Defining the limits of detection for chromosome rearrangements in the preimplantation embryo using next generation sequencing

Cuman, Carly; Beyer, C; Brodie, D.; Fullston, Tod; Lin, Jane I.; Willats, Elissa; Zander-Fox, Deirdre; Mullen, J. A.

doi:10.1093/humrep/dey227

Cited by 17 publications

(14 citation statements)

References 17 publications

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“…Preimplantation genetic testing for structural rearrangements (PGT-SR) is performed only when a patient or her partner is known to carry a balanced rearrangement, otherwise, routine preimplantation genetic testing for aneuploidy (PGT-A) is performed (9)(10)(11)(12)(13)(14). Approximately 1/500 individuals carry a balanced chromosomal rearrangement, and this frequency is approximately 1/100 in the in vitro fertilization (IVF) patient population (5,(15)(16)(17)(18).…”

mentioning

confidence: 99%

Criteria to evaluate patterns of segmental and complete aneuploidies in preimplantation genetic testing for aneuploidy results suggestive of an inherited balanced translocation or inversion

Snider¹,

Darvin²,

Spor³

et al. 2021

F&S Reports

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Objective: To define criteria for determining when preimplantation genetic testing for aneuploidy (PGT-A) results are suggestive of a potential balanced chromosomal rearrangement in the egg or sperm source and warrant karyotyping. Design: Performance evaluation of criteria developed to assess PGT-A results for patterns of imbalances suggestive of a balanced chromosomal rearrangement in the egg or sperm source. Setting: A single PGT-A laboratory and multiple in vitro fertilization centers. Patients: Reproductive couples who underwent routine PGT-A testing. Interventions: Karyotyping of reproductive couples for whom patterns of imbalances observed in PGT-A results suggested a balanced chromosomal rearrangement in the egg or sperm source. Main Outcome Measures: Correct or incorrect flagging of predicted translocation in either the egg or sperm source based on chromosome analysis. Results: Proposed criteria correctly predicted a balanced reciprocal translocation in 97% of cases (n ¼ 33), a (13;14) Robertsonian translocation in all cases (n ¼ 3), and an inversion in all cases (n ¼ 2). Other criteria evaluated were determined to be ineffective because of relatively low occurrences that met the criteria and/or low predictive value. Conclusions: Our results showed that the proposed criteria were effective for evaluating patterns of imbalances observed in PGT-A results suggestive of a potential chromosomal rearrangement in the egg or sperm source. Our proposed criteria can be employed by clinicians in the in vitro fertilization setting in combination with a patient's reproductive history to identify PGT-A patients who are likely carriers of balanced chromosomal rearrangements. (Fertil Steril Rep Ò 2021;2:72-9. Ó2020 by American Society for Reproductive Medicine.

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mentioning

confidence: 99%

Criteria to evaluate patterns of segmental and complete aneuploidies in preimplantation genetic testing for aneuploidy results suggestive of an inherited balanced translocation or inversion

Snider¹,

Darvin²,

Spor³

et al. 2021

F&S Reports

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“…Both array-CGH and NGS have been designed for calling whole chromosome abnormalities and even though the manufacturer states the limit of detection to be 20 Mb, other groups have reportedly validated the technology for the detection of segmental aneuploidies < 20 Mb [13][14][15]. Our group has similarly validated the detection of segmental aneuploidies below 10 Mb [5]. Therefore, for patients with chromosome rearrangements involving translocated segments < 20 Mb (such as the current case study), the best platform to use will depend on the chromosome regions involved and the results of in-house validation.…”

Section: Chromosome 19mentioning

confidence: 79%

“…next-generation sequencing (NGS) or array comparative genomic hybridisation) did not have the resolution required to detect the smaller segments that would result from this translocation (i.e. 659 kb and 7.8 Mb) [5]. As a result, Karyomapping was investigated.…”

Section: Test Validation/feasibilitymentioning

confidence: 99%

Preimplantation genetic testing using Karyomapping for a paternally inherited reciprocal translocation: a case study

