Genetic Mosaicism in Embryos: In Between Normal & Abnormal

One of the biggest developments has been in preimplantation genetic testing (PGT), which has become much more widely used thanks to improved technology.

Traditional Preimplantation Genetic Testing

There are two main types of PGT.

• Preimplantation genetic diagnosis (PGD) is used when couples have a known or suspected genetic disorder such as cystic fibrosis or sickle cell anemia.
• Preimplantation genetic screening (PGS), on the other hand, looks for chromosomal abnormalities like Down syndrome. PGS checks whether any of the 23 chromosome pairs have too many or too few chromosomes – a condition called aneuploidy. PGS is also commonly used to reduce miscarriage risk or improve implantation rates, especially in women at higher risk for chromosomal abnormalities.

Both PGD and PGS aim to identify embryos most likely to result in a healthy pregnancy and reduce the chance of implantation failure or birth defects.

How Next-Generation Sequencing Improves Embryo Selection

To perform this testing, embryos are allowed to grow for five to six days until they reach the blastocyst stage. At this point, around five cells from the trophectoderm (the part that will become the placenta) are sampled. These cells are then analyzed using next-generation sequencing (NGS), a powerful tool that detects chromosomal errors.

Until recently, NGS could only provide two results: normal or abnormal. A result like 46XX or 46XY would be considered chromosomally normal, while extra or missing chromosomes would indicate an abnormality like Down syndrome.

Transferring a single normal embryo typically leads to a higher implantation success rate and lower risk of miscarriage.

What Is Mosaicism?

Thanks to newer technology, NGS can now identify a third category: mosaicism.

Mosaic embryos contain a mix of normal and abnormal cells. For example, a blastocyst with about 120 cells might have mostly normal cells and a few abnormal ones (low-level mosaic), or vice versa (high-level mosaic).

Here’s how mosaicism is classified:

• Less than 20% abnormal cells = normal
• 20–40% abnormal cells = low-level mosaic
• 40–80% abnormal cells = high-level mosaic
• More than 80% abnormal cells = abnormal

Unlike chromosomal abnormalities present at fertilization, mosaicism develops afterward and doesn’t increase with parental age. 

Should Mosaic Embryos Be Transferred?

Some fertility centers have chosen to transfer mosaic embryos when no normal ones are available. These transfers generally have lower pregnancy rates and higher miscarriage rates, but research shows they rarely result in children with congenital abnormalities. Outcomes tend to be “all or nothing” - either implantation fails, or a healthy child is born.

Important Exceptions

Not all mosaic embryos are safe to transfer. Some should never be used due to the risk of severe health issues.

For example:

• Extra chromosome 21 can lead to Down syndrome
• Extra chromosomes 13 or 18 are linked to serious birth defects
• Chromosomes 2, 7, and 16 can result in growth issues and preterm birth
• Chromosomes 14 and 15 may cause a condition called uniparental disomy, which is associated with neonatal complications

If no normal embryos are available, some mosaic embryos may still be considered for transfer, depending on which chromosomes are affected.

More Research Is Needed

There's still a lot we don’t know about mosaicism. For example, confined placental mosaicism – when abnormal cells are limited to the placenta while the fetus is normal – might occur later in pregnancy.

Understanding when and how mosaicism develops could help doctors make better decisions about embryo transfer.

In Summary

Mosaicism is not a new concept, but recent advances in genetic testing have allowed us to detect it more accurately.

Here’s what we know so far:

• Mosaic embryo transfer should only be considered when no normal embryos are available.
• These transfers may result in lower success rates, but healthy live births are possible.
• Genetic counseling is essential before proceeding.
• Amniocentesis should be performed during pregnancy to confirm fetal health.
• Ongoing research is vital to better understand risks and outcomes.

If you have questions about mosaicism or genetic testing during IVF, speak with your fertility specialist or genetic counselor to make informed decisions.