Unstable Ring Chromosome 21 Reveals Tissue-Specific Mosaicism Behind Down Syndrome-Like Features

An 8-month-old boy in Mexico City whose facial features and medical problems suggested Down syndrome, but who lacked the full classical presentation, has turned out to carry one of the rarest and most structurally complex rearrangements of chromosome 21 described to date. Geneticists at the National Institute of Pediatrics report that the child carries a constitutional non-supernumerary ring chromosome 21 — a circular chromosome formed when the ends of chromosome 21 break and fuse — combined with a large duplication and a terminal deletion on the same chromosome. Their detailed cytogenomic analysis, published in Frontiers in Genetics, revealed four distinct cell clones distributed differently across blood, oral mucosa, and urinary epithelium, offering a vivid illustration of how an unstable ring chromosome can generate tissue-specific mosaicism and reshape a clinical phenotype.

Ring chromosome 21 syndrome is a rare genomic disorder that accounts for roughly 7.1 percent of ring chromosome syndrome cases reported worldwide between 1962 and 2022. Its clinical manifestations are strikingly heterogeneous, ranging from developmental delay and intellectual disability to epilepsy, growth impairment, congenital malformations, dysmorphic features, infertility, and even acute B-cell lymphoblastic leukemia. This variability reflects several interacting pathogenic mechanisms: mitotic instability of the ring itself, gene dosage imbalance caused by segmental deletions and duplications, and mosaicism that differs from one tissue to another. Depending on which segments of chromosome 21 are retained, lost, or amplified, patients with constitutional ring 21 may show either a classic Down syndrome phenotype or a more complex, DS-like picture produced by concurrent copy number imbalances.

The proband in this report was the first full-term child of healthy, non-consanguineous parents, delivered by cesarean section at 40 weeks of gestation with a birth weight of 2.36 kilograms. He was referred during his first two months of life for intestinal atresia, and exploratory surgery revealed a Meckel diverticulum, which was resected. Dysmorphic features and a systolic murmur noted during that admission prompted a genetics consultation. At evaluation, the boy showed microcephaly, a broad forehead with bitemporal narrowing, sparse eyebrows, upslanting palpebral fissures, bilateral epicanthal folds, telecanthus, malar flattening, anteverted nares, a thin upper lip, downturned mouth corners, low-set ears, and a low posterior hairline. His extremities showed persistent fetal fingertip pads, a slightly marked single transverse palmar crease, and abnormal plantar creases.

Additional findings deepened the clinical puzzle. Brainstem auditory evoked potentials revealed moderate conductive hearing loss in the right ear, the child developed myopia of −3.5 diopters, and seizures began at 9 months of age. Brain MRI showed supratentorial ventriculomegaly, thinning of the corpus callosum, a retrocerebellar arachnoid cyst, subcortical atrophy, diffuse periventricular gliosis, and reduced caliber of the right internal carotid artery. Echocardiography identified an ostium secundum atrial septal defect. Down syndrome was initially suspected, but the phenotype was not fully consistent with the classical form: marked brachycephaly, pronounced epicanthal folds, and the typical hand and foot anomalies were absent or only mildly expressed. By 3 years of age, follow-up photographs showed persistence of several dysmorphic features, although the DS-like facial gestalt appeared less evident than in infancy. The child has since learned to walk unaided, communicates with babbling and gestures, has begun using disyllabic words, and receives language therapy and long-term multidisciplinary care.

The laboratory workup combined classical and molecular cytogenetics. G-banded metaphase analysis of stimulated peripheral blood lymphocytes, evaluated at a resolution of 450 to 550 bands across 100 metaphases, revealed a mosaic karyotype with four cell lines: a minor line missing chromosome 21 entirely, a predominant line carrying a duplicated monocentric ring chromosome, a small line with an isodicentric ring, and a line with a single ring. SNP-array analysis on genomic DNA from peripheral blood then pinpointed the dosage changes: an 18.77-megabase copy number gain at 21q21.2-q22.3 and a 3.09-megabase terminal copy number loss at 21q22.3, reported against the GRCh37/hg19 assembly. Notably, the SNP array classified these imbalances as non-mosaic, likely because the duplicated ring clone predominated in the myeloid-lineage cells that supplied the DNA, underscoring how different analytical platforms can sample different biological realities.

Fluorescence in situ hybridization using probes for the chromosome 13/21 alpha-satellite sequence, the RUNX1 locus, the Down syndrome critical region, and the 21q subtelomere resolved the ring structures and enabled the study of mosaicism across three tissues representing different embryonic germ layers: stimulated peripheral blood lymphocytes, oral mucosa epithelial cells, and urinary sediment epithelial cells, with at least 100 nuclei scored per tissue. The single ring clone, which produces partial monosomy 21 through loss of the terminal 21q22.3 subtelomeric region, appeared at low levels of 7 to 9 percent in all tissues. The duplicated monocentric ring — carrying an inverted duplication of 21q21.2-q22.3 that includes RUNX1 and the DSCR alongside the terminal deletion — was the predominant clone at 81 to 86 percent in lymphocytes and oral mucosa. The isodicentric ring, which duplicates the already duplicated ring and yields partial pentasomy of 21q21.2-q22.3, was detected at 2 to 7 percent. Most strikingly, complete ring loss, producing full monosomy 21, was seen in only 3 percent of lymphocytes and oral mucosa cells but in 50 percent of urinary sediment epithelial cells.

