Non-Invasive Prenatal Diagnosis: A Comparison of Cell Free Fetal DNA (cffDNA) Based Screening and Fetal Nucleated Red Blood Cell (fnRBC) Initiated Testing

Authors

  • Zhiyong Xu, MS
  • Jiansheng Xie, MD, PhD
  • Jinlai Meng, MD, PhD
  • Peining Li, PhD
  • Xinghua Pan, MD, PhD
  • Qinghua Zhou, PhD

Keywords:

non-invasive prenatal diagnosis (NIPD), cell-free fetal DNA (cffDNA), fetal nucleated red blood cell (fnRBC)

Abstract

Current prenatal diagnosis uses non-invasive procedures of maternal serum screening and ultrasound exam to evaluate the risk of chromosomal abnormalities and invasive procedures of chorionic villus sampling and amniocentesis for the diagnosis of cytogenomic abnormalities and gene mutations. The discovery of cell free fetal DNA (cffDNA) in maternal blood prompted the application of massive parallel sequencing to screen fetal aneuploidies. The multi-center large-scale validation of cffDNA based prenatal screening has resulted in rapid integration of this close-to-diagnostic non-invasive procedure into clinical application. Further improvement of this approach could lead to the screening of pathogenic copy number variants and known disease-causing gene mutations. The success from cffDNA fuels efforts in isolating circulating fetal nucleated red blood cells (fnRBCs) for direct non-invasive prenatal testing of fetal genetic disorders. Various isolation and enrichment methods based on the physical and biologic features of the fnRBCs have been developed but the analytic and clinical validities have not yet been established. The cffDNA based prenatal screening has significantly reduced unnecessary invasive procedures. Future breakthrough on fnRBC initiated prenatal testing will further shift the paradigm toward non-invasive prenatal diagnosis.    

[N A J Med Sci. 2013;6(4):194-199.   DOI:  10.7156/najms.2013.0604194]

