OBJECTIVE: To clarify the genetic diagnosis of two children with ring chromosome 18 and explore their mechanisms and clinical phenotypes.
METHODS: Two patients treated at the Children\'s Hospital of Henan Province respectively in June 2022 and March 2023 were selected as the study subjects. Genetic testing and diagnosis were carried out through copy number variation sequencing (CNV-seq), G-banded chromosomal karyotyping, and whole exome sequencing (WES).
RESULTS: Child 1 had mainly manifested developmental delay, white matter hypoplasia, type 1 diabetes mellitus, and micropenis. He was found to have a chromosomal karyotype of 46,XY,r(18)(p11.21q22.1)[40]/46,XY[7], and CNV-seq results showed that he has a 14.86 Mb deletion at 18p11.21p11.32 and a 14.02 Mb deletion at 18q22.1q23. Child 2 had peculiar facial features, delayed white matter myelination, developmental delay, atrial septal defect, severe sensorineural deafness, and congenital laryngeal stridor. He was found to have a chromosomal karyotype of 46,XY,r(18)(p11.2q23). CNV-seq result proved that he had a 14.86 Mb deletion at 18p11-21p11.32 and a 20.74 Mb deletion at 18q21.32q23. WES has failed to detect single nucleotide variants (SNVs) in either child, but revealed a large segmental deletion at chromosome 18 in both of them.
CONCLUSIONS: Both children were diagnosed with ring chromosome 18 syndrome. The different size of the deletional fragments in the 18q region and mosaicism of ring chromosome 18 in child 1 may underlay the variation in their clinical phenotypes. The type 1 diabetes mellitus and micropenis noted in both children are novel features for ring chromosome 18 syndrome.

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Well-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings. Both types of amplicons share the same spectrum of structural variants (SVs), show higher SV frequencies in Chr12 than in co-amplified segments, have SVs that fuse the telomeric ends of co-amplified chromosomes, and lack interspersed deletions. Combined with the finding of cells with transient rod-shaped structures in tumors with ring chromosomes, this suggests a stepwise process starting with the gain of Chr12 material that, after remodeling which does not fit with classical chromothripsis, forms a dicentric structure with other chromosomes. Depending on if and when telomeres from other chromosomes are captured, circularized or linear gain of 12q sequences will predominate.

暂无摘要。

OBJECTIVE: To assess the value of optical genome mapping (OGM) for the detection of chromosomal structural abnormalities including ring chromosomes, balanced translocations, and insertional translocations.
METHODS: Clinical data of four patients who underwent pre-implantation genetic testing concurrently with OGM and chromosomal microarray analysis at the Center of Reproductive Medicine of the Sixth Affiliated Hospital of Sun Yat-sen University from January to October 2022 due to chromosomal structural abnormalities were selected as the study subjects. Some of the results were verified by multi-color fluorescence in situ hybridization.
RESULTS: The OGM has successfully detected a balanced translocation and fine mapped the breakpoints in a patient. Among two patients with insertional translocations, OGM has provided more refined breakpoint locations than karyotyping analysis in a patient who had chromosome 3 inserted into chromosome 6 and determined the direction of the inserted fragment. However, OGM has failed to detect the chromosomal abnormality in a patient with chromosome 8 inserted into the Y chromosome. It has also failed to detect circular signals in a patient with ring chromosome mosaicism.
CONCLUSIONS: OGM has successfully detected chromosomal structural variations in the four patients and provided assistance for their diagnosis.

暂无摘要。

Gene amplification is a crucial process in cancer development, leading to the overexpression of oncogenes. It manifests cytogenetically as extrachromosomal double minutes (dmin), homogeneously staining regions (hsr), or ring chromosomes (r). This study investigates the prevalence and distribution of these amplification markers in a survey of 80 131 neoplasms spanning hematologic disorders, and benign and malignant solid tumors. The study reveals distinct variations in the frequency of dmin, hsr, and r among different tumor types. Rings were the most common (3.4%) sign of amplification, followed by dmin (1.3%), and hsr (0.8%). Rings were particularly frequent in malignant mesenchymal tumors, especially liposarcomas (47.5%) and osteosarcomas (23.4%), dmin were prevalent in neuroblastoma (30.9%) and pancreatic carcinoma (21.9%), and hsr frequencies were highest in head and neck carcinoma (14.0%) and neuroblastoma (9.0%). Combining all three amplification markers (dmin/hsr/r), malignant solid tumors consistently exhibited higher frequencies than hematologic disorders and benign solid tumors. The structural characteristics of these amplification markers and their potential role in tumorigenesis and tumor progression highlight the complex interplay between cancer-initiating gene-level alterations, for example, fusion genes, and subsequent amplification dynamics. Further research integrating cytogenetic and molecular approaches is warranted to better understand the underlying mechanisms of these amplifications, in particular, the enigmatic question of why certain malignancies display certain types of amplification. Comparing the present results with molecular genetic data proved challenging because of the diversity in definitions of amplification across studies. This study underscores the need for standardized definitions in future work.

Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs-90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.

OBJECTIVE: To carry out cyto- and molecular genetic analysis for a fetus with a ring chromosome identified through non-invasive prenatal testing (NIPT).
METHODS: A pregnant woman presented at the Shengjing Hospital Affiliated to China Medical University on May 11, 2021 was selected as the study subject. Maternal peripheral blood sample was screened by NIPT, and G-banded chromosomal karyotyping was carried out on amniotic fluid and peripheral blood samples from the couple. The fetus and the pregnant woman were also subjected to genomic copy number variation sequencing (CNV-seq), chromosomal microarray analysis (CMA), and fluorescence in situ hybridization (FISH) assay.
RESULTS: NIPT result suggested that the fetus had monomeric mosaicism or fragment deletion on chromosome 13. G banded chromosomal analysis showed that both the fetus and its mother had a karyotype of 47,XX,der(13)(pter→p11::q22→q10),+r(13)(::p10::q22→qter::), whilst her husband had a normal karyotype. FISH has verified the above results. No abnormality was detected with CNV-seq and CMA in both the fetus and the pregnant woman.
CONCLUSIONS: The ring chromosome 13 in the fetus has derived from its mother without any deletion, duplication and mosaicism. Both the fetus and the pregnant woman were phenotypically normal.

Ring chromosomes (RCs) are a structural aberration that can be tolerated better in acrocentric or gonosomal chromosomes. Complete RCs arise from telomere-telomere fusions. Alternatively, genomic imbalances corresponding to the ends of the chromosomal arms can be seen with RC formation. RCs are unstable in mitosis, result in mosaicism, and are associated with a \"ring syndrome,\" which presents with growth and development phenotypes and differs from those features more frequently observed with pure terminal copy number changes. Due to variability in mosaicism, size, and genomic content, clear genotype-phenotype correlations may not always be possible. Given the rarity of RCs, this historical data is invaluable. We performed a retrospective review of individuals bearing RCs to investigate the incidence in our laboratory. This work details the methods and features seen in association with twenty-three autosomal RCs. In decreasing order, the most frequently seen autosomal RCs were 18, 22, 4, 13, 17, and 9. The additional cases detail clinical and cytogenomic events similar to those reported in RCs. As methodologies advance, insights may be gleaned from following up on these cases to improve genotype-phenotype correlations and understand the cryptic differences or other predisposing factors that lead to ring formation and development.