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Genomic Applications in Pathology pp 561–582Cite as

Sequencing Cell-Free DNA in the Maternal Circulation to Screen for Down Syndrome, Other Common Trisomies, and Selected Genetic Disorders

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Abstract

Up to three-quarters of pregnant women in the USA receive prenatal screening for Down syndrome (DS) and other fetal disorders. Historically, such testing has been based on combinations of maternal age, biochemical markers, and ultrasound findings with maximal detection rate for Down syndrome of 90% (sensitivity) at a false-positive rate of 2% (1-specificity) in a general pregnancy population. In 1997, a group from Hong Kong identified “fetal” cell-free (cf)DNA in maternal circulation. Unlike serum screening, cfDNA screening for Down syndrome is based directly on detection of extra chromosome 21 material from the fetal/placental unit. Following the 2011 publication of a prospective clinical trial of cfDNA, the first commercial prenatal screening test for Down syndrome based on circulating cfDNA was introduced into clinical practice. Among over 2000 DS and 200,000 euploid samples successfully tested, the detection rate for Down syndrome by a variety of cfDNA methods is presently over 99%, with a false-positive rate of about 0.2%. Multiple methodologies introduced by different laboratories have also shown detection rates at or above 95% for both trisomy 18 and trisomy 13. Occasionally (<1% to 5%), cfDNA testing fails to provide a usable results. Many of the commercial cfDNA tests also can identify the fetal sex as well as the common sex chromosome aneuploidies. This chapter discusses the use of cfDNA for the common autosomal trisomies, sex chromosome aneuploidies, microdeletions, nonviable chromosome disorders, emerging applications, technical limitations, emerging social and ethical issues, and areas for future study.

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References

  1. Wald NJ. The definition of screening. J Med Screen. 2001;8(1):1.

    CAS  PubMed  Google Scholar 

  2. Down JLH. Observations on an ethnic classification of idiots. London Hosp Rep. 1866;3:259–62.

    Google Scholar 

  3. Lejeune J, Gautier M, Turpin R. Study of somatic chromosomes from 9 mongoloid children. C R Hebd Seances Acad Sci. 1959;248(11):1721–2.

    CAS  PubMed  Google Scholar 

  4. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217–27.

    Google Scholar 

  5. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol. 1984;148(7):886–94.

    CAS  PubMed  Google Scholar 

  6. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet. 1984;1(8383):926–9.

    CAS  PubMed  Google Scholar 

  7. Palomaki GE, Haddow JE. Maternal serum alpha-fetoprotein, age, and Down syndrome risk. Am J Obstet Gynecol. 1987;156(2):460–3.

    CAS  PubMed  Google Scholar 

  8. Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn. 1987;7(9):623–30.

    CAS  PubMed  Google Scholar 

  9. Canick JA, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down’s syndrome. Br J Obstet Gynaecol. 1988;95(4):330–3.

    CAS  PubMed  Google Scholar 

  10. Haddow JE, Palomaki GE, Knight GJ, Foster DL, Neveux LM. Second trimester screening for Down’s syndrome using maternal serum dimeric inhibin A. J Med Screen. 1998;5:115–9.

    CAS  PubMed  Google Scholar 

  11. Lambert-Messerlian G, Kloza EM, Williams J 3rd, Loucky J, O'Brien B, Wilkins-Haug L, et al. Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies. Genet Med. 2014;16(5):419–22.

    CAS  PubMed  Google Scholar 

  12. Wald N, Stone R, Cuckle HS, Grudzinskas JG, Barkai G, Brambati B, et al. First trimester concentrations of pregnancy associated plasma protein A and placental protein 14 in Down’s syndrome. BMJ. 1992;305(6844):28.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Spencer K, Macri JN, Aitken DA, Connor JM. Free beta-hCG as first-trimester marker for fetal trisomy. Lancet. 1992;339(8807):1480.

    CAS  PubMed  Google Scholar 

  14. Szabo J, Gellen J. Nuchal fluid accumulation in trisomy-21 detected by vaginosonography in first trimester. Lancet. 1990;336(8723):1133.

