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.
Which is the prevalent type of mosaicism
affecting human mosaic embryos?
Single whole chromosome aneuploidy is the
most prevalent form of mosaicism in preimplantation embryos with a majority
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:
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