Delivery of a chromosomally normal child from an oocyte with reciprocal aneuploid polar bodies

Scott, Richard T.; Treff, Nathan R.; Stevens, John; Forman, Eric J.; Hong, K.H.; Katz‐Jaffe, Mandy G.; Schoolcraft, William B.

doi:10.1007/s10815-012-9746-6

Cited by 28 publications

(5 citation statements)

References 16 publications

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“…This resulted in a normal chromosome 13 complement in the embryo ( Fig. 2c ), a spontaneous correction similar to what has previously been observed 23 . Thus, information of both polar bodies is required to infer maternal aneuploidies in the fertilized zygote.…”

Section: Resultssupporting

confidence: 82%

“…In order to apply this technology to an aneuploid embryo, the specific trisomy would need to be detected prior to CRISPR/Cas9 injection. Embryos with a potential trisomy due to errors in maternal meiosis could be identified by polar body analyses, which is feasible and compatible with live birth 23 . While the first polar body can be biopsied at fertilization, the second becomes available within 4-5h after fertilization.…”

Section: Discussionmentioning

confidence: 99%

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DNA Double Strand Breaks cause chromosome loss through sister chromatid tethering in human embryos

Turocy

Marin

et al. 2022

Preprint

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Genome editing by DNA double-strand breaks (DSB) is currently being investigated as a tool to treat or even prevent heritable diseases. However, DNA repair mechanisms in the human embryo remain poorly understood and DSBs may result in chromosome loss. Here we provide evidence of whole and segmental chromosome loss in over one third of chromosomes 16, 17 and X targeted by CRISPR/Cas9-induced DNA DSB, including pericentromeric and mid-arm sites. Chromosomal changes were asymmetric relative to the Cas9 cut site: segmental losses occurred on both centric as well as acentric chromosome arms, while gains were exclusively found on acentric arms, suggesting that centromeres in broken chromosomes continued to mediate sister chromatid separation. Using this pattern of chromosomal errors, we were able to define new genomic coordinates of the active centromere on chromosome 16. Asymmetry was also found in the attrition of gDNA at the break site: attrition occurred centromeric of the DSB, while telomeric to the break, chromosomal ends were protected. Thus, spindle forces at centromeres and end tethering and protection at DSBs are antagonistic forces that interfere with accurate segregation of sister chromatids. Thereby, a single DSB is sufficient to result in the loss of a chromosome from the embryo. These results highlight the risks of aneuploidy in CRISPR/Cas9 genome editing, while also providing a mechanism for mitotically acquired aneuploidy caused by DNA breaks in human embryos.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

DNA Double Strand Breaks cause chromosome loss through sister chromatid tethering in human embryos

Turocy

Marin

et al. 2022

Preprint

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show abstract

“…With comprehensive screening of both polar bodies, cases in which there are isolated reciprocal aneuploidies with normal segregation of all other chromosomes in maternal meiosis have an opportunity to produce a euploid embryo. A case report was recently published in which a euploid embryo that had a loss of chromosome 21 in the first polar body and a balancing gain in the second polar body was transferred and delivered, indicating that these embryos can possess reproductive potential (Scott et al ., 2012). …”

Section: Introductionmentioning

confidence: 99%

Embryos whose polar bodies contain isolated reciprocal chromosome aneuploidy are almost always euploid

et al. 2012

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STUDY QUESTIONWhen a chromosome aneuploidy is detected in the first polar body and a reciprocal loss or gain of the same chromosome is detected in the second polar body, is the resulting embryo usually aneuploid for that chromosome?SUMMARY ANSWERWhen reciprocal aneuploidy occurs in polar bodies, the resulting embryo is usually normal for that chromosome, indicating that premature separation of sister chromatids (PSSC)—not non-disjunction—likely occurred in meiosis I.WHAT IS KNOWN ALREADYSingle-nucleotide polymorphism-based microarray analysis can be used to accurately determine the chromosomal status of polar bodies and embryos. Sometimes, the only abnormality found is a reciprocal gain or loss of one or two chromosomes in the two polar bodies. Prediction of the status of the resulting embryo in these cases is problematic.STUDY DESIGN, SIZE, DURATIONBlinded microarray analysis of previously diagnosed aneuploid embryos that had reciprocal polar body aneuploidy.MATERIALS, SETTING, METHODSIVF cycles were performed between 2008 and 2011 in patients aged 40 ± 3 years (range 35–47 years) with an indication for polar body-based aneuploidy screening. Thirty-five aneuploid vitrified Day 3 embryos were warmed, cultured to Day 5 and biopsied for microarray analysis. Predictions were made for the ploidy status of the embryo if PSSC or non-disjunction had occurred. The signal intensity for the aneuploid chromosome in the first polar body was compared between those that resulted in euploid and aneuploid embryos.MAIN RESULTS AND THE ROLE OF CHANCEAmong 34 embryos with evaluable results, 31 were euploid on re-analysis. Of 43 chromosomes that had reciprocal aneuploidy in the polar bodies, 41 were disomic in the embryo, indicating that PSSC was likely to have occurred 95% (95% confidence interval 85–99%) of the time. The log 2 ratio signal intensity from the chromosomes that underwent non-disjunction, resulting in unbalanced embryos, were outliers when compared with those that underwent PSSC.LIMITATIONS, REASONS FOR CAUTIONAlthough most embryos with reciprocal aneuploid polar bodies were euploid, it is unknown whether they maintain equivalent reproductive potential when transferred. Further study is needed to determine whether these embryos should be re-biopsied and considered for transfer.WIDER IMPLICATIONS OF THE FINDINGSThis study is consistent with increasing evidence that PSSC is the primary cause of meiosis I errors in embryos from women of advanced reproductive age. Clinicians should be cautious in interpreting results from polar body aneuploidy screening, especially when only the first polar body is tested.STUDY FUNDING/COMPETING INTEREST(S)None.

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“…Even if no euploid embryos have been obtained at the blastocyst stage, there is no reason to assume that the limitation of PB screening observed here is unique to abnormal oocytes and embryos of poor prognosis AMA patients. Indeed, it has recently been demonstrated in a younger population that when reciprocal aneuploidy occurs from meiosis I premature separation of sister chromatids and compensation in meiosis II, the resulting embryo is usually normal for that chromosome (Forman et al, 2013) and also capable of producing a chromosomally normal child (Scott et al, 2012b). However, we agree that the reproductive potential of these embryos should be further evaluated.…”

mentioning

confidence: 60%

Reply: Questions about the accuracy of polar body analysis for preimplantation genetic screening

Capalbo

Bono²,

Spizzichino³

et al. 2013

Human Reproduction

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Delivery of a chromosomally normal child from an oocyte with reciprocal aneuploid polar bodies

Cited by 28 publications

References 16 publications

DNA Double Strand Breaks cause chromosome loss through sister chromatid tethering in human embryos

DNA Double Strand Breaks cause chromosome loss through sister chromatid tethering in human embryos

Embryos whose polar bodies contain isolated reciprocal chromosome aneuploidy are almost always euploid

Reply: Questions about the accuracy of polar body analysis for preimplantation genetic screening

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