Clinical Re-biopsy of Segmental Gains-the Primary Source of Preimplantation Genetic Testing False Positives

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2022 Apr 23

PMID 35460491

Authors

Steve Grkovic

Maria V Traversa

Mark Livingstone

Steven J McArthur

Affiliations

Soon will be listed here.

Abstract

Purpose: Does re-biopsy of blastocysts classified as abnormal (ABN) due to segmental aneuploidy (SA) have clinical utility?

Methods: The live birth (LB) outcomes of mosaic SAs, compared to other categories, were determined after transfer of 3084 PGT-A tested blastocysts. An initial 12-month trial thawed 111 blastocysts classified as ABN due to a SA for clinical re-biopsy, with an additional 58 from a subsequent 16-month revised protocol. Where re-biopsy failed to corroborate the original classification, blastocysts were reported as mosaic and suitable for clinical use.

Results: Segmental mosaics had a LB rate (54.1%) which was indistinguishable from that of euploid (53.7%). Numeric mosaics had statistically significant (P < 0.05) reduced LB rates compared to euploid, with high-level numerics (19.2%) also exhibiting a significant reduction compared to low level (42.3%). Of the initial 111 blastocysts with SAs, 85 could be re-biopsied. Segmental gains became suitable for re-biopsy at a high rate (90.9%), with 84.2% (16/19) of these reclassified as mosaic. Only 73.0% of deletions and complex changes were suitable for re-biopsy, of which 73.0% (46/63) were confirmed ABN. The subsequent 16-month period primarily focused on gains, confirming the high rate at which they can be reclassified as clinically useable.

Conclusions: Blastocysts harboring mosaic segmental duplications, rather than SAs in general, are the primary source of false-positive PGT-A results and represent a category with a LB rate similar to that of euploid. A high degree of confidence in the reliability of PGT-A results can be maintained by performing confirmatory clinical TE biopsies.

Citing Articles

Healthy live births achieved from embryos diagnosed as non-mosaic segmental aneuploid.

Besser A, Weidenbaum E, Buldo-Licciardi J, McCaffrey C, Grifo J, Blakemore J J Assist Reprod Genet. 2024; 41(12):3379-3385.

PMID: 39384706 PMC: 11707125. DOI: 10.1007/s10815-024-03282-8.

Comparison of euploid blastocyst expansion with subgroups of single chromosome, multiple chromosome, and segmental aneuploids using an AI platform from donor egg embryos.

Hori K, Hori K, Kosasa T, Walker B, Ohta A, Ahn H J Assist Reprod Genet. 2023; 40(6):1407-1416.

PMID: 37071320 PMC: 10310614. DOI: 10.1007/s10815-023-02797-w.

References

Neal S, Sun L, Jalas C, Morin S, Molinaro T, Scott Jr R . When next-generation sequencing-based preimplantation genetic testing for aneuploidy (PGT-A) yields an inconclusive report: diagnostic results and clinical outcomes after re biopsy. J Assist Reprod Genet. 2019; 36(10):2103-2109. PMC: 6823328. DOI: 10.1007/s10815-019-01550-6. View

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View

Warburton D . De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet. 1991; 49(5):995-1013. PMC: 1683246. View

Traversa M, Carey L, Leigh D . A molecular strategy for routine preimplantation genetic diagnosis in both reciprocal and Robertsonian translocation carriers. Mol Hum Reprod. 2010; 16(5):329-37. DOI: 10.1093/molehr/gaq013. View

Magli M, Albanese C, Crippa A, Terzuoli G, La Sala G, Tabanelli C . Permanence of de novo segmental aneuploidy in sequential embryo biopsies. Hum Reprod. 2020; 35(4):759-769. DOI: 10.1093/humrep/deaa025. View

Treff N, Franasiak J . Detection of segmental aneuploidy and mosaicism in the human preimplantation embryo: technical considerations and limitations. Fertil Steril. 2016; 107(1):27-31. DOI: 10.1016/j.fertnstert.2016.09.039. View