    CAS  PubMed  Google Scholar 

  15. Zimmermann R, Hucha A, Savoldelli G, Binkert F, Achermann J, Grudzinskas JG. Serum parameters and nuchal translucency in first trimester screening for fetal chromosomal abnormalities. Br J Obstet Gynaecol. 1996;103(10):1009–14.

    CAS  PubMed  Google Scholar 

  16. Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down’s syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med. 1999;341(7):461–7.

    CAS  PubMed  Google Scholar 

  17. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen. 2003;10(2):56–104.

    CAS  PubMed  Google Scholar 

  18. Palomaki GE, Knight GJ, Ashwood ER, Best RG, Haddow JE. Screening for down syndrome in the United States: results of surveys in 2011 and 2012. Arch Pathol Lab Med. 2013;137(7):921–6.

    PubMed  Google Scholar 

  19. Palomaki GE, Ashwood ER, Best RG, Lambert-Messerlian G, Knight GJ. Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States? Genet Med. 2015;17(11):897–900.

    CAS  PubMed  Google Scholar 

  20. Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks: a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol. 2002;20(3):219–25.

    CAS  PubMed  Google Scholar 

  21. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076):485–7.

    CAS  PubMed  Google Scholar 

  22. Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318–22.

    CAS  PubMed  Google Scholar 

  23. Chen XQ, Stroun M, Magnenat JL, Nicod LP, Kurt AM, Lyautey J, et al. Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med. 1996;2(9):1033–5.

    CAS  PubMed  Google Scholar 

  24. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med. 1996;2(9):1035–7.

    CAS  PubMed  Google Scholar 

  25. Odeh M, Granin V, Kais M, Ophir E, Bornstein J. Sonographic fetal sex determination. Obstet Gynecol Surv. 2009;64(1):50–7.

    PubMed  Google Scholar 

  26. Devaney SA, Palomaki GE, Scott JA, Bianchi DW. Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis. JAMA. 2011;306(6):627–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Clausen FB, Christiansen M, Steffensen R, Jorgensen S, Nielsen C, Jakobsen MA, et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D- pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Transfusion. 2012;52(4):752–8.

    CAS  PubMed  Google Scholar 

  28. Chiu RW, Chan KC, Gao Y, Lau VY, Zheng W, Leung TY, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008;105(51):20458–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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 U S A. 2008;105(42):16266–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011;342:c7401.

    PubMed  PubMed Central  Google Scholar 

  31. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, 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.e1–11.

    Google Scholar 

  32. Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, Burke J, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. 2011;57(7):1042–9.

    CAS  PubMed  Google Scholar 

  33. Sparks AB, Wang ET, Struble CA, Barrett W, Stokowski R, McBride C, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn. 2012;32(1):3–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    CAS  Google Scholar 

  35. Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn. 2012;32(13):1233–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gil MM, Akolekar R, Quezada MS, Bregant B, Nicolaides KH. Analysis of cell-Free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther. 2014;35(3):156–73.

    CAS  PubMed  Google Scholar 

  37. Gil MM, Quezada MS, Revello R, Akolekar R, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2015;45(3):249–66.

    CAS  PubMed  Google Scholar 

  38. Taylor-Phillips S, Freeman K, Geppert J, Agbebiyi A, Uthman OA, Madan J, et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open. 2016;6(1):e010002.

    PubMed  PubMed Central  Google Scholar 

  39. Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG. 2017;124(1):32–46.

    CAS  PubMed  Google Scholar 

  40. Iwarsson E, Jacobsson B, Dagerhamn J, Davidson T, Bernabe E, Heibert Arnlind M. Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population – a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017;96(1):7–18.

    CAS  PubMed  Google Scholar 

  41. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):302–14.

    CAS  PubMed  Google Scholar 

  42. Jin J, Yang J, Chen Y, Huang J. Systematic review and meta-analysis of non-invasive prenatal DNA testing for trisomy 21: implications for implementation in China. Prenat Diagn. 2017;37(9):864–73.

