Non-invasive pre-implantation genetic testing of human embryos: an emerging concept

Preimplantation genetic testing for aneuploidy (PGT-A) is widely used to select embryos having normal ploidy for transfer, but they require an invasive embryo biopsy procedure that may cause harm to the embryos and offspring. Therefore, a non-invasive approach to select embryos with normal ploidy for implantation is highly demanded. Non-invasive chromosome screening (NICS) methods have been proposed and applied in clinical practices, but a large-scale validation versus invasive preimplantation genetic testing (PGT) and the whole embryo ploidy has not yet been reported. In this study, by using the whole embryo as a gold standard, we validated NICS assay in a total of 265 donated human embryos and compared its performance with conventional trophectoderm (TE) biopsy PGT. The NICS assay showed promising performance, which is comparable to PGT-TE [sensitivity: 87.36 versus 89.66%; specificity: 80.28 versus 82.39%; negative predictive value (NPV): 91.2 versus 92.86%; positive predictive value (PPV): 73.08 versus 75.73%]. Additionally, NICS provides a scoring system for prioritizing embryo: embryos can be categorized into three groups with euploid prediction probabilities of 90.0, 27.8, and 72.2% for group euploid (A), aneuploid (B), and multiple abnormal chromosomes (MAC) (C), respectively. When an addition of TE assay is provided as a secondary validation, the accuracy significantly increases from 72.2 to 84.3% for group B and from 27.8 to 83.3% for group C. Our results suggest that NICS is a good rule in assay for identifying chromosomal normal embryos for transfer and might serve as a non-invasive approach for prioritizing embryos instead of preventing transfer of aneuploid and MAC embryos. It will help to ensure the safety of offspring and efficient utilization of embryos.

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The Technological Advances in Embryo Selection and Genetic Testing: A Look Back at the Evolution of Aneuploidy Screening and the Prospects of Non-Invasive PGT

Reproductive Medicine ◽

10.3390/reprodmed2010004 ◽

2021 ◽

Vol 2 (1) ◽

pp. 26-34

Author(s):

Channing Burks ◽

Kristin Van Heertum ◽

Rachel Weinerman

Keyword(s):

Genetic Testing ◽

Subsequent Development ◽

Embryo Selection ◽

Human Embryos ◽

Comparative Genomic ◽

Aneuploidy Screening ◽

Preimplantation Genetic Testing ◽

Blastomere Biopsy ◽

Non Invasive ◽

Technological Advances

Since the birth of the first IVF baby, Louise Brown, in 1978, researchers and clinicians have sought ways to improve pregnancy outcomes through embryo selection. In the 1990s, blastomere biopsy and fluorescence in situ hybridization (FISH) were developed in human embryos for the assessment of aneuploidy and translocations. Limitations in the number of chromosomes that could be assayed with FISH lead to the development of comparative genomic hybridization (CGH); however, pregnancy rates overall were not improved. The later development of trophectoderm biopsy with comprehensive chromosome screening (CCS) technologies, as well as the subsequent development of next-generation sequencing (NGS), have shown much greater promise in improving pregnancy and live birth rates. Recently, many studies are focusing on the utilization of non-invasive preimplantation genetic testing (niPGT) in an effort to assess embryo ploidy without exposing embryos to additional interventions.

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Is there still a rationale for non-invasive PGT-A by analysis of cell-free DNA released by human embryos into culture medium?

Human Reproduction ◽

10.1093/humrep/deab042 ◽

2021 ◽

Vol 36 (5) ◽

pp. 1186-1190

Author(s):

Raoul Orvieto ◽

Adva Aizer ◽

Norbert Gleicher

Keyword(s):

