Mosaicism: What We Know, What We Don’t Know

By Jenna Miller — June 16, 2020

5 min read

Embryonic chromosomal mosaicism has been one of the hottest topics in the ART community for the past few years. Opinions about mosaicism are many and varied. As CooperGenomics’ clinical science liaison, clinicians frequently ask me for help navigating this cacophonic environment. How can they sift through all this information to establish sound clinic policies and counsel patients accurately? I tell them that the key is to distinguish fact from conjecture. Here’s a cheat sheet of what we know about mosaicism and what remains to be determined.

Mosaicism is Not New

  • Mosaicism is the presence of two or more distinct populations of cells with different genotypes in the same individual1.
  • General mosaicism was first discovered over 90 years ago2 and mosaic embryos have always existed, both in vitro and in vivo. The only difference now is that we’re aware of it.
  • Mosaicism has been seen for decades in many different medical specialties, including perinatology, pediatrics, and oncology. All cancerous cells are technically a mosaic cell line.
  • Mosaicism is “new” to ART because next generation sequencing, introduced in 2014, is the first PGT-A platform to consistently detect chromosomal mosaicism in embryos.

PGT-A is a Screening Test

  • PGT-A gives risk estimates. Specifically, it estimates the likelihood for an embryo to be successful when transferred. Embryos called euploid have the best chance to result in a live birth, while embryos called aneuploid are very unlikely to give the desired outcome. But PGT-A cannot give absolute, yes-or-no answers about an embryo’s potential. That’s why it’s considered a screening test rather than a diagnostic test.
  • PGT-A assumes that the cells in the trophectoderm (TE) biopsy are representative of the inner cell mass (ICM). Most of the time that’s true, but occasionally it’s not3. Hence mosaicism.
  • Rebiopsy studies indicate that a euploid TE biopsy is highly predictive of a euploid inner cell mass, and an aneuploid TE biopsy is highly predictive of some degree of aneuploidy in the inner cell mass. But mosaic TE biopsies are less predictive of the inner cell mass; the ICM could be euploid, aneuploid, or mosaic as well3.
  • Most PGT-A platforms currently have an estimated 97-98% accuracy rate4. This is determined by the genomic technology’s ability to accurately determine the genetic makeup of the cells in the biopsy. It does not take biopsy representativeness into account.

Rates of Mosaicism Differ by IVF and PGT-A Lab

  • Various PGT-A laboratories report mosaicism at different rates, due to both technical limitations in detection of mosaicism as well as laboratory policies and practices. Mosaicism thresholds in particular play a significant role. For example, at CooperGenomics we are confident in our NGS platform’s ability to accurately detect a mosaic signal from 20%-80%. Other PGT labs with narrower limits for what they’ll call mosaic will report mosaics less often. Labs also set different policies for which chromosomes or copy number variants they will report as mosaic.
  • On the IVF side, different embryology labs can also have widely varying mosaicism rates5. This indicates that specific procedures can influence the likelihood for an embryo to develop a mosaic change. Many lab and treatment factors have been implicated in mosaicism rates, such as stimulation, culture media, pH, temperature, oxygen levels, and laser use. There is not yet a single smoking gun6.
  • More research is needed to determine which factors contribute most strongly to the incidence of embryonic chromosomal mosaicism.

Mosaic Embryos Implant Less, Miscarry More, and Result in Live Births Less Often Than Euploids 

  • Early accounts of healthy babies born from mosaic embryos took the ART world by storm. Clinicians and patients alike began asking in earnest: what is the reproductive potential of a mosaic embryo? Data to answer this question is still incoming, but a handful of studies make one thing clear: mosaic embryos have less reproductive potential than embryos found to be euploid, but they do make babies.
  • Initial studies suggested that mosaic embryos have a 15% ongoing pregnancy rate7,8. More recent research has shown a 30-40% ongoing pregnancy/live birth rate9,10,11,12.
  • Some studies have reported mosaic embryos display a miscarriage rate ranging from 25% to a whopping 56%7,9.
  • Evidence conflicts on the potentials of low vs high level mosaics and segmental vs whole chromosome mosaics8,11.
  • We cannot yet make definitive conclusions about the level of mosaicism, the number of chromosomes with a mosaic finding, or the impact of mosaic aneuploidy on specific chromosomes. Hopefully with time, and more data, these associations will become clearer.

No Data on Long-Term Health Outcomes 

  • The oldest babies born from known mosaic transfers are approximately six years old13.
  • Only a few hundred babies have been born from mosaic transfer and the health and development of these babies is not being routinely tracked.
  • There is currently no evidence that babies born from mosaic embryos have poorer health outcomes.
  • Concrete data on long-term health for these children is likely several years away and at this time we cannot reassure patients about possible health implications for children born from mosaic transfers.

