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Ring 18 Molecular Assessment and Clinical Consequences Erika Carter,1 Patricia Heard,1 Minire Hasi,1 Bridgette Soileau,1 Courtney Sebold,1,2 Daniel E

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Ring 18 Molecular Assessment and Clinical Consequences Erika Carter,1 Patricia Heard,1 Minire Hasi,1 Bridgette Soileau,1 Courtney Sebold,1,2 Daniel E RESEARCH ARTICLE Ring 18 Molecular Assessment and Clinical Consequences Erika Carter,1 Patricia Heard,1 Minire Hasi,1 Bridgette Soileau,1 Courtney Sebold,1,2 Daniel E. Hale,1 and Jannine D. Cody1,2* 1Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas 2Chromosome 18 Registry and Research Society, San Antonio, Texas Manuscript Received: 4 April 2014; Manuscript Accepted: 12 September 2014 Ring chromosome 18 is a rare condition which has predomi- nantly been described by case reports and small case series. We How to Cite this Article: assessed a cohort of 30 individuals with ring 18 using both Carter E, Heard P, Hasi M, Soileau B, microarray comparative genomic hybridization (aCGH) and Sebold C, Hale DE, Cody JD. 2015. Ring 18 fluorescence in situ hybridization (FISH). We determined that molecular assessment and clinical each participant had a unique combination of hemizygosity for consequences. the p and q arms. Four ring chromosomes had no detectable deletion of one of the chromosome arms using aCGH. However, Am J Med Genet Part A 167A:54–63. two of these ring chromosomes had telomeric sequences detected using FISH. These data confirm the importance of molecular and cytogenetic analysis to determine both chromosome content and Genest et al., 1963]. The presumption was that ring chromo- morphology. We failed to find dramatic changes in mosaicism somes were formed by the joining of the two ends of the percentage between cytogenetic measurements made at the time normally linear chromosome. Thus, a ring formation led to a of diagnosis and those made years later at the time of this study, netlossofmaterialfrombothendsofthechromosome.Asearly demonstrating that dynamic ring mosaicism is unlikely to be a as 1963, de Grouchy [1965] appreciated that individuals with major cause of phenotypic variability in the ring 18 population. ring 18 had a composite phenotype of 18p- and 18q- [1963]. Lastly, we present data on the clinical features present in our Additionally, he noted that the variable phenotype between cohort, though the extreme genotypic variability makes it im- patients with ring 18 indicated that different individuals had possible to draw direct genotype-phenotype correlations. Future different degrees of hemizygosity for each chromosome arm, work will focus on determining the role of specific hemizygous even predicting that the gene for aural atresia would be on distal genes in order to create individualized projections of the effect of 18q. Forty-nine years later the gene for aural atresia was indeed each person’s specific ring 18 compliment. identified at 18q23 [Feenstra et al., 2011]. Ó 2014 Wiley Periodicals, Inc. A unique feature of ring chromosomes in comparison with other types of derivative chromosomes is their dynamic quality. In Key words: chromosome 18; ring chromosome 18; mosaicism humans, as in maize and Drosophila, ring chromosomes appear to be unstable, generating multiple mitotically derivative cell lines within any one individual. Ring stability after successive mitoses was more recently investigated in vitro [Sodre´ et al., 2010]. In cultured cells from six patients with a ring chromosome, the percent INTRODUCTION of cells with a karyotype of 46,r(N) was reduced over time and the percent of cells monosomic for the ring chromosome or containing Although ring chromosomes have long been appreciated in maize a derivative of the ring chromosome was increased at the second [McClintock, 1932] and Drosophila [Morgan 1933], knowledge of time point. their existence in human cells was limited to irradiated cell lines or tumor cells until 1962. In the next two years,several groups reported individuals with constitutional ring chromosomes [Lindsten and Conflict of interest: none. ÃCorrespondence to: Tillinger, 1962; Wang et al., 1962; Genest et al., 1963]. Since then Janine D Cody, Department of Pediatrics, UT Health Science Center, ring chromosomes have been described originating from all human 7703 Floyd Curl rive, San Antonio, TX 78229. chromosomes [Kosztolanyi 2009]. E-mail: [email protected] Ring chromosome 18 was among the first to be identified in Article first published online in Wiley Online Library humans. In fact, patients in two of the first three human ring (wileyonlinelibrary.com): 22 October 2014 chromosome reports likely had ring 18 [Wang et al., 1962; DOI 10.1002/ajmg.a.36822 Ó 2014 Wiley Periodicals, Inc. 54 CARTER ET AL. 55 In addition to variable chromosome arm hemizygosity and resolution array comparative genomic hybridization (aCGH) in mosaicism, it has been appreciated that the formation of the conjunction with FISH to determine if there were unique properties ring chromosome itself often resulted in duplications just proximal of ring chromosome18 such as breakpoint