Journal of Fetal Medicine

, Volume 5, Issue 2, pp 113–119 | Cite as

Non-invasive Prenatal Testing: A Unique Approach with Single Nucleotide Polymorphism

  • Rupin Dhamankar
  • Elizabeth Valenti
  • Herman L. Hedriana
Review Article


The purpose of this review is to demonstrate the unique properties of a single nucleotide polymorphism (SNP)-based approach in non-invasive prenatal testing (NIPT). The identification of cell free fetal DNA in the plasma of pregnant women led to the development of NIPT. This can be performed with either a quantitative approach (massively parallel shotgun sequencing, chromosome selective sequencing) or a qualitative approach (SNP-based). NIPT tests have been shown to have superior performance as a screen for common fetal chromosome abnormalities compared with maternal serum screening. At low fetal fractions, NIPT sensitivity falls, particularly when quantitative methods are used. A SNP-based approach allows both accurate assessment of fetal fraction, and a robust test performance at lower fetal fractions. The ability of the SNP-based approach to screen for vanishing twins and maternal copy number variants reduces false positives; and the ability to make high confidence calls at lower fetal fraction, minimizes discordance between the NIPT result and the true fetal status.


cffDNA NIPT SNP-based NIPT Fetal fraction NIPS Prenatal diagnosis 


Compliance with Ethical Standards


Rupin Dhamankar and Elizabeth Valenti are Natera Inc employees; Herman Hedriana was a former Natera employee.


