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Detailed investigation into the mosaic embryo karyotypes: multicenter data from 2280 trophectoderm biopsies obtained during preimplantation genetic testing cycles in IVF

Fiorentino, F1 , Spinella, F1 , Victor, A2 , Barnes, F2 , Zouves, C2 , Greco, E3 , Ruberti A 3 , Cursio E 3 , Varricchio MT3 , Biricik, A1 , Makieva S 1 , Corti L 4 , Viganò P 4 , Bianchi V 5 , Surdo M1 , Minasi MG3 , and Viotti M2 .
1 .Genoma, Molecular Genetics Laboratories, Rome italy; 2 .Zouves Foundation for Reproductive Medicine, Foster City, California, USA. 3European Hospital, Rome, Italy. 4 . Obstetrics and Gynecology San Raffaele Scientific Institute, Milan, 5 .Future for Family, Bologna, Italy.

Study question:
Which is the prevalent type of mosaicism affecting human mosaic embryos?

Summary answer:
Single whole chromosome aneuploidy is the most prevalent form of mosaicism in preimplantation embryos with a majority involving gains.

What is known already:
Chromosomal mosaic embryos are characterized by the presence of chromosomally different cell lines within the same embryo. Mosaicism may involve whole-chromosome, segmental (or partial), complex or a combination of such aneuploidies. We previously demonstrated that the reproductive potential of mosaic embryos is affected by the complexity of and the number of aneuploid cells present in trophectoderm (TE) biopsy. We also observed that the mosaicism involved specific chromosomes and that single (sub-chromosomal or whole-chromosome) aneuploidy was the prevalent type of chromosomal mosaicism. However, our study involved a limited number of mosaic embryos and data available were insufficient to test this hypothesis.

Study design, size, duration:
This is a large-scale multicenter study on mosaic embryos to examine the patterns and prevalence of chromosome specific mosaicism in TE samples. The cohort consisted of 2280 consecutive mosaic embryos collected between May2016-May2019. All embryos were cultured to blastocyst stage; TE biopsy was performed on Day-5 or Day6/7of development. TE biopsies underwent comprehensive chromosome screening utilizing validated next generation sequencing (NGS). TE biopsies were classified as mosaic if they had 20%-80% abnormal cells.

Participants/materials, setting, methods:
Mosaic embryos composed of mosaic chromosomes only were analyzed. Mosaicism was tabulated per chromosome, and chromosomal constitution and incidence of different type of mosaic embryos were also analyzed. For statistical analysis mosaic embryos were divided in three groups: whole-chromosome, segmental and mixed mosaicism. In addition, whole-chromosome and segmental mosaicism were divided based on chromosomal constitution in single (monosomy or trisomy), double, and complex aneuploidy (more than two different aneuploidies) group.

Main results and the role of chance:
A total of 4850 aneuploidies were detected, whole-chromosome (3547/4850;74%) occurred more frequently than segmental (1303/4850; 26%) mosaicism (P<0.01). The highest prevalence of whole-chromosome imbalance leading to aneuploidy was seen for chromosome 14, 18, 21, 22 and X, while for segmental mosaicism was seen for chromosomes 1,2,5, and 16. Mosaicism rates for these chromosomes did not statistically vary when stratified by maternal age. For whole-chromosome mosaicism, trisomy was significantly more frequent than monosomy (p<0.05) but for segmental mosaicism trisomy was less frequent (P<0005). Regarding the type of mosaic embryos, 53% (1209/2278) were found to be composed of whole chromosomes, 30% (694/2278) of structural aneuploidies and 17% (375/2278) contained both whole-chromosomal and structural aneuploidies. Of the whole-chromosome embryos, single aneuploidy was significantly more frequent than complex (53%, vs 28%;p<0.001), and double aneuploidy (53%, vs 19%;p<0.001). Similarly, when grouped based on structural abnormalities, single segmental aneuploidy was significantly more frequent than double (80% vs 16%; p<0.0001) or complex segmental aneuploidy (80% vs. 4%; p<0.001). Structural mosaic and whole-chromosome aneuploidy blastocysts with >50% aneuploid cells accounted for 11% and 14% of analysed embryos, respectively.

Limitations, reasons for caution:
This study was retrospective, demonstrating the relative frequency of different type of mosaic embryos but not offering any direct insight into the clinical relevance of the findings. Additional clinical data must be obtained to evaluate the clinical implication of chromosomal mosaicism in mosaic embryo outcome.

Wider implications of the findings:
Our findings reported the prevalence of the different kind of mosaicism in human blastocyst. Furthermore the study provides a detailed description of the prevalence, distribution and level of mosaicism for each chromosome involved in mosaicism. These results contribute to the understanding of the nature and origin of mosaic embryos.