The plans for this year’s NIPT and PGT conferences, like many others, were quickly derailed by the COVID-19 pandemic. The ESHG and ESHRE Annual Meetings were moved to virtual space and even though the format was a new experience, the science did not disappoint. Here we will share some of the highlights from the sessions.
ESHG 2020.2 Virtual Event
The number of presentations in the Reproductive Health area has been increasing during the last few years at the ESHG meetings, and this year was no different with three sessions dedicated to Reproductive Health:
- What to expect from Prenatal Diagnostics?
- From carrier screening to Infertility and Fetal Diagnostics
- Embryo and Placenta: Equal Partners
There was also an industry symposium from PerkinElmer that discussed their NIPT solution using the Vanadis system. A number of posters were presented on the topic of NIPT and PGT testing, new methods, analytical approaches, implementation of testing in different countries, and LGC SeraCare presented a poster discussing our newest NIPT reference materials.
Sequence or not to sequence? What is the value of WGS/WES in prenatal diagnostics?
One of the most debated topics was the future beyond the NIPT as we know it now and the clinical utility of prenatal whole-genome sequencing (WGS). The questions centered around how many conditions are resolved by WGS, reporting of incidental findings, and most critical of all – would the huge amount of information lead to better clinical care? Let’s look at some of the arguments presented.
WGS as well as whole-exome sequencing (WES) are both technically possible from prenatal amniocentesis samples. They are both already carried out in a limited number of cases. So, what do the results suggest? A Prenatal Assessment of Genomes and Exomes (PAGE) study1 that carried out WES in cases of fetal structural anomalies detected by ultrasound, showed a diagnostic yield of 8 to 10%. An inclusion of probably diagnostic variants in addition to known pathogenic variants increased the diagnostic yield to 12.5%. However, the ability to diagnose a condition seems to vary between studies and in an earlier talk during the same symposium, Professor Deborah Krakow mentioned 62 to 80% diagnostic yields in prenatal WES when used for bone dysplasias. In fact, according to her, WES was more successful at identifying an underlying cause of dysplasia than panels. The obvious disparity between the diagnostic yields is not unexpected. Structural anomalies detected by ultrasound frequently involve multiple organs and do not have to be the result of single gene disorders.
The ethical issues of prenatal testing and use of new technologies were discussed by Professor Yael Hashiloni-Dolev. She raised the issue of whether increased testing is leading to improvement of patient care. This discussion around Pandora’s Pregnancy2 was extremely important by showing that an increased drive to more advanced technologies in prenatal testing does not necessarily translate into more definitive and actionable health information.
Among the reproductive health highlights from the meeting, were presentations by Dr. Alka Chaubey from PerkinElmer and Dr. Barbara Pasini from the University of Turin. They discussed the implementation of the Vanadis system for NIPT testing, addressing both the cost and ease of deployment that is frequently indicated as a barrier by the labs offering such testing or wanting to implement it.
ESHRE 2020 Virtual Event
The annual ESHRE meeting also had many great presentations. Those that were most interesting to me related to the application of NGS in screening, testing and diagnostics. A number of sessions discussed preimplantation genetic testing (PGT):
- PGT consortium data summary for 2018
- Reproductive (Epi) genetics 1 and 2
- Cooper Surgical industry workshop discussing their newest improvements in PGT-A testing
- Poster session on PGT
- COVID-19 in early pregnancy
The opening PGT presentation came from the ESHRE PGT consortium summarizing 2018 data from participating centers. This very comprehensive review was packed with data submitted by the member institutions. It discussed what tests are performed and technologies involved as well as outcomes of embryo transfers following PGT testing. The data from 2018 was compared to 2017. One of the less-expected observations was that while PGT-A (preimplantation genetic testing for aneuploidies) and PGT-M (preimplantation genetic testing for monogenic disorders) consistently account for over 70% of preimplantation screening, there was a slight decrease in reports of PGT-A tests performed in 2018 vs 2017. This has been in part, attributed to the way the reporting has been done and thus changes are coming to simplify it and increase reporting from participating laboratories.