    PubMed  Google Scholar 

  43. Chen EZ, Chiu RW, Sun H, Akolekar R, Chan KC, Leung TY, et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS One. 2011;6(7):e21791.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Savva GM, Walker K, Morris JK. The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21 (Down syndrome). Prenat Diagn. 2010;30(1):57–64.

    PubMed  Google Scholar 

  45. Gruchy N, Blondeel E, Le Meur N, Joly-Helas G, Chambon P, Till M, et al. Pregnancy outcomes in prenatally diagnosed 47, XXX and 47, XYY syndromes: a 30-year French, retrospective, multicentre study. Prenat Diagn. 2016;36(6):523–9.

    PubMed  Google Scholar 

  46. Mennuti MT, Chandrasekaran S, Khalek N, Dugoff L. Cell-free DNA screening and sex chromosome aneuploidies. Prenat Diagn. 2015;35(10):980–5.

    CAS  PubMed  Google Scholar 

  47. Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, et al. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem. 2014;60(1):251–9.

    PubMed  Google Scholar 

  48. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87(1):81–3.

    CAS  PubMed  Google Scholar 

  49. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88(2):622–6.

    CAS  PubMed  Google Scholar 

  50. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011;13(11):913–20.

    CAS  PubMed  Google Scholar 

  51. Kalousek DK, Howard-Peebles PN, Olson SB, Barrett IJ, Dorfmann A, Black SH, et al. Confirmation of CVS mosaicism in term placentae and high frequency of intrauterine growth retardation association with confined placental mosaicism. Prenat Diagn. 1991;11(10):743–50.

    CAS  PubMed  Google Scholar 

  52. Hartwig TS, Ambye L, Sorensen S, Jorgensen FS. Discordant non-invasive prenatal testing (NIPT) – a systematic review. Prenat Diagn. 2017;37(6):527–39.

    PubMed  Google Scholar 

  53. Malvestiti F, Agrati C, Grimi B, Pompilii E, Izzi C, Martinoni L, et al. Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis. Prenat Diagn. 2015;35(11):1117–27.

    CAS  PubMed  Google Scholar 

  54. Kalousek DK, Vekemans M. Confined placental mosaicism. J Med Genet. 1996;33(7):529–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schreck RR, Falik-Borenstein Z, Hirata G. Chromosomal mosaicism in chorionic villus sampling. Clin Perinatol. 1990;17(4):867–88.

    CAS  PubMed  Google Scholar 

  56. Stone JF, Sandberg AA. Sex chromosome aneuploidy and aging. Mutat Res. 1995;338(1–6):107–13.

    CAS  PubMed  Google Scholar 

  57. Yao H, Zhang L, Zhang H, Jiang F, Hu H, Chen F, et al. Noninvasive prenatal genetic testing for fetal aneuploidy detects maternal trisomy X. Prenat Diagn. 2012;32(11):1114–6.

    PubMed  Google Scholar 

  58. Curnow KJ, Wilkins-Haug L, Ryan A, Kirkizlar E, Stosic M, Hall MP, et al. Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstet Gynecol. 2015;212(1):79.e1–9.

    CAS  Google Scholar 

  59. Bianchi DW, Chudova D, Sehnert AJ, Bhatt S, Murray K, Prosen TL, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA. 2015;314(2):162–9.

    CAS  PubMed  Google Scholar 

  60. Amant F, Verheecke M, Wlodarska I, Dehaspe L, Brady P, Brison N, et al. Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing. JAMA Oncol. 2015;1(6):814–9.

    PubMed  Google Scholar 

  61. Snyder HL, Curnow KJ, Bhatt S, Bianchi DW. Follow-up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: implications for management and counseling. Prenat Diagn. 2016;36(3):203–9.

    PubMed  PubMed Central  Google Scholar 

  62. Osborne CM, Hardisty E, Devers P, Kaiser-Rogers K, Hayden MA, Goodnight W, et al. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn. 2013;33(6):609–11.