  1. 1.
    Russo ML, Blakemore KJ. A historical and practical review of first trimester aneuploidy screening. Sem Fetal Neonatal Med. 2014;19(3):183–7. Scholar
  2. 2.
    Norton ME, Jacobsson B, Swamy GK, Laurent LC, Ranzini AC, Brar H, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372(17):1589–97. PubMed PMID: 25830321.CrossRefPubMedGoogle Scholar
  3. 3.
    American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics, Committee on Genetics, Society for Maternal-Fetal Medicine. Practice bulletin no. 162: prenatal diagnostic testing for genetic disorders. Obstet Gynecol. 2016;127(5):e108–22. Scholar
  4. 4.
    Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, et al. Presence of fetal DNA in maternal plasma and serum. Lancet (London, England). 1997;350(9076):485–7. Scholar
  5. 5.
    Hui L, Hutchinson B, Poulton A, Halliday J. Population-based impact of noninvasive prenatal screening on screening and diagnostic testing for fetal aneuploidy. Genet Med. 2017;19:1338. Scholar
  6. 6.
    Ashoor G, Syngelaki A, Poon LC, Rezende JC, Nicolaides KH. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’ gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol. 2013;41(1):26–32. Scholar
  7. 7.
    Boon EMJ, Faas BHW. Benefits and limitations of whole genome versus targeted approaches for noninvasive prenatal testing for fetal aneuploidies. Prenat Diagn. 2013;33(6):563–8. Scholar
  8. 8.
    Sayres LC, Cho MK. Cell-free fetal nucleic acid testing: a review of the technology and its applications. Obstet Gynecol Surv. 2011;66(7):431–42. Scholar
  9. 9.
    Dohm JC, Lottaz C, Borodina T, Himmelbauer H. Substantial biases in ultra-short read data sets from high-throughput DNA sequencing. Nucleic Acids Res. 2008;36(16):e105. Scholar
  10. 10.
    Curnow KJ, Wilkins-Haug L, Ryan A, Kirkizlar E, Stosic M, Hall MP, et al. Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstet Gynecol. 2015;212(1):79.e1–9. Scholar
  11. 11.
    Allyse M, Minear MA, Berson E, Sridhar S, Rote M, Hung A, et al. Non-invasive prenatal testing: a review of international implementation and challenges. Int J Women’s Health. 2015;7:113–26. Scholar
  12. 12.
    Iwarsson E, Jacobsson B, Dagerhamn J, Davidson T, Bernabé E, Heibert Arnlind M. Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population—a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017;96(1):7–18. Scholar
  13. 13.
    Gil MM, Quezada MS, Revello R, 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(3):249–66. Scholar
  14. 14.
    Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol. 2014;211(5):527.e1–17. Scholar
  15. 15.
    Porreco RP, Garite TJ, Maurel K, Marusiak B, Ehrich M, van den Boom D, et al. Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. Am J Obstet Gynecol. 2014;211(4):365.e1–12. Scholar
  16. 16.
    Zhao C, Tynan J, Ehrich M, Hannum G, McCullough R, Saldivar J-S, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem. 2015;61(4):608–16. Scholar
  17. 17.
    Wapner RJ, Babiarz JE, Levy B, Stosic M, Zimmermann B, Sigurjonsson S, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. 2015;212(3):332.e1–9. Scholar
  18. 18.
    Martin K, Iyengar S, Kalyan A, Lan C, Simon AL, Stosic M, et al. Clinical experience with a single-nucleotide polymorphism-based non-invasive prenatal test for five clinically significant microdeletions. Clin Genet. 2018;93(2):293–300. Scholar
  19. 19.
    Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011;13:913. Scholar
  20. 20.
    Gregg AR, Skotko BG, Benkendorf JL, Monaghan KG, Bajaj K, Best RG, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2016;18(10):1056–65. Scholar
  21. 21.
    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(7):667–74. Scholar
  22. 22.
    Allen R, Kezmarsky P, Lescale L. False negative NIPT and potential implications for genetic counseling. ACMG annual clinical genetics meeting 2013, Abstract 47; Phoenix2013.Google Scholar
  23. 23.
    Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine. Practice bulletin no. 163: screening for fetal aneuploidy. Obstet Gynecol. 2016;127(5):e123–37. Scholar
  24. 24.
    Hui L, Bethune M, Weeks A, Kelley J, Hayes L. Repeated failed non-invasive prenatal testing owing to low cell-free fetal DNA fraction and increased variance in a woman with severe autoimmune disease. Ultrasound Obstet Gynecol. 2014;44(2):242–3. Scholar
  25. 25.
    Pergament E, Cuckle H, Zimmermann B, Banjevic M, Sigurjonsson S, Ryan A, et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. 2014;124(2 Pt 1):210–8. Scholar
  26. 26.
    Taneja PA, Snyder HL, de Feo E, Kruglyak KM, Halks-Miller M, Curnow KJ, et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 cases. Prenat Diagn. 2016;36(3):237–43. Scholar
  27. 27.
    Ryan A, Hunkapiller N, Banjevic M, Vankayalapati N, Fong N, Jinnett KN, et al. Validation of an enhanced version of a single-nucleotide polymorphism-based noninvasive prenatal test for detection of fetal aneuploidies. Fetal Diagn Ther. 2016;40(3):219–23. Scholar
  28. 28.
    Niles KM, Murji A, Chitayat D. Prolonged duration of persistent cell free fetal DNA from a vanishing twin. Ultrasound Obstet Gynecol. 2018. Scholar
  29. 29.
    Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, et al. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem. 2014;60(1):251–9. Scholar
  30. 30.
    Russell LM, Strike P, Browne CE, Jacobs PA. X chromosome loss and ageing. Cytogenet Genome Res. 2007;116(3):181–5. Scholar
  31. 31.
    Rava RP, Srinivasan A, Sehnert AJ, Bianchi DW. Circulating fetal cell-free DNA fractions differ in autosomal aneuploidies and monosomy X. Clin Chem. 2014;60(1):243–50. Scholar
  32. 32.
    Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing. Clin Chem. 2010;56(8):1279–86. Scholar
  33. 33.
    Liao H, Liu S, Wang H. Performance of non-invasive prenatal screening for fetal aneuploidy in twin pregnancies: a meta-analysis. Prenat Diagn. 2017;37(9):874–82. Scholar
  34. 34.
    Palomaki GE, Kloza EM, O’Brien BM, Eklund EE, Lambert-Messerlian GM. The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population. Genet Med. 2017;19:778. Scholar
  35. 35.
    Hoskovec JM, Bennett RL, Carey ME, DaVanzo JE, Dougherty M, Hahn SE, et al. Projecting the supply and demand for certified genetic counselors: a workforce study. J Genet Couns. 2018;27(1):16–20. Scholar

Copyright information

© Society of Fetal Medicine 2018

Authors and Affiliations

  • Rupin Dhamankar
    • 1
  • Elizabeth Valenti
    • 1
  • Herman L. Hedriana
    • 2
  1. 1.Natera, IncSan CarlosUSA
  2. 2.Division of Maternal-Fetal Medicine, Department of Obstetrics and GynocologyUniversity of California Davis Health SystemSacramentoUSA

Personalised recommendations