Beyer

Lewis

Willats

et al. 2019

J Assist Reprod Genet

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Purpose Preimplantation genetic testing (PGT) using Karyomapping is used to screen embryos for single gene disorders prior to implantation. While Karyomapping is not designed to screen for abnormalities in chromosome copy number, this testing is based upon a genome-wide analysis of single nucleotide polymorphisms (SNP) and, as such, some chromosome abnormalities are detected. The aim of this study was to validate whether Karyomapping could provide reliable and accurate PGT for a paternal 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. Methods Feasibility/validation for PGT was performed using DNA from the couple, as well as DNA from the paternal parents and from a previous unbalanced pregnancy. Karyomapping was performed using Illumina's HumanKaryomap-12 BeadChip microarray technology. SNP analysis was performed using BlueFuse Multi software (Illumina). Transmission of the translocation was assessed through the analysis of SNP markers on the chromosome regions of interest. Results PGT-SR was determined to be feasible as chromosomal SNP analysis could reliably distinguish normal/balanced outcomes from all unbalanced outcomes. The couple transferred a normal/balanced embryo in an elective single embryo transfer procedure following 2 IVF/PGT-SR cycles. A clinical pregnancy was achieved. Conclusion This is the first report of PGT-SR test validation using Karyomapping for a 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. Karyomapping may offer a means of detecting unbalanced forms of chromosome rearrangements when other PGT platforms fail.

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“…Nonetheless, a relatively rough resolution (10Mb) assured the detection capability of confirming newborns with normal chromosomal profiles, that is, providing an opportunity to those slightly abnormal embryos for self-correction. In 2018, a study pointed out the ability to detect a segmental aneuploidy of <10 Mb is not guaranteed and multiple other factors must be taken into account when using the technology for an inherited segmental change (28). The low Kappa values that reflected the predictive value for chromosomal profiles between TE biopsies and born baby confirmed the possible self-correction mechanisms during the development of embryos.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Concordance between the Baby Produced by Preimplantation Genetic Testing Embryo and the Trophectoderm Biopsy: a Retrospective Study

Yao¹,

Wang²,

Zeng³

et al. 2021

Preprint

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BackgroundChromosomal mosaicism and aneuploidies are routine phenomena throughout human pre- and post-implantation development. The benefit of implanting mosaicism or aneuploidies is still controversial. The purposes of the study are to investigate the developmental potential of embryos with chromosomally segmental or mosaic abnormalities, and whether precise Next Generation Sequencing (NGS) resolution would reduce the development of an abnormal embryo in preimplantation genetic testing (PGT) cycles.MethodsThe peripheral blood of 17 PGT babies were collected for single nucleotide polymorphism (SNP) array and were compared with trophectoderm (TE) biopsy results at different NGS resolutions.Results76.5% (13/17) of babies’ peripheral blood chromosome analysis was consistent with 10Mb TE biopsies and 58.8% (10/17) of babies’ analysis was consistent with 4Mb TE biopsies. 2 babies who had euploid TE showed abnormal peripheral blood chromosome analysis. 17.6% (3/17) embryos with aberrant TE biopsies produced healthy babies. Although the sensitivity of 10Mb was lower than 4Mb (25% vs. 50%), the specificity (100% vs. 76.9%), PPV (100% vs. 40%) and diagnostic accuracy (82.4% vs. 70.6%) of 10Mb showed better results than 4Mb.Conclusion(s)The chromosomal results between peripheral blood samples and TE biopsies of born babies are not completely congruent. Aneuploid and mosaic embryos have potential to produce healthy babies, whereas normal embryos also have chance to produce babies with chromosomal abnormalities. In spite of low sensitivity of both resolutions, 10Mb has higher specificity, PPV and diagnostic accuracy than 4Mb. It is suggested that TE biopsy be analyzed in both 10Mb and 4Mb resolutions to uncover severely adverse chromosomal aberrations but use 10Mb resolution to guide transfer.Trial registrationThe study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100042522).

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Defining the limits of detection for chromosome rearrangements in the preimplantation embryo using next generation sequencing

Abstract: N/A.

Cited by 17 publications

References 17 publications

Criteria to evaluate patterns of segmental and complete aneuploidies in preimplantation genetic testing for aneuploidy results suggestive of an inherited balanced translocation or inversion

Criteria to evaluate patterns of segmental and complete aneuploidies in preimplantation genetic testing for aneuploidy results suggestive of an inherited balanced translocation or inversion

Preimplantation genetic testing using Karyomapping for a paternally inherited reciprocal translocation: a case study

Chromosomal Concordance between the Baby Produced by Preimplantation Genetic Testing Embryo and the Trophectoderm Biopsy: a Retrospective Study

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