The clinicians´ dilemma with mosaicism—an insight from inner cell mass biopsies

Lawrenz, Barbara; Khatib, Ibrahim El; Liñán, Alberto; Bayram, A; Arnanz, Ana; Chopra, Rupali; Munck, N De; Fatemi, Human M.

doi:10.1093/humrep/dez055

Cited by 51 publications

(39 citation statements)

References 45 publications

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“…In addition, 147 embryos were from patients who had an abnormal karyotype were used for analysis of positive controls. 36 2018 May 24 NGS Whole blastocyst NGS Tsuiko 37 2018 June 14 NGS ICM NGS Popovic 38 2018 July 58 NGS TE/ICM NGS Chuang 39 2018 December 29 NGS TE/ICM NGS Victor 16 2019 January 100 NGS TE/ICM NGS Victor 40 2019 February 8 NGS TE/ICM NGS Popovic 41 2019 April 45 NGS Blastocyst outgrowth NGS Lawrenz 42 2019 June 84 NGS TE/ICM NGS Huang 43 2019 July 50 NGS Whole blastocyst NGS Treff 44 2019 August 14 NGS TE SNP array Munne 45 2020 January 57 NGS TE NGS Ou 46 2020 January 63 NGS Whole blastocyst NGS Sachdev 47 2020 February 32 NGS TE/ICM NGS Girardi 9 2020 March 88 NGS TE/ICM NGS Navratil 48 2020 April 75 NGS TE/Whole blastocyst NGS Rubio 49 2020 May 64 NGS ICM NGS Lin 50 2020 June 41 NGS ICM NGS Abbreviations: aCGH, array comparative hybridization; CGH, comparative genomic hybridization; ICM, inner cell mass; NGS, next-generation sequencing; qPCR, quantitative real-time PCR; PGT-A, preimplantation genetic testing for aneuploidy; SNP, single nucleotide polymorphism; TE, trophectoderm.…”

Section: Resultsmentioning

confidence: 99%

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

Marín

Treff

2020

Prenatal Diagnosis

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Preimplantation genetic testing for aneuploidy (PGT-A) reduces miscarriage risk, increases the success of IVF, shortens time to pregnancy, and reduces multiple gestation rates without compromising outcomes. The progression of PGT-A has included common application of next-generation sequencing (NGS) from single nucleotide polymorphism microarray, quantitative real-time PCR, and array comparative hybridization platforms of analysis. Additional putative advances in PGT-A capability include classifying embryos as mosaic and predicting the presence of segmental imbalance. A critical component in the process of technical validation of these advancements involves evaluation of concordance between reanalysis results and initial testing results. While many independent studies have investigated the concordance of results obtained from the remaining embryo with the original PGT-A diagnosis, compilation and systematic analysis of published data has not been performed. Here, we review results from 26 primary research articles describing concordance in 1271 human blastocysts from 2260 pairwise comparisons. Results illustrate significantly higher discordance from PGT-A methods which utilize NGS and include prediction of mosaicism or segmental imbalance. These results suggest caution when considering new iterations PGT-A.

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Section: Resultsmentioning

confidence: 99%

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

Marín

Treff

2020

Prenatal Diagnosis

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“…Mosaic values in iPGT-A ranged from 2% to 50% ( Orvieto et al ., 2016 ; Huang et al ., 2017 ; Popovic et al ., 2018 ; Chuang et al . 2018 ; Tsuiko et al ., 2018 : Lawrenz et al ., 2019 ; Victor et al ., 2019b ), even with the use of the NGS platform and relatively similar populations. Munné et al .…”

Section: Discussionmentioning

confidence: 99%

Relationship between age and blastocyst chromosomal ploidy analyzed by noninvasive preimplantation genetic testing for aneuploidies (niPGT-A)

