Towards New Approaches to Evaluate Dynamic Mosaicism in Ring Chromosome 13 Syndrome

Abstract

Individuals with ring chromosome 13 may show characteristics observed in a deletion syndrome and could present a set of dismorphies along with intellectual disability, according to chromosomal segments involved in the genetic imbalance. Nevertheless, ring anomalies likewise is called “dynamic mosaicism”, phenomena triggered by the inner instability concerning the ring structure, thus leading to the establishment of different cell clones with secondary aberrations. Phenotypic features, such as growth failure and other anomalies in patients with this condition have been associated with an inherent ring chromosome mitotic instability, while recent studies offer evidence on a role played by the differential loss of genes implicated in development. Here, we observed similar mosaicism rates and specific gene loss profile among three individuals with ring chromosome 13 using GTW-banding karyotype analyses along with FISH and CGH-array approaches. Karyotypes results were: patient 1—r(13)(p13q32.3), patient 2—r(13)(p11q33.3), and patient 3—r(13)(p12q31.1). Array-CGH has revealed qualitative genetic differences among patients in this study and it was elusive in precise chromosomal loss statement, ranging from 13 Mb, 6.8 Mb, and 30 Mb in size. MIR17HG and ZIC2 loss was observed in a patient with digital anomalies, severe growth failure, microcephaly and corpus callosum agenesis while hemizygotic EFNB2 gene loss was identified in two patients, one of them with microphtalmia. According to these findings, it can be concluded that specific hemizygotic loss of genes related to development, more than dynamic mosaicism, may be causative of congenital anomalies shown in patients with ring 13 chromosome.

Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report

“…A comparable finding was reported in a case of r(13), with 1% of micronucleated cells and 40% of these MN containing sequences derived from chromosome 13 [ 20 ]. Petter et al [ 21 ] also found MN in three cases of r(13); all exhibiting chromosome 13 signals, as confirmed by WCP13. These findings support the hypothesis that the structure of ring chromosomes inherently leads to their exclusion from the main nucleus as MN.…”

“…In conclusion, ring chromosome syndrome is a pathological entity with significant variability due to factors including the affected chromosome, gene loss, positional effects of genes near breakpoints, and unbalanced segregation following ring chromosome sister chromatid exchange. Although previous work has suggested instability associated with chromosome rings, the evidence has been inconclusive [ 15 – 21 ]. Remarkably, we have demonstrated an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus.…”

Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly

“…While we assessed an intentionally diverse set of rearrangements, future application of our methods to larger sets of specific rearrangement types (and with T2T references beyond a single haploid assembly) is poised to contribute answers to additional long-standing questions about their formation and biology, for example: the preference for certain chromosomes in Robertsonian translocations 52,53 ; the properties of fused or dicentric centromeres 52,60 ; the frequency of fusion genes/enhancer swapping; position effects on gene expression [61][62][63][64] ; and the biology of subsequent mitotic/meiotic errors (i.e. "tissue-specific dynamic mosaicism") 65 .…”

Cytogenetic and molecular characterization of a patient having infertility and mild intellectual disability with a very rare unstable ring chromosome 13

“…Due to variations in chromosomal regions implicated in genetic imbalance, r(13) may manifest with a variety of dysmorphic features as well as intellectual impairments. 6 The different phenotype of the patients with r(13) is not only associated with large deletions of the q arm of chromosome 13 but also related to several factors such as mosaicism of the ring chromosome. Ring abnormalities are sometimes referred to as "dynamic mosaicism," a phenomenon caused by internal instability in the ring structure, which results in the formation of distinct cell clones with secondary chromosomal aberrations.…”