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.

Figure 1

Left to right, patients 1, 2, and 3 and their respective ring chromosome 13 (bottom).

Figure 2

WCP13 probe (green): (a) patient 2, normal 13 and monocentric ring; (b) patient 1, two monocentric rings and normal 13; (c) patient 3, normal 13 and marker with positive hybridization (arrow); (d) patient 2, normal 13 and dicentric ring; (e) patient 1, single normal 13 in a monosomic cell; (f) patient 1, on the left, metaphase with monocentric ring and normal 13, near an interphasic nucleus bordered by a micronuclei, the latter also showing positive hybridization.

Figure 3

Rb1 (red)/Tel13q (green) probes: (a) patient 1, monocentric ring showing Rb1 signal and no Tel13q; (b) patient 2, single normal 13 in a monosomic cell; (c) patient 3, dicentric ring presenting double Rb1 signal; (d) Patient 2, marker chromosome without both Rb1 and Tel13q signals; (e) Patient 2, two dicentric rings with double Rb1 signal each; (f) Patient 3, normal cell.

Figure 4

Schematic distribution of deleted genes and sizes of deletions of probands (red bars). Order of appearance of genes in the bands does not necessarily reflect the actual sequence in the chromosome (ideogram from above extracted from UCSC Genome Browser Gateway).

Figure 5

aCGH profile indicating the segment deletions on chromosome 13q.