Ring chromosome 20

Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis

Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.

The Prader-Willi syndrome (PWS) critical region on 15q11–q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins’ fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. “Grandmatrilineal” inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study

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