Читать книгу Genetic Disorders and the Fetus - Группа авторов - Страница 82

A wide range in the frequency of chromosomal aneuploidy in human oocytes has been reported (17–70 percent), but most of these studies have been performed on poor‐quality oocytes left over after the failure of IVF attempts. A high rate of hypohaploidy observed in oocytes was considered to be artificially induced by spreading techniques, so aneuploidy rate was calculated by doubling the number of hyperhaploid oocytes. This ignores chromatid malsegregation and/or chromosome lagging events, contradicting the results of the observation that the rate of hypohaploidy is higher than the rate of hyperhaploidy.⁹⁹ Cytogenetic analysis of unfertilized oocytes was also improved by parthenogenetic activation of human oocytes.¹⁰⁰

As mentioned, an attempt at noninvasive cytogenetic analysis of oocytes was undertaken in the early 1980s through visualization of the second polar body chromosomes by transplanting the polar body into a fertilized egg.³³ The success rate of visualization of polar body chromosomes was then improved by different methods, demonstrating the practical implication of polar body analysis for chromosomal errors originating from maternal meiosis,^101–103 in contrast to the report on the uselessness of the first polar body for this purpose.¹⁰⁴ Various approaches were explored in the attempt to visualize the chromosomes of the first and second polar bodies, as well as of the biopsied blastomeres, including nuclear transfer, electrofusion, and chemical methods.^{102, 105, 106} However, the major progress in chromosome analysis of oocytes and embryos was achieved with introduction of the fluorescence in situ hybridization (FISH) technique,^107–113 microarray technology, and NGS. Our meiosis data based on the analysis of 22,986 oocytes detected 9,812 aneuploid oocytes (46.8 percent), originating comparably from the first and second meiotic divisions. Overall, meiotic division errors were observed in 33.1 percent of oocytes in meiosis I, 38.1 percent in meiosis II, and 28.8 percent in both.

Although the aneuploidy rate in embryos is comparable to that in oocytes, the types of anomalies in the oocytes and embryos were significantly different,^114–116 also showing inconsistency between the expected and observed frequency of some types of aneuploidies. In our current practice of PGT‐A, the analysis of 2,922 blastocysts, 56.0 percent of embryos were aneuploid, comprising 13.0 percent monosomy, 13.0 percent trisomy, 8.0 percent numerical mosaic, 14.0 percent segmental mosaic, and 8.0 percent complex errors.⁴⁸ It is of interest that no age dependence was revealed for monosomies in embryos, suggesting that the rate of monosomies detected in embryo by PGT‐A may be of artefactual nature.

A possible explanation for this discordance is that the majority of monosomies detected in embryos are derived from mitotic errors, assuming technical causes are excluded. In fact, a significant proportion of the cleavage‐stage monosomies appeared to be euploid after their reanalysis.^{117, 118} No monosomies, except monosomy 21, are detected after implantation, so either they are eliminated before implantation or have no biological significance, reflecting the poor viability of the monosomic embryos and their degenerative changes. In one relevant study the progression and survival of different types of chromosome abnormalities were followed up in 2,204 fertilized oocytes.¹¹⁹ A variety of chromosome abnormalities was detected, including many types of errors not recorded later in development. However, these appeared to be tolerated until activation of the embryonic genome, after which there were declines in frequency. Nevertheless, many aneuploid embryos still successfully reach the blastocyst stage, even if some chromosome errors present during preimplantation development are not seen in later pregnancy.