Noninvasive Prenatal Testing for Chromosomal and Genetic Conditions

Abstract

Recent advances in molecular genetics and next‐generation DNA (deoxyribonucleic acid) sequencing have generated a new approach to identifying foetuses at increased risk of chromosomal and genetic conditions by measuring cell‐free DNA in maternal plasma. This so‐called noninvasive method utilises cell‐free DNA of placental origin in maternal blood to achieve unprecedented accuracy as a prenatal screening test for Down syndrome. The technology has also created new opportunities for noninvasive testing for single gene disorders, microdeletion syndromes and genome‐wide chromosomal abnormalities.

Key Concepts

  • Cell‐free DNA derived from the placenta is detectable in the plasma of pregnant women from early gestation.
  • Noninvasive prenatal diagnosis (NIPD) of foetal conditions caused by paternally inherited genes can be performed by PCR‐based assays on cell‐free DNA in maternal plasma.
  • NIPD for foetal sex and foetal Rhesus blood group is clinically available in many countries.
  • Next‐generation DNA sequencing technology has facilitated the development of noninvasive prenatal screening tests for chromosomal disorders such as trisomy 21 (Down syndrome).
  • Noninvasive prenatal testing (NIPT) using cell‐free DNA is the most accurate screening test for trisomy 21 to date but still does not have diagnostic accuracy.
  • Invasive testing with amniocentesis or chorionic villus sampling remains the gold standard for prenatal diagnosis of chromosomal disorders.
  • The scope of chromosomal and genetic disorders detectable using cell‐free DNA is expanding rapidly, creating new ethical and medical issues.

Keywords: cell‐free DNA; noninvasive prenatal testing; noninvasive prenatal diagnosis; chromosomal abnormalities; prenatal screening; trisomy 21; Down syndrome; DNA sequencing; foetal abnormalities; single gene disorders

Figure 1. Counting principle of DNA sequencing of maternal plasma for foetal aneuploidy.
Figure 2. Timeline of commercially available NIPT assays for chromosome abnormalities.
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References

Akolekar R, Beta J, Picciarelli G, et al. (2015) Procedure‐related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta‐analysis. Ultrasound in Obstetrics Gynecology 45: 16–26. DOI: 10.1002/uog.14636.

Alberry M, Maddocks D, Jones M, et al. (2007) Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenatal Diagnosis 27: 415–418. DOI: 10.1002/pd.1700.

American College of Obstetricians and Gynecologists (2015) Cell‐free DNA screening for fetal aneuploidy. Committee Opinion No. 640. Obstetrics and Gynecology 126: e31–e37.

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. American Journal of Obstetrics and Gynecology 206 (322): e321–e325.

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 in Obstetrics and Gynecology 41: 26–32.

Benn P, Curnow KJ, Chapman S, et al. (2015a) An economic analysis of cell‐free DNA non‐invasive prenatal testing in the US General Pregnancy Population. PLoS One 10 (7): e0132313.

Benn P, Borrell A, Chiu RW, et al. (2015b) Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenatal Diagnosis 35: 725–734.

Bianchi DW, Parker RL, Wentworth J, et al. (2014) DNA sequencing versus standard prenatal aneuploidy screening. New England Journal of Medicine 370: 799–808.

Bianchi DW, Chudova D, Sehnert AJ, et al. (2015) Noninvasive prenatal testing and incidental detection of occult maternal malignancies. Journal of the American Medical Association 312 (2): 162–169.

Canick JA, Palomaki GE, Kloza EM, et al. (2013) The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenatal Diagnosis 33: 667–674.

Chan LL and Jiang P (2015) Bioinformatics analysis of circulating cell‐free DNA sequencing data. Clinical Chemistry. ePub ahead of print. DOI: 10.1016/j.clinbiochem.2015.04.022.

Chen EZ, Chiu RWK, Sun H, et al. (2011) Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS One 6: e21791.

Chitty LS, Mason S, Barrett A, et al. (2015) Non‐invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next generation sequencing allows for a safer, more accurate and comprehensive approach. Prenatal Diagnosis. ePub ahead of print. DOI: 10.1002/pd.4583.