    PubMed  Google Scholar 

  63. Snyder MW, Gammill HS, Shendure J. Copy-number variation and false positive results of prenatal screening. N Engl J Med. 2015;373(26):2585.

    PubMed  PubMed Central  Google Scholar 

  64. Zhou X, Sui L, Xu Y, Song Y, Qi Q, Zhang J, et al. Contribution of maternal copy number variations to false-positive fetal trisomies detected by noninvasive prenatal testing. Prenat Diagn. 2017;37(4):318–22.

    CAS  PubMed  Google Scholar 

  65. Bianchi DW, Parsa S, Bhatt S, Halks-Miller M, Kurtzman K, Sehnert AJ, et al. Fetal sex chromosome testing by maternal plasma DNA sequencing: clinical laboratory experience and biology. Obstet Gynecol. 2015;125(2):375–82.

    CAS  PubMed  Google Scholar 

  66. Gregg AR, Skotko BG, Benkendorf JL, Monaghan KG, Bajaj K, Best RG, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2016;18(10):1056–65.

    CAS  PubMed  Google Scholar 

  67. Eiben B, Krapp M, Borth H, Kutur N, Kreiselmaier P, Glaubitz R, et al. Single nucleotide polymorphism-based analysis of cell-free fetal DNA in 3000 cases from Germany and Austria. Ultrasound Int Open. 2015;1(1):E8–E11.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. McLennan A, Palma-Dias R, da Silva Costa F, Meagher S, Nisbet DL, Scott F. Noninvasive prenatal testing in routine clinical practice--an audit of NIPT and combined first-trimester screening in an unselected Australian population. Aust N Z J Obstet Gynaecol. 2016;56(1):22–8.

    PubMed  Google Scholar 

  69. Quezada MS, Gil MM, Francisco C, Orosz G, Nicolaides KH. Screening for trisomies 21, 18 and 13 by cell-free DNA analysis of maternal blood at 10-11 weeks' gestation and the combined test at 11-13 weeks. Ultrasound Obstet Gynecol. 2015;45(1):36–41.

    CAS  PubMed  Google Scholar 

  70. Zhang H, Gao Y, Jiang F, Fu M, Yuan Y, Guo Y, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol. 2015;45(5):530–8.

    CAS  PubMed  Google Scholar 

  71. Lau TK, Cheung SW, Lo PS, Pursley AN, Chan MK, Jiang F, et al. 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 Obstet Gynecol. 2014;43(3):254–64.

    CAS  PubMed  Google Scholar 

  72. Zhou Q, Pan L, Chen S, Chen F, Hwang R, Yang X, et al. Clinical application of noninvasive prenatal testing for the detection of trisomies 21, 18, and 13: a hospital experience. Prenat Diagn. 2014;34(11):1061–5.

    PubMed  Google Scholar 

  73. Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine. Practice Bulletin No. 163: screening for fetal aneuploidy. Obstet Gynecol. 2016;127(5):e123–37.

    Google Scholar 

  74. Grati FR, Bajaj K, Zanatta V, Malvestiti F, Malvestiti B, Marcato L, et al. Implications of fetoplacental mosaicism on cell-free DNA testing for sex chromosome aneuploidies. Prenat Diagn. 2017;37:1017.

    CAS  PubMed  Google Scholar 

  75. Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119(5):890–901.

    CAS  PubMed  Google Scholar 

  76. Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn. 2013;33(7):667–74.

    CAS  PubMed  Google Scholar 

  77. Sarno L, Revello R, Hanson E, Akolekar R, Nicolaides KH. Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. Ultrasound Obstet Gynecol. 2016;47(6):705–11.

    CAS  PubMed  Google Scholar 

  78. Canick JA, Kloza EM, Lambert-Messerlian GM, Haddow JE, Ehrich M, van den Boom D, et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012;32(8):730–4.

    CAS  PubMed  Google Scholar 

  79. Choi H, Lau TK, Jiang FM, Chan MK, Zhang HY, Lo PS, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013;33(2):198–200.

