Meiotic and Mitotic Origin of Aneuploidies Detected in Preimplantation Genetic Testing

Abstract

Over 90% of aneuploidies originate from maternal meiosis, with the only established cause of aneuploidy being maternal age. So it is not surprising that the reproductive age is the major indication for preimplantation genetic testing for chromosomal aneuploidy (PGT-A), which allows couples with advanced reproductive age to achieve their reproductive goals without risk for fetal loss or birth of an affected child. This is achieved through detecting and avoiding from transfer a considerable proportion of embryos with different abnormalities, which according to our experience is as high as 56.9% (1661 of 2922 blastocysts samples tested by NGS). Of these abnormalities, 8% (133 of 1661) were with mosaicism and 14.4% (240/1661) were found to have segmental chromosome abnormalities. Of these, 63.3% (154/240) were found to have one deletion, 8.3% (20/240) one duplication and 28.4% (66/240) multiple segmental abnormalities. The smallest abnormality identified was 5.8 Mb, while the largest was 139.6 MB. The p to q arm ratio of these abnormalities was found to be 1.03. Mosaicism of segmental abnormalities was observed in 59% of samples identified. Segmental chromosome abnormalities were most commonly found in chromosomes 1 (32/240; 13.3%), 5 (22/240; 9/2%), and 4 (21/240; 8.8%). No chromosome 22 or Y chromosome abnormalities were identified in this cohort. Only three of these segmental anomalies were of meiotic origin, detected also in parents, while others were de novo events, of which biological and clinical significance is unknown. These are clearly post-meiosis errors, but their impact cannot be evaluated. It cannot be excluded that they are technical errors, or chromosome specific differences of completion of S period of cell cycle. Difference in the replication pattern of certain chromosomes were demonstrated long time ago, depending on maternal and paternal origin of homologous chromosomes and on differences of cell type tested, so segmental errors may reflect a tissue specific differences of DNA replication. Technical errors cannot be excluded either in detection of mosaicism, as it may be affected by chromosome drifting caused by cell damage during blastocyst biopsy, or by the choice of methodology for 24-chromosome aneuploidy testing. One of the he major factors in reproductive outcome of mosaicism is their meiotic or meiotic origin. For example, the experience on the establishment of embryonic stem cell lines demonstrated a higher success rate of obtaining embryonic stem cell lines from mitotic rather than meiotic trisomics. While, it is not always possible to distinguish the origin of mosaicism, the available data on the prevalence and types of meiotic and mitotic error, to be summarized in this presentation, may be useful for evaluating their corresponding impact depending on the mosaicism origin.