Nichtinvasive Pränataldiagnostik

ETS und NGS-basierte Tests

Non-invasive prenatal diagnostics

ETS and NGS-based tests

Zusammenfassung

Das Ersttrimesterscreening zur Risikobestimmung für die Trisomien 21, 18 und 13 hat sich in den letzten 15 Jahren in Deutschland etabliert. Die optimale Durchführung setzt die Einhaltung bestimmter Messkriterien beim Ultraschall und bei der biochemischen Analyse voraus sowie die Benutzung evaluierter Risikoberechnungsprogramme wie dem Berechnungsprogramm PRC der Fetal Medicine Foundation Deutschland (FMF-D). Durch die neue Version des Berechnungsprogramms PRC konnten die Trisomie-21-, -18- und -13-Detektionsraten erhöht werden bei gleichzeitiger Senkung der Falsch-positiv-Raten, was einen großen Fortschritt verglichen mit der mütterlichen Altersindikation darstellt.

Durch die Analyse der zellfreien fetalen DNA aus dem mütterlichen Plasma können seit 2 Jahren aber wesentlich bessere Screeningvorhersagen getroffen werden. Über 99 % aller Trisomie-21-Schwangerschaften können mit dieser Methodik als Risikogruppe beschrieben werden. Die Falsch-positiv-Rate liegt unter 1 %. Durch diese Methode ist ein Paradigmenwechsel in der Pränataldiagnostik zu erwarten.

Abstract

First trimester screening for the risk evaluation of trisomy 21, 18 and 13 has become established in Germany over the last 15 years. Optimal implementation requires the use of certain measurement criteria in ultrasound and biochemical analyses as well as the use of an evaluated risk calculation program. In Germany individual risk calculation is mostly performed using the PRC calculation program from the Fetal Medicine Foundation Germany (FMF-D). By using a new version trisomy 21, 18 and 13 detection rates could be increased while reducing false positive rates which represents significant progress compared to the maternal age indications.

By analyzing cell-free fetal DNA from maternal plasma significantly better prediction rates could be achieved in screening within the last 2 years. Approximately 99 % of trisomy 21 pregnancies can be described as a risk group with this methodology. The false positive rate is below 1 %. By using this method a paradigm shift in the prenatal diagnostics can be expected.

This is a preview of subscription content, log in to check access.

Abb. 1

Literatur

  1. 1

    Tabor A, Alfirevic Z (2010) Update on procedure-related risks for prenatal diagnosis techniques. Fetal Diagn Ther 27(1):1–7

    PubMed  Article  Google Scholar 

  2. 2

    Gendiagnostik-Kommission am Robert Koch-Institut 2013: Richtlinie der Gendiagnostik-Kommission (GEKO) für die Anforderungen an die Durchführung der vorgeburtlichen Risikoabklärung sowie an die insoweit erforderlichen Maßnahmen zur Qualitätssicherung gemäß § 23 Abs. 2 Nr. 5 GenDG in der Fassung vom 12.04.2013 veröffentlicht und in Kraft getreten am 22.04.2013

  3. 3

    Kagan KO, Wright D, Etchegaray A, Zhou Y, Nicolaides KH (2009) Effect of deviation of nuchal translucency measurements on the performance of screening for trisomy 21. Ultrasound Obstet Gynecol 33(6):657–664

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Kagan KO, Cicero S, Staboulidou I, Wright D, Nicolaides KH (2009) Fetal nasal bone in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 33(3):259–264

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Kagan KO, Valencia C, Livanos P, Wright D, Nicolaides KH (2009) Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11 + 0 to 13 + 6 weeks of gestation. Ultrasound Obstet Gynecol 33(1):18–22

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Maiz N, Wright D, Ferreira AFA, Syngelaki A, Nicolaides KH (2012) A mixture model of ductus venosus pulsatility index in screening for aneuploidies at 11–13 weeks’ gestation. Fetal Diagn Ther 31(4):221–229

    PubMed  Article  Google Scholar 

  7. 7

    Wright D, Spencer K, Kagan K K, Tørring N, Petersen OB, Christou A et al (2010) First-trimester combined screening for trisomy 21 at 7–14 weeks’ gestation. Ultrasound Obstet Gynecol 36(4):404–411

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Merz E, Eiben B, Thode C (2014) Die neue Ersttrimestersoftware PRC 3.0 der FMF-Deutschland. Frauenarzt 55:2

    Google Scholar 

  9. 9

    Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH (2008) Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free-hCG and pregnancy-associated plasma protein-A. Hum Reprod 23(9):1968–1975

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Nicolaides KH, Spencer K, Avgidou K et al (2005) Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 25:221–226

