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Single-cell sequencing shows mosaic aneuploidy in most human embryos
Sarah A. Robertson, Robert I. Richards
Sarah A. Robertson, Robert I. Richards
Published March 15, 2024
Citation Information: J Clin Invest. 2024;134(6):e179134. https://doi.org/10.1172/JCI179134.
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Single-cell sequencing shows mosaic aneuploidy in most human embryos

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Abstract

Mammalian preimplantation embryos often contain chromosomal defects that arose in the first divisions after fertilization and affect a subpopulation of cells — an event known as mosaic aneuploidy. In this issue of the JCI, Chavli et al. report single-cell genomic sequencing data for rigorous evaluation of the incidence and degree of mosaic aneuploidy in healthy human in vitro fertilization (IVF) embryos. Remarkably, mosaic aneuploidy occurred in at least 80% of human blastocyst-stage embryos, with often less than 20% of cells showing defects. These findings confirm that mosaic aneuploidy is prevalent in human embryos, indicating that the process is a widespread event that rarely has clinical consequences. There are major implications for preimplantation genetic testing of aneuploidy (PGT-A), a test commonly used to screen and select IVF embryos for transfer. The application and benefit of this technology is controversial, and the findings provide more cause for caution on its use.

Authors

Sarah A. Robertson, Robert I. Richards

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Figure 1

Different genetic analysis platforms have a varying capacity to detect mosaic aneuploidy in blastocyst-stage embryos.

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Different genetic analysis platforms have a varying capacity to detect m...
Embryos may be euploid (100% normal cells), aneuploid (100% abnormal cells), or mosaic aneuploid, with varying proportions of cells in the inner cell mass and/or trophectoderm affected by numerical and/or structural chromosomal defects. sc-Karyo-Seq analysis of all cells recovered from blastocysts offers high sensitivity and specificity, accurately detecting mosaic aneuploidy in even a small minority of cells. Bulk sequencing techniques analyze entire embryos or embryo parts and have lower sensitivity and specificity than sc-Karyo-Seq, only detecting aneuploidy when at least 20% of the cells in a sample are aneuploid. PGT-A is a clinical test utilizing bulk sequencing to analyze small segments of four to six trophectoderm cells recovered from embryos via biopsy. PGT-A frequently fails to correctly classify aneuploid status in mosaic aneuploid embryos due to low sensitivity of bulk sequencing techniques and spatial heterogeneity of chromosome status, meaning that the segment is not informative of the entire embryo. When none or less than 20% of cells in a segment are aneuploid, the test may return a negative or inconclusive result even when aneuploidy exists. When more than 20% of cells in a segment are aneuploid, the test may return a positive result even if most of the cells in an embryo are normal.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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