Unique Genomic Structure and Distinct Mitotic Behavior of Ring Chromosome 21 in Two Unrelated Cases

Abstract

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.

Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells

“…Due to the severity of these large-scale aberrations affecting multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have so far been proposed. During cell division ring chromosomes can exhibit unstable behavior, leading to continuous production of aneuploid progeny with low viability and high cellular death rate 3-9 . The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems.…”

Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum

“…The clinical features are likely caused by the compound effects of mitotic instability of the ring chromosome and a gene dosage effect resulting from segmental deletions/duplications in the process of ring formation. Furthermore, the phenotypes are highly variable [Zhang et al, 2012]. In a recent report, a prenatal case, determined at 22 weeks of gestation because of hyperechogenic cardiac foci and intrauterine growth restriction, revealed a mosaic r(21) male karyotype.…”

Fluorescence In situ Hybridization: Cell-Based Genetic Diagnostic and Research Applications

“…Subtelomeric and interstitial FISH probes have been used to define the intactness of the ring chromosome and the level of mosaicism (Zhang et al, 2004; Xu F. et al, 2013). A cytogenomic approach combining chromosome, FISH, and microarray analyses has been recommended for characterizing the genomic structure, mitotic instability, and mechanisms of ring formation for cases with a ring chromosome (Zhang et al, 2012). sSMC are extra centric chromosome fragments usually in the forms of an inverted duplication or a small ring chromosome and present in 0.043% of newborn children.…”