Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression

Abstract

Aneuploidy in preimplantation embryos is a major cause of human reproductive failure. Unlike uniformly aneuploid embryos, embryos diagnosed as diploid-aneuploid mosaics after preimplantation genetic testing for aneuploidy (PGT-A) can develop into healthy infants. However, the reason why these embryos achieve full reproductive competence needs further research. Current RNA sequencing techniques allow for the investigation of the human preimplantation transcriptome, providing new insights into the molecular mechanisms of embryo development. In this prospective study, using euploid embryo gene expression as a control, we compared the transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism. A total of 25 samples were analyzed from 14 blastocysts with previous PGT-A diagnosis, including five low-level mosaic embryos and four high-level mosaic embryos. Global gene expression profiles visualized in cluster heatmaps were correlated with the original PGT-A diagnosis. In addition, gene expression distance based on the number of differentially expressed genes increased with the mosaic level, compared to euploid controls. Pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos. Retrospective analysis of the duration of blastomere cell cycles in mosaic embryos revealed several mitotic delays compared to euploid controls, providing additional evidence of the mosaic status. Overall, these findings suggest that embryos with mosaic results are not simply a misdiagnosis by-product, but may also have a genuine molecular identity that is compatible with their reproductive potential.

Re-Examination of PGT-A Detected Genetic Pathology in Compartments of Human Blastocysts: A Series of 23 Cases

“…In the case that a decision is made to transfer such an embryo into the uterus, the pregnancy shall be managed with ultimate caution. The latter justifies the dire need for additional differential diagnosis techniques based on entirely innovative approaches, such as differential gene expression in mosaic blastocysts [ 66 ]. These technologies may suggest innovative diagnostic criteria allowing for the mosaic chromosomal constitution of a blastocyst to be verified.…”

Developmental perturbation in human embryos: Clinical and biological significance learned from time‐lapse images

“…Although not proven, mitotic errors during early embryonic division are considered to result in slower cleavage, longer cell cycles, and subsequently delayed blastocyst formation. 164 , 165 , 166 These embryos have an intrinsic capacity for self‐correction, which may occur through selective apoptosis and reduced proliferation of aneuploid cells. 32 , 167 , 168 A recent study proposed four models for self‐correction: (1) embryonic mortality, (2) aneuploidy rescue, (3) preferential allocation, and (4) clonal depletion.…”

Single-cell Transcriptomics of Postimplantation Embryos: Unveiling Aneuploidy Effects and Lineage Dynamics

“…Currently, single-cell omics studies on preimplantation human embryos have revealed that aneuploidy signi cantly disrupts gene expression and regulation both in cis and in trans 7 . Aneuploid cells in preimplantation embryos are often enriched for genes related to cellular stress and proliferation suppression, leading to reduced cell tness and developmental delay [7][8][9][10][11] . Moreover, in cancer cells where aneuploidy is also commonly observed, the transcriptomic effects of aneuploidy are mainly linked to a dysregulated cell cycle and metabolism, further contributing to genome instability in a vicious cycle 1 .…”