clusters which might to the deletion breakpoint in 21% of ring chromosome cases [Rossi guide future work to identify dosage sensitive genes and direct et al., 2008]. This phenomenon was first described by Ballif et al. clinical management. [2003] in the formation of human terminal deletions of chromo- some 1p. We have also reported this phenomenon in individuals METHODS with 18q deletions [Heard et al., 2009 Cody et al., 2014]. These data imply that the mechanism of formation of a ring chromosome and a Participants are enrolled in a longitudinal study of individuals with terminal deletion may be similar. chromosome 18 abnormalities at the Chromosome 18 Clinical Determining the phenotypic effects of a ring chromosome is thus Research Center. The study has been approved by the Institutional complicated by multiple factors, including the variable extent and Review Board of the University of Texas Health Science Center at location of hemizygosity, the presence of duplications within the San Antonio. All participants have provided informed consent for ring, somatic mosaicism, and ring instability. their participation. A criterion for enrollment is the submission of Although there have been numerous case reports and small series the original cytogenetic and/or cytogenomic diagnostic laboratory of individuals with Ring 18, these individual reports use a variety of report. Additional medical records are also collected, abstracted, techniques and technologies to assess genotype, making these data and entered into our database. incomplete and difficult to compile and compare. We wished to Blood samples were obtained from the affected individual and assess our large cohort of individuals with ring 18 using a high his/her biological parents for chromosome preparations, DNA FIG. 1. Molecular analysis of the content of 30 ring chromosomes. These data are presented as custom tracks in the UCSC Genome Bowser. Across the top of the figure, the red box around the chromosome ideogram indicates that the image below includes the entire length of the chromosome. Below the ideogram, each horizontal (gold) bar indicates the intact region of each participant’s chromosome 18. At the end of each bar is a darker region indicating the breakpoint region. In most cases this region is too small to be visible in this figure. Regions present in duplicate are indicated by the darker (red) bars. The participant numbers are listed down the left hand side. The thick vertical bars indicated the location of the centromere. The parental origin for those on whom we could gather the data is aligned with each individual’s molecular data. Individuals whose telomeres were detected by FISH are indicated by the star at the telomere position. Several regions with clinical significance are indicated by the bracketed regions. 56 TABLE I. Cytogenetic and Molecular Findings % of cells with each type of chromosome 18 compliment 18, 18 18,0 18, 18, 18, 18, Type of derivative aCGH breakpoints Parental origin of ring Study # (normal) r(18) r(18)X2 r(18)X3 der(18) chromosome determined chromosome 1 100 xP 2 100 xM 3 100 x 8 100 x 11 100 p and q prox dups P 12 100 q prox dup M 19 100 xP 21 100 xP 22 100 x 23 100 xM 24 100 q prox dup 26 100 x 27 100 x 29 100 x 30 100 x 32 100 q prox dup 51387 xM 7 793 xP 9 694 p prox dup P 10 397 x 13 15 85 xM 14 694 x AMERICAN JOURNAL OF MEDICAL GENETICS 16 15 85 xP 17 11 82 4 3 x 4 90 10 18p- p prox dup P 6 90 10 18p- x M 15 81 18 9% double ring and 9% 2 xP double rings 20 52 48 inv18 q prox dup P 25 11 13 76 4 cell lines/3 mar no identifiable deletion chromosomes 28 56 11 33 no identifiable deletion Mosaicism numbers in bold italic are from our studies. Other mosaicism data are from the diagnostic cytogenetic report. x indicates that hemizygosity was determined using aCGH. The numbers in bold italics are our laboratory’s data as opposed to data from our participants medical records. PART A CARTER ET AL. 57 isolation, and creation of immortalized cell lines. Genotyping was performed on DNA from a peripheral blood samples by microarray comparative genomic hybridization (aCGH) using the Agilent system and a custom oligonucleotide array containing 32,000 oligonucleotides across chromosome 18 and 12,000 across the remainder of the genome as previously described [Heard et al., 2009]. Parental origin of the abnormal chromosome was also determined as previously described using PCR-based poly- morphic microsatellites [Heard et al., 2009]. Mosaicism studies were performed on interphase cells and metaphase nuclei from PHA-stimulated lymphocyte cultures from peripheral blood samples by fluorescence in situ hybridization (FISH) analysis using Vysis CEP 18 (a satellite), Telvysion 18p and 18q probes (Abbott Molecular Inc., Des Plaines, IL). Hybridization and post-hybridization washes were performed according to the manufacturer’s protocol and the signals were enumerated using a fluorescence microscope. In order to determine the levels of mosaicism in participants without previous mosaicism studies, one hundred metaphase nuclei were analyzed using centromeric and telomeric probes.
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