Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities

Abstract

Embryonic mosaicism, defined as the presence of karyotypically distinct cell lines within an embryo, has been frequently reported with a high incidence in preimplantation embryos derived from IVF and is thought to be one of the major biological limitations for the routine application of PGD for aneuploidies (PGD-A). The incidence of mosaicism in preimplantation embryos is in fact reported to be between 4 and 90%. However, these data are in sharp contrast with what is known from clinical pregnancies, where true foetal mosaicism is observed in less than 0.5% of cases. Here, we challenge these previous observations in preimplantation embryos, presenting an alternative perspective, which also considers the impact of technical variation to diagnose mosaicism as one possible cause contributing to overestimation of the incidence of mosaicism in embryos. Although euploid/aneuploid mosaicism may be present in blastocysts, the possibility of detecting this phenomenon within a single trophectoderm biopsy represents a contemporary challenge to bring about improvement to the practice of PGD-A. The purpose of this opinion paper is to provide a critical review of the literature, provide a possible alternative interpretation of the data, and discuss future challenges with diagnosing mosaicism in PGD-A cycles.

Keywords: ICSI outcome; IVF; PGD PGS; chromosomal abnormalities; embryo selection; mosaicism.

Figure 1

Proposed model for the strength of evidence when studying mosaicism in cleavage and blastocyst stage embryos. Even though one aneuploidy or two inconsistent aneuploidies provides a lower level of reliability it has been the most common criteria for defining mosaicism in preimplantation embryos. The highest level of evidence for identifying genuine mosaicism is a double biopsy and blinded analysis showing reciprocal aneuploidies. In this case the influence of technical errors is expected to be marginal. Despite being the primary method for clinical diagnosis by many laboratories, intermediate log2 ratios represents the lowest strength of evidence for true mosaicism.

Figure 2

Summary of data from relevant CCS studies on the cytogenetic constitution of ICM and TE samples from disaggregated human blastocysts. No sign of preferential allocation or confinement of chromosomally abnormal cells to the TE or ICM lineage was observed. The fact that results were almost identical for samples from the TE and ICM indicates that data obtained from a sample of a few cells biopsied from the blastocyst TE can generally be considered representative of the ICM chromosomal complement. Data taken from Northrop et al. (2010), Fragouli et al. (2008), Johnson et al. (2010) and Capalbo et al. (2014).