Preimplantation Genetic Testing for Single Gene Conditions and Aneuploidy

Abstract

It is now over 30 years since the first pregnancies and live births following IVF, embryo biopsy and preimplantation genetic testing (PGT) were reported in 1990. Since then, methods for genetic analysis at the single-cell level have evolved alongside the rapid advances in human genetics and sequencing of the human genome. With the development of methods for whole genome amplification, such as multiple displacement amplification (MDA), genome-wide analysis is now possible. This has led to the development of microarray or next generation sequencing (NGS) based methods for genome-wide haplotyping of parental chromosomes in embryo samples and enabled universal linkage-based testing for monogenic diseases combined with molecular cytogenetic analysis of chromosome abnormalities. These comprehensive methods have also recently been exploited to calculate polygenic risk scores for common multifactorial conditions, such as diabetes, cardiovascular disease, and cancer. Although controversial, polygenic risk scoring may have a role for reducing residual risk of breast cancer, for example, in combination with PGT for pathogenic variants. Finally, there is now evidence that cell-free DNA in spent culture medium at the blastocyst stage may originate from nuclear DNA shedding from the trophectoderm. In the future, therefore, it may be possible to use this cell-free DNA for genome-wide analysis and comprehensive PGT to avoid embryo biopsy.