Affiliations

1 Genetics Division, Department of Morphology and Genetics, Federal University of São Paulo, Botucatu Street 740, Zip Code 04023-900, São Paulo, Brazil

2 Genetics Unit, Instituto da Criança, University of São Paulo, Avenue Dr. Enéas Carvalho de Aguiar 647, Zip Code 05403-000, São Paulo, Brazil

3 Department of Psychobiology, Federal University of São Paulo, Rua Botucatu, 740, Zip Code 04023-900, São Paulo, Brazil

4 Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Pa 19104, Philadelphia, Pennsylvania, USA

5 Gynecology and Obstetricy Division, School of Medicine of ABC, Avenue Príncipe de Gales 821, Zip Code 09060-650, São Paulo, Brazil

6 Department of Pathology, LIM 03, University of São Paulo, Avenue Dr. Enéas Carvalho de Aguiar 647, Zip Code 05403-000, São Paulo, Brazil

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BMC Medical Genetics 2011, 12:171  doi:10.1186/1471-2350-12-171

Published: 21 December 2011



The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.


Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent in situ Hybridization).


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).


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).