References

1. Walknowska J, Conte FA, Grumbach MM. Practical and theoretical implications of fetal-maternal lymphocyte transfer. Lancet. 1969;1(7606):1119-1122.
2. Bianchi DW, Flint AF, Pizzimenti MF, Knoll JHM, Latt SA. Isolation of fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad Sci USA. 1990;87(9):3279-3283.
3. Bianchi DW, Mahr A, Zickwolf GK, et al. Detection of fetal cells with 47,XY,+21 karyotype in maternal peripheral blood. Hum Genet. 1992;90(4):368-370.
4. Ganshirt D, Garritsen HS, Holzgreve W. Fetal cells in maternal blood. Curr Opinion Obstet Gynecol. 1995;7(2):103-108.
5. Lo YMD, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076): 485-487.
6. Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ. et al. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diagn. 2002;22(10):946-948.
7. Chiu RW, Lau TK, Cheung PT, et al. Noninvasive prenatal exclusion of congenital adrenal hyperplasia by maternal plasma analysis: a feasibility study. Clin Chem. 2002; 48(5):778-780.
8. Ding C, Chiu RWK, Lau TK, et al. MS analysis of single-nucleotide differences in circulating nucleic acids: Application to noninvasive prenatal diagnosis. Proc Natl Acad Sci USA. 2004;101(29):10762-10767.
9. Tong YK, Ding C, Chiu RWK, et al. Noninvasive prenatal detection of fetal trisomy 18 by epigenetic allelic ratio analysis in maternal plasma: Theoretical and empirical considerations. Clin Chem. 2006;52(12):2194-2202.
10. 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(42): 16266-16271.
11. 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(51):20458-20463.
12. Lo YMD, Chan KC, Sun H, et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med. 2010;2(61), 61ra91.
13. Chiu RWY, Akolekar R, Zheng YWL, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. Br Med J. 2011;342:c7401.
14. Polomaki GE, Kloza Em, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study. Genet Med. 2011;13(11):913-920.
15. Polomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: An international collaborative study. Genet Med. 2012;14(3):296-305.
16. Fleischhacker M, Schmidt B, Weickmann S, et al. Methods for isolation of cell-free plasma DNA strongly affect DNA yield. Clin Chim Acta. 2011;412(23-24):2085-2088.
17. 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.
18. White HE, Dent CL, Hall VJ, Crolla JA, Chitty LS. Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis. PloS One. 2012;7(9):e45073.
19 Wei Y, Xu F, Li P. Technology-driven and evidence-based genomic analysis for integrated pediatric and prenatal genetics evaluation. J Genet Genomics. 2013;40(1):1-12.
20 Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204(3):205.e1-e11.
21. 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(4):319.e1-9.
22. Norton ME, Brar H, Weiss J, et al. 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(2):137.e1-8.
23 Dan S, Wang W, Ren J, et al. Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat Diagn. 2012;32(13):1225-1232.
24. 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(5):374.e1-6.
25. Jiang F, Ren J, Chen F, et al. Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med Genomics. 2012;5:57.
26. Mazloom AR, Džakula Ž, Oeth P, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn. 2013;33(6):591-597.
27. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119(5):890-901.
28 Benn P, Borrell A, Cuckle H, et al. Prenatal detection of Down syndrome using massively parallel sequencing (MPS): A rapid reponse statement from a committee on behalf of the board of the international society for prenatal diagnosis. Prenat Diagn. 2012;32(1):1-2.
29. Gregg AR, Gross SJ. Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013;15(5):395-398.
30. Lapaire O, Holzgreve W, Oosterwijk JC, Brinkhaus R, Bianchi DW. Georg Schmorl on trophoblasts in the maternal circulation. Placenta. 2007;28(1):1-5.
31. Huppertz B, Kingdom, JC. Apoptosis in the trophoblast--role of apoptosis in placental morphogenesis. J Soc Gynecol Investig. 2004;11(6):353-362.
32. Slunga-Tallberg A, El-Rifai W, Keinanen M, et al. Maternal origin of nucleated erythrocytes in peripheral venous blood of pregnant women. Hum Genet. 1995;96(1):53-57.
33. Takabayashi H, Kuwabara S, Ukita T, et al. Development of non-invasive fetal DNA diagnosis from maternal blood. Prenat Diagn. 1995;15(1):74-77.
