Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis
Year: 2026
Type: article
Study design: Case Report
Abstract: Introduction Ring chromosome 21 (r (21)) is a rare constitutional rearrangement involving terminal deletions and significant phenotypic heterogeneity. High-resolution genomic analyses have demonstrated that ring chromosomes may harbor complex genomic imbalances and dynamic mosaicism. However, the contributions of ring chromosome instability, tissue-specific mosaicism, and complex dosage imbalance to the clinical phenotype remain poorly understood. Case Presentation We report an 8-month-old boy with developmental delay, congenital heart disease, hearing impairment, structural brain abnormalities, and dysmorphic features suggestive of Down syndrome (DS), although lacking the complete classical phenotype. Cytogenomic analyses identified a constitutional non-supernumerary r (21) associated with a 18.77-Mb duplication of 21q21.2-q22.3 and a 3.09-Mb terminal deletion of 21q22.3. Fluorescence in situ hybridization (FISH) resolved the ring chromosome structure, identifying four instability-derived clones, and demonstrated tissue-specific mosaicism across lymphocytes, oral mucosa epithelial cells, and urinary sediment epithelial cells, with a duplicated monocentric r (21) as the predominant clone. Comparison with the four previously reported constitutional non-supernumerary r (21) cases revealed a recurrent combination of Down syndrome critical region (DSCR) duplication and terminal 21q deletion, despite substantial phenotypic variability. Discussion and Conclusion This study expands the clinical and cytogenomic spectrum associated with constitutional non-supernumerary r (21). Tissue-specific mosaicism and recurrent genomic imbalances suggest that the DS-like phenotype cannot be explained solely by dosage alterations involving the classical or highly restricted DSCR. Our findings suggest a mechanism in which dynamic ring chromosome instability, and the cumulative dosage imbalance of multiple chromosome 21 genes, contribute to the phenotypic variability observed in these patients. Additional well-characterized cases are essential for refining the genotype–phenotype correlations of this rare genomic disorder.
Source: Frontiers in Genetics
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223562683