Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

EA Chavli, SJ Klaasen, D Van Opstal… - The Journal of …, 2024 - Am Soc Clin Investig
EA Chavli, SJ Klaasen, D Van Opstal, JSE Laven, GJPL Kops, EB Baart
The Journal of Clinical Investigation, 2024Am Soc Clin Investig
Aneuploidy, a deviation from the normal chromosome copy number, is common in human
embryos and is considered a primary cause of implantation failure and early pregnancy loss.
Meiotic errors lead to uniformly abnormal karyotypes, while mitotic errors lead to
chromosomal mosaicism: the presence of cells with at least two different karyotypes within
an embryo. Knowledge about mosaicism in blastocysts mainly derives from bulk DNA
sequencing of multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples …
Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and is considered a primary cause of implantation failure and early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic errors lead to chromosomal mosaicism: the presence of cells with at least two different karyotypes within an embryo. Knowledge about mosaicism in blastocysts mainly derives from bulk DNA sequencing of multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect an average net gain or loss of DNA above a detection threshold of 20-30%. To accurately assess mosaicism, we separated the TE and ICM of 55 good quality surplus blastocysts and successfully applied single-cell whole genome sequencing (scKaryo-seq) on 1057 cells. Mosaicism involving numerical and structural chromosome abnormalities was detected in 82% of the embryos, where most abnormalities affected less than 20% of the cells. Structural abnormalities, potentially caused by replication stress and DNA damage, were observed in 69% of the embryos. In conclusion, our findings indicated that mosaicism is prevalent in good-quality blastocysts, while these blastocysts would likely be identified as normal with current bulk DNA sequencing techniques used for preimplantation genetic testing for aneuploidy (PGT-A).
The Journal of Clinical Investigation