Mechanisms of ring chromosome formation, ring instability and clinical consequences

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

Ring chromosome instability evaluation in six patients with autosomal rings

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 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

Wide Clinical Variability in Cat Eye Syndrome Patients: Four Non-Related Patients and Three Patients from the Same Family

A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter -&gt; q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling. Copyright (C) 2012 S. Karger AG, Base

Clinical, Cytogenetic, And Molecular Characterization Of Six Patients With Ring Chromosomes 22, Including One With Concomitant 22q11.2 Deletion

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints-unique for each patient-could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder. © 2014 Wiley Periodicals, Inc.164716591665Anderlid, B.M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M., FISH-mapping of a 100-kb terminal 22q13 deletion (2002) Hum Genet, 110, pp. 439-443Assumpcao Jr., F.B., Brief report: A case of chromosome 22 alteration associated with autistic syndrome (1998) J Autism Dev Disord, 28, pp. 253-256Baumer, A., Dutly, F., Balmer, D., Riegel, M., Tukel, T., Krajewska-Walasek, M., Schinzel, A.A., High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions (1998) Hum Mol Genet, 7, pp. 887-894Cusmano-Ozog, K., Manning, M.A., Hoyme, H.E., 22q13.3 deletion syndrome: A recognizable malformation syndrome associated with marked speech and language delay (2007) Am J Med Genet C Semin Med Genet, 145 C, pp. 393-398De Mas, P., Chassaing, N., Chaix, Y., Vincent, M.C., Julia, S., Bourrouillou, G., Calvas, P., Bieth, E., Molecular characterisation of a ring chromosome 22 in a patient with severe language delay: A contribution to the refinement of the subtelomeric 22q deletion syndrome (2002) J Med Genet, 39, pp. e17Delahaye, A., Toutain, A., Aboura, A., Dupont, C., Tabet, A.C., Benzacken, B., Elion, J., Drunat, S., Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3 (2009) Eur J Med Genet, 52, pp. 328-332Devriendt, K., Fryns, J.P., Mortier, G., van Thienen, M.N., Keymolen, K., The annual incidence of DiGeorge/velocardiofacial syndrome (1998) J Med Genet, 35, pp. 789-790Dhar, S.U., del Gaudio, D., German, J.R., Peters, S.U., Ou, Z., Bader, P.I., Berg, J.S., Sahoo, T., 22q13.3 deletion syndrome: Clinical and molecular analysis using array CGH (2010) Am J Med Genet A, 152 A, pp. 573-581Funderburk, S.J., Sparkes, R.S., Klisak, I., Phenotypic variation in two patients with a ring chromosome 22 (1979) Clin Genet, 16, pp. 305-310Giza, J., Urbanski, M.J., Prestori, F., Bandyopadhyay, B., Yam, A., Friedrich, V., Kelley, K., Goldfarb, M., Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2 (2010) J Neurosci, 30, pp. 14805-14816Goizet, C., Excoffier, E., Taine, L., Taupiac, E., El Moneim, A.A., Arveiler, B., Bouvard, M., Lacombe, D., Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH (2000) Am J Med Genet, 96, pp. 839-844Guilherme, R.S., de Freitas Ayres Meloni, V., Sodre, C.P., Christofolini, D.M., Pellegrino, R., de Mello, C.B., Conlin, L.K., Melaragno, M.I., Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14 (2010) Am J Med Genet A, 152 A, pp. 2865-2869Guilherme, R.S., Meloni, V.F., Kim, C.A., Pellegrino, R., Takeno, S.S., Spinner, N.B., Conlin, L.K., Melaragno, M.I., Mechanisms of ring chromosome formation, ring instability and clinical consequences (2011) BMC Med Genet, 12, p. 