Embryonic mosaicism: defining prevalence in terms of clinical relevance

Chromosomal mosaicism, the presence of two or more cell lines in human preimplantation embryos, has conceived a new complexity for clinicians in the fields of IVF and PGS alike. The exact prevalence of mosaicism and the reproductive potential of each individually diagnosed mosaic embryo remains unknown. Various outcomes associated with the transfer of mosaic embryos include failed implantation, miscarriage, healthy live birth, or live birth with defects. By defining the prevalence of mosaicism based on clinical significance, we can potentially improve the reporting of mosaic embryos and help clinicians and patients understand what a mosaic result means for the long-term potential of the embryo. To report the overall incidence of mosaicism in human preimplantation embryos following PGS and define the frequency of mosaicism based on clinical relevance. In this study, 500 profiles from trophectoderm biopsies of human blastocysts were investigated. Comprehensive chromosome screening was performed on embryo biopsy samples utilizing next generation sequencing (NGS). Embryos were diagnosed as euploid, aneuploid (whole aneuploidies and/or segmental aneuploidies), or mosaic aneuploid. The overall incidence of mosaicism was 5.4% (27/500). This rate included embryos with only a mosaic diagnosis and those with a combined aneuploid and mosaic result. The incidence of mosaicism defined as clinically relevant was 2.4% (12/500). Embryos diagnosed with mosaicism of clinical relevance included those embryos showing only aneuploidies in a mosaic pattern (with no additional chromosomes showing uniform aneuploidy) and did not involve a mosaic monosomy or trisomy affecting chromosomes 13, 16,18, 21, X, and/or Y. It is the policy of our company to interpret any mosaic monosomy or trisomy profile involving chromosomes 13,16,18, 21, X and/or Y as purely aneuploid due to the risk of live birth and/or miscarriage. Additionally, if there is a mosaic diagnosis of a specific embryo paired with one or more full aneuploidies, then only the fully aneuploid results are reported. The presence of mosaicism in human preimplantation embryos has been well described, albeit with a wide-ranged of frequency. However, to our knowledge, the incidence of mosaicism based on clinical significance has not been published. Here we demonstrate the incidence of embryos with clinical relevance rate of mosaicism to be 2.4%. This relatively small percentage of affected embryos will require further consideration regarding their ultimate fate (i.e. to discard or not to discard?). Although it is the policy of our company not to recommend the transfer of mosaic embryos, these embryos may be available for transfer following genetic counseling to understand the potential issues that may arise with the transfer of embryos diagnosed as mosaic during PGS. Since we do not report mosaic results that involve chromosomes implicated in live births (13, 18, 21, X, and Y) or for chromosome 16 (the most common abnormality observed in miscarriages), we can prospectively provide an improved reproductive predictive value for those embryos diagnosed as mosaic.