Skip to main content
SpringerLink
Log in

Placental mosaicism for Trisomy 13: a challenge in providing the cell-free fetal DNA testing

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

We investigated the disagreement between the positive cell-free fetal DNA test for trisomy 13 and the standard cytogenetic diagnosis of one case.

Methods

Cell-free fetal DNA testing was performed by massively parallel sequencing. We used conventional cytogenetic analysis to confirm the commercial cell-free fetal DNA testing. Additionally, postnatal fluorescent in situ hybridization (FISH) testing was performed on placental tissues.

Results

The cell-free fetal DNA testing result was positive for trisomy 13. G-banded analysis of amniotic fluid was normal, 46, XY. FISH testing of tissues from four quadrants of the placenta demonstrated mosaicism for trisomy 13.

Conclusions

A positive cell-free fetal DNA testing result may not be representative of the fetal karyotype because of placental mosaicism. Cytogenetic analysis should be performed when abnormal cell-free fetal DNA test results are obtained.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med. 2009;360:2556–62.

    Article  CAS  PubMed  Google Scholar 

  2. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011;342:c7401.

    Article  PubMed Central  PubMed  Google Scholar 

  3. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol. 2007;110:1459–67.

    Article  Google Scholar 

  4. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol. 2007;110:687–94.

    Article  PubMed  Google Scholar 

  5. Morris JK, Waters JJ, de Souza E. The population impact of screening for Down syndrome: audit of 19326 Invasive diagnostic tests in England and Wales in 2008. Prenat Diagn. 2012;32:596–601.

    Article  PubMed  Google Scholar 

  6. Shaffer LG, Bui TH. Molecular cytogenetic and rapid aneuploidy detection methods in prenatal diagnosis. Am J Med Genet C: Semin Med Genet. 2007;145C:87–98.

    Article  CAS  Google Scholar 

  7. Hui L, Bianchi DW. Recent advances in the prenatal interrogation of the human fetal genome. Trends. 2013;29:84–91.

    Article  CAS  Google Scholar 

  8. Sparks AB, Wang ET, Struble CA, Barrett W, Stokowski R, McBride C, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn. 2012;6:1–7.

    Google Scholar 

  9. Sparks AB, Struble CA, Wang ET, Song K, Oliphant A. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;206(319):e1–9.

    PubMed  Google Scholar 

  10. Ashoor G, Syngelaki A, Wagner M, Birdir C, Nicolaides KH. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;206(322):e1–5.

    PubMed  Google Scholar 

  11. Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. 2013;33:575–9.

    Article  CAS  PubMed  Google Scholar 

  12. Lau TK, Jiang FM, Stevenson RJ, Lo TK, Chan LW, Chan MK, et al. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat Diagn. 2013;33:602–8.

    Article  CAS  PubMed  Google Scholar 

  13. American College of Obstetricians and Gynecologists. First-trimester screening for fetal aneuploidy; ACOG committee opinion no. 296.Washington, DC: The College; 2004.

  14. Chetty S, Garabedian MJ, Norton ME. Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening. Prenat Diagn. 2013;33:542–6.

    Article  PubMed  Google Scholar 

  15. Chiu RW, Lo YM. Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clin Chem Lab Med. 2013;51:197–204.

    CAS  PubMed  Google Scholar 

  16. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62:768–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn. 2013;16:1–8.

    Google Scholar 

  18. Faas BH, de Ligt J, Janssen I, Eggink AJ, Wijnberger LD, van Vugt JM, et al. Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells. Expert Opin Biol Ther. 2012;12 Suppl 1:S19–26.

    Article  CAS  PubMed  Google Scholar 

  19. Chen EZ, Chiu RW, Sun H, Akolekar R, Chan KC, Leung TY, et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS One. 2011;6:e21791.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Mennuti MT, Cherry AM, Morrissette JJ, Dugoff L. Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol. 2013. doi:10.1016/j.ajog. 2013.03.027.

    PubMed  Google Scholar 

  21. Jalal SM, Law ME, Carlson RO, Dewald GW. Prenatal detection of aneuploidy by directly labeled multicolored probes and interphase fluoresence in situ hybridization. Mayo Clin Proc. 1998;73:132–7.

    Article  CAS  PubMed  Google Scholar 

  22. Aviram-Goldring A, Daniely M, Dorf H, Chaki R, Goldman B, Barkai G. Use of interphase fluorescence in situ hybridization in third trimester fetuses with anomalies and growth retardation. Am J Med Genet. 1999;87:203–6.

    Article  CAS  PubMed  Google Scholar 

  23. Wray AM, Landy HJ, Meck JM. Patient decisions regarding prenatal aneuploid fluorescence in situ hybridization results. Int J Gynaecol Obstet. 2007;96:103–7.

    Article  CAS  PubMed  Google Scholar 

  24. Tsui NB, Wong BC, Leung TY, Lau TK, Chiu RW, Lo YM. Non-invasive prenatal detection of fetal trisomy 18 by RNA-SNP allelic ratio analysis using maternal plasma SERPINB2 mRNA: a feasibility study. Prenat Diagn. 2009;29:1031–7.

    Article  CAS  PubMed  Google Scholar 

  25. Tong YK, Jin S, Chiu RW, Ding C, Chan KC, Leung TY, et al. Non-invasive prenatal detection of trisomy 21 by an epigenetic-genetic chromosome-dosage approach. Clin Chem. 2010;56:90–8.

