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The ring chromosome 21[r(21)] syndrome is a rare disorder, and mainly occurs as a de novo event. However, a wide variation of the phenotype has been reported in r(21) cases depending on breakpoints, loss of genetic material, and mosaicism of cells with r(21) and monosomy 21, causing copy number alterations. A 29-month-old female was referred to the centre for seizures, developmental delay, microcephaly, hypotonia, deafness, and other congenital abnormalities. Physical examination revealed short stature and multiple facial dysmorphism. She was unable to sit, walk or stand by herself. Cytogenetic study with GTG banding revealed a karyotype of mos 46,XX,r(21)(p11.1q22.12)[70]/45,XX,-21[10]/47,XX,r(21),+r(21)[1]/46,XX[10]. Additionally, molecular cytogenetics refined the breakpoints and characterized the deleted region (RP11-410P24/CHR21: 32849565-33019511) in the clone with the r(21) as ~12–14 Mb contiguous region at 21q22.12 to 21qter. The present study has accurately detected copy number alterations caused by ring chromosome formation. The basis of the UCSC Genome Browser on Human (GRCh38/hg38) analysis suggests hemizygous expression of a deleted critical region of chromosome 21 in ring chromosome cell lines. This is likely to be the underlying cause of the present phenotypes in the patient. Overall, the genotype–phenotypic correlation in r(21) cases remains widely diverse, most likely due to tissue-specific mosaicism of the 45, XX,-21 cell line. [ABSTRACT FROM AUTHOR]

Azoospermia can be diagnosed with spermiogram analysis, and karyotyping is the golden standard to explain the etiology. In this study, we investigated two male cases with azoospermia and male infertility for chromosomal abnormalities. Their phenotypes and physical and hormonal examinations were both normal. In karyotyping G-banding and NOR staining, a rare ring chromosome 21 abnormality was detected in the cases and no microdeletion in chromosome Y. Ring abnormality, deletion size, and deleted regions were shown with subtelomeric FISH (.ish r(21)(p13q22.3?)(D21S1446-)) and array CGH analyses. Due to the findings, bioinformatics, protein, and pathway analyses were done to detect a candidate gene through common genes in two cases' deleted regions or ring chromosome 21. [ABSTRACT FROM AUTHOR]

Objective: We present diagnosis and molecular cytogenetic characterization of a pure ring chromosome [r(21)] with a 4.657-Mb 21q22.3 deletion. Case report: A 44-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype 46,XX,r(21)(p11.2q22.3). Prenatal ultrasound findings were unremarkable. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed a 4.657-Mb deletion at 21q22.3. The parental karyotypes were normal. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism and clinodactyly. Postnatal cytogenetic analysis of umbilical cord revealed a karyotype of 46,XX,r(21)(p11.2q22.3). aCGH analysis of umbilical cord revealed the result of arr 21q22.3 (43,427,188–48,084,156) × 1.0 with a 4.657-Mb 21q22.3 deletion encompassing 57 Online Mendelian Inheritance in Man (OMIM) genes including TRPM2, TSPEAR, COL18A1, COL6A1, COL6A2, LSS, PCNT, DIP2A, S100B and PRMT2. Metaphase fluorescence in situ hybridization (FISH) analysis of the umbilical cord fibroblasts confirmed a 21q22.3 deletion. Conclusion: Prenatal diagnosis of an r(21) should include molecular cytogenetic characterization such as aCGH and FISH to determine the extent of the 21q22.3 deletion.