The authors propose a stepwise sequence of events to explain this clonal diversity. First, terminal breaks in both chromosome arms fused end-to-end to form the initial single ring. Next, unequal intrachromosomal recombination within that ring generated the duplicated monocentric ring with partial trisomy of 21q21.2-q22.3. A subsequent duplication of this already duplicated ring produced the isodicentric form. Finally, the ring’s intrinsic mitotic instability led to chromosome loss in some cells, generating complete monosomy 21. The markedly higher frequency of monosomic cells in urinary sediment suggests pronounced ring instability within epithelial lineages. Because urinary sediment contains exfoliated epithelial cells from the renal tubules, renal pelvis, ureters, bladder, and urethra, the authors suggest this may reflect broader epithelial mosaicism rather than a change confined to the urinary tract. They also caution that technical factors in interphase FISH of urinary sediment — sample volume, mixed cell types, and nuclear signal overlap — can produce false positives, so such findings should be confirmed by complementary methods.

The tissue differences also track with cell biology. Epithelial tissues undergo continuous physiological renewal, whereas peripheral blood T lymphocytes largely remain quiescent in the G0 phase until antigenic stimulation, dividing far less often under normal conditions. The greater cumulative mitotic activity of epithelial tissues may therefore explain the increased diversity of instability-derived clones there, including the isodicentric ring and complete monosomy 21. Despite these differences, the duplicated monocentric ring remained well represented in every tissue examined, indicating that the main genomic imbalance underlying the patient’s phenotype is the combination of partial trisomy of 21q21.2-q22.3 and terminal monosomy of 21q22.3. The authors emphasize that multi-tissue cytogenomic analysis is essential for revealing tissue-specific mosaicism and improving genotype-phenotype correlations in constitutional ring chromosome disorders.

To place their patient in context, the team searched PubMed through June 2026 for comparable cases of constitutional non-supernumerary ring 21 with concurrent 21q deletions and duplications involving the DSCR, and identified five previously reported cases, one of which — a 17-week fetus — was excluded from phenotypic comparison. The remaining four pediatric patients shared features with the present case, including growth delay, global developmental delay, hypotonia, cranial dysmorphism, and ophthalmological, cardiac, and gastrointestinal abnormalities. In contrast, the characteristic craniofacial and limb features of classic Down syndrome were absent or mildly expressed in most patients. Notably, several manifestations uncommon in classic DS appeared across the group, including structural brain abnormalities such as cerebral asymmetry, holoprosencephaly, and corpus callosum flattening, as well as seizures and genital anomalies.

Comparative genomic analysis showed that all patients carried a complete or partial duplication of the classical DSCR, and the duplicated interval consistently included the predicted triplosensitive genes KCNJ6, DYRK1A, and ERG. However, the copy number status of the highly restricted DSCR, a 34-kilobase interval defined on GRCh37/hg19, varied among cases — duplicated in the present patient and two others, deleted in one, and normal in another — despite broadly similar clinical manifestations. Recurrent imbalances outside the DSCR involved additional predicted triplosensitive genes such as TIAM1 and ITSN1, while the recurrent terminal deletions shared a minimal set of predicted haploinsufficient genes, DIP2A and COL6A1. ClinGen dosage sensitivity curations assign only limited evidence to several of these genes, but their functions relate to neuronal development, and their recurrent involvement suggests that dosage changes may contribute to the neurological features of this disorder. The authors conclude that neither the classical nor the highly restricted DSCR alone can explain the phenotypic variability; rather, dynamic ring chromosome mosaicism and cumulative dosage imbalance of multiple chromosome 21 genes, both inside and outside the DSCR, jointly shape the outcome. Because both parents had normal karyotypes, the abnormality was judged de novo and the recurrence risk considered low, though familial transmission from mosaic carriers has been documented, so a small residual risk cannot be excluded. As a retrospective, observational, single-patient study, the report’s correlations remain provisional, and the authors stress that additional well-characterized cases are essential to refine the clinical spectrum of this rare genomic disorder.

Subject of Research: Tissue-specific mosaicism and genotype-phenotype correlations in constitutional non-supernumerary ring chromosome 21

Article Title: Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis

Article References: Martínez Anaya, D., Zinser Sainas, A., Cruz Cruz, M., Yáñez-Félix, A. L., Salas Labadía, C., Orta Barcenas, C. A., Sosa Sánchez, D. A., Yokoyama Rebollar, E., & Pérez-Vera, P. (2026). Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis. Frontiers in Genetics, 17, Article 1958717. https://doi.org/10.3389/fgene.2026.1958717

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1958717

Keywords: ring chromosome 21, mosaicism, Down syndrome critical region, copy number imbalance, FISH, SNP array, dosage-sensitive genes, genotype-phenotype correlation, case report, cytogenomics, partial trisomy 21, partial monosomy 21