Culture Media ◽

Chromosomal Rearrangements ◽

Primary Source ◽

Normal Pregnancy ◽

Early Embryo ◽

Human Embryos ◽

Cell Debris ◽

Cell Free Dna ◽

Non Invasive ◽

Free Dna

Abstract Human embryos utilise an array of processes to eliminate the very high prevalence of aneuploid cells in early embryo stages. Human embryo self-correction was recently demonstrated by their ability to eliminate/expel abnormal blastomeres as cell debris/fragments. A whole genome amplification study has demonstrated that 63.6% of blastocysts expelled cell debris with abnormal chromosomal rearrangements. Moreover, 55.5% of euploid blastocysts expel aneuploid debris, strongly suggesting that the primary source of cell free DNA in culture media is expelled aneuploid blastomeres and/or their fragments. Such a substantial ability to self-correct downstream from the blastocyststage, therefore, renders any chromosomal diagnosis at the blastocyststage potentially useless, and this, unfortunately, also must particularly include non-invasive PGT-A based on cell-free DNA in spent medium. High rates of false-positive diagnoses of human embryos often lead to non-use and/or disposal of embryos with entirely normal pregnancy potential. Before adopting yet another round of unvalidated PGT-A as a routine adjunct to IVF, we here present facts that deserve to be considered.

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NON-INVASIVE PREIMPLANTATION GENETIC TESTING (NIPGT) FOR ANEUPLOIDY AND STRUCTURAL REARRANGEMENTS USING NEXT GENERATION SEQUENCING (NGS) ON SPENT CULTURE MEDIA (SCM)

Fertility and Sterility ◽

10.1016/j.fertnstert.2021.07.609 ◽

2021 ◽

Vol 116 (3) ◽

pp. e224-e225

Author(s):

Dimitra Christopikou ◽

Stephen Davies ◽

Stavroula Zaxaria ◽

Erika Tsorva ◽

Andriani Karagianni ◽

...

Keyword(s):

Genetic Testing ◽

Next Generation Sequencing ◽

Culture Media ◽

Structural Rearrangements ◽

Next Generation ◽

Preimplantation Genetic Testing ◽

Non Invasive ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

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Erratum to “Modelling a risk classification of aneuploidy in human embryos using non-invasive morphokinetics” [Reprod. BioMed. Online 26 (2013) 477–485]

Reproductive BioMedicine Online ◽

10.1016/j.rbmo.2013.04.008 ◽

2013 ◽

Vol 27 (1) ◽

pp. 107 ◽

Cited By ~ 2

Author(s):

Alison Campbell ◽

Simon Fishel ◽

Natalie Bowman ◽

Samantha Duffy ◽

Mark Sedler ◽

...

Keyword(s):

Risk Classification ◽

Human Embryos ◽

Non Invasive

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Is the ‘serious’ factor in germline modification really relevant? A response to Kleiderman, Ravitsky and Knoppers

Journal of Medical Ethics ◽

10.1136/medethics-2019-105744 ◽

2019 ◽

Vol 46 (2) ◽

pp. 151-152 ◽

Cited By ~ 1

Author(s):

Iñigo De Miguel Beriain

Keyword(s):

Genetic Testing ◽

Human Embryos ◽

Human Beings ◽

Preimplantation Genetic Testing ◽

Underlying Factor ◽

Genome Modification ◽

Germline Modification ◽

Serious Disease

Should we use human germline genome modification (HGGM) only when serious diseases are involved? This belief is the underlying factor in the article written by Kleiderman, Ravitsky and Knoppers to which I now respond. In my opinion, the answer to this question should be negative. In this paper, I attempt to show that there are no good reasons to think that this technology should be limited to serious diseases once it is sufficiently proven to be safe and efficient. In fact, opting otherwise would negatively harm human beings’ right to the highest standard of health that unmodified embryos could promote. Therefore, the issue should not be so much to define adequately what a serious disease is, but rather to elucidate whether this concept should play any role beyond the context of preimplantation genetic testing (PGT). This paper argues that we should not accept the similarity between technologies such as PGT and HGGM because they face different challenges and offer totally different possibilities. Therefore, we are in urgent need to build a completely new ethical architecture that covers the application of germline editing in human embryos. As a part of that process, a much deeper debate on the necessity of distinguishing different disease types is required.

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