Chiu RW, Chan KC, Gao Y, et al. (2008) Non‐invasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proceedings of the National Academy of Sciences 105: 20458–20463.

Clausen FB, Steffensen R, Christiansen M, et al. (2014) Routine noninvasive prenatal screening for fetal RHD in plasma of RhD‐negative pregnant women – 2 years of screening experience from Denmark. Prenatal Diagnosis. DOI: 10.1002/pd.4419.

Dondorp W, de Wert G, Bombard Y et al. (2015) Non‐invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations. European Journal of Human Genetics. ePub ahead of print. DOI: 10.1038/ejhg.2015.56.

Fan HC, Blumenfeld YJ, Chitkara U, et al. (2008) Non‐invasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proceedings of the National Academy of Sciences 105: 16266–16271.

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

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

Gil MM, Quezada MS, Revello R, et al. (2015) Analysis of cell‐free DNA in maternal blood in screening for fetal aneuploidies: updated meta‐analysis. Ultrasound in Obstetrics and Gynecology 45 (3): 249–266.

de Graaf G, Haveman M, Hochstenbach R et al. (2011) Changes in yearly birth prevalence rates of children with Down syndrome in the period 1986–2007 in The Netherlands. Journal of Intellectual Disability Research 55: 462–473.

Gross SJ, Stosic M, McDonald‐McGinn DM, et al. (2015) Clinical experience with single‐nucleotide polymorphism‐based noninvasive prenatal screening for 22q11.2 deletion syndrome. Ultrasound in Obstetrics and Gynecology. DOI: 10.1002/uog.15754.

Guibert J, Benachi A, Grebille AG, et al. (2003) Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique. Human Reproduction 18: 1733–1736.

Gupta AK, Holzgreve W, Huppertz B, et al. (2004) Detection of fetal DNA and RNA in placenta‐derived syncytiotrophoblast microparticles generated in vitro. Clinical Chemistry 50: 2187–2190.

Helgeson J, Wardrop J, Boomer T, et al. (2015) Clinical outcome of subchromosomal events detected by whole genome noninvasive prenatal testing. Prenatal Diagnosis 35: 1–6.

Hill M, Finning K, Martin P, et al. (2011) Non‐invasive prenatal determination of fetal sex: translating research into clinical practice. Clinical Genetics 80: 68–75.

Hui L, Vaughan JI and Nelson M (2008) Effect of labor on postpartum clearance of cell‐free fetal DNA from the maternal circulation. Prenatal Diagnosis 28: 304–308. DOI: 10.1002/pd.1975.

Hui L, Maron JL and Gahan PB (2015a) Other body fluids as non‐invasive sources of cell‐free DNA/RNA. In: Gahan PB (ed) Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring, pp. 295–324. Dordrecht: Springer.

Hui L, Muggli E and Halliday JL (2015b) Population‐based trends in prenatal screening and diagnosis for aneuploidy: a retrospective analysis of 38 years of state‐wide data. BJOG. ePub ahead of print. DOI: 10.1111/1471-0528.13488.

de Jong A, Maya I and van Lith JM (2015) Prenatal screening: current practice, new developments, ethical challenges. Bioethics 29 (1): 1–8.

Juneau K, Bogard PE, Huang S, et al. (2014) Microarray‐based cell‐free DNA analysis improves noninvasive prenatal testing. Fetal Diagnosis and Therapy 36 (4): 282–286.

Kinnings SL, Geis JA, Almasri E, et al. (2015) Factors affecting levels of circulating cell‐free fetal DNA in maternal plasma and their implications for noninvasive prenatal testing. Prenatal Diagnosis 35: 816–822.

Lam KW, Jiang P, Liao GJ, et al. (2012) Non‐invasive prenatal diagnosis of monogenic diseases by targeted massively parallel sequencing of maternal plasma: application to b‐thalassemia. Clinical Chemistry 58: 1467–1475.

Lau TK, Cheung SW, Lo PSS, et al. (2014) Non‐invasive prenatal testing for fetal chromosomal abnormalities by low‐coverage whole‐genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center. Ultrasound in Obstetrics and Gynecology 43: 254–264.

