Abstract
PurposeA subset of preimplantation stage embryos may possess mosaicism of chromosomal constitution, representing a possible limitation to the clinical predictive value of comprehensive chromosome screening (CCS) from a single biopsy. However, contemporary methods of CCS may be capable of predicting mosaicism in the blastocyst by detecting intermediate levels of aneuploidy within a trophectoderm biopsy. This study evaluates the sensitivity and specificity of aneuploidy detection by two CCS platforms using a cell line mixture model of a mosaic trophectoderm biopsy.MethodsFour cell lines with known karyotypes were obtained and mixed together at specific ratios of six total cells (0:6, 1:5, 2:4, 3:3, 4:2, 5:1, and 6:0). A female euploid and a male trisomy 18 cell line were used for one set, and a male trisomy 13 and a male trisomy 15 cell line were used for another. Replicates of each mixture were prepared, randomized, and blinded for analysis by one of two CCS platforms (quantitative polymerase chain reaction (qPCR) or VeriSeq next-generation sequencing (NGS)). Sensitivity and specificity of aneuploidy detection at each level of mosaicism was determined and compared between platforms.ResultsWith the default settings for each platform, the sensitivity of qPCR and NGS were not statistically different, and 100 % specificity was observed (no false positives) at all levels of mosaicism. However, the use of previously published custom criteria for NGS increased sensitivity but also significantly decreased specificity (33 % false-positive prediction of aneuploidy).ConclusionsBy demonstrating increased false-positive diagnoses when reducing the stringency of predicting an abnormality, these data illustrate the importance of preclinical evaluation of new testing paradigms before clinical implementation.
Highlights
Comprehensive methods for preimplantation aneuploidy screening have become a common part of infertility care
Considerable attention has been given to the ability of contemporary comprehensive chromosome screening (CCS) platforms to detect mosaicism
There are many factors to consider [17, 18], including predictive value of the biopsy for the remaining embryo and for actual clinical outcomes, the limits of detection when mosaicism is present within an individual trophectoderm biopsy, the developmental fate of different diploid/aneuploid compositions, and the chromosome specific and monosomy/trisomy-specific impact on development
Summary
Comprehensive methods for preimplantation aneuploidy screening have become a common part of infertility care. The use of preimplantation screening (PGS) and the ability to diagnose aneuploidy of all 24 human chromosomes and improvement in the accuracy of amplification strategies represent important advancements that have clearly improved outcomes when applied to embryo selection strategies for patients undergoing IVF treatment [1,2,3,4]. The observed improvements in clinical outcomes are based on the simple fact that approximately one third of human preimplantation embryos are chromosomally abnormal. In some cases, post-fertili zation mitotic errors in chromosome segregation have been observed [5]. These errors lead to chromosomal mosaicism within the developing embryo and represent a complex
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