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Fetal DNA detection in maternal plasma throughout gestation

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Abstract

The presence of fetal DNA in maternal plasma may represent a source of genetic material which can be obtained noninvasively. We wanted to assess whether fetal DNA is detectable in all pregnant women, to define the range and distribution of fetal DNA concentration at different gestational ages, to identify the optimal period to obtain a maternal blood sample yielding an adequate amount of fetal DNA for prenatal diagnosis, and to evaluate accuracy and predictive values of this approach. This information is crucial to develop safe and reliable non-invasive genetic testing in early pregnancy and monitoring of pregnancy complications in late gestation. Fetal DNA quantification in maternal plasma was carried out by real-time PCR on the SRY gene in male-bearing pregnancies to distinguish between maternal and fetal DNA. A cohort of 1,837 pregnant women was investigated. Fetal DNA could be detected from the sixth week and could be retrieved at any gestational week. No false-positive results were obtained in 163 women with previous embryo loss or previous male babies. Fetal DNA analysis performed blindly on a subset of 464 women displayed 99.4, 97.8 and 100% accuracy in fetal gender determination during the first, second, and third trimester of pregnancy, respectively. No SRY amplification was obtained in seven out of the 246 (2.8%) male-bearing pregnancies. Fetal DNA from maternal plasma seems to be an adequate and reliable source of genetic material for a noninvasive prenatal diagnostic approach.

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References

  • Atkinson AC (1980) A note on the generalized information criterion for the choice of a model. Biometrika 67:413–418

    Google Scholar 

  • Bianchi DW (1998) Current knowledge about fetal blood cells in the maternal circulation. J Perinat Med 26:175–185

    CAS  PubMed  Google Scholar 

  • Birch L, English CA, O’Donoghue K, Barigye O, Fisk NM, Keer JT (2005) Accurate and robust quantification of circulating fetal and total DNA in maternal plasma from 5 to 41 weeks of gestation. Clin Chem 51:312–320

    Article  CAS  PubMed  Google Scholar 

  • Chiu RW, Poon LL, Lau TK, Leung TN, Wong EM, Lo YM (2001) Effects of blood-processing protocols on fetal and total DNA quantification in maternal plasma. Clin Chem 47:1607–1613

    Google Scholar 

  • Costa JM, Benachi A, Gautier E, Jouannic JM, Ernault P, Dumez Y (2001) First-trimester fetal sex determination in maternal serum using real-time PCR. Prenat Diagn 21:1070–1074

    Article  CAS  PubMed  Google Scholar 

  • Costa JM, Giovangrandi Y, Ernault P, Lohmann L, Nataf V, El Halali N, Gautier E (2002) Fetal RHD genotyping in maternal serum during the first trimester of pregnancy. Br J Haematol 119:255–260

    Article  PubMed  Google Scholar 

  • Cremonesi L, Galbiati S, Foglieni B, Smid M, Gambini D, Ferrari A, Viora E, Campogrande M, Pagliano M, Travi M, Piga A, Restagno G, Ferrari M (2004) Feasibility study for a microchip-based approach for noninvasive prenatal diagnosis of genetic diseases. Ann NY Acad Sci 1022:105–112

    Article  CAS  PubMed  Google Scholar 

  • Ding C, Chiu RW, Lau TK, Leung TN, Chan LC, Chan AY, Charoenkwan P, Ng IS, Law HY, Ma ES, Xu X, Wanapirak C, Sanguansermsri T, Liao C, Ai MA, Chui DH, Cantor CR, Lo YM (2004) MS analysis of single-nucleotide differences in circulating nucleic acids: application to noninvasive prenatal diagnosis. Proc Natl Acad Sci USA 101:10762–10767

    Article  CAS  PubMed  Google Scholar 

  • Falcinelli C, Battafarano S, Neri C, Mazza V, Ranzi A, Volpe A, Forabosco A (1999) First-trimester fetal sex prediction by deoxyribonucleic acid analysis of maternal peripheral blood. Am J Obstet Gynecol 181:675–680

    CAS  PubMed  Google Scholar 

  • Finning KM, Martin PG, Soothill PW, Avent ND (2002) Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service. Transfusion 42:1079–1085

    Article  CAS  PubMed  Google Scholar 

  • Fucharoen G, Tungwiwat W, Ratanasiri T, Sanchaisuriya K, Fucharoen S (2003) Prenatal detection of fetal hemoglobin E gene from maternal plasma. Prenat Diagn 23:393–396

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ, Rodriguez de Alba M, Lorda-Sanchez I, Diaz-Recasens J, Gallardo E, Ayuso C, Ramos C (2002) Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diagn 22:946–948

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Gonzalez MC, Trujillo MJ, Rodriguez de Alba M, Garcia-Hoyos M, Lorda-Sanchez I, Diaz-Recasens J, Ayuso C, Ramos C (2003) Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR. Prenat Diagn 23:232–234

    Article  CAS  PubMed  Google Scholar 

  • Johnson KL, Dukes KA, Vidaver J, LeShane ES, Ramirez I, Weber WD, Bischoff FZ, Hahn S, Sharma A, Dang DX, Hire LM, Bianchi DW, Simpson JL, Holzgreve W, Elias S, Klinger KW (2004) Interlaboratory comparison of fetal male DNA detection from common maternal plasma samples by real-time PCR. Clin Chem 50:516–521

    Article  CAS  PubMed  Google Scholar 

  • Leung TN, Zhang J, Lau TK, Hjelm NM, Lo YM (1998) Maternal plasma fetal DNA as a marker for preterm labour. Lancet 352:1904–1905