171Hunter, A.G., Ray, M., Wang, H.S., Thompson, D.R., Phenotypic correlations in patients with ring chromosome 22 (1977) Clin Genet, 12, pp. 239-249Ishmael, H.A., Cataldi, D., Begleiter, M.L., Pasztor, L.M., Dasouki, M.J., Butler, M.G., Five new subjects with ring chromosome 22 (2003) Clin Genet, 63, pp. 410-414Jacquemont, M.L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., Amiel, J., Philippe, A., Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders (2006) J Med Genet, 43, pp. 843-849Jeffries, A.R., Curran, S., Elmslie, F., Sharma, A., Wenger, S., Hummel, M., Powell, J., Molecular and phenotypic characterization of ring chromosome 22 (2005) Am J Med Genet A, 137 A, pp. 139-147Kosho, T., Matsushima, K., Sahashi, T., Mitsui, N., Fukushima, Y., Sobajima, H., Ohashi, H., Ring syndrome" involving chromosome 2 confirmed by FISH analysis using chromosome-specific subtelomeric probes (2005) Genet Couns, 16, pp. 65-70Le Caignec, C., Boceno, M., Jacquemont, S., Nguyen, T., Tich, S., Rival, J.M., David, A., Inherited ring chromosome 8 without loss of subtelomeric sequences (2004) Ann Genet, 47, pp. 289-296Lejeune, J., On the duplication of circular structures (1968) Ann Genet, 11, pp. 71-77Luciani, J.J., de Mas, P., Depetris, D., Mignon-Ravix, C., Bottani, A., Prieur, M., Jonveaux, P., Mattei, M.G., Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: Cytogenetic, molecular, and clinical analyses of 32 new observations (2003) J Med Genet, 40, pp. 690-696MacLean, J.E., Teshima, I.E., Szatmari, P., Nowaczyk, M.J., Ring chromosome 22 and autism: Report and review (2000) Am J Med Genet, 90, pp. 382-385Nesslinger, N.J., Gorski, J.L., Kurczynski, T.W., Shapira, S.K., Siegel-Bartelt, J., Dumanski, J.P., Cullen Jr., R.F., McDermid, H.E., Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3 (1994) Am J Hum Genet, 54, pp. 464-472Phelan, K., McDermid, H.E., The 22q13.3 deletion syndrome (Phelan-McDermid Syndrome) (2012) Mol Syndromol, 2, pp. 186-201Prasad, C., Prasad, A.N., Chodirker, B.N., Lee, C., Dawson, A.K., Jocelyn, L.J., Chudley, A.E., Genetic evaluation of pervasive developmental disorders: The terminal 22q13 deletion syndrome may represent a recognizable phenotype (2000) Clin Genet, 57, pp. 103-109Precht, K.S., Lese, C.M., Spiro, R.P., Huttenlocher, P.R., Johnston, K.M., Baker, J.C., Christian, S.L., Ledbetter, D.H., Two 22q telomere deletions serendipitously detected by FISH (1998) J Med Genet, 35, pp. 939-942Ritter, C.L., Steele, M.W., Wenger, S.L., Cohen, B.A., Chromosome mosaicism in hypomelanosis of Ito (1990) Am J Med Genet, 35, pp. 14-17Saitta, S.C., Harris, S.E., Gaeth, A.P., Driscoll, D.A., McDonald-McGinn, D.M., Maisenbacher, M.K., Yersak, J.M., Emanuel, B.S., Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion (2004) Hum Mol Genet, 13, pp. 417-428Sarasua, S.M., Dwivedi, A., Boccuto, L., Rollins, J.D., Chen, C.F., Rogers, R.C., Phelan, K., Collins, J.S., Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome) (2011) J Med Genet, 48, pp. 761-766Sarasua, S.M., Dwivedi, A., Boccuto, L., Chen, C.F., Sharp, J.L., Rollins, J.D., Collins, J.S., Dupont, B.R., 22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome (2013) Genet Med, 31, p. 144Schinzel, A., (2001) Catalogue of unbalanced chromosome aberrations in man, , 2nd edition. Berlin, Germany: Walter de GruyterSovner, R., Stone, A., Fox, C., Ring chromosome 22 and mood disorders (1996) J Intellect Disabil Res, 40, pp. 82-86Vermeesch, J.R., Baten, E., Fryns, J.P., Devriendt, K., Ring syndrome caused by ring chromosome 7 without loss of subtelomeric sequences (2002) Clin Genet, 62, pp. 415-41