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Merz E, Thode C, Eiben B et al (2011) Individualized correction for maternal weight in calculating the risk of chromosomal abnormalities with first-trimester screening data. Ultraschall Med 32:33–39

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Eiben B, Thode C, Merz E (2011) Das Ersttrimesterscreening und die neue Risikoberechnungssoftware der Fetal Medicine Foundation Deutschland. Medgen Springer-Verlag 23:453–456

    Google Scholar 

  13. 13

    Holzgreve W, Garritsen HS, Ganshirt-Ahlert D (1992) Fetal cells in the maternal circulation. J Reprod Med 37:410–418

    CAS  PubMed  Google Scholar 

  14. 14

    Bianchi DW, Simpson JL, Jackson LG et al (2002) 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 22:609–615

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Lo YM, Corbetta N, Chamberlain PF et al (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–487

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Lo YM, Chan KC, Sun H et al (2010) Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2:61ra91

  17. 17

    Lo YM, Tein MS, Lau TK et al (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 62:768–775

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18

    Wegner RD, Stumm M (2011) Zytogenetische Methoden in der Pränataldiagnostik. Medgen 23:457–462

    Article  Google Scholar 

  19. 19

    Mennuti TM, Cherry AM, Morrissette JJ, Lorraine D (2013) Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy? Am J Obstet Gynecol 209(5):415–419

    PubMed  Article  Google Scholar 

  20. 20

    Fan HC, GuW, Wang J et al (2012) Non-invasive prenatal measurement of the fetal genome. Nature 487:320–324

  21. 21

    Metzker ML (2010) Sequencing technologies – the next generation. Nat Rev Genet 11:31–46

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Ashoor G, Syngelaki A, Poon LC et al (2013) Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’ gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 41:26–32

    CAS  PubMed  Article  Google Scholar 

  23. 23

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

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. 24

    Wang E, Batey A, Struble C et al (2013) Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma. Prenat Diagn 33:662–666

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Stumm M, Entezami M, Trunk N et al (2012) Noninvasive prenatal detection of chromosomal aneuploidies using different next generation sequencing strategies and algorithms. Prenat Diagn 32:569–577

    PubMed  Article  Google Scholar 

  26. 26

    Sparks AB, Wang ET, Struble CA et al (2012) Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 32:3–9

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  27. 27

    Palomaki GE, Kloza EM, Lambert-Messerlian GM et al (2011) DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 13:913–920

    CAS  PubMed  Article  Google Scholar 

  28. 28

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

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Chiu RW, Chan KC, Gao Y et al (2008) Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Nat Acad Sci USA 105:20458–20463

  30. 30

    Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE (2013) The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn 33:667–674

  31. 31

    Zimmermann B, Hill M, Gemelos G et al (2012) Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn 32:1233–1241

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. 32

    Dhallan R, Guo X, Emche S et al (2007) A non-invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet 369:474–481

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Gesetz über genetische Untersuchungen bei Menschen (Gendiagnostikgesetz – GenDG). http://www.gesetze-im-internet.de/bundesrecht/gendg/gesamt.pdf. Zugegriffen: 7. Dez. 2013

  34. 34

    Gendiagnostik-Kommission am Robert Koch-Institut (2014) „Zur Einordnung der nicht-invasiven Pränataldiagnostik (NIPD)“ vom 12.3.2014

  35. 35

    Grati FR, Barlocco A, Grimi B et al (2010) Chromosome abnormalities investigated by non-invasive prenatal testing account for approximately 50 % of fetal unbalances associated with relevant clinical phenotypes. Am J Med Genet 152A:1434–1442

    PubMed  Google Scholar 

  36. 36

    Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G (2012) Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 207(5):374.e1–e6

    PubMed  Article  Google Scholar 

  37. 37

    Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF et al (2014) DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 370(9):799–808

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Kagan KO, Staboulidou I, Syngelaki A et al (2010) The 11–13-week scan: diagnosis and outcome of holoprosencephaly, exomphalos and megacystis. Ultrasound Obstet Gynecol 36:10–14

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Norton ME, Brar H, Weiss J et al (2012) 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 207:137.e1–8

    PubMed  Google Scholar 

  40. 40

    Ashoor G, Syngelaki A, Wagner M et al (2012) Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol 206:322.e1–5

    PubMed  Google Scholar 

  41. 41

    Ashoor G, Syngelaki A, Wang E et al (2013) Trisomy 13 detection in the first trimester of pregnancy using a chromosome-selective cell-free DNA analysis method. Ultrasound Obstet Gynecol 41:21–25

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Huang X, Zheng J, Chen M et al (2014) Noninvasive prenatal testing of trisomies 21 and 18 by massively parallel sequencing of maternal plasma DNA in twin pregnancies. Prenat Diagn 34:335