    Article  CAS  PubMed  Google Scholar 

  26. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, et al. Non-invasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204(205):e1–e11.

    Google Scholar 

  27. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: non-invasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532–4.

    Article  Google Scholar 

  28. Benn P, Cuckle H, Pergament E. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol. 2013;42:15–33. doi:10.1002/uog.12513.

    Article  CAS  PubMed  Google Scholar 

  29. Madhusudan D, Sumedha S, Sumita A. Prenatal Screening Methods for Aneuploidies. N Am J Med Sci. 2013;5:182–90. doi:10.4103/1947-2714.109180.

    Article  Google Scholar 

  30. Hui L. Non-invasive prenatal testing for fetal aneuploidy: charting the course from clinical validity to clinical utility. Ultrasound. 2013;41:2–6.

    CAS  Google Scholar 

  31. Chiu RW, Chan KC, Gao Y, Lau VY, Zheng W, Leung TY, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008;105:20458–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hall AL, Drendel HM, Verbrugge JL, Reese AM, Schumacher KL, Griffith CB, et al. Positive cell-free fetal DNA testing for trisomy 13 reveals confined placental mosaicism. Genet Med. 2013. doi:10.1038/gim.2013.26.

    Google Scholar 

  33. Flori E, Doray B, Gautier E, Kohler M, Ernault P, Flori J, et al. Circulating cell-free fetal DNA in maternal serum appears to originate from cyto- and syncytio-trophoblastic cells.Case report. Hum Reprod. 2004;19:723–4.

    Article  CAS  PubMed  Google Scholar 

  34. Bianchi DW. Circulating fetal DNA: its origin and diagnostic potential-a review. Placenta. 2004;25(Suppl):S93–S101.

    Article  CAS  PubMed  Google Scholar 

  35. Alberry M, Maddocks D, Jones M, Abdel Hadi M, Abdel-Fattah S, Avent N, et al. Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenat Diagn. 2007;27:415–8.

    Article  CAS  PubMed  Google Scholar 

  36. Gahan PB, Swaminathan R. Circulating nucleic acids in plasma and serum. Recent developments. Ann N Y Acad Sci. 2008;1137:1–6.

    Article  CAS  PubMed  Google Scholar 

  37. Rosner M, Hengstschläger M. Amniotic fluid stem cells and fetal cell microchimerism. Trends Mol Med. 2013;19:271–2.

    Article  CAS  PubMed  Google Scholar 

  38. Kalousek DK, Vekemans M. Confined placental mosaicism. J Med Genet. 1996;33:529–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kalousek DK, Dill FJ. Chromosomal mosaicism confined to the placenta in human conceptions. Science. 1983;221(4611):665–7.

    Article  CAS  PubMed  Google Scholar 

  40. Viot G. Confined placental mosaicism: definition, consequences and outcome. J Gynecol Obstet Biol Reprod. 2002;31(1 Suppl):2S70–4.

    CAS  Google Scholar 

  41. Phillips OP, Tharapel AT, Lerner JL, Park VM, Wachtel SS, Shulman LP. Risk of fetal mosaicism when placental mosaicism is diagnosed by chorionic villus sampling. Am J Obstet Gynecol. 1996;174:850–5.

    Article  CAS  PubMed  Google Scholar 

  42. Wapner RJ. Invasive prenatal diagnostic techniques. Semin Perinatol. 2005;29:401–4.

    Article  PubMed  Google Scholar 

  43. Chan Wong E, Hatakeyama C, Minor A, Ma S. Investigation of confined placental mosaicism by CGH in IVF and ICSI pregnancies. Placenta. 2012;33:202–6.

    Article  CAS  PubMed  Google Scholar 

  44. Baffero GM, Somigliana E, Crovetto F, Paffoni A, Persico N, Guerneri S, et al. Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome. Prenat Diagn. 2012;32:1102–8.

    Article  PubMed  Google Scholar 

  45. Toutain J, Labeau-Gaüzere C, Barnetche T, Horovitz J, Saura R. Confined placental mosaicism and pregnancy outcome: a distinction needs to be made between types 2 and 3. Prenat Diagn. 2010;30:1155–64.

    Article  PubMed  Google Scholar 

  46. Simpson JL. Is cell-free fetal DNA from maternal blood finally ready for prime time? Obstet Gynecol. 2012;119:883–5.

    Article  PubMed  Google Scholar 

  47. Wright C, Quake SR, Bianchi D, Wald NJ. Community corner: opening the Pandora’s box of prenatal genetic testing. Nat Med. 2011;17:250–1.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Prenatal Diagnosis and Reproductive Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130021, China

    Xiang-Yin Liu, Hong-Guo Zhang, Rui-Xue Wang, Shuang Chen, Xiao-Wei Yu & Rui-Zhi Liu

Authors
  1. Xiang-Yin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-Guo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui-Xue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Wei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui-Zhi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui-Zhi Liu.

Additional information

Capsule Reported one challenge case to cell-free fetal DNA testing, positive for trisomy 13 but disagree with the standard cytogenetic diagnosis results because of placental mosaicism.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, XY., Zhang, HG., Wang, RX. et al. Placental mosaicism for Trisomy 13: a challenge in providing the cell-free fetal DNA testing. J Assist Reprod Genet 31, 589–594 (2014). https://doi.org/10.1007/s10815-014-0182-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-014-0182-7

Keywords

Search

Navigation