Skip to main content
SpringerLink
Log in

Non-invasive Prenatal Screening for Fetal Aneuploidy: Comparison with Cytogenetic Results

  • Cytogenetics (CL Martin & E Williams, Section Editors)
  • Published:
Current Genetic Medicine Reports Aims and scope Submit manuscript

Abstract

Non-invasive prenatal screening (NIPS) for fetal aneuploidy detection using cell-free fetal DNA from maternal circulation has been rapidly adopted for use in high-risk pregnancies since its inception in 2011. While most published NIPS studies are written from the clinical validation, obstetric, or technological viewpoints, in this review we summarize the published cytogenetics laboratory experience with this technology. A total of 528 NIPS positive cases were compared to cytogenetic results and the overall true-positive rate was 77 % (95 % CI 73.3–80.6) for all aneuploidies (407/528). Sixty percent (n = 317) showed increased risk for trisomy 21 and had a positive predictive value (PPV) of 92 % (95 % CI 88.2–94.6). The PPV for trisomy 18 was 69 % (95 % CI 59.3–78.1), 49 % (95 % CI 35.1–63.2) for trisomy 13, and 35 % (95 % CI 22.9–48.9) for combined sex chromosome abnormalities. This technology is rapidly expanding to include testing for microdeletion syndromes. In our limited experience with 18 cases referred to our laboratories after microdeletion-positive NIPS, only two were confirmed by cytogenetics, resulting in a PPV of 11 % (95 % CI 1.4–34.7). We discuss the reasons for discordant results which include confined placental mosaicism, vanishing co-twin, maternal mosaicism, maternal neoplasia, counting algorithms, and laboratory error.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Gregg AR, Gross SJ, Best RG, Monaghan KG, Bajaj K, Skotko BG, Thompson BH, Watson, MS, for The noninvasive prenatal screening work group of the American College of Medical Genetics and Genomics. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013; 15:395–8. This is the policy statement by the American College of Medical Genetics regarding the utility and limitations of NIPS.

  2. • The American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal Fetal Medicine Publications Committee. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No 545. December 2012. This is the policy statement by the American College of Obstetrics and Gynecology regarding the utility and limitations of NIPS.

  3. •• Gil MM, Quezada MS, Akolekar R, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2015;45:249–66. Meta-analysis of 37 NIPS studies analyzing detection rates and false positive rates for various aneuploidies.

  4. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Am J Obstet Gynecol. 2012;119(5):890–901.

    Article  CAS  Google Scholar 

  5. Palomaki GE, Decio C, Kolza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaboration study. Genet Med. 2012;14(3):296–305.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB, Rodriguez MH, Williams J III, Mitchell ME, Adair CD, Lee H, Jacobsson B, Tomlinson MW, Oepkes D, Oepkes D, Hollemon D, Sparks AB, Oliphant A, Song K. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207:137e1–8.

    Article  Google Scholar 

  7. 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 

  8. Choy KW, Kwok KY, Lau ET, Tang MH, Pursley A, Smith J, Cheung SW, Leung TY, Petal A. Discordant karyotype results among non-invasive prenatal screening positive cases. American Society of Human Genetics 63rd Annual Meeting, October 22–26, 2013 Boston. Abstract #19.

  9. Meck JM, Kramer Dugan E, Aviram A, Trunca C, Riethmaier D, Pineda-Alvarez D, Aradhya S, Richard G, Gomez A, Shulman L, MS, Klein RT, MS, Matyakhina L. Non-Invasive Prenatal Screening: A Cytogenetic Perspective. 2014 ACMG Annual Clinical Genetics Meeting.

  10. Cherry AM, Williams JM, Manning MA. Accuracy of non-invasive prenatal screening for trisomies 13, 18 and 21 and sex chromosome aneuploidy. 43rd Biennial American Cytogenetics Conference. Cytogenet Genome Res. 2014;142:226–56.

