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Is the Polar Body Approach Best for Preimplantation Genetic Screening?

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Is the Polar Body Approach Best for Preimplantation Genetic Screening? Joy Delhanty Department of Obstetrics and Gynaecology University College London London, UK Declared no potential conflict of interest Is the polar body approach best for preimplantation genetic screening? Joy Delhanty Director,UCL Centre for PGD Institute for Women’s Health, UCL London, UK Preimplantation genetic screening Aim: To select oocytes or embryos with the optimal chance of giving an ongoing pregnancy by eliminating those with detectable chromosomal anomalies Material: • First polar body +/- second PB • Single blastomere from cleavage embryo - day 3 • Clump of cells from trophectoderm of blastocyst - day 5 Aneuploidy in female gametes May arise at several stages: • During mitotic divisions prior to meiosis • At anaphase of meiosis I - non-disjunction of whole chromosomes; anaphase lag • At anaphase of meiosis II - non-disjunction of chromatids; anaphase lag Array CGH - Ist and 2nd PBs - Fragouli et al., 2011 Mol Hum Reprod - online April 14th • 308 oocytes • 70 women average age 40.8yrs (34-47) • Aneuploidy rate 70% (1st & 2nd PB results) - after MI 40% abnormal - after MII 50% abnormal • MI errors - whole chromosome errors: 86 • Chromatid errors: 143 (62%) • Concluded need to test both PBs to detect all aneuploidy The contribution of mitotic versus post-zygotic aneuploidy • By day 3, 60% of IVF embryos have at least one abnormal cell • Evidence from CGH analysis suggests an average of 30% of cleavage embryos have meiotic errors • At blastocyst, 56% of embryos chromosomally abnormal for mean maternal age of 38 years • Again, 30% meiotic errors found, and overall 33% were mosaic (Fragouli & Wells, CGR, 2011) • At both stages, substantial proportion of post-zygotic events lead to aneuploidy The principles of polar body diagnosis • With few exceptions, analysis of 1st PB will predict chromosome status of mature Metaphase II oocyte • Gain of chromosome material in 1st PB will be mirrored by reciprocal loss in MII oocyte • Loss of material in 1st PB will predict gain in the MII oocyte Biopsied cell(s) Biopsied cell(s) DNA Whole genome amplification Combined labelled & control and biopsied cell(s) DNA Control DNA Biopsied cell(s) DNA A. B. Metaphase Array CGH CGH 1:1 3:2 1:2 Normal Trisomy Monosomy Normal Monosomy Trisomy Bu. M1 oocyte - euploid Ki. Oocyte. Female, +6, +22 , +X (3 chromatids) Ki. PB: -6, -22, -X (but only missing 1 chromatid) Array CGH of 1st PBs - Gabriel et al., 2011. J.Med. Genet. 48:433-7 Array CGH • 164 1st PBs ONLY • 25 women - average age: 40.1 (29-50) • Overall aneuploidy rate: 52.4% • Chromosome errors: 20 • Chromatid errors: 236 (92%) • Concluded whole chromosome non-disjunction not the predominant mechanism CGH analysis - Ist and 2nd PBs - Fragouli et al., 2011 Mol Hum Reprod - online April 14th Metaphase CGH • 308 oocytes • 70 women average age 40.8yrs (34 - 47) • Aneuploidy rate 70% (1st & 2nd PB results) - after MI 40% abnormal - after MII 50% abnormal • MI errors - whole chromosome errors: 86 • Chromatid errors: 143 (62%) • Concluded need to test both PBs to detect all aneuploidy Unexpected findings • Chromatid errors are far more common than whole chromosome errors • Meiosis II errors are at least as common as meiosis I errors • Both likely to be in part due to the advanced age of the patient groups Implications of the unexpected findings • Even if errors involving single chromatids can be detected in the 1st PB, the outcome wrt the chromosome status of the zygote cannot be predicted until after 2nd PB formation - post fertilisation • Expected that 50% of chromatid errors found in 1st PB will not lead to an abnormal zygote • Failure to test the 2nd PB will result in non - detection of 50% of errors Conclusions • Biopsy and analysis of the 1st PB alone may improve success rate of IVF in women at increased risk of meiotic aneuploidy • But greater accuracy and efficiency will be gained by inclusion of 2nd PB testing. • PB testing will not detect post-zygotic errors; trophectoderm biopsy may be the method of choice where several embryos are likely to reach this stage .
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