Novel Research Details Incidence of Ploidy Abnormalities

DENVER — Genetic testing and algorithms revealed that over 1% of more than 96,000 blastocyst-stage embryos had ploidy abnormalities, or atypical numbers of chromosomes.

In total, ploidy abnormalities were detected in 1.15% (CI 95% 1.0-1.2) of embryos after clinical pre-implantation genetic testing, of which 0.9% were triploidy (embryos with an extra set of chromosomes), 0.2% were haploidy (missing a set of chromosomes), and 0.05% were isodiploidy (both sets of chromosomes come from one parent), reported Ludovica Picchetta, MSc, of Juno Genetics in Rome, during a presentation at the American Society for Reproductive Medicine annual meeting.

“Human pre-implantation embryos are routinely screened for single chromosomal aneuploidies using pre-implantation genetic testing for aneuploidy (PGT-A),” Picchetta told MedPage Today. However, embryos can be affected by more complex abnormalities on the whole haploid set of chromosomes, which are “highly detrimental to embryo development and are rarely seen in later stages.”

Hence, Picchetta and her team sought to better understand the origins of ploidy abnormalities. Using PGT-A and targeted next-generation sequencing (NGS), the researchers “discovered that over 1% of embryos resulting from normal fertilization have a ploidy abnormality.”

Specifically, among 41 triploid embryos, 94.6% had maternal origin, with 26.8% due to meiosis I errors and 73.2% due to meiosis II errors. Maternal age, which is already known to be a risk factor for aneuploidy, was found to also be a risk factor for triploid conceptions.

Meanwhile, 85.7% of the 14 haploid embryos had an absence of paternal genome.

Normal embryos have one set of maternal chromosomes and one set of paternal chromosomes. “Haploidy typically occurred due to the absence of a paternal genome, while triploidy and isodiploidy were primarily caused by errors during the female meiotic divisions,” Picchetta explained.

In addition, triploid embryos with lower numbers of recombination, the genetic exchange that occurs during meiosis, were more prone to additional aneuploidies. Seventeen percent of triploid embryos had no recombination events and they were more likely to have additional aneuploidies compared with those with normal recombination.

“This suggests that a lack of recombination during maternal meiosis may contribute to triploid conceptions,” Picchetta said.

She concluded that the team’s findings “underscore the importance of including ploidy testing alongside standard aneuploidy testing, especially for women of advanced maternal age,” which “could help identify embryos with ploidy abnormalities early on.”

Rachel Weinerman, MD, an ob/gyn and reproductive endocrinologist at Case Western Reserve University in Cleveland, who was not involved in the study, told MedPage Today that this research proves “that you can get a lot of information from embryos that we don’t typically test for in PGT-A.”

“I think having this kind of information can be very helpful for counseling patients as to, ultimately, what is going to optimize their success if they are having recurrent abnormalities in their embryos,” she said.

Weinerman explained that the team used “a sophisticated genetic test that has the option of looking at the specific origin of the chromosomes in the egg to know if it came from the mom or from the dad,” adding that this type of technology is newer and more accurate than previous methods.

She also pointed out that all of the analyzed embryos were made with intracytoplasmic sperm injection (ICSI), in which a single sperm is injected into an egg. Thus, it makes sense that the majority of triploid embryos were maternal triploid, though in conventional insemination, paternal triploid is more common.

On an even more granular level, Weinerman noted that more errors occurred during meiosis II, which doesn’t occur until a sperm fertilizes an egg, and this raises the interesting question “is it an egg and sperm problem, or is it just an egg problem?” For instance, “is this only due to egg quality, or is this due to something about the relationship between the egg and the sperm when they try to join together?”

For this study, Picchetta and team analyzed 96,660 trophectoderm biopsies from ICSI-derived blastocyst-stage human embryos using PGT-A with targeted NGS and single nucleotide polymorphism (SNP) genotyping in order to detect standard aneuploidies as well as ploidy abnormalities. Through testing, they determined the meiotic phase of origin of ploidy abnormalities and assessed recombination events in triploid embryos. SNP microarray and global screening array were used to validate the developed algorithms and to prove biological coherence.

Picchetta noted that a limitation to the study was that all embryos were derived from ICSI and replicating analysis using embryos from traditional in vitro fertilization could lead to more “paternal” defects, such as dispermy. Also, not all embryos in the study were confirmed as two pronuclei through time-lapse microscopy; some were classified based on static observation, though Picchetta said she does not anticipate that would wildly change the findings because of the study’s large sample size.