Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis
- 1Genetics and Cancer Laboratory, National Pediatric Institute, Mexico City, Mexico
- 2Department of Human Genetics, National Pediatric Institute, Mexico City, Mexico
- 3Specialized Genetic Analysis Laboratory Mexico (LAGEM), Mexico City, Mexico
Abstract
IntroductionRing 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 PresentationWe 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 ConclusionThis 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.
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BibTeX
@article{anaya2026dynamic,
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}},
author = {Daniel Martínez Anaya and Alejandro Zinser Sainas and Marelen Cruz Cruz and Ana Lucía Yáñez-Félix and Consuelo Salas Labadía and Carlos Andre Orta Barcenas and David Arturo Sosa Sánchez and Emiy Yokoyama Rebollar and Patricia Pérez-Vera},
journal = {Frontiers in Genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1958717},
url = {https://doi.org/10.3389/fgene.2026.1958717},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis
AU - Daniel Martínez Anaya
AU - Alejandro Zinser Sainas
AU - Marelen Cruz Cruz
AU - Ana Lucía Yáñez-Félix
AU - Consuelo Salas Labadía
AU - Carlos Andre Orta Barcenas
AU - David Arturo Sosa Sánchez
AU - Emiy Yokoyama Rebollar
AU - Patricia Pérez-Vera
PY - 2026
DA - 2026/10/25
JO - Frontiers in Genetics
DO - 10.3389/fgene.2026.1958717
UR - https://doi.org/10.3389/fgene.2026.1958717
AB - IntroductionRing 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 PresentationWe 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 ConclusionThis 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.
SN - 1664-8021
ER -