  43. 43

    Fairbrother G, Johnson S, Musci TJ et al (2013) Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population. Prenat Diagn 33:580–583

    PubMed  Article  Google Scholar 

  44. 44

    Mulvey S, Wallace EM (2000) Women’s knowledge of and attitudes to first and second trimester screening for Down’s syndrome. BJOG 107:1302–1305

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Eiben B, Hall M, Ludwig M et al (2013) Ein neuer nichtinvasiver Pränataltest. Frauenarzt 54:768–770

    Google Scholar 

  46. 46

    Eiben B, Thode C, Merz E (2013) Nichtinvasive Pränataldiagnostik – Serumtestsysteme zur Erfassung von Chromosomenanomalien. Gynakol Geburtsh 18:34–37

    Google Scholar 

  47. 47

    Eiben B, Glaubitz R, Merz E (2012) Trisomie-21-Analyse aus mütterlichem Blut. Frauenarzt 53:834–835

    Google Scholar 

  48. 48

    Tercanli S, Vial Y, Merz E (2013) Nicht invasiver Chromosomentest wirft neue Fragen in der Pränataldiagnostik nach der Bedeutung des Ultraschalls und Fragen nach neuen Screeningstrategien auf. Ultraschall Med 34:417–420

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Stellungnahme der Deutschen Gesellschaft für Humangenetik (GfH) zur Analyse fetaler DNA aus dem mütterlichen Blut. http://www.gfhev.de/de/leitlinien/LL_und_Stellungnahmen/2012_11_12_GfH_Stellungnahme_Analyse_fetale_DNA.pdf. Zugegriffen: 7. Dez. 2013

  50. 50

    Kagan KO, Hoopmann M, Hammer R, Stressig R, Kozlowski P (2014) Screening for chromosomal abnormalities by first trimester combined screening and non-invasive prenatal testing. Ultraschall Med (In press)

  51. 51

    Kagan KO, Wright D, Baker A, Sahota D, Nicolaides KH (2008) Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 31(6):618–624

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Maiz N, Valencia C, Kagan KO et al (2009) Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 33:512–517

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Kagan KO, Eiben B, Kozlowski P (2014) Combined first trimester screening and cell-free fetal DNA – “next generation screening”. Ultraschall Med 35(3):229–236

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Kagan K, Hoopmann M, Kozlowski P (2012) Assessment of foetal DNA in maternal blood – a useful tool in the hands of prenatal specialists. Geburtsh Frauenheilkd 72(11):998–1003

    CAS  Article  Google Scholar 

  55. 55

    Salomon LJ, Alfirevic Z, Bilardo CM et al (2013) ISUOG practice guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 41:102–113

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Kitzman JO, Snyder MW, Ventura M et al (2012) Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med 4:137ra76

  57. 57

    Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH (2011) Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11–13 weeks. Prenat Diagn 31:66–74

    PubMed  Article  Google Scholar 

  58. 58

    Nanda S, Akolekar R, Sarquis R et al (2011) Maternal serum adiponectin at 11 to 13 weeks of gestation in the prediction of macrosomia. Prenat Diagn 31:479–483

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Kagan KO, Hoopmann M, Abele H et al (2012) First-trimester combined screening for trisomy 21 with different combinations of placental growth factor, free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 40:530–535

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Poon LC, Musci T, Song K et al (2013) Maternal plasma cell-free fetal and maternal DNA at 11–13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal Diagn Ther 33:215–223

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Papantoniou N, Bagiokos V, Agiannitopoulos K et al (2013) RASSF1A in maternal plasma as a molecular marker of preeclampsia. Prenat Diagn 33:682–687

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Bernd Eiben.

Ethics declarations

Interessenkonflikt

Potenzieller Interessenkonflikt: B. Eiben und R. Glaubitz sind Mitarbeiter der amedes Laborgruppe, die den Panoramatest in Deutschland vertreibt. K.O. Kagan gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eiben, B., Glaubitz, R. & Kagan, K. Nichtinvasive Pränataldiagnostik. medgen 26, 382–390 (2014). https://doi.org/10.1007/s11825-014-0021-3

Download citation

Schlüsselwörter

  • Ersttrimesterscreening
  • Nackentransparenz
  • Sonographische Untersuchung
  • NIPT
  • Zellfreie fetale DNA
  • Detektionsraten
  • Trisomie 21, 18, 13
  • Monosomie X

Keywords

  • First trimester screening
  • Nuchal translucency
  • Sonography
  • Non-invasive prenatal testing
  • Cell-free fetal DNA
  • Detection rate
  • Trisomy 21, 18, 13
  • Monosomy X