Embryos of robertsonian translocation carriers exhibit a mitotic interchromosomal effect that enhances genetic instability during early development

Abstract

Balanced chromosomal rearrangements represent one of the most common forms of genetic abnormality affecting approximately 1 in every 500 (0.2%) individuals. Difficulties processing the abnormal chromosomes during meiosis lead to an elevated risk of chromosomally abnormal gametes, resulting in high rates of miscarriage and/or children with congenital abnormalities. It has also been suggested that the presence of chromosome rearrangements may also cause an increase in aneuploidy affecting structurally normal chromosomes, due to disruption of chromosome alignment on the spindle or disturbance of other factors related to meiotic chromosome segregation. The existence of such a phenomenon (an inter-chromosomal effect--ICE) remains controversial, with different studies presenting contradictory data. The current investigation aimed to demonstrate conclusively whether an ICE truly exists. For this purpose a comprehensive chromosome screening technique, optimized for analysis of minute amounts of tissue, was applied to a unique collection of samples consisting of 283 oocytes and early embryos derived from 44 patients carrying chromosome rearrangements. A further 5,078 oocytes and embryos, derived from chromosomally normal individuals of identical age, provided a robust control group for comparative analysis. A highly significant (P = 0.0002) increase in the rate of malsegregation affecting structurally normal chromosomes was observed in association with Robertsonian translocations. Surprisingly, the ICE was clearly detected in early embryos from female carriers, but not in oocytes, indicating the possibility of mitotic rather than the previously suggested meiotic origin. These findings have implications for our understanding of genetic stability during preimplantation development and are of clinical relevance for patients carrying a Robertsonian translocation. The results are also pertinent to other situations when cellular mechanisms for maintaining genetic fidelity are relaxed and chromosome rearrangements are present (e.g. in tumors displaying chromosomal instability).

Figure 1. Microarray-CGH analysis of an embryo from a Robertsonian translocation carrier.

Cytogenetic analysis of a cleavage stage embryo from a Robertsonian translocation carrier- 46,XY,t(13;15)(q21.3;q11.2). Microarray-CGH revealed monosomy 13, presumably resulting from a meiotic error due to problems processing the rearranged chromosomes. An additional aneuploidy unrelated to the Robertsonian translocation (monosomy for chromosome 1) was also detected. The two monosomies are indicated by the altered ratio of fluorescence related to the test (embryo) and reference (46,XY) DNA samples. All of the probes corresponding to chromosomes 1 and 13 have test/reference ratios less than 0.3.