Technologies in Reproductive Screening and Diagnosis SIG Update

Natalie Chandler, FRCPath, PhD
Francesca Romana Grati, MSCs, PhD

Co-Chairs, Technologies in Reproductive Screening and Diagnosis SIG

Following the long COVID-related delay, it was great that we were finally able to come together (whether in person or virtually) at the ISPD 2022 Technologies in Reproductive Screening and Diagnosis SIG breakfast. Thank you to all those that attended the meeting. The session started with a talk from Prof. Sandi Deans who gave an update on the EQA schemes offered by GENQA, demonstrating that the range of schemes available is increasing with the complexity of genetic testing now offered in the prenatal setting. Prof. Yuval Yaron then gave a talk on expanded carrier screening with the need for all individuals to be offered the same test irrespective of self-reported ethnicity and the pros and cons of targeted vs NGS tests. Finally, Prof. Brynn Levy gave an overview of the optical genome mapping technique and how it gives higher resolution than karyotyping and array, down to gene level, with clinical examples where this has had an impact. Brynn informed us that a study is being launched looking at the use of optical genome mapping in prenatal diagnosis, and we look forward to hearing the outcomes of that study.

There were also two technology-based post-conference workshops. The first was on exome sequencing. Talks in this session encompassed the principles of exome sequencing in the prenatal setting, the newly published ISPD Position Statement on the use of genome‐wide sequencing for prenatal diagnosis, assessing the quality of prenatal exome sequencing, the importance of data sharing and the development of a fetal section in the ClinVar database and the value of exome sequencing in obstetric situations other than when anomalies are identified in fetuses by imaging. The session concluded with some cases and a panel discussion which highlighted the many challenges encountered when offering these services. This is rapidly developing area as indicated by numerous publications including two special editions of the prenatal diagnosis journal (Fetal Sequencing: Progress, Challenges and the Future (part 1); Fetal Sequencing: Progress, Challenges and the Future (part 2)). Not everything could be covered within this workshop, therefore we recommend anyone with an interest in this field to have a look at these special issues.

The second workshop was on the hot topics in 2022 of Non Invasive Prenatal Testing (NIPT).  Talks in this session encompassed the new developments in cell-free and cell-based non-invasive prenatal screening and diagnosis, including the expanded possibilities to screen for whole genome aneuploidy and offer prenatal diagnosis for monogenic disorders. In addition, approaches for diagnostic confirmation after a high risk NIPT result, consequences of the diagnosis of fetal disorders with universal cfDNA testing and informational and counseling needs were also covered. Publications regarding some of these talks can be consulted as open access resources (  ; ).

Another standout talk from the conference was the Pioneer Award lecture from Prof. Dennis Lo, who discussed the discoveries from his laboratory in relation to “fragmentomics” and the detection of longer cell free fetal DNA fragments. Prof. Lo then went on to demonstrate how these discoveries can be applied to for the non-invasive diagnosis of single gene disorders. For more information on this work please see Yu et al. (2021) (Single-molecule sequencing reveals a large population of long cell-free DNA molecules in maternal plasma | PNAS).

Away from the conference, we would like to draw your attention to a systematic evidence review (SER) on evaluating NIPS/T performance in a general-risk population that has been published by ACMG (Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies. Genet Med. 2022 Jul;24(7):1379-1391 and Genet Med. 2022 Sep;24(9):1992).

In addition to the detection of common trisomies (T21, T18, T13), studies examining detection of sex chromosome aneuploidies (SCA), rare autosomal trisomies (RAT), copy number variants (CNV), maternal conditions, no results as well as studies assessing the psychological and economic impact of NIPS, the rate of subsequent diagnostic testing and the change in birth rates have been included. Performance in singleton and multifetal pregnancies for the different chromosomal conditions have been also reviewed.

This SER reports:

  • High performance of NIPS/T to screen for the common trisomies in a general population

  • NIPS/T is also effective and accurate for SCA

  • The performance of NIPS is significantly poorer when targeting RATs and CNVs; for RATs, this is mainly due to the rarity and the insufficient data available to properly develop a method that can distinguish between clinically relevant RATs found in the fetus vs confined placental mosaicism.

Interestingly, numerous limitations have been highlighted regarding the quality of the studies included in the review which identify interesting areas of improvements for future clinical studies and when reviewing manuscripts submitted for publication from such studies during peer-review. These are:

  • Difficulties in distinguishing between low- and high-risk cohorts in individual studies;

  • Variable initial gestational ages for testing;

  • Lack of information due incomplete follow up to identify TNs and FNs through diagnostic testing;

  • Fetal outcomes and newborn phenotype mostly relied on assessment methodologies that may introduce error;

  • Absence of standardization of laboratory techniques used, including sequencing methods, or cutoffs for test failures or screen positives;

  • Limited ability of comparisons between studies, because there is no standardized testing method, fetal fraction cutoffs and calculation methods;

  • Limited studies with economic analyses and evaluating the psychosocial outcome of individuals undergoing NIPS

Conducting appropriate studies to address all this missing information, including a comprehensive ascertainment of clinical outcomes to calculate the TN rate, would help to develop best practice guidelines and improve patient care.

On another note, we would like to alert ISPD members of the Community options within ISPD. Under each Special Interest Group is a Community tab option (Technologies in Reproductive Screening and Diagnosis SIG - International Society for Prenatal Diagnosis. You can log in and start a discussion topic. There will be links and additional resources added to the library over time. This could be a great support during these uncertain times!