Lench N, Barrett A, Fielding S, et al. (2013) The clinical implementation of non‐invasive prenatal diagnosis for single‐gene disorders: challenges and progress made. Prenatal Diagnosis 33 (6): 555–562.

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

Lo YM, Zhang J, Leung TN, et al. (1999) Rapid clearance of fetal DNA from maternal plasma. American Journal of Human Genetics 64: 218–224.

Lui YY, Chik KW, Chiu RW, et al. (2002) Predominant hematopoietic origin of cell‐free DNA in plasma and serum after sex‐mismatched bone marrow transplantation. Clinical Chemistry 48 (3): 421–427.

Lun FM, Tsui NB, Chan KC, et al. (2008) Non‐invasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proceedings of the National Academy of Sciences 105: 19920–19925.

Mazloom AR, Liu T, Lefkowitz R, et al. (2015) Karyotype level non‐invasive prenatal testing by sequencing of circulating cell‐free DNA from maternal plasma. Prenatal Diagnosis 35 (66): P2–P37.

Nicolaides KH (2011) Screening for fetal aneuploidies at 11 to 13 weeks. Prenatal Diagnosis 31: 7–15.

Nicolaides KH, Syngelaki A, Gil M, et al. (2013) Validation of targeted sequencing of single‐nucleotide polymorphisms for non‐invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenatal Diagnosis 33: 575–579.

Snijders RJ, Noble P, Sebire N, et al. (1998) 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 352: 343–346.

Sparks AB, Struble CA, Wang ET, et al. (2012) Noninvasive prenatal detection and selective analysis of cell‐free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. American Journal of Obstetrics and Gynecology 206 (319): e311–e319.

Srinivasan A, Bianchi DW, Huang H, et al. (2013) Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. American Journal of Human Genetics 92: 167–176.

Tabor A and Alfirevic Z (2010) Update on procedure‐related risks for prenatal diagnosis techniques. Fetal Diagnosis and Therapy 27: 1–7.

Wald NJ, Rodeck C, Hackshaw AK, et al. (2003) First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Journal of Medical Screenining 10: 56–104.

Wang Y, Chen Y, Tian F, et al. (2014) Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clinical Chemistry 60 (1): 251–259.

Wapner RJ, Babiarz JE, Levy B, et al. (2015) Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. American Journal of Obstetrics and Gynecology 212: 332.e1–332.e9.

Warsof SL, Larion S and Abuhamad AZ (2015) Overview of the impact of noninvasive prenatal testing on diagnostic procedures. Prenatal Diagnosis. ePub ahead of print. DOI: 10.1002/pd.4601.

Yu SC, Jiang P, Choy KW, et al. (2013) Noninvasive prenatal molecular karyotyping from maternal plasma. PLoS One 8: e60968. DOI: 10.1371/journal.pone.0060968.

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. Prenatal Diagnosis 32: 1233–1241.

Further Reading

Allyse M, Minear MA, Berson E, et al. (2015) Non‐invasive prenatal testing: a review of international implementation and challenges. International Journal of Women's Health 7: 113–126.

Chitty LS and Lo YMD (2015) Noninvasive prenatal screening for genetic diseases using massively parallel sequencing of maternal plasma DNA. Cold Spring Harbor Perspectives in Medicine. ePub ahead of print. DOI: 10.1101/cshperspect.a023085.

Royal College of Obstetricans and Gynaecologists (2014) Non‐invasive Prenatal Testing For Chromosome Abnormality Using Maternal Plasma DNA. Scientific impact paper No. 15. https://www.rcog.org.uk/globalassets/documents/guidelines/sip_15_04032014.pdf.

Sachs A, Blanchard L, Buchanan A, et al. (2015) Recommended pre‐test counselling points for noninvasive prenatal testing using cell‐free DNA: a 2015 perspective. Prenatal Diagnosis 35: 968–971.

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How to Cite close
Hui, Lisa(Jan 2016) Noninvasive Prenatal Testing for Chromosomal and Genetic Conditions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024388]