Skip to main content
SpringerLink
Log in

Prenatal Screening of Single-Gene Disorders from Maternal Blood

  • Molecular Diagnostic
  • Published:
American Journal of Pharmacogenomics

Abstract

Fetal cells and cell-free fetal DNA can be found circulating in maternal blood. Fetal cells recovered from maternal blood provide the only source of pure fetal DNA for noninvasive prenatal DNA diagnosis. Fetal nucleated erythrocytes (NRBCs) are considered the most suitable maternally-circulating fetal cells for this purpose, because they are not commonly found in the peripheral blood of healthy adults and are most abundant in the fetus during early gestation. Because fetal cells in maternal blood are extremely rare, a definitive separation method has not yet been established. Fetal NRBCs can be enriched from maternal blood via fluorescence- or magnetic-activated cell sorting, density gradients, immuno-magnetic beads or micromanipulation. Fetal cells are identified by Giemsa staining, hybridization with Y-chromosome specific probes, PCR-detection of a specific paternal allele, or immunostaining for fetal cell antigens. Amplification of fetal DNA sequences by primer extension preamplification and PCR has allowed prenatal screening for Duchenne muscular dystrophy and the fetal RhD blood type. Sequence-specific hybridization has been used to detect sickle cell anemia and β-thalassemia prenatally in heterozygous carriers of these disorders.

The use of cell-free fetal DNA in maternal plasma for the diagnosis of single-gene disorders is limited to disorders caused by a paternally inherited gene or a mutation that can be distinguished from the maternally inherited counterpart. At present, fetal gender can be determined from maternal plasma. When a pregnant woman is a heterzygous carrier of an X-linked disorder, the determination of fetal gender is clinically very informative for first-step screening to avoid invasive amniocentesis. The non-invasive prenatal diagnosis of genetic disorders should be applied to pregnant women with a definite risk for a specific single-gene disorder.

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

Table I
Fig. 1

Similar content being viewed by others

References

  1. Firth HV, Boyd PA, Chamberlain PF, et al. Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet 1994; 343(8905): 1069–71

    Article  PubMed  CAS  Google Scholar 

  2. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down’s syndrome in early pregnancy. BMJ 1988; 297(6653): 883–7

    Article  PubMed  CAS  Google Scholar 

  3. Wald NJ, Densem JW, George L, et al. Prenatal screening for Down’s syndrome using inhibin-A as a serum marker. Prenat Diagn 1996; 16(2): 143–53

    Article  PubMed  CAS  Google Scholar 

  4. Snijders RJ, Noble P, Sebire N, et al. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998; 352(9125): 343–6

    Article  PubMed  CAS  Google Scholar 

  5. Walknowska J, Conte F, Grumbach M. Practical and theoretical implications of fetal/maternal lymphocyte transfer. Lancet 1969; 1: 1119–22

    Article  PubMed  CAS  Google Scholar 

  6. Johnson A, Wapner RJ, Davis GH, et al. Mosaicism in chorionic villus sampling: An association with poor perinatal outcome. Obstet Gynecol 1990; 75: 573–7

    PubMed  CAS  Google Scholar 

  7. Bianchi DW, Zickwolf GK, Weil GJ, et al. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A 1996; 93(2): 705–8

    Article  PubMed  CAS  Google Scholar 

  8. Bianchi DW, Flint AF, Pizzimenti MF, et al. Isolation of fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad Sci U S A 1990; 87(9): 3279–83

    Article  PubMed  CAS  Google Scholar 

  9. 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): 53–7

    Article  PubMed  CAS  Google Scholar 

  10. Troeger C, Zhong XY, Burgemeister R, et al. Approximately half of the erythroblasts in maternal blood are of fetal origin. Mol Hum Reprod 1999; 5(12): 1162–5

    Article  PubMed  CAS  Google Scholar 

  11. Zheng YL, Zhen DK, DeMaria MA, et al. Search for the optimal fetal cell antibody: results of immunophenotyping studies using flow cytometry. Hum Genet 1997; 100(1): 35–42

    Article  PubMed  CAS  Google Scholar 

  12. Ganshirt-Ahlert D, Borjesson-Stoll R, Burschyk M, et al. Detection of fetal trisomies 21 and 18 from maternal blood using triple gradient and magnetic cell sorting. Am J Reprod Immunol 1993; 30(2-3): 194–201

    PubMed  CAS  Google Scholar 

  13. 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): 368–70

    Article  PubMed  CAS  Google Scholar 

  14. Simpson JL, Elias S. Isolating fetal cells from maternal blood. Advances in prenatal diagnosis through molecular technology. JAMA 1993; 270(19): 2357–61