Induced pluripotent stem cells (iPSCs) from patients are an attractive disease model to study tissues with poor accessibility such as the brain. Using this approach, we and others have shown that trisomy 21 results in genome-wide transcriptional dysregulations. The effects of loss of genes on chromosome 21 is much less characterized. Here, we use patient-derived neural cells from an individual with neurodevelopmental delay and a ring chromosome 21 with two deletions spanning 3.8 Mb at the terminal end of 21q22.3, containing 60 protein-coding genes. To investigate the molecular perturbations of the partial monosomy on neural cells, we established patient-derived iPSCs from fibroblasts retaining the ring chromosome 21, and we then induced iPSCs into neuroepithelial stem cells. RNA-Seq analysis of NESCs with the ring chromosome revealed downregulation of 18 genes within the deleted region together with global transcriptomic dysregulations when compared to euploid NESCs. Since the deletions on chromosome 21 represent a genetic "contrary" to trisomy of the corresponding region, we further compared the dysregulated transcriptomic profile in with that of two NESC lines with trisomy 21. The analysis revealed opposed expression changes for 23 genes on chromosome 21 as well as 149 non-chromosome 21 genes. Taken together, our results bring insights into the effects on the global and chromosome 21 specific gene expression from a partial monosomy of chromosome 21qter during early neuronal differentiation. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) from patients are an attractive disease model to study tissues with poor accessibility such as the brain. Using this approach, we and others have shown that trisomy 21 results in genome-wide transcriptional dysregulations. The effects of loss of genes on chromosome 21 is much less characterized. Here, we use patient-derived neural cells from an individual with neurodevelopmental delay and a ring chromosome 21 with two deletions spanning 3.8 Mb at the terminal end of 21q22.3, containing 60 protein-coding genes. To investigate the molecular perturbations of the partial monosomy on neural cells, we established patient-derived iPSCs from fibroblasts retaining the ring chromosome 21, and we then induced iPSCs into neuroepithelial stem cells. RNA-Seq analysis of NESCs with the ring chromosome revealed downregulation of 18 genes within the deleted region together with global transcriptomic dysregulations when compared to euploid NESCs. Since the deletions on chromosome 21 represent a genetic “contrary” to trisomy of the corresponding region, we further compared the dysregulated transcriptomic profile in with that of two NESC lines with trisomy 21. The analysis revealed opposed expression changes for 23 genes on chromosome 21 as well as 149 non-chromosome 21 genes. Taken together, our results bring insights into the effects on the global and chromosome 21 specific gene expression from a partial monosomy of chromosome 21qter during early neuronal differentiation.

Objective: To present the perinatal findings and molecular cytogenetic characterization of prenatally detected mosaic r(21). Materials, Methods, and Results: A 29-year-old primigravid woman underwent amniocentesis at 22 weeks’ gestation because of hyperechogenic cardiac foci and intrauterine growth restriction. Amniocentesis revealed a karyotype of 46,XY,r(21)[15]/45,XY,–21[5]. The parental karyotypes were normal. The woman requested repeat amniocentesis. Oligonucleotide-based array comparative genomic hybridization was applied to the uncultured amniocytes, rapidly detecting a 2.09-Mb deletion of 21q21.1–q21.2 (21,495,262–23,580,815 bp) and a 5.03-Mb deletion of 21q22.3–q22.3 (41,887,412–46,914,715 bp). Cytogenetic analysis revealed a karyotype of 46,XY,r(21)[8]/45,XY,–21[3]/46,XY,idic r(21)[1]. The pregnancy was terminated, and a malformed fetus was delivered with clinodactyly, short big toes, separation between the first and second toes, prominent nasal bridge, downward slanting palpebral fissures, protuberant occiput, prominent forehead, broad anteverted nasal tip, long philtrum, thin upper lip, small mouth, and micrognathia. The placenta had a karyotype of 46,XY,r(21)[83]/45,XY,–21[11]/46,XY,idic r(21)[6], and the cord blood lymphocytes had a karyotype of 46,XY,r(21)[88]/45,XY,–21[9]/46,XY,idic r(21)[3]. Polymorphic DNA marker analysis determined a maternal origin for the deletion. Conclusion: An extra interstitial 21q deletion can be associated with mosaic r(21) in addition to a terminal 21q deletion. aCGH is useful in determining the breakpoints and associated subtle structural abnormalities in cases of prenatally detected ring chromosome in order to facilitate genetic counseling.

