The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans

Abstract

The clinical consequences of mosaicism depend on which chromosome is involved, and when and where an error occurs. Mitotic rescue of a meiotic error or a very early mitotic error will typically lead to general mosaicism while a mitotic error at a specific cell lineage point typically leads to confined mosaicism. The clinical consequences of mosaicism are dependent on numerous aspects, with the consequences being unique for each event.

Human embryo mosaicism: did we drop the ball on chromosomal testing?

“…Mosaicism can manifest in two forms: general and confined. General mosaicism is detected by pre-implantation genetic screening and leads to mosaicism within both the placenta and fetus proper [20]. Just because an embryo is mosaic at the time of early testing does not mean that those cell lines will propagate throughout development.…”

“…Recent literature has suggested that the use of a threshold to guide reporting of a mosaic result has no biological or clinical validity, and any level of mosaicism should be reported as such, irrespective of the fraction of abnormal cells in the sample [26]. Indeed, although mosaicism is recognized as prevalent within IVF-created embryos, the level at which mosaicism switches from problematic to clinically nonrelevant is undetermined [20,26]. Scott and Galliano (2016) have proposed a stratification of PGS diagnoses of disomic and monosomic or trisomic embryos, with an additional category of mosaicism that would ideally represent those embryos at highest risk of having a truly mosaic complement [28].…”

Irregular cleavage of early preimplantation human embryos: characteristics of patients and pregnancy outcomes

“…Chavez et al [10] observed that the generation of partial chromosomal gains and losses were restricted primarily to embryos with mitotic errors. During the first mitotic divisions in human preimplantation development, improper segregation of chromosomes might occur, causing high rates of aneuploidy and mosaicism [11]. Several studies showed that a majority of preimplantation embryos are diploid-aneuploid mosaic [12][13][14].…”

“…It is likely that mosaic embryos with a low number of abnormal blastomeres have self-correction mechanisms that enable normal implantation [13,14]. It has been shown that abnormal cells can be forced away from the embryonic inner cell mass leading to a viable euploid embryo [11]. There may be preferential growth of euploid blastomeres and/or reduced division of aneuploid cells.…”

Quality control standards in PGD and PGS

“…The embryos can be biopsied by the embryologists at the zygote stage (removal of the first and second polar body), cleavage stage (removal of 1-2 blastomeres from the 6-8 cell embryo) and blastocyst stage (removal of some trophectoderm cells) (Harton et al, 2011a). Up until recently, almost all PGD cycles were performed on blastomeres after cleavage stage biopsy (Harper et al, 2012, Moutou et al, 2014, but numerous studies have found that cleavage stage embryos exhibit high levels of chromosomal mosaicism, which means that biopsied cells may not be representative of the rest of the embryo (Harper et al, 1995, Munne et al, 1995, Fragouli et al, 2011, Taylor et al, 2014a. This is especially important when trying to perform PGD for a chromosome abnormality.…”