    Article  CAS  Google Scholar 

  • Lo YM (1999) Fetal RhD genotyping from maternal plasma. Ann Med 31:308–312

    CAS  PubMed  Google Scholar 

  • Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–487

    Article  CAS  PubMed  Google Scholar 

  • Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, Wainscoat JS, Johnson PJ, Chang AM, Hjelm NM (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 62:768–775

    Article  CAS  PubMed  Google Scholar 

  • Lo YM, Lau TK, Zhang J, Leung TN, Chang AM, Hjelm NM, Elmes RS, Bianchi DW (1999a) Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin Chem 45:1747–1751

    CAS  Google Scholar 

  • Lo YM, Zhang J, Leung TN, Lau TK, Chang AM, Hjelm NM (1999b) Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 64:218–224

    Article  CAS  Google Scholar 

  • Nasis O, Thompson S, Hong T, Sherwood M, Radcliffe S, Jackson L, Otevrel T (2004) Improvement in sensitivity of allele-specific PCR facilitates reliable noninvasive prenatal detection of cystic fibrosis. Clin Chem 50:694–701

    Google Scholar 

  • R Development Core Team (2004) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

  • Rijnders RJ, Christiaens GC, Soussan AA, van der Schoot CE (2004) Cell-free fetal DNA is not present in plasma of nonpregnant mothers. Clin Chem 50:679–681 (author reply 681)

    Google Scholar 

  • Rouillac-Le Sciellour C, Puillandre P, Gillot R, Baulard C, Metral S, Le Van Kim C, Cartron JP, Colin Y, Brossard Y (2004) Large-scale pre-diagnosis study of fetal RHD genotyping by PCR on plasma DNA from RhD-negative pregnant women. Mol Diagn 8:23–31

    PubMed  Google Scholar 

  • Saito H, Sekizawa A, Morimoto T, Suzuki M, Yanaihara T (2000) Prenatal DNA diagnosis of a single-gene disorder from maternal plasma. Lancet 356:1170

    Article  CAS  PubMed  Google Scholar 

  • Sekizawa A, Kondo T, Iwasaki M, Watanabe A, Jimbo M, Saito H, Okai T (2001) Accuracy of fetal gender determination by analysis of DNA in maternal plasma. Clin Chem 47:1856–1858

    Google Scholar 

  • Smid M, Lagona F, Papasergio N, Ferrari A, Ferrari M, Cremonesi L (1997) Influence of gestational age on fetal deoxyribonucleic acid retrieval in maternal peripheral blood. Am J Obstet Gynecol 177:1517–1522

    CAS  PubMed  Google Scholar 

  • Smid M, Galbiati S, Vassallo A, Gambini D, Ferrari A, Restagno G, Viora E, Pagliano M, Calza S, Ferrari M, Cremonesi L (2003a) Fetal DNA in maternal plasma in twin pregnancies. Clin Chem 49:1526–1528

    Article  CAS  Google Scholar 

  • Smid M, Galbiati S, Vassallo A, Gambini D, Ferrari A, Viora E, Pagliano M, Restagno G, Ferrari M, Cremonesi L (2003b) No evidence of fetal DNA persistence in maternal plasma after pregnancy. Hum Genet 112:617–618

    Google Scholar 

  • Wataganara T, LeShane ES, Farina A, Messerlian GM, Lee T, Canick JA, Bianchi DW (2003) Maternal serum cell-free fetal DNA levels are increased in cases of trisomy 13 but not trisomy 18. Hum Genet 112:204–208

    CAS  PubMed  Google Scholar 

  • Zhong XY, Laivuori H, Livingston JC, Ylikorkala O, Sibai BM, Holzgreve W, Hahn S (2001) Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol 184:414–419

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Telethon, Project number GGP02015 (L.C.), MIUR Cofin 2002 (A.F.).

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Authors and Affiliations

  1. Unit of Genomics for Diagnosis of Human Pathologies, IRCCS H. San Raffaele, Via Olgettina 58, 20132, Milan, Italy

    Silvia Galbiati, Maurizio Ferrari & Laura Cremonesi

  2. Department of Obstetrics and Gynecology, IRCCS H. San Raffaele, Milan, Italy

    Maddalena Smid, Dania Gambini & Augusto Ferrari

  3. Struttura Complessa Genetica Molecolare, A.O.O.I.R.M.-S. Anna, Torino, Italy

    Gabriella Restagno

  4. Centro di Ecografia e Diagnosi Prenatale, Ospedale S. Anna, Torino, Italy

    Elsa Viora, Mario Campogrande & Simona Bastonero

  5. Cattedra A, Università di Torino, Torino, Italy

    Marco Pagliano

  6. Sezione di Statistica Medica e Biometria, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia, Brescia, Italy

    Stefano Calza

  7. Diagnostica e Ricerca S. Raffaele S.p.A., H. San Raffaele, Milan, Italy

    Maurizio Ferrari

Authors
  1. Silvia Galbiati
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  2. Maddalena Smid
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  3. Dania Gambini
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  4. Augusto Ferrari
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  5. Gabriella Restagno
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  6. Elsa Viora
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  7. Mario Campogrande
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  8. Simona Bastonero
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  9. Marco Pagliano
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  10. Stefano Calza
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  11. Maurizio Ferrari
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  12. Laura Cremonesi
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Corresponding author

Correspondence to Laura Cremonesi.

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Galbiati, S., Smid, M., Gambini, D. et al. Fetal DNA detection in maternal plasma throughout gestation. Hum Genet 117, 243–248 (2005). https://doi.org/10.1007/s00439-005-1330-z

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  • DOI: https://doi.org/10.1007/s00439-005-1330-z

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