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The application of sensitive genetic technologies, capable of detecting mutations and chromosome abnormalities in minute tissue samples (and even single cells), has provided an unprecedented insight into the molecular mechanisms governing the earliest stages of human development. In a clinical context, the utilisation of these methods has allowed detection of disease causing mutations and aneuploidies in preimplantation embryos generated using in vitro fertilisation (IVF) technology, assisting patients seeking to avoid the transmission of serious inherited conditions and also aiding infertile couples hoping to maximise the chances of achieving a viable pregnancy when having IVF treatment. Preimplantation genetic testing (PGT), as this approach is known, has undergone much development during the thirty years that it has been available and continues to evolve. There has been increasing interest in the analysis of embryonic DNA found in the medium in which the embryo is cultured or in the fluid that fills the blastocoel cavity at the blastocyst stage of development. The aim is to use this material to perform a genetic assessment of the embryo, thereby avoiding the need to biopsy any of its cells. In theory, this should significantly reduce the costs of PGT related to equipment and labour and eliminate any risk to the embryo associated with biopsy. Methods for non-invasive PGT (niPGT) are still in being optimised, but thus far reported accuracy rates have been inferior to those achieved using embryo biopsy. It is clear that further technical development is needed if non-invasive methods of genetic testing are to replace or supplement traditional forms of PGT. Another way to reduce the costs of PGT is to harness powerful new DNA sequencing technologies in order to create methods that allow the detection of multiple pathogenic mutations with a single protocol. Taken to its ultimate extent, this could involve sequencing of the entire genome of the embryo biopsy specimens, although this remains relatively expensive at the current time. While such an approach could deliver a comprehensive genetic evaluation of a patient’s embryos, there are technical challenges, not only with the generation of accurate sequence data, but also with the clinical interpretation of any variants detected. The possibility that the entire genome of embryos could be revealed, and that the information could be used to select one for transfer to the uterus over another, also raises ethical concerns. Controversially, PGT has recently been applied to polygenic disorders, where combinations of genetic factors each contribute to an overall risk of disease. In most cases, such tests are not diagnostic and instead look at the relative probability of developing disease, which in many cases have a late onset. While PGT for polygenic disorders and the prospect of whole genome sequencing of embryos have been the subjects of much debate, perhaps the most ethically challenging development in the field of preimplantation genetics concerns the potential clinical application of genome editing technologies. Such methods hold great promise as a means to correct inherited mutations associated with serious conditions and would allow the discard of affected embryos to be avoided. However, the safety of these methods remains to be determined and application at the preimplantation stage is especially controversial due to the high likelihood that the germinal cells would be altered, meaning that any changes would be transmitted to future generations. Genome editing has enormous research and clinical potential, but more work is needed to confirm its safety, efficacy and ethical desirability when applied to gametes and preimplantation embryos.

Original publication

DOI

10.1016/B978-0-12-816561-4.00016-8

Type

Chapter

Book title

Human Reproductive Genetics: Emerging Technologies and Clinical Applications

Publication Date

01/01/2020

Pages

255 - 269