34. Bianchi DW, Simpson JL, Jackson LG, et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn. 2002;22(7):609-615.
1. Walknowska J, Conte FA, Grumbach MM. Practical and theoretical implications of fetal-maternal lymphocyte transfer. Lancet. 1969;1(7606):1119-1122.
2. Bianchi DW, Flint AF, Pizzimenti MF, Knoll JHM, Latt SA. Isolation of fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad Sci USA. 1990;87(9):3279-3283.
3. Bianchi DW, Mahr A, Zickwolf GK, et al. Detection of fetal cells with 47,XY,+21 karyotype in maternal peripheral blood. Hum Genet. 1992;90(4):368-370.
4. Ganshirt D, Garritsen HS, Holzgreve W. Fetal cells in maternal blood. Curr Opinion Obstet Gynecol. 1995;7(2):103-108.
5. Lo YMD, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076): 485-487.
6. Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ. et al. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diagn. 2002;22(10):946-948.
7. Chiu RW, Lau TK, Cheung PT, et al. Noninvasive prenatal exclusion of congenital adrenal hyperplasia by maternal plasma analysis: a feasibility study. Clin Chem. 2002; 48(5):778-780.
8. Ding C, Chiu RWK, Lau TK, et al. MS analysis of single-nucleotide differences in circulating nucleic acids: Application to noninvasive prenatal diagnosis. Proc Natl Acad Sci USA. 2004;101(29):10762-10767.
9. Tong YK, Ding C, Chiu RWK, et al. Noninvasive prenatal detection of fetal trisomy 18 by epigenetic allelic ratio analysis in maternal plasma: Theoretical and empirical considerations. Clin Chem. 2006;52(12):2194-2202.
10. 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(42): 16266-16271.
11. 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(51):20458-20463.
12. Lo YMD, Chan KC, Sun H, et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med. 2010;2(61), 61ra91.
13. Chiu RWY, Akolekar R, Zheng YWL, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. Br Med J. 2011;342:c7401.
14. Polomaki GE, Kloza Em, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study. Genet Med. 2011;13(11):913-920.
15. Polomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: An international collaborative study. Genet Med. 2012;14(3):296-305.
16. Fleischhacker M, Schmidt B, Weickmann S, et al. Methods for isolation of cell-free plasma DNA strongly affect DNA yield. Clin Chim Acta. 2011;412(23-24):2085-2088.
17. 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.
18. White HE, Dent CL, Hall VJ, Crolla JA, Chitty LS. Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis. PloS One. 2012;7(9):e45073.
19 Wei Y, Xu F, Li P. Technology-driven and evidence-based genomic analysis for integrated pediatric and prenatal genetics evaluation. J Genet Genomics. 2013;40(1):1-12.
20 Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204(3):205.e1-e11.
21. 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(4):319.e1-9.
22. Norton ME, Brar H, Weiss J, et al. 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(2):137.e1-8.
23 Dan S, Wang W, Ren J, et al. Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat Diagn. 2012;32(13):1225-1232.
24. 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(5):374.e1-6.
25. Jiang F, Ren J, Chen F, et al. Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med Genomics. 2012;5:57.
26. Mazloom AR, Džakula Ž, Oeth P, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn. 2013;33(6):591-597.
27. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119(5):890-901.
28 Benn P, Borrell A, Cuckle H, et al. Prenatal detection of Down syndrome using massively parallel sequencing (MPS): A rapid reponse statement from a committee on behalf of the board of the international society for prenatal diagnosis. Prenat Diagn. 2012;32(1):1-2.
29. Gregg AR, Gross SJ. Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013;15(5):395-398.
30. Lapaire O, Holzgreve W, Oosterwijk JC, Brinkhaus R, Bianchi DW. Georg Schmorl on trophoblasts in the maternal circulation. Placenta. 2007;28(1):1-5.
31. Huppertz B, Kingdom, JC. Apoptosis in the trophoblast--role of apoptosis in placental morphogenesis. J Soc Gynecol Investig. 2004;11(6):353-362.
32. Slunga-Tallberg A, El-Rifai W, Keinanen M, et al. Maternal origin of nucleated erythrocytes in peripheral venous blood of pregnant women. Hum Genet. 1995;96(1):53-57.