Genetic Counseling is Critical

  • The PGDIS and CoGEN guidelines both emphasize that genetic counseling is critical for those considering mosaic embryo transfer14,15.
  • Genetic counselors can investigate the level of mosaicism seen, the chromosome involved in the mosaicism, what genes are likely impacted, and what (if any) reports of affected individuals or pregnancies exist16.
  • Everyone perceives risk differently. Genetic counselors are trained to help patients explore their own risk tolerance levels. Genetic counselors are particularly adept at melding the science and the psychosocial. That may be the most important skill of all when counseling a patient about mosaic transfer. Genetic counselors really are indispensable in this process.

Clearly much about mosaicism remains unknown. But we know many patients are willing to utilize these mosaic embryos despite having missing information. Hopefully with time, we will have more concrete information to give our patients to help them answer the difficult question: should I transfer my mosaic embryo?


Sources:

1Nusbaum, RL, McInnes, RR, Willard, HF. Genetics in medicine. 7th ed. Philadelphia: Saunders, 2007.

2 Sturtevant, AH. The claret mutant type of Drosophila simulans: a study of chromosome elimination and cell-lineage. Zeitschrift für Wissenschaftliche Zoologie 1929;135:323–356.

3 Popovic, M, Dhaenens, L, Taelman, J, Dheedene, A, Bialecka, M, De Sutter, P, Chuva de Sousa Lopes, SM, Menten, B, Heindryckx, B. Extended in vitro culture of human embryos demonstrates the complex nature of diagnosing chromosomal mosaicism from a single trophectoderm biopsy. Hum Reprod 2019;34(4):758-769.

4 Friedenthal, J, Maxwell, SM, Tiegs, AW, Besser, AG, McCaffrey, C, Munné, S, Noyes, N, Grifo, JA. Clinical error rates of next generation sequencing and array comparative genomic hybridization with single thawed euploid embryo transfer. Eur J Med Genet 2020;63(5): 103852. doi:10.1016/j.ejmg.2020.103852.

5 Sachdev NM, Ribustello L, Liu E, McCulloh DH, Grifo J, Munne S. The rate of mosaic embryos from donor egg as detected by next generation sequencing (NGS) varies by IVF laboratory. Fertil Steril 2016;106:e156–e157.

6 Swain, JE. Controversies in ART: can the IVF lab influence preimplantation embryo aneuploidy? Reprod Biomed Online 2019;39(4):599-607.

7 Fragouli, E, Alfarawati, S, Spath, K, Babariya, D, Tarozzi, N, Borini, A, Wells, D. Analysis of implantation and ongoing pregnancy rates following the transfer of mosaic diploid-aneuploid blastocysts. Hum Genet 2017;136(7):805-819.

8 Spinella, F, Fiorentino, F, Biricik, A, Bono, S, Ruberti, A, Cotroneo, E, Baldi, M, Cursio, E, Minasi MG, Greco E. Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments. Fertil Steril 2018;109(1):77-83.

9 Munne, S, Blazek, J, Large, M, Martinez-Ortiz, PE, Nisson, H, Liu, E, Tarozzi, M, Borini, A, Becker, A, Zhang, J, Maxwell, S, Grifo, J, Babariya, D, Wells, D, Fragouli, E. Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next generation sequencing. Fertil Steril 2017;108(1):62-71.

10 Munne, S, Spinella, F, Grifo, J, Zhang, J, Parriego Beltran, M, Fragouli, E, Fiorentino, F. Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution next generation sequencing – further insights. Eur J Med Gen 2020;63(2):103741.

11 Victor, AR, Tyndall, JC, Brake, AJ, Lepkowsky, LT, Murphy AE, Griffin, DK, McCoy RC, Barnes, FL, Zouves, CG, Viotti, M. One hundred mosaic embryos transferred prospectively in a single clinic: exploring when and why they result in healthy pregnancies. Fertil Steril 2019;111(2):280-293.

12 Viotti, M, Victor, A, Brake, A, Munne, S, Barnes, F, Zouves, C. Mosaic embryos – a comprehensive and powered analysis of clinical outcomes [abstract]. Fertil Steril 2019;112(3): Suppl e33.

13 Greco, E, Minasi, MG, Fiorentino, F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. NEJM 2015;272(21): 2089-90.

14 Preimplantation Genetic Diagnosis International Society. “PGDIS POSITION STATEMENT ON THE TRANSFER OF MOSAIC EMBRYOS IN PREIMPLANTATION GANETIC TESTING FOR ANEUPLOIDY (PGT-A).” PGDIS, 27, May 2019, https://pgdis.org/docs/newsletter_052719.pdf

15 IVF-Worldwide. “COGEN Position Statement on Chromosomal Mosaicism Detected in Preimplantation Blastocyst Biopsies.” https://ivf-worldwide.com/cogen/general/cogen-statement.html

16 Besser, AG, Mounts, EL. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening. Reprod Biomed Online 2017;34(4):369-374.