    Google Scholar 

  11. Meck JM, Kramer DE, Aviram A, Aviram A, Trunca C, Riethmaier D, Pineda-Alvarez D, Aradhya S, Richard G, Gomez A, Shulman L, Klein R, Matyakhina L. Non-invasive prenatal screening from viewpoint of the cytogenetics laboratory. 43rd Biennial American Cytogenetics Conference. Cytogenet Genome Res. 2014;142:226–56.

    Google Scholar 

  12. Patel A, Cvjetkovic N, Fosler L, Van den Veyver I, Peacock S, Breman A, Smith J. Discordant karyotypes among positive NIPT highlight the importance of invasive confirmatory testing. 43rd Biennial American Cytogenetics Conference. Cytogenet Genome Res. 2014;142:226–56.

    Google Scholar 

  13. • Meck JM, Kramer Dugan E, Matyakhina L, Aviram A, Trunca C, Pineda-Alvarez D, Aradhya W, Klein RT, Cherry AM. Non-invasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. Am J Obstet Gynecol. 2015. doi:10.1016/j.ajog.2015.04.001. The most comprehensive study to date of the post-NIPS population being referred for follow-up cytogenetic testing and comparison between NIPS and karyotype.

  14. Wang J-C, Sahoo T, Schonberg S, Kopita KA, Ross L, Patek K, Strom CM. Discordant noninvasive prenatal testing and cytogenetic results: a study of 109 consecutive cases. Genet Med. 2015;17:234–6.

    Article  CAS  PubMed  Google Scholar 

  15. Cheung SW, Patel A, Leung TY. Accurate description of DNA-based noninvasive prenatal screening. N Engl J Med. 2015;372:1675–7.

    Article  PubMed  Google Scholar 

  16. Gardner RJM, Sutherland GR, Shaffer LG. Chromosome abnormalities and genetic counseling. 4th ed. New York: Oxford University Press; 2012. p. 444.

    Google Scholar 

  17. Crane JP, Cheung SW. An embryogenic model to explain cytogenetic inconsistencies observed in chorionic villus versus fetal tissue. Prenat Diagn. 1988;8:119–29.

    Article  CAS  PubMed  Google Scholar 

  18. Ledbetter DH, Zachary JM, Simpson JL, Golbus MS, Pergament E, et al. Cytogenetic results from the US collaborative study on CVS. Prenat Diagn. 1992;12:317–45.

    Article  CAS  PubMed  Google Scholar 

  19. Miny P, Hammer P, Gerlach B, Tercanli S, Horst J, Holzgreve W, Eiben B. Mosaicism and accuracy of prenatal diagnoses after chorionic villus sampling and placental biopsies. Prenat Diagn. 1991;11:581–9.

    Article  CAS  PubMed  Google Scholar 

  20. Robinson WP, Penaherrera MS, Jiang R, et al. Assessing the role of placental trisomy in preeclampsia and intrauterine growth restriction. Prenat Diagn. 2010;30:1–8.

    Article  PubMed  Google Scholar 

  21. Curnow KJ, Wilkins-Haug L, Ryan A, Kırkızlar E, Stosic M, Hall MP, Sigurjonsson S, Demko Z, Rabinowitz M, Gross SJ. Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism based noninvasive prenatal test. Am J Obstet Gynecol. 2015;212:79.e1–9.

    Article  CAS  Google Scholar 

  22. •• Bianchi DW, Wilkins-Haug L. Integration of noninvasive DNA testing for aneuploidy into prenatal care. What has happened since the rubber met the road? Clin Chem. 2014;60:78–87. Excellent overview of the different technical approaches to NIPS and how it has performed in the “real world”.

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

    Article  CAS  PubMed  Google Scholar 

  24. Hahn S, Huppertz B, Holzgreve W. Fetal cells and cell free fetal nucleic acids in maternal blood. New tools to study abnormal placentation? Placenta. 2005;26:515–26.

    Article  CAS  PubMed  Google Scholar 

  25. Sekizawa A, Yokokawa K, Sugito Y, Iwasaki M, Yukimoto Y, Ichizuka K, Saito H, Okai T. Evaluation of bidirectional transfer of plasma DNA through the placenta. Hum Genet. 2003;113:307–10.