Babariya D, Fragouli E, Alfarawati S, Spath K, Wells D . The incidence and origin of segmental aneuploidy in human oocytes and preimplantation embryos. Hum Reprod. 2017; 32(12):2549-2560. DOI: 10.1093/humrep/dex324. View

McArthur S, Leigh D, Marshall J, Gee A, De Boer K, Jansen R . Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. Prenat Diagn. 2008; 28(5):434-42. DOI: 10.1002/pd.1924. View

Zhou S, Cheng D, Ouyang Q, Xie P, Lu C, Gong F . Prevalence and authenticity of de-novo segmental aneuploidy (>16 Mb) in human blastocysts as detected by next-generation sequencing. Reprod Biomed Online. 2018; 37(5):511-520. DOI: 10.1016/j.rbmo.2018.08.006. View

10.

Victor A, Tyndall J, Brake A, Lepkowsky L, Murphy A, Griffin D . One hundred mosaic embryos transferred prospectively in a single clinic: exploring when and why they result in healthy pregnancies. Fertil Steril. 2019; 111(2):280-293. DOI: 10.1016/j.fertnstert.2018.10.019. View

11.

Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C . Chromosome instability is common in human cleavage-stage embryos. Nat Med. 2009; 15(5):577-83. DOI: 10.1038/nm.1924. View

12.

Zhang S, Tan K, Gong F, Gu Y, Tan Y, Lu C . Blastocysts can be rebiopsied for preimplantation genetic diagnosis and screening. Fertil Steril. 2014; 102(6):1641-5. DOI: 10.1016/j.fertnstert.2014.09.018. View

13.

Srebniak M, Joosten M, Knapen M, Arends L, Polak M, van Veen S . Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017; 51(4):445-452. DOI: 10.1002/uog.17533. View

14.

Giardino D, Corti C, Ballarati L, Colombo D, Sala E, Villa N . De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn. 2009; 29(3):257-65. DOI: 10.1002/pd.2215. View

15.

Veerappa A, V Suresh R, Vishweswaraiah S, Lingaiah K, Murthy M, Manjegowda D . Global patterns of large copy number variations in the human genome reveal complexity in chromosome organization. Genet Res (Camb). 2015; 97:e18. PMC: 6863650. DOI: 10.1017/S0016672315000191. View

16.

Girardi L, Serdarogullari M, Patassini C, Poli M, Fabiani M, Caroselli S . Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos. Am J Hum Genet. 2020; 106(4):525-534. PMC: 7118577. DOI: 10.1016/j.ajhg.2020.03.005. View

17.

Navratil R, Horak J, Hornak M, Kubicek D, Balcova M, Tauwinklova G . Concordance of various chromosomal errors among different parts of the embryo and the value of re-biopsy in embryos with segmental aneuploidies. Mol Hum Reprod. 2020; 26(4):269-276. PMC: 7187872. DOI: 10.1093/molehr/gaaa012. View

18.

De Vos A, Van Landuyt L, De Rycke M, Verdyck P, Verheyen G, Buysse A . Multiple vitrification-warming and biopsy procedures on human embryos: clinical outcome and neonatal follow-up of children. Hum Reprod. 2020; 35(11):2488-2496. DOI: 10.1093/humrep/deaa236. View

19.

Cram D, Leigh D, Handyside A, Rechitsky L, Xu K, Harton G . PGDIS Position Statement on the Transfer of Mosaic Embryos 2019. Reprod Biomed Online. 2019; 39 Suppl 1:e1-e4. DOI: 10.1016/j.rbmo.2019.06.012. View

20.

Lawrenz B, El Khatib I, Linan A, Bayram A, Arnanz A, Chopra R . The clinicians´ dilemma with mosaicism-an insight from inner cell mass biopsies. Hum Reprod. 2019; 34(6):998-1010. DOI: 10.1093/humrep/dez055. View