    Article  PubMed  CAS  Google Scholar 

  15. Hamada H, Arinami T, Kubo T, et al. Fetal nucleated cells in maternal peripheral blood: frequency and relationship to gestational age. Hum Genet 1993; 91(5): 427–32

    Article  PubMed  CAS  Google Scholar 

  16. Sohda S, Arinami T, Hamada H, et al. The proportion of fetal nucleated red blood cells in maternal blood: estimation by FACS analysis. Prenat Diagn 1997; 17(8): 743–52

    Article  PubMed  CAS  Google Scholar 

  17. Bianchi DW, Williams JM, Sullivan LM, et al. PCR quantitation of fetal cells in maternal blood in normal and aneuploid pregnancies. Am J Hum Genet 1997; 61(4): 822–9

    Article  PubMed  CAS  Google Scholar 

  18. Holzgreve W, Ghezzi F, Di Naro E, et al. Disturbed feto-maternal cell traffic in preeclampsia. Obstet Gynecol 1998; 91 (5 Pt 1): 669–72

    Article  PubMed  CAS  Google Scholar 

  19. Al-Mufti R, Lees C, Albaiges G, et al. Fetal cells in maternal blood of pregnancies with severe fetal growth restriction. Hum Reprod 2000; 15(1): 218–21

    Article  PubMed  CAS  Google Scholar 

  20. Takabayashi H, Kuwabara S, Ukita T, et al. Development of non-invasive fetal DNA diagnosis from maternal blood. Prenat Diagn 1995; 15(1): 74–7

    Article  PubMed  CAS  Google Scholar 

  21. Samura O, Sekizawa A, Zhen DK, et al. Comparison of fetal cell recovery from maternal blood using a high density gradient for the initial separation step: 1.090 versus 1.119 g/ml. Prenat Diagn 2000; 20(4): 281–6

    Article  PubMed  CAS  Google Scholar 

  22. Sekizawa A, Farina A, Zhen DK, et al. Improvement of fetal cell recovery from maternal blood: suitable density gradient for FACS separation. Fetal Diagn Ther 1999; 14(4): 229–33

    Article  PubMed  CAS  Google Scholar 

  23. DeMaria MA, Zheng YL, Zhen D, et al. Improved fetal nucleated erythrocyte sorting purity using intracellular antifetal hemoglobin and Hoechst 33342. Cytometry 1996; 25(1): 37–45

    Article  PubMed  CAS  Google Scholar 

  24. Bianchi DW, Zickwolf GK, Yih MC, et al. Erythroid-specific antibodies enhance detection of fetal nucleated erythrocytes in maternal blood. Prenat Diagn 1993; 13(4): 293–300

    Article  PubMed  CAS  Google Scholar 

  25. Bianchi DW, Simpson JL, Jackson LG, et al. Fetal cells in maternal blood: NIFTY clinical trial interim analysis. DM-STAT. NICHD fetal cell study (NIFTY) group. Prenat Diagn 1999; 19(10): 994–5

    Article  PubMed  CAS  Google Scholar 

  26. Farina A, Bianchi DW. Fetal cells in maternal blood as a second non-invasive step for fetal Down syndrome screening. Prenat Diagn 1998; 18: 983–4

    Article  PubMed  CAS  Google Scholar 

  27. Zhang N, Cui X, Schmitt K, et al. Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci U S A 1992; 89: 5847–51

    Article  PubMed  CAS  Google Scholar 

  28. Kristjansson K, Chong SS, Van den Veyver IB, et al. Preimplantation single cell analysis of dystrophin gene deletions using whole genome amplification. Nature Genet 1994; 6: 19–23

    Article  PubMed  CAS  Google Scholar 

  29. Sekizawa A, Kimura T, Sasaki M, et al. Prenatal diagnosis of Duchenne muscular dystrophy using a single fetal nucleated erythrocyte in maternal blood. Neurology 1996; 46(5): 1350–3

    Article  PubMed  CAS  Google Scholar 

  30. Sekizawa A, Watanabe A, Kimura T, et al. Prenatal diagnosis of the fetal RhD blood type using a single fetal nucleated erythrocyte from maternal blood. Obstet Gynecol 1996; 87(4): 501–5

    Article  PubMed  CAS  Google Scholar 

  31. Sekizawa A, Taguchi A, Watanabe A, et al. Analysis of HLA-DQ alpha sequences for prenatal diagnosis in single fetal cells from maternal blood. Hum Genet 1998; 102(4): 393–6

    Article  PubMed  CAS  Google Scholar 

  32. Watanabe A, Sekizawa A, Taguchi A, et al. Prenatal diagnosis of ornithine transcarbamylase deficiency by using a single nucleated erythrocyte from maternal blood. Hum Genet 1998; 102(6): 611–5