    Article  CAS  PubMed  Google Scholar 

  26. 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;33:667–74.

    Article  CAS  PubMed  Google Scholar 

  27. Smith K, Lowther G, Maher E, Hourihan T, Wilkinson T, Wolstenholme J. The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS. Experience from the ACC UK collaborative study. Prenat Diagn. 1999;19:817–26.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, Han X, Hu W, Ma D, Cram D, Cheng W. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem. 2014;60:251–9.

    Article  CAS  PubMed  Google Scholar 

  29. Lau TK, Cheung WS, Lo PSS, Pursley AN, Chan MK, Jiang F, Zhang H, Wang W, Jong LFJ, Yuen OKC, Chan HYC, Chan WSK, Choy KW. Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage whole-genome sequencing of maternal plasma DNA. Review of, consecutive cases in a single center. Ultrasound Obstet Gynecol. 1982;2014(43):254–64.

    Google Scholar 

  30. Wang S, Huang S, Ma L, Liang L, Zhang J, Zhang J, Cram DS. Maternal X chromosome copy number variations are associated with discordant fetal sex chromosome aneuploidies detected by noninvasive prenatal testing. Clin Chim Acta. 2015;444:113–6.

    Article  CAS  PubMed  Google Scholar 

  31. Lun FMK, Chiu RWK, Chan KCA, Leung TY, Lau TK, Lo YMD. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin Chem. 2008;54:1664–72.

    Article  CAS  PubMed  Google Scholar 

  32. Nowinski GP, Van Dyke DL, Tilley BC, Jacobsen G, Babu VR, Worsham MJ, Wilson GN, Weiss L. The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am J Hum Genet. 1990;46:1101–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Russell LM, Strike P, Browne CE, Jacobs PA. X chromosome loss and aging. Cytogenet Genome Res. 2007;116:181–5.

    Article  CAS  PubMed  Google Scholar 

  34. Horsman DE, Dill FJ, McGillivray BC, Kalousek DK. X chromosome aneuploidy in lymphocyte cultures from women with recurrent spontaneous abortions. Am J Med Genet. 1987;28:981–7.

    Article  CAS  PubMed  Google Scholar 

  35. Giacono MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD. Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas. 1998;17:89–97.

    Article  Google Scholar 

  36. Osborne CM, Hardisty E, Devers P, Kaiser-Rogers K, Hayden MA, Goodnight W, Vora NL. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn. 2013;22:609–11.

    Article  Google Scholar 

  37. Dharajiya N, Monroe T, Farkas DH, Boomer T, Wardrop J, Jesiolowski J, almasri E, Zhao C, Deciu C, Saldivar J. Adventitious detection of maternal neoplasia during noninvasive prenatal testing (NIPT). AMP 2014 Abstract G45.

  38. Peters DG, Yatsenko SA, Surt U, Rajkovic A. Recent advances of genomic testing in perinatal medicine. Semin Perinatol. 2015;39:44–54.

    Article  PubMed  Google Scholar 

  39. Snyder MW, Simmons LE, Kitzman JO, Coe BP, Henson JM, Daza RM, Eichler EE, Shendure J, Gammill HS. Copy-number variation and false positive prenatal aneuploidy screening results. New Engl J Med. 2015;372:1639–45.

    Article  CAS  PubMed  Google Scholar 

  40. Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci USA. 2008;105:16266–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Chiu RWK, Chan KCA, Gao Y, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci USA. 2008;105:20458–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. 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 

  43. Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X and Y using targeted sequencing of polymorphic loci. Prenat Diagn. 2012;32:1233–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Juneau K, Bogard PE, Huang S, Mohseni M, Wang ET, Ryvkin P, Kingsley C, Struble CA, Oliphant A, Zahn JM. Microarray-based cell-free DNA analysis improves noninvasive prenatal testing. Fetal Diagn Ther. 2014;36:282–6.

