Segmental aneuploids: the main source for PGT-A false positives?

Researchers in a 2022 study found that some segmental aneuploids, that only have a partial chromosomal abnormality, might not be aneuploid after all.

PGT-A is a technique that determines whether an embryo is euploid, and has the right number of chromosomes (2 copies of 23 chromosomes), or is aneuploid, and doesn’t. Besides having the right number of chromosomes, PGT-A can also detect if there are large pieces of chromosomes missing or duplicated. You can see this below:

Check my complete guide to PGT-A to get more background on PGT-A (aka PGS testing).

An example of a segmental aneuploidy is Cri-du-chat (cat’s cry) syndrome. Here, a piece of chromosome 5 is missing which can lead to serious cognitive and developmental disabilities. Infants with this syndrome have a high-pitched cry that sounds like the meowing of a cat due to issues with the larynx.

Because of the risk of developing a syndrome, embryos that are diagnosed with a segmental aneuploidy are typically not considered for transfer. However, mosaic embryos with segmental aneuploidies (“segmental mosaics”) have been found to have superior success rates compared to other mosaic types. Additionally, rebiopsy of segmental aneuploids (not mosaics) often doesn’t match the initial biopsy (Navratil et al. 2020), which suggests the possibility that segmental aneuploids might actually be mosaic.

---

Grkovic et al. (2022), in their new study, modified their practice (at 6 clinic locations) so any segmental aneuploid was rebiopsied. The embryo’s status was reclassified based on the second biopsy.

For the first biopsy, the researchers classified any segmental aneuploid into one of five different categories:

• Simple gain [ie. dup(16)(q23.2-qter)]
• Complex gain [has more than 1 gain, ie. dup(16)(q23.2-qter), dup(20)(p13-p11)]
• Simple loss [ie. del(16)(q23.2-qter)]
• Complex loss [has more than 1 loss, ie. del(16)(q23.2-qter), del(20)(p13-p11)]
• Both [has both a gain and a loss, usually on the same chromosome, ie. del(16)(q23.2-qter), dup(16)(p13-p11)]

As an example, let’s pretend we have an embryo that was biopsied once with a simple gain segmental aneuploid dup(16)(q23.2-qter). Let’s say a second biopsy is done and this gives a euploid result. Since there’s 2 biopsies, both biopsies need to be considered to fully diagnose the embryo. Because there is a mix of both aneuploid and euploid cells, the embryo is a mosaic:

In total, 40.2% (33/82) of segmental aneuploids in their study were reclassified as mosaic. In other words, 40.2% of segmental aneuploids were actually eligible for transfer after a rebiopsy!

They looked at the types of segmental aneuploidies (defined above) that were reclassified as mosaics:

• 84.2% (16/19) of simple gain segmental aneuploids were reclassified as mosaic
• 30.0% (3/10) of complex gain segmental aneuploids were reclassified as mosaic
• 33.3% (7/21) of simple loss segmental aneuploids were reclassified as mosaic
• 25.0% (6/24) of complex loss segmental aneuploids were reclassified as mosaic
• 12.5% (1/8) of both segmental aneuploids were reclassified as mosaic

21 (63.6%) of these embryos had a euploid result for the second biopsy. As for the 49 segmental aneuploids that were rebiopsied and confirmed abnormal, 6 had a whole chromosome affected (the same chromosome as the segmental aneuploidy) and the rest had the same or a similar segmental aneuploidy on the same chromosome.

So simple gain segmental aneuploids have the highest (84.2%) chance of actually being mosaic. These were reclassified as segmental mosaics, which previously have been shown to be superior in terms of success rates. In a separate analysis, the researchers compared outcomes for 207 segmental mosaic and 2159 euploid transfers which they found indistinguishable:

Obviously, this is a pretty small sample size (82 in all), but it does illustrate the benefit of rebiopsying segmental aneuploids. In a separate analysis between 2016 and 2020 at their IVF centers, the researchers found about 470 of 14,705 embryos (3.2%) tested as segmental aneuploid. Based on the analysis above, 40.2% of these false positive “aneuploids” (or nearly 200 embryos) could have been reclassified as mosaic and transferred.

You might be wondering about whole chromosome aneuplodies and whether or not these should be rebiopsied. A previous study showed that rebiopsy of whole aneuploids is mostly concordant with the ICM. Interestingly, they also found that the concordance dropped when the embryo was a segmental aneuploid.

Have a segmental aneuploid that you can’t transfer? This data suggests to rebiopsy it – it might just be a mosaic!

Reference

Grkovic S, Traversa MV, Livingstone M, McArthur SJ. Clinical re-biopsy of segmental gains-the primary source of preimplantation genetic testing false positives. J Assist Reprod Genet. 2022 Jun;39(6):1313-1322. doi: 10.1007/s10815-022-02487-z. Epub 2022 Apr 23. PMID: 35460491; PMCID: PMC9174409.

If you liked this post and want to support what I do, please consider a paid subscription, Patreon or donate through PayPal!

 

---

About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

---