Clinical use of monopronucleated zygotes following blastocyst culture and preimplantation genetic screening, including verification of biparental chromosome inheritance

Bradley, Cara K.; Traversa, M.; Hobson, Natalie; Gee, Alison; McArthur, Steven J.

doi:10.1016/j.rbmo.2017.03.013

Cited by 41 publications

(59 citation statements)

References 36 publications

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“…(2013) showing no significant differences in euploidy rates between Day-3 embryos from 0PNs, 1PNs and 2PNs. More recent findings show that aneuploidy rates did not differ significantly between 1PN and 2PN blastocysts (39.3 versus 36.5%, respectively) ( Bradley et al , 2017 ) and no significant difference between euploid 0PN and 2PN PGT-M blastocysts ( Yao et al , 2016 ). Collectively, these observations further strengthen the argument in favour of their use in IVF.…”

Section: Discussionmentioning

confidence: 89%

“…More importantly in cycles where only 0PN-derived embryos were available their transfer yielded pregnancies, which resulted in the birth of healthy babies ( Manor et al , 1996 ; Yin et al , 2016 ). Similarly to 0PNs, successful development to term has been reported following transfers of 1PN-derived embryos ( Staessen et al , 1993 ; Dasig et al , 2004 ; Itoi et al , 2015 ; Bradley et al , 2017 ; Mateo et al , 2017b ) and previous cytogenetic analyses report the detection of 1PN diploid embryos albeit with high variabilty (2.2–80.5%, reviewed in Rosenbusch (2014 )). Several groups have thus advocated that a considerable loss of zygotes can be overcome by implementing a genetic analysis technology to confirm bi-parental diploidy in the embryos developing from 0PN and 1PN zygotes ( Levron et al , 1995 ; Li et al , 2015 ; Bradley et al , 2017 ; Capalbo et al , 2017 ; Mateo et al , 2017a , b ).…”

Section: Introductionmentioning

confidence: 89%

“…Genome-wide technologies such as array comparative genomic hybridization (aCGH) or low pass next generation sequencing (NGS) which are routinely used for embryonic aneuploidy testing (PGT-A) cannot map ploidy anomalies because normalization eliminates ploidy information. Therefore, recent exploratory studies opted for complementary strategies (first line and second line) such as the combined use of aCGH/NGS and short tandem repeat (STR) analysis or targeted NGS coupled with quantitative PCR (qPCR) to obtain proof of bi-parental diploidy ( Bradley et al , 2017 ; Capalbo et al , 2017 ). Both studies provide further evidence that PN number scoring is an inefficient tool for embryonic ploidy prediction.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide haplotyping embryos developing from 0PN and 1PN zygotes increases transferrable embryos in PGT-M

et al. 2018

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STUDY QUESTIONCan genome-wide haplotyping increase success following preimplantation genetic testing for a monogenic disorder (PGT-M) by including zygotes with absence of pronuclei (0PN) or the presence of only one pronucleus (1PN)?SUMMARY ANSWERGenome-wide haplotyping 0PNs and 1PNs increases the number of PGT-M cycles reaching embryo transfer (ET) by 81% and the live-birth rate by 75%.WHAT IS KNOWN ALREADYAlthough a significant subset of 0PN and 1PN zygotes can develop into balanced, diploid and developmentally competent embryos, they are usually discarded because parental diploidy detection is not part of the routine work-up of PGT-M.STUDY DESIGN, SIZE, DURATIONThis prospective cohort study evaluated the pronuclear number in 2229 zygotes from 2337 injected metaphase II (MII) oocytes in 268 cycles. PGT-M for 0PN and 1PN embryos developing into Day 5/6 blastocysts with adequate quality for vitrification was performed in 42 of the 268 cycles (15.7%). In these 42 cycles, we genome-wide haplotyped 216 good quality embryos corresponding to 49 0PNs, 15 1PNs and 152 2PNs. The reported outcomes include parental contribution to embryonic ploidy, embryonic aneuploidy, genetic diagnosis for the monogenic disorder, cycles reaching ETs, pregnancy and live birth rates (LBR) for unaffected offspring.PARTICIPANTS/MATERIALS, SETTING, METHODSBlastomere DNA was whole-genome amplified and hybridized on the Illumina Human CytoSNP12V2.1.1 BeadChip arrays. Subsequently, genome-wide haplotyping and copy-number profiling was applied to investigate the embryonic genome architecture. Bi-parental, unaffected embryos were transferred regardless of their initial zygotic PN score.MAIN RESULTS AND THE ROLE OF CHANCEA staggering 75.51% of 0PN and 42.86% of 1PN blastocysts are diploid bi-parental allowing accurate genetic diagnosis for the monogenic disorder. In total, 31% (13/42) of the PGT-M cycles reached ET or could repeat ET with an unaffected 0PN or 1PN embryo. The LBR per initiated cycle increased from 9.52 to 16.67%.LIMITATIONS, REASONS FOR CAUTIONThe clinical efficacy of the routine inclusion of 0PN and 1PN zygotes in PGT-M cycles should be confirmed in larger cohorts from multicenter studies.WIDER IMPLICATIONS OF THE FINDINGSGenome-wide haplotyping allows the inclusion of 0PN and 1PN embryos and subsequently increases the cycles reaching ET following PGT-M and potentially PGT for aneuploidy (PGT-A) and chromosomal structural rearrangements (PGT-SR). Establishing measures of clinical efficacy could lead to an update of the ESHRE guidelines which advise against the use of these zygotes.STUDY FUNDING/COMPETING INTEREST(S)SymBioSys (PFV/10/016 and C1/018 to J.R.V. and T.V.), the Horizon 2020 WIDENLIFE: 692065 to J.R.V., T.V., E.D., A.D. and M.Z.E. M.Z.E., T.V. and J.R.V. co-invented haplarithmisis (‘Haplotyping and copy-number typing using polymorphic variant allelic frequencies’), which has been licensed to Agilent Technologies. H.M. is fully supported by the (FWO) (ZKD1543-ASP/16). The authors have no competing interests to declare.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Genome-wide haplotyping embryos developing from 0PN and 1PN zygotes increases transferrable embryos in PGT-M

et al. 2018

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“…In PGD programs it is not uncommon for embryos to fail genetic testing, and in our own clinic we have previously reported a failure rate of 5.0% from more than 5,000 PGS blastocysts with the use of CGH or NGS (17). This is similar to others, including Capalbo et al who reported a failure rate of 2.7% from almost 1,000 PGS blastocysts with the use of CGH (24) and Minasi et al who reported a failure rate of 4.9% from 1,122 blastocysts screened for inherited genetic disorders in combination with PGS using CGH (25).…”

Section: Discussionmentioning

confidence: 89%

“…Blastocyst biopsies were screened for chromosome content (for both the detection of gross aneuploidy in PGS patients as well as the detection of malsegregants for translocation PGD patients) as described previously (17). In brief, DNA was amplified with the use of the Sureplex whole genome amplification kit (Rubicon Genomics), then analyzed by means of CGH with the use of either Agilent 60K oligonucleotide microarrays (Agilent Technologies) or Bluegnome 24 Sure BAC arrays (Illumina), or alternatively by NGS performed with the use of the Veriseq PGS kit and Miseq sequencer (Illumina).…”

Section: Preimplantation Genetic Screeningmentioning

confidence: 99%