Chromosomal mosaicism in human embryos: a variant of normal development or pathology?

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Objective: To analyze the current data on chromosomal mosaicism in human embryos and the mechanisms of its formation, as well as its clinical significance in the context of assisted reproductive technologies.

Materials and methods: This is a systematic review of the literature that includes the analysis of the results of preimplantation genetic testing for aneuploidy (PGT-A), data on sequencing of individual embryo cells, and outcomes of cryocycles with mosaic embryo transfer.

Results: Modern diagnostic methods reveal a wide spectrum of chromosomal mosaicisms, depending on the technology used and the interpretation criteria. Sequencing of individual cells demonstrates a high prevalence of mosaicism in human embryos with an average proportion of aneuploid cells of 25%. Self-correction mechanisms include selective apoptosis of aneuploid cells controlled by bone morphogenetic protein (BMP4), preferential division of euploid cells, and slowing proliferation of aneuploid blastomeres. Meta-analysis of 1,106 cryocycles showed no significant differences in reproductive outcomes with mosaicism levels below 50%. Segmental chromosomal abnormalities are associated with more favorable outcomes compared to numerical anomalies. Prenatal diagnosis confirms normal fetal karyotype in 86% of cases following mosaic embryo transfer.

Conclusion: Research findings indicate insufficient diagnostic significance of single trophectoderm biopsy for assessing chromosomal status of the entire embryo. The high frequency of mosaicism and the ability of an embryo to self-correct make it possible to consider a certain level of chromosomal mosaicism as a normal variant of embryonic development. This justifies a revision of the criteria for selecting embryos for transfer, with a greater tolerance for low-level mosaicism.

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作者简介

Guzel Savostina

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

编辑信件的主要联系方式.
Email: g_savostina@oparina4.ru
ORCID iD: 0009-0006-8294-011X

PhD, obstetrician-gynecologist, Department of Assisted Reproductive Technologies, Junior Researcher at the Laboratory of Applied Transcriptomics,
Department of Systems Biology in Reproduction

俄罗斯联邦, 4, Oparina str., Moscow, 117997

Angelika Timofeeva

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: a_timofeeva@oparina4.ru
ORCID iD: 0000-0003-2324-9653

PhD, Head of the Laboratory of Applied Transcriptomics, Department of Systems Biology in Reproduction, Institute of Translational Medicine

俄罗斯联邦, 4, Oparina str., Moscow, 117997

Аlexey Ekimov

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: a_ekimov@oparina4.ru
ORCID iD: 0000-0001-5029-0462

PhD, Head of the Laboratory of Preimplantation Genetic Testing and Genetic Diagnostics

俄罗斯联邦, 4, Oparina str., Moscow, 117997

Svetlana Perminova

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: s_perminova@oparina4.ru
ORCID iD: 0000-0003-4438-1354

Dr. Med. Sci., Professor, Leading Researcher, Department of Assisted Reproductive Technologies

俄罗斯联邦, 4, Oparina str., Moscow, 117997

Tatyana Nazarenko

Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: t_nazarenko@oparina4.ru
ORCID iD: 0000-0002-5823-1667

Dr. Med. Sci., Professor, Head of the Institute of Reproduction, Head of the Department of Assisted Reproductive Technologies

