Non-invasive Pre-implantation Genetic Testing of Human Embryos

An Emerging Concept

C. Farra; F. Choucair; J. Awwad


Hum Reprod. 2018;33(12):2162-2167. 

In This Article

Abstract and Introduction


The accurate genetic screening of pre-implantation embryos currently entails the use of technically challenging and biologically invasive biopsies of the human embryos. Investigating a more conservative sampling approach has emerged as a timely and desired alternative. Circulating cell-free embryonic DNA is present in the blastocoel fluid and spent culture media of blastocysts, and this has lately been sought as an attractive source of genetic information. The genetic analysis of cell-free embryonic DNA has been reported, to be useful in evaluating the genetic constitution of embryos; thus, providing a potential alternative to conventional biopsy-derived pre-implantation genetic testing (PGT). In this review, we have summarized these non-invasive alternative applications of PGT and discussed their current limitations and future clinical implications


It is estimated that about 20–80% of human embryos are chromosomally aneuploid (Hassold and Hunt, 2001; Vera-Rodriguez et al., 2015). This phenomenon is the result of meiotic and mitotic developmental errors and appears to occur at a much higher frequency in humans than in experimental animals (Bond and Chandley, 1983). Established means of pre-implantation embryo genetic profiling entail the collection of embryo-derived material for genetic testing. Many studies on Day-3 embryo biopsies showed reassuring long-term neonatal outcomes (Desmyttere et al., 2008; Liebaers et al., 2009), and no significant differences in developmental morbidities and major congenital abnormalities among children born from biopsied embryos compared to children normally conceived (Nekkebroeck et al., 2008; Harper et al., 2012). The safety profile of conventional pre-implantation genetic testing (PGT), however, has been contested by other investigators in view of reports suggesting that the invasive removal of cells from pre-implantation embryos may interfere with embryonic development. Besides from invasive disruptive handling, embryo biopsies also require dedicated equipment and highly trained personnel, which amount to a measurable commitment in time and cost. Taken together, while embryo biopsy remains the cornerstone for PGT, interest in investing non-invasive alternatives seems very timely, reasonable and could improve the cost-efficiency and safety of the procedure.

Although first detected in adult blood in 1948 (Mandel, 1948), cell-free DNA has recently gained scientific interest. The isolation of cell-free DNA of fetal origin in the peripheral blood of pregnant women (Lo et al., 1997) has revolutionized the field of prenatal aneuploidy screening and has been established as the primary source of genetic information for non-invasive prenatal testing (Huppertz and Kingdom, 2004). More recently, human embryos were demonstrated to release DNA fragments into their environment (Assou et al., 2014). Cell-free DNA has been recovered from blastocoel fluid (BF) and spent culture media, but their significance to the embryonic genome has not been fully elucidated (Assou et al., 2014; Wu et al., 2015). The recognition of these nucleic acids in combination with improved genetic sequencing technology could prove to be the key elements required for a major breakthrough in the concept of non-invasive pre-implantation genetic testing (NI-PGT).