Some of the highlights from other sessions:
- The mechanisms of changes in fertility with age were presented by Dr. Jennifer Gruhn3. She discussed how the alterations in chromosome separation affect fertility. The weakening of chromosomal connections with age is leading to the loss of centromeric cohesion affecting small and medium chromosomes. On the other hand, the whole chromosome non-disjunction of larger chromosomes is mainly found in younger females.
- Embryo mosaicism is a very important topic for PGT and assisted reproductive technologies (ART). Mosaicism is not uncommon; however, it can affect an outcome of embryo transfer. The important question is if mosaic embryos should be transferred or not? In general, they have not been considered useful or suitable for transfer. Francesca Spinella, from Genoma, presented work on mosaicism in embryos, indicating that whole chromosome mosaics have the most negative outcomes.
- An emerging trend in PGT analysis is the development and increasing use of non-invasive PGT methods. Four of the poster presentations used PGT-A with culture media as a sample source for DNA testing. However, a very different method was presented by Overture Life in two posters describing a metabolomic analysis of the spent media to predict embryo viability.
COVID-19 and pregnancy
As the COVID-19 pandemic continues, more questions emerge about the effects of the SARS-CoV-2 infection on women’s health. Mindful of the Zika infection's effects on fetal development, both patients and clinicians are searching for answers. The key question is whether the virus can be transmitted to the fetus through the placenta. Dr. Gulam Bahadur from the North Middlesex University Hospital NHS Trust, presented data that at this moment, we cannot dismiss the possibility of a vertical transmission of SARS-CoV-24. What is needed currently is prevention of infection in pregnant women and more data on pregnancy outcomes and infection status of the newborns.
As the pandemic was developing, telemedicine usage was increasing. The needs of pregnant women have to be particularly recognized. Dr. Meenakshi Choudhary outlined the best practices of managing women undergoing fertility treatment during the last day’s discussion on COVID-19 in pregnancy. These practices are not limited to just Artificial Reproductive Technology (ART) pregnancies but are applicable to all pregnancies during the pandemic. Being able to support women by utilizing telemedicine and only bringing them into the hospital when essential, can reduce their risk of infection. Dr. Scott Nelson from the University of Glasgow and Fertility Partnership showed how strict testing for SARS-CoV-2 by RT-PCR and serology, across all the sites, helped them provide a safer environment for patients and staff.
What are the takeaways for Reproductive Health from ESHG and ESHRE?
PGT methods continue to evolve with more developments in non-invasive PGT. Mosaisicm remains the main unsolved problem for PGT methods. The discussion though continues about suitability of implanting mosaic embryos. The main argument is centered around the fact that current sampling methods rely on biopsies of trophoblasts which can be mosaic, but the embryo can still be completely normal. The key to a successful embryonic development here seems to be in the level of mosaicism identified in embryos.
NIPT continues to expand but many groups are now looking beyond the traditional NIPT into WES/WGS for diagnostics of fetal anomalies identified in prenatal screening. Interestingly, many poster presentations focused on improving quality and reproducibility of prenatal screening methods. These posters focused on evaluation of sample storage and impact of extraction method on cfDNA quality but also on bioinformatic analysis of the data from NGS-based NIPT methods.
As we look beyond basic testing and into implementing WES/WGS for prenatal testing, there will be many challenges to overcome and we will need to standardize various steps of the process to improve diagnostic yield. Additionally, there are many ethical and legal questions regarding fetal or newborn WES/WGS applications.
- Lord, J. et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393, 747–757 (2019), PMID: 30712880.
- Hashiloni-Dolev, Y., Nov-Klaiman, T. & Raz, A. Pandora’s pregnancy: NIPT, CMA, and genome sequencing—A new era for prenatal genetic testing. Prenat. Diagn. 39, 859–865 (2019), PMID: 31161621.
- Zielinska, A. P. et al. Meiotic Kinetochores Fragment into Multiple Lobes upon Cohesin Loss in Aging Eggs. Curr. Biol. 29, 3749-3765.e7 (2019), PMID: 31679939.
- Bahadur, G. et al. Adverse outcomes in SAR-CoV-2 (COVID-19) and SARS virus related pregnancies with probable vertical transmission. Jornal Brasileiro de Reproducao Assistida 24 351–357 (2020), PMID: 32662955.