In this report, we describe a patient with azoospermia in conjection with de novo ring chromosome 21 and monosomy 21 mosaicism. Inter-phase fluorescence in situ hybridisation ( FISH) studies on uncultured peripheral blood and epithelial cells obtained by buccal smear revealed that 25% of the uncultured blood cells and 11% of the epithelial cells were monosomic for chromosome 21. Y chromosome microdeletion analysis ruled out the presence of any genomic deletions in the azoospermic factor a,b,c regions on the long arm of chromosome Y. Additionally, through subtelomeric FISH analysis, it was found that there was no deletion in the subtelomeric region of ring chromosome 21. Our results indicate that ring chromosome 21 is a rare, but recurrent chromosomal abnormality in male factor infertility. Furthermore, in individuals with ring chromosome 21, defective spermatogenesis is not associated with the deletion of any gene or genes located in the subtelomeric region of chromosome 21. [ABSTRACT FROM AUTHOR]

Abstract: We present perinatal findings and molecular cytogenetic characterization of a prenatally detected sacrococcygeal teratoma associated with mosaic r(21). This is the first report of mosaic r(21) presenting with a fetal sacrococcygeal teratoma. We discuss cytogenetic abnormalities associated with fetal sacrococcygeal teratomas. [Copyright &y& Elsevier]

Abstract: Ring chromosome 21 syndrome is a rare clinical condition. Most of the patients have a recognizable phenotype and multisystem involvement is described. Structural neurologic anomalies have also been described, but waddling gait due to lower motor neuron involvement has not been previously reported in association with ring 21. [Copyright &y& Elsevier]

A ring chromosome replacing a normal chromosome could involve variable structural rearrangements and mitotic instability. However, most previously reported cases lacked further genomic characterization. High-resolution oligonucleotide array comparative genomic hybridization with single-nucleotide polymorphism typing (aCGH+SNP) was used to study 2 unrelated cases with a ring chromosome 21. Case 1 had severe myopia, hypotonia, joint hypermobility, speech delay, and dysmorphic features. aCGH detected a 1.275-Mb duplication of 21q22.12-q22.13 and a 6.731-Mb distal deletion at 21q22.2. Case 2 showed severe growth and developmental retardations, intractable seizures, and dysmorphic features. aCGH revealed a contiguous pattern of a 3.612- Mb deletion of 21q22.12-q22.2, a 4.568-Mb duplication of 21q22.2-q22.3, and a 2.243-Mb distal deletion at 21q22.3. Mitotic instability was noted in 13, 30, and 76% of in vitro cultured metaphase cells, interphase cells, and leukocyte DNA, respectively. The different phenotypes of these 2 cases are likely associated with the unique genomic structure and distinct mitotic behavior of their ring chromosome 21. These 2 cases represent a subtype of ring chromosome 21 probably involving somatic dicentric ring breakage and reunion. A cytogenomic approach is proposed for characterizing the genomic structure and mitotic instability of ring chromosome abnormalities. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Verhoeven WMA, Bon BV, Egger JIM, Hoischen A, Doelman JC. An adult female patient with ring chromosome 21: behavioural phenotype and results of high-resolution molecular characterisation. Objective: A female adult patient with mild to moderate mental retardation and minor dysmorphisms was referred for neuropsychiatric examination because of psychotic and autistic symptoms and impulsive behaviours. Methods: Standardized neuropsychiatric and neuropsychological assessment as well as detailed somatic and neurological examination was performed. For genetic analysis, karyotyping, whole genome array analysis, and high-resolution detailed analysis of chromosome 21 were carried through. Results: Karyotyping showed a de novo ring chromosome 21: 46,XX,der(21)r(21)(p11q22.3). High-resolution array analysis demonstrated a complex aberration consisting of an interstitial duplication in 21q21.1, an interstitial deletion in 21q22.2q22.3, an interstitial deletion in 21q22.3 and a terminal deletion of 21q22.3. Apart from mild dysmorphisms, visual and auditory impairments, and infertility, no somatic or neurological abnormalities were found. A formal psychiatric diagnosis could not be established. The behavioural problems and the supposed psychiatric symptoms could be related to her disharmonic social cognitive profile. The behaviour normalized after the patient returned to a stable and structured living environment. Conclusion: High-resolution micro-array analysis techniques are essential to substantiate the genotype–phenotype correlation in patients with r(21) and other genetic disorders. Moreover, the results of this study stress the importance of the recognition of alexithymia as a potential cause for behavioural problems and psychiatric symptoms in patients with mental retardation in general. [ABSTRACT FROM AUTHOR]