俄罗斯联邦, 4, Oparina str., Moscow, 117997

参考

  1. Boklage C.E. Survival probability of human conceptions from fertilization to term. Int. J. Fertil. 1990; 35(2): 75, 79-94.
  2. Cram D.S., Leigh D., Handyside A., Rechitsky L., Xu K., Harton G. et al. PGDIS position statement on the transfer of mosaic embryos 2019. Reprod. Biomed. Online. 2019; 39(S.1): e1-e4. https://dx.doi.org/10.1016/j.rbmo.2019.06.012
  3. Vera-Rodríguez M., Michel C.-E., Mercader A., Bladon A.J., Rodrigo L., Kokocinski F. et al. Distribution patterns of segmental aneuploidies in human blastocysts identified by next-generation sequencing. Fertil. Steril. 2016; 105(4): 1047-55. https://dx.doi.org/10.1016/j.fertnstert.2015.12.022
  4. Rodrigo L., Clemente-Ciscar M., Campos-Galindo I., Peinado V., Simón C., Rubio C. Characteristics of the IVF cycle that contribute to the incidence of mosaicism. Genes (Basel). 2020; 11(10): 1151. https://dx.doi.org/10.3390/genes11101151
  5. Schmitz J., Watrin E., Lénárt P., Mechtler K., Peters J.M. Sororin is required for stable binding of cohesin to chromatin and for sister chromatid cohesion in interphase. Curr. Biol. 2007; 17(7): 630-6. https://dx.doi.org/10.1016/j.cub.2007.02.029
  6. Kitajima T.S., Kawashima S.A., Watanabe Y. The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis. Nature. 2004; 427(6974): 510-7. https://dx.doi.org/10.1038/nature02312
  7. Webster A., Schuh M. Mechanisms of aneuploidy in human eggs. Trends Cell Biol. 2017; 27(1): 55-68. https://dx.doi.org/10.1016/j.tcb.2016.09.002
  8. Смирнова А.А., Зыряева Н.А., Аншина М.Б. Возрастные изменения и риск хромосомных аномалий в ооцитах человека (обзор литературы). Проблемы репродукции. 2019; 25(2): 16-26. [Smirnova A.A., Zyriaeva N.A., Anshina M.B. Age-related changes and risk of chromosomal incompetence in human oocytes (literature review). Russian Journal of Human Reproduction. 2019; 25(2): 16-26 (in Russian)]. https://dx.doi.org/10.17116/repro20192502116
  9. Harris K., Fitzgerald O., Paul R.C., Macaldowie A., Lee E., Chambers G.M. Assisted reproductive technology in Australia and New Zealand 2014. Sydney: National Perinatal Epidemiology and Statistics Unit, the University of New South Wales; 2016. 85 p. Available at: https://www.unsw.edu.au/content/dam/pdfs/medicine-health/npesu/research-reports/2023-12-npesu/2024-01-Assisted-reproductive-technology-in-Australia-and-New-Zealand-2014.pdf
  10. Moghadam A.R.E., Moghadam M.T., Hemadi M., Saki G. Oocyte quality and aging. JBRA Assist. Reprod. 2022; 26(1): 105-22. https://dx.doi.org/10.5935/1518-0557.20210026
  11. Bolton H., Graham S.J.L., Van der Aa N., Kumar P., Theunis K., Fernandez Gallardo E. et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat. Commun. 2016; 7: 11165. https://dx.doi.org/10.1038/ncomms11165
  12. Yang M., Rito T., Metzger J., Naftaly J., Soman R., Hu J. et al. Depletion of aneuploid cells in human embryos and gastruloids. Nat. Cell Biol. 2021; 23(4): 314-21. https://dx.doi.org/10.1038/s41556-021-00660-7
  13. Taylor T.H., Gitlin S.A., Patrick J.L., Crain J.L., Wilson J.M., Griffin D.K. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum. Reprod. Update. 2014; 20(4): 571-81. https://dx.doi.org/10.1093/humupd/dmu016
  14. Harton G.L., Cinnioglu C., Fiorentino F. Current experience concerning mosaic embryos diagnosed during preimplantation genetic screening. Fertil. Steril. 2017; 107(5): 1113-9. https://dx.doi.org/10.1016/j.fertnstert.2017.03.016