33. Takabayashi H, Kuwabara S, Ukita T, et al. Development of non-invasive fetal DNA diagnosis from maternal blood. Prenat Diagn. 1995;15(1):74-77.
34. Bianchi DW, Simpson JL, Jackson LG, et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn. 2002;22(7):609-615.
35. Purwosunu Y, Sekizawa A, Farina A, et al. Enrichment of NRBC in maternal blood: a more feasible method for noninvasive prenatal diagnosis. Prenat Diagn. 2006;26(6):545-547.
36. Sekizawa A, Purwosunu Y, Farina A, et al. Development of noninvasive fetal DNA diagnosis from nucleated erythrocytes circulating in maternal blood. Prenat Diagn. 2007;27(9):846-848.
37. Kwon KH, Jeon YJ, Hwang HS, et al. A high yield of fetal nucleated red blood cells isolated using optimal osmolality and a double-density gradient system. Prenat Diagn. 2007;27(13):1245-1250.
38. Huang R, Barber TA, Schmidt MA, et al. A microfluidics approach for the isolation of nucleated red blood cells (NRBCs) from the peripheral blood of pregnant women. Prenat Diagn. 2008;28(10):892-899.
39. Lim KH, Salahuddin S, Qiu L, et al. Light-scattering spectroscopy differentiates fetal from adult nucleated red blood cells: may lead to noninvasive prenatal diagnosis. Opt lett. 2009;34(9):1483-1485.
40. Ponnusamy S, Zhang H, Kadam P, et al. Membrane proteins of human fetal primitive nucleated red blood cells. J Proteomics. 2012;75(18):5762-5773.
41. Zimmermann S, Hollmann C, Stachelhaus SA. Unique monoclonal antibodies specifically bind surface structures on human fetal erythroid blood cells. Exp Cell Res. 2013; 319(17):2700-2707.
42. Coskun S, Alsmadi O. Whole genome amplification from a single cell: a new era for preimplantation genetic diagnosis. Prenat Diagn. 2007;27(4):297-302.
43. Peng W, Takabayashi H, Ikawa K. Whole genome amplification from single cells in preimplantation genetic diagnosis and prenatal diagnosis. Eu J Obstet Gyneco Reproduc Biol. 2007;131(1):13-20.
44. Zheng Y-M, Wang N, Li L, Jin F. Whole genome amplification in preimplantation genetic diagnosis. J Zhejiang Univ-Sci B. 2011;12(1):1-11.
45. Telenius H, Carter NP, Bebb CE, et al. Degenerate oligonucleotide-primed PCR: General amplification of target DNA by a single degenerate primer. Genomics. 1992;13(3):718-725.
46. Dean FB, Hosono S, Fang L, et al. Comprehensive human genome amplification using multiple displacement amplification. Proc Natl Acad Sci USA. 2002;99(8):5261-5266.
47. Pan X, Urban AE, Palejev D, et al. A procedure for highly specific, sensitive, and unbiased whole-genome amplification. Proc Natl Acad Sci USA. 2008;105(42):15499-15504.
48. Zhang C, Zhang C, Chen S, et al. A single cell level based method for copy number variation analysis by low coverage massively parallel sequencing. PloS One. 2013;8(1): e54236.
49. Chen YL, Hung CC, Lin SY, et al. Successful application of the strategy of blastocyst biopsy, vitrification, whole genome amplification, and thawed embryo transfer for preimplantation genetic diagnosis of neurofibromatosis type 1. Taiwan J Obstet Gynecol. 2011;50(1):74-78.
50. Jorgez CJ, Bischoff FZ. Improving enrichment of circulating fetal DNA for genetic testing: size fractionation followed by whole gene amplification. Fetal Diagn Ther. 2009;25(3):314-319.
51. Zong C, Lu S, Chapman AR, Xie XS. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012;338(6114):1622-1626.
52. Li P, Pomianowski P, DiMaio SM, et al. Genomic characterization of prenatally detected chromosomal structural abnormalities using oligonucleotide array comparative genomic hybridization. Am J Med Genet. 2011;155A(7):1605-1615.
53. Hui L, Bianchi DW, Recent advances in the prenatal interrogation of the human fetal genome. Trends Genet. 2013;29:84-91.
54. Benn P, Cuckle H, Pergament E. Non-invasive prenatal diagnosis for Down syndrome: the paradigm will shift, but slowly. Ultrasound Obstet Gynecol. 2012;39(2):127-130.

Downloads

Published

2013-10-30

How to Cite

Xu, MS, Z., Xie, MD, PhD, J., Meng, MD, PhD, J., Li, PhD, P., Pan, MD, PhD, X., & Zhou, PhD, Q. (2013). Non-Invasive Prenatal Diagnosis: A Comparison of Cell Free Fetal DNA (cffDNA) Based Screening and Fetal Nucleated Red Blood Cell (fnRBC) Initiated Testing. North American Journal of Medicine and Science, 6(4). Retrieved from https://najms.com/index.php/najms/article/view/233

Issue

Section

Review