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

Abstract

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