Objective: We present diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 21 [r(21)]., Case Report: A 17-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of an abnormal result of the first-trimester maternal serum screening for Down syndrome with a free β-hCG level of 1.736 multiples of the median (MoM), a pregnancy associated plasma protein-A (PAPP-A) level of 0.275 MoM, a placental growth factor (PlGF) level of 0.281 MoM, a Down syndrome risk of 1:222 and a preeclampsia risk of 1:175. Cytogenetic analysis of cultured amniocytes revealed the result of 46,XX,r(21) (p12q22.3)[19]/45,XX,-21[13]. Array comparative genomic hybridization (aCGH) analysis of cultured amniocytes revealed the result of arr [GRCh37] 21q11.2q22.2 (15,485,008-40,625,594) × 1∼2, 21q22.2q22.3 (40,703,792-46,682,184) × 2∼3, 21q22.3 (46,761,631-48,084,156) × 1, consistent with mosaic monosomy 21 and r(21) (p12q22.3). The pregnancy was subsequently terminated, and a malformed fetus was delivered with low-set ears and hypotelorism. Postnatal cytogenetic analysis revealed a karyotype of 46,XX,r(21) (p12q22.3)[30]/45,XX,-21[8]/46,XX,idic r(21) (p12q22.3)[2] in the cord blood, 46,XX,r(21) (p12q22.3)[34]/45,XX,-21[6] in the skin, 46,XX,r(21) (p12q22.3)[37]/45,XX,-21[3] in the umbilical cord and 46,XX,dup(21) (q22.2q22.3)[32]/46,XX,r(21) (p12q22.3)[8] in the placenta. aCGH analysis of cord blood revealed the result of arr 21q11.2q22.2 (15,499,847-40,662,581) × 2.3, arr 21q22.2q22.3 (40,703,792-46,682,184) × 3.6, arr 21q22.3 (46,761,632-48,090,317) × 1, consistent with mosaic duplication of 21q11.2-q22.2 and 21q22.2-q22.3, and a 1.33-Mb 21q22.3 deletion encompassing the genes of COL18A1, SLC19A1, PCBP3, COL6A1, COL6A2, FTCD, LSS, MCM3AP, YBEY, PCNT, DIP2A, S100B and PRMT2., Conclusion: Mosaic r(21) at amniocentesis may be associated with monosomy 21, idic r(21) and dup(21), and low PAPP-A and low PlGF in the first-trimester maternal serum screening., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

This report describes a case of mosaic Down syndrome due to an unusual karyotype in a patient conceived by assisted reproductive techniques and cryopreservation. The chromosomal complement consists of two different cell lines, one predominantly trisomic with a derivative chromosome due to a Robertsonian translocation (21;21) and another carrying a ring chromosome 21. The present work analyses the different mechanisms that could have led to mosaicism. [ABSTRACT FROM AUTHOR]

An 8 year old boy with ring chromosome 21 who was susceptible to sinorespiratory infections due to hypogammaglobulinaemia is reported. He presented with the characteristic features of monosomy 21 syndrome, such as psychomotor retardation, hypertonia, large saccular ears, prominent nasal bridge, micrognathia, thrombocytopenia, and patent ductus arteriosus. His serum IgG concentration was less than 1.5 g/l at 3 years and 6 months of age after repeated hospitalisations with pneumonia, otitis media, and convulsions. Regular replacement of intravenous gammaglobulin effectively reduced such infectious episodes. A predisposition to infection in patients with ring chromosome 21 may be explained by hypogammaglobulinaemia and merit treatment with gammaglobulin. [ABSTRACT FROM AUTHOR]