    Article  PubMed  Google Scholar 

  45. Benn P. Non-invasive prenatal testing using cell free DNA in maternal plasma: recent developments and future prospects. J Clin Med. 2014;3:537–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. • Wapner RJ, Babiarz JE, Levy B, Stosic M, Zimmermann B, Sigurjonsson S, Wayham N, Ryan A, Banjevic M, Lacroute P, Hu J, Hall MP, Demko Z, Siddiqui A, Rabinowitz M, Groww SJ, Hill M, Benn P. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. AJOG. 2015;212:332.e1–9. The best study to date of the performance of NIPS (SNP-based) for 5 microdeletion syndromes.

  47. Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol. 2012;207:374.e1–376.e6.

    Article  Google Scholar 

  48. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ, CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799–808.

    Article  CAS  PubMed  Google Scholar 

  49. Song Y, Liu C, Qi H, Zhang Y, Bian X, Liu J. Noninvasive prenatal testing of fetal aneuploidies by massively parallel sequencing in a prospective Chinese population. Prenat Diagn. 2013;33:700–6.

    Article  PubMed  Google Scholar 

  50. Norton ME, Jacobsson B, Swamy GK, Laurent LC, Ranzini AC, Brar H, Tomlinson MW, Pereira L, Spitz JL, Hollemon D, Cuckle H. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372:1589–97.

    Article  CAS  PubMed  Google Scholar 

  51. Quezada MS, Gil MM, Francisco C, Orosz G, Nicolaides KH. Screening for trisomies 21, 18 and 13 by cell-free DNA analysis of maternal blood at 10–11 weeks’ gestation and the combined test at 11–13 weeks. Ultrasound Obstet Gynecol. 2015;45:36–41.

    Article  CAS  PubMed  Google Scholar 

  52. Grati FR, Malvestiti F, Ferreira JCPB, Bajaj K, Gaetani E, Agrati C, Grimi B, Dulcetti F, Ruggeri AM, De Toffol S, Maggi F, Wapner R, Gross S, Simoni G. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med. 2014;16:620–4.

    Article  PubMed  Google Scholar 

  53. Grati FR, Malvestiti F, Grimi B, Liuti R, Agrati C, Gaetani E, Milani S, Martinoni L, Zanatta V, Gallazzi G, Maggi F, Simoni G. Increased risk after noninvasive prenatal screening on cel-free DNA circulating in maternal blood: does a new indication for invasive prenatal diagnosis require new criteria for confirmatory cytogenetic analysis? Prenat Diagn. 2015;35:308–9.

    Article  CAS  PubMed  Google Scholar 

  54. Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, Zimmermann B, Hill M, Sigurjonsson S, Ryan A, Banjevic M, Kolacki PL, Koch SW, Strom CM, Rabinowitz M, Benn P. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol. 2014;211:527.e1–17.

    Article  Google Scholar 

  55. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Eng J Med. 2012;367:2175–84.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Kyle Retterer, M.S. for his contribution to statistical analyses.

Disclosure

JM Meck works for a genetic testing company that performs FISH, chromosome analysis, and microarray. AM Cherry works for a university laboratory that also performs the above testing. GV Putcha is currently self-employed, and is a former employee of Ariosa Diagnostics. At this time, none of the authors work for or have a financial relationship with a company performing NIPS.

Human and Animal Rights and Informed Consent

All patients included in this study sign informed consent which gives permission to publish their results while maintaining anonymity.

Author information

Authors and Affiliations

  1. GeneDx, Gaithersburg, MD, USA

    Jeanne M. Meck

  2. Stanford University School of Medicine, Palo Alto, CA, USA

    Athena M. Cherry

  3. Los Altos Hills, CA, 94022, USA

    Girish V. Putcha

Authors
  1. Jeanne M. Meck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Girish V. Putcha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Athena M. Cherry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeanne M. Meck.

Additional information

This article is part of the Topical Collection on Cytogenetics.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meck, J.M., Putcha, G.V. & Cherry, A.M. Non-invasive Prenatal Screening for Fetal Aneuploidy: Comparison with Cytogenetic Results. Curr Genet Med Rep 3, 127–136 (2015). https://doi.org/10.1007/s40142-015-0072-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40142-015-0072-z

Keywords

Search

Navigation