Vagnini

Petersen

Renzi

et al. 2020

JBRA

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Objective: To assess the relationship between human blastocyst chromosomal ploidy established by niPGT-A and increasing age. Methods: This is a prospective multicenter study carried out by ten assisted reproduction centers after their embryologists acquired training and validated their results with the previous use of niPGT-A. A total of 94 couples with indication for niPGT-A due to increase maternal age, male factor, repeated implantation failures, recurrent abortion or because they requested niPGT-A were included in this study. The couples had no karyotype abnormalities. After ICSI, the embryos were cultured until blastocyst stage using one or two step culture systems, single or sequential media respectively, at 37ºC in an atmosphere of 6-7% CO2 and 5-20% O2 incubators. On day 3, we re-evaluated cleavage embryos to complete cumulus cells removal. The embryos were then cultured in individual well, with 20µl of medium under oil until they reached blastocyst stage. The blastocysts were vitrified and stored in liquid nitrogen. After that, the spent blastocyst culture medium (20µl) was transferred to a PCR tube and sent for analysis in the genetic laboratory, where it was stored at -80ºC until sequencing. A total of 243 samples of spent blastocyst culture medium were collected on the 5th/6th day. Cell-free DNA secreted on culture medium was amplified using NICS Sample Preparation Kit (Yikon Genomics), based on the MALBAC technology. After whole genome amplification, the DNA was measured using a Qubit 2.0 fluorometer and subjected to next generation sequencing (NGS) using Illumina MiSeq ® platform. The data were analyzed using the ChromGo ® software (Yikon Genomics). Results: The mean age of the patients was 38±4.08 years with an interval of 20-44 years. The euploid was diagnosed in 36.4% (80/220) of cases, aneuploidy in 31.3% (69/220), and mosaicism in 32.3% (71/220; with ≥60% aneuploidy) of blastocysts. Mosaic values ranged from 29.8% to 33.8% in different age groups. Individually, the most frequent chromosomal abnormality was XXY (Klinefelter Syndrome) occurring in 18 cases, followed by chromosome 21 (trisomy/monosomy) in 8 cases. The niPGT-A data showed a ≥60% incidence of aneuploid cells in all cases of chromosomal mosaicism (n=71). Conclusion: A high degree of mosaicism with aneuploidy cells was detected, and some hypotheses were suggested for this data (niPGT-A sensitivity in detecting the self-correction of chromosomal abnormalities phenomenon). However, it did not vary remarkably with age. On the other hand, euploidy levels had a negative correlation with age and aneuploidy levels had a positive relationship. This is the first report in the literature to relate chromosomal ploidy in blastocysts using niPGT-A and increasing patient age.

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“…A study by Sachdev and colleagues investigated 32 blastocysts and calculated per chromosome concordances between TE biopsy and ICM biopsy, determining rates of 99.5% for euploid results, 97.3% for aneuploid results, but only 35.2% for mosaic results [134]. A study by Lawrenz and colleagues compared PGT-A results from three biopsies for each of the 84 embryos included in the study: one blastomere biopsy, one TE biopsy, and one ICM biopsy [135]. The ploidy concordance between the blastomere and ICM was 69.8% for aneuploidy and 90.3% for euploidy, but concordance was higher between TE and ICM, namely 92.5% for aneuploidy and 93.2% for euploidy.…”

Section: How Reliable Is Pgt-a?mentioning

confidence: 99%

Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements

Viotti

2020

Genes

106

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There is a high incidence of chromosomal abnormalities in early human embryos, whether they are generated by natural conception or by assisted reproductive technologies (ART). Cells with chromosomal copy number deviations or chromosome structural rearrangements can compromise the viability of embryos; much of the naturally low human fecundity as well as low success rates of ART can be ascribed to these cytogenetic defects. Chromosomal anomalies are also responsible for a large proportion of miscarriages and congenital disorders. There is therefore tremendous value in methods that identify embryos containing chromosomal abnormalities before intrauterine transfer to a patient being treated for infertility—the goal being the exclusion of affected embryos in order to improve clinical outcomes. This is the rationale behind preimplantation genetic testing for aneuploidy (PGT-A) and structural rearrangements (-SR). Contemporary methods are capable of much more than detecting whole chromosome abnormalities (e.g., monosomy/trisomy). Technical enhancements and increased resolution and sensitivity permit the identification of chromosomal mosaicism (embryos containing a mix of normal and abnormal cells), as well as the detection of sub-chromosomal abnormalities such as segmental deletions and duplications. Earlier approaches to screening for chromosomal abnormalities yielded a binary result of normal versus abnormal, but the new refinements in the system call for new categories, each with specific clinical outcomes and nuances for clinical management. This review intends to give an overview of PGT-A and -SR, emphasizing recent advances and areas of active development.

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The clinicians´ dilemma with mosaicism—an insight from inner cell mass biopsies

Cited by 51 publications

References 45 publications

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

Relationship between age and blastocyst chromosomal ploidy analyzed by noninvasive preimplantation genetic testing for aneuploidies (niPGT-A)

Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements

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