  15. Kahraman S., Cetinkaya M., Yuksel B., Yesil M., Cetinkaya C.P. Birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report. Hum. Reprod. 2020; 35(3): 727-33. https://dx.doi.org/10.1093/humrep/dez309
  16. Maxwell S.M., Colls P., Hodes-Wertz B., McCulloh D.H., McCaffrey C., Wells D. et al. Why do euploid embryos miscarry? A case-control study comparing the rate of aneuploidy within presumed euploid embryos that resulted in miscarriage or live birth using next-generation sequencing. Fertil. Steril. 2016; 106(6): 1414-9. https://dx.doi.org/10.1016/j.fertnstert.2016.08.017
  17. Capalbo A., Poli M., Rienzi L., Girardi L., Patassini C., Fabiani M. et al. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am. J. Hum. Genet. 2021; 108(12): 2238-47. https://dx.doi.org/10.1016/j.ajhg.2021.11.002
  18. Popovic M., Dheedene A., Christodoulou C., Taelman J., Dhaenens L., Van Nieuwerburgh F. et al. Chromosomal mosaicism in human blastocysts: the ultimate challenge of preimplantation genetic testing? Hum. Reprod. 2018; 33(7): 1342-54. https://dx.doi.org/10.1093/humrep/dey106
  19. Viotti M., Victor A.R., Barnes F.L., Zouves C.G., Besser A.G., Grifo J.A. et al. Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use. Fertil. Steril. 2021; 115(5): 1212-24. https://dx.doi.org/10.1016/j.fertnstert.2020.11.041
  20. Макарова Н.П., Екимов А.Н., Кулакова Е.В., Драпкина Ю.С., Сысоева А.П., Краснова Н.А., Калинина Е.А. Особенности мозаицизма у эмбрионов человека в программах лечения бесплодия методами вспомогательных репродуктивных технологий. Акушерство и гинекология. 2021; 7: 144-51. [Makarova N.P., Ekimov A.N., Kulakova E.V., Drapkina Yu.S., Sysoeva A.P., Krasnova N.A., Kalinina E.A. Characteristics of embryonic mosaicism in infertility treatment with assisted reproductive technologies. Obstetrics and Gynecology. 2021; (7): 144-51 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.7.144-151
  21. Zhang L., Wei D., Zhu Y., Gao Y., Yan J., Chen Z.J. Rates of live birth after mosaic embryo transfer compared with euploid embryo transfer. J. Assist. Reprod. Genet. 2019; 36(2): 165-72. https://dx.doi.org/10.1007/s10815-018-1322-2
  22. Girardi L., Figliuzzi M., Poli M., Serdarogullari M., Patassini C., Caroselli S. et al. The use of copy number loads to designate mosaicism in blastocyst stage PGT-A cycles: fewer is better. Hum. Reprod. 2023; 38(5): 981-91. https://dx.doi.org/10.1093/humrep/dead049
  23. Zhai F., Kong S., Song S., Guo Q., Ding L., Zhang J. et al. Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development. Cell Discov. 2024; 10(1): 98. https://dx.doi.org/10.1038/s41421-024-00719-3
  24. Starostik M.R., Sosina O.A., McCoy R.C. Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism. Genome Res. 2020; 30(6): 814-25. https://dx.doi.org/10.1101/gr.262774.120
  25. Zhou F., Wang R., Yuan P., Ren Y., Mao Y., Li R. et al. Reconstituting the transcriptome and DNA methylome landscapes of human implantation. Nature. 2019; 572(7771): 660-4. https://dx.doi.org/10.1038/s41586-019-1500-0
  26. Sheltzer J.M., Torres E.M., Dunham M.J., Amon A. Transcriptional consequences of aneuploidy. Proc. Natl. Acad. Sci. USA. 2012; 109(31): 12644-9. https://dx.doi.org/10.1073/pnas.1209227109
  27. Greco E., Minasi M.G., Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N. Engl. J. Med. 2015; 373(21): 2089-90. https://dx.doi.org/10.1056/NEJMc1500421