    Article  PubMed  CAS  Google Scholar 

  33. Cheung MC, Goldberg JD, Kan YW. Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood. Nat Genet 1996; 14(3): 264–8

    Article  PubMed  CAS  Google Scholar 

  34. Zhen DK, Wang JY, Falco VM, et al. Poly-FISH: a technique of repeated hybridizations that improves cytogenetic analysis of fetal cells in maternal blood. Prenat Diagn 1998; 18(11): 1181–5

    Article  PubMed  CAS  Google Scholar 

  35. Sekizawa A, Samura O, Zhen DK, et al. Fetal cell recycling: diagnosis of gender and RhD genotype in the same fetal cell retrieved from maternal blood. Am J Obstet Gynecol 1999; 181 (5 Pt 1): 1237–42

    Article  PubMed  CAS  Google Scholar 

  36. Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350(9076): 485–7

    Article  PubMed  CAS  Google Scholar 

  37. Lo YM, Tein MS, Lau TK, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 1998; 62(4): 768–75

    Article  PubMed  CAS  Google Scholar 

  38. Lo YM, Zhang J, Leung TN, et al. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 1999; 64: 218–24

    Article  PubMed  CAS  Google Scholar 

  39. Sekizawa A, Kondo T, Saito H, et al. Accuracy of noninvasive fetal gender detection from maternal plasma. Clin Chem. In press

  40. Lo YM, Hjelm NM, Fidler C, et al. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 1998; 339(24): 1734–8

    Article  PubMed  CAS  Google Scholar 

  41. Faas BH, Beuling EA, Christiaens GC, et al. Detection of fetal RhD-specific sequences in maternal plasma. Lancet 1998; 352: 1196

    Article  PubMed  CAS  Google Scholar 

  42. Saito H, Sekizawa A, Morimoto T, et al. Prenatal DNA diagnosis of a single-gene disorder from maternal plasma. Lancet 2000; 356(9236): 1170

    Article  PubMed  CAS  Google Scholar 

  43. Shiang R, Thompson L, Zhu Y, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994; 78: 335–42

    Article  PubMed  CAS  Google Scholar 

  44. Amicucci P, Gennarelli M, Novelli G, et al. Prenatal diagnosis of myotonic dystrophy using fetal DNA obtained from maternal plasma. Clin Chem 2000; 46(2): 301–2

    PubMed  CAS  Google Scholar 

  45. Leung TN, Zhang J, Lau TK, et al. Maternal plasma fetal DNA as a marker for preterm labour. Lancet 1998; 352(9144): 1904–5

    Article  PubMed  CAS  Google Scholar 

  46. Lo YM, Leung TN, Tein MS, et al. Quantitative abnormalities of fetal DNA in maternal serum in preeclampsia. Clin Chem 1999; 45(2): 184–8

    PubMed  CAS  Google Scholar 

  47. Lo YM, Lau TK, Zhang J, et al. Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin Chem 1999; 45(10): 1747–51

    PubMed  CAS  Google Scholar 

  48. Zhong X, Burk MR, Troeger C, et al. Fetal DNA in maternal plasma is elevated in pregnancies with aneuploid fetuses. Prenat Diagn 2000; 20(10): 795–8

    Article  PubMed  CAS  Google Scholar 

  49. Ohashi Y, Miharu N, Honda H, et al. Quantitation of fetal DNA in maternal serum in normal and aneuploid pregnancies. Hum Genet 2000. In press

    Google Scholar 

  50. Al-Mufti R, Hambley H, Farzaneh F, et al. Investigation of maternal blood enriched for fetal cells: role in screening and diagnosis of fetal trisomies. Am J Med Genet 1999; 85(1): 66–75

    Article  PubMed  CAS  Google Scholar 

  51. Sekizawa A, Samura O, Zhen D, et al. Apoptosis in fetal nucleated erythrocytes circulating in maternal blood. Prenat Diagn 2000; 20(11): 886–9

    Article  PubMed  CAS  Google Scholar 

  52. Zhong XY, Holzgreve W, Li JC, et al. High levels of fetal erythroblasts and fetal extracellular DNA in the peripheral blood. Prenat Diagn 2000; 20: 838–41

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Showa University School of Medicine, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan

    Akihiko Sekizawa &  Hiroshi Saito

Authors
  1. Akihiko Sekizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Saito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sekizawa, A., Saito, H. Prenatal Screening of Single-Gene Disorders from Maternal Blood. Am J Pharmacogenomics 1, 111–117 (2001). https://doi.org/10.2165/00129785-200101020-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129785-200101020-00004

Keywords

Search

Navigation