  28. Capalbo A., Poli M., Rienzi L., Girardi L., Patassini C., Fabiani M. Mosiac preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am. J. Hum. Genet. 2021; 108(12): 2238-47. https://dx.doi.org/10.1016/j.ajhg.2021.11.002
  29. Rosenbluth E.M., Shelton D.N., Wells L.M., Sparks A.E.T., Van Voorhis B.J. Human embryos secrete microRNAs into culture media--a potential biomarker for implantation. Fertil. Steril. 2014; 101(5): 1493-500. https://dx.doi.org/10.1016/j.fertnstert.2014.01.058
  30. Timofeeva A.V., Fedorov I.S., Shamina M.A., Chagovets V.V., Makarova N.P., Kalinina E.A. et al. Clinical relevance of secreted small noncoding RNAs in an embryo implantation potential prediction at morula and blastocyst development stages. Life (Basel). 2021; 11(12): 1328. https://dx.doi.org/10.3390/life11121328
  31. Coll L., Parriego M., Palacios G., Garcia S., Boada M., Coroleu B. et al. Do reproductive history and information given through genetic counselling influence patients' decisions on mosaic embryo transfer? Prenat. Diagn. 2022; 42(13): 1674-82. https://dx.doi.org/10.1002/pd.6267
  32. Grati F.R., Gallazzi G., Branca L., Maggi F., Simoni G., Yaron Y. An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening. Reprod. Biomed. Online. 2018; 36(4): 442-9. https://dx.doi.org/10.1016/j.rbmo.2018.01.005
  33. Zhang Y.X., Chen J.J., Nabu S., Yeung Q.S.Y., Li Y., Tan J.H. et al. The pregnancy outcome of mosaic embryo transfer: a prospective multicenter study and meta-analysis. Genes (Basel). 2020; 11(9): 973. https://dx.doi.org/10.3390/genes11090973
  34. Mourad A., Antaki R., Bissonnette F., Baini O.A., Saadeh B., Jamal W. Evidence-based clinical prioritization of embryos with mosaic results: a systematic review and meta-analysis. J. Assist. Reprod. Genet. 2021; 38(11): 2849-60. https://dx.doi.org/10.1007/s10815-021-02279-6
  35. Ma Y., Liu L.-W., Liu Y., Shi G., Ai X., Hou W. et al. Which type of chromosomal mosaicism is compatible for embryo transfer: a systematical review and meta-analysis. Arch. Gynecol. Obstet. 2022; 306(6): 1901-11. https://dx.doi.org/10.1007/s00404-022-06511-6
  36. Hong Y.M., Kim S.H., Park H.J., Ryu H.M., Cha D.H., Kim M.Y. et al. Prenatal ultrasound findings and chromosomal outcomes of pregnancies with mosaic embryo transfer. Diagnostics (Basel). 2024; 14(24): 2795. https://dx.doi.org/10.3390/diagnostics14242795
  37. Wang Y., Wang Z., Wu X., Ling X., Zhang J., Liu M. Clinical outcomes of subtypes of mosaic single aneuploid embryos after preimplantation genetic testing for aneuploidy. J. Assist. Reprod. Genet. 2023; 40(3): 639-52. https://dx.doi.org/10.1007/s10815-023-02728-9
  38. Hallisey S.M., Koniares K., Taggar A., Godiwala P.N., Grow D.R. Assessing patient compliance with recommended prenatal testing and identifying pregnancy and neonatal outcomes after mosaic embryo transfer. Fertil. Steril. 2022; 118(4): e355. https://dx.doi.org/10.1016/j.fertnstert.2022.09.166
  39. Abhari S., Kawwass J.F. Pregnancy and neonatal outcomes after transfer of mosaic embryos: a review. J. Clin. Med. 2021; 10(7): 1369. https://dx.doi.org/10.3390/jcm10071369
  40. Franasiak J.M. Mosaic embryo transfer: a cautionary tale. F. S. Rep. 2022; 3(3): 179-80. https://dx.doi.org/10.1016/j.xfre.2022.07.005
  41. Huang K.L., Tsai C.C., Cheng H.H., Huang Y.J., Lai Y.J., Wu C.H. et al. Whether to transfer mosaic embryos: a cytogenetic view of true mosaicism by amniocentesis. Reprod. Biomed. Online. 2021; 42(6): 1146-54. https://dx.doi.org/10.1016/j.rbmo.2021.03.003

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