    CAS  PubMed  Google Scholar 

  80. Pan M, Li FT, Li Y, Jiang FM, Li DZ, Lau TK, et al. Discordant results between fetal karyotyping and non-invasive prenatal testing by maternal plasma sequencing in a case of uniparental disomy 21 due to trisomic rescue. Prenat Diagn. 2013;33(6):598–601.

    PubMed  Google Scholar 

  81. Jensen TJ, Dzakula Z, Deciu C, van den Boom D, Ehrich M. Detection of microdeletion 22q11.2 in a fetus by next-generation sequencing of maternal plasma. Clin Chem. 2012;58(7):1148–51.

    CAS  PubMed  Google Scholar 

  82. Peters D, Chu T, Yatsenko SA, Hendrix N, Hogge WA, Surti U, et al. Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. N Engl J Med. 2011;365(19):1847–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Srinivasan A, Bianchi D, Liao W, Sehnert A, Rava R. 52: Maternal plasma DNA sequencing: effects of multiple gestation on aneuploidy detection and the relative cell-free fetal DNA (cffDNA) per fetus. Am J Obstet Gynecol. 2013;208(1, Suppl):S31.

    Google Scholar 

  84. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Martin K, Iyengar S, Kalyan A, Lan C, Simon AL, Stosic M, et al. Clinical experience with a single-nucleotide polymorphism-based noninvasive prenatal test for five clinically significant microdeletions. Clin Genet. 2018;93:293. https://doi.org/10.1111/cge.13098.

    Article  CAS  PubMed  Google Scholar 

  86. Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, Quake SR. Non-invasive prenatal measurement of the fetal genome. Nature. 2012;487(7407):320–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kitzman JO, Snyder MW, Ventura M, Lewis AP, Qiu R, Simmons LE, et al. Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. 2012;4(137):137ra76.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. Chan KC, Jiang P, Sun K, Cheng YK, Tong YK, Cheng SH, et al. Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends. Proc Natl Acad Sci U S A. 2016;113(50):E8159–E68.

    PubMed  PubMed Central  Google Scholar 

  90. Bodian DL, Klein E, Iyer RK, Wong WS, Kothiyal P, Stauffer D, et al. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genet Med. 2016;18(3):221–30.

    PubMed  Google Scholar 

  91. Christensen CM. The innovator’s dilemma: when new technologies cause great firms to fail. Boston: Harvard Business Review Press; 1997.

    Google Scholar 

  92. Hwang J, Christensen CM. Disruptive innovation in health care delivery: a framework for business-model innovation. Health Aff. 2008;27(5):1329–35. 10.1377/hlthaff.27.5.1329

    Google Scholar 

  93. ACOG. Committee Opinion No. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120(6):1532–4.

    Google Scholar 

  94. Benn P, Borrell A, Crossley J, Cuckle H, Dugoff L, Gross S, et al. Aneuploidy screening: a position statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, January 2011. Prenat Diagn. 2011;31(6):519–22.

    PubMed  Google Scholar 

  95. Devers PL, Cronister A, Ormond KE, Facio F, Brasington CK, Flodman P. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the national society of genetic counselors. J Genet Couns. 2013;22(3):291–5.

    PubMed  Google Scholar 

  96. Gregg AR, Gross SJ, Best RG, Monaghan KG, Bajaj K, Skotko BG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. 2013;15(5):395–8.

    CAS  PubMed  Google Scholar 

  97. Langlois S, Brock JA, Genetics C, Wilson RD, Audibert F, Brock JA, et al. Current status in non-invasive prenatal detection of down syndrome, trisomy 18, and trisomy 13 using cell-free DNA in maternal plasma. J Obstet Gynaecol Can. 2013;35(2):177–81.

    PubMed  Google Scholar 

  98. Ashoor G, Syngelaki A, Wang E, Struble C, Oliphant A, Song K, et al. Trisomy 13 detection in the first trimester of pregnancy using a chromosome-selective cell-free DNA analysis method. Ultrasound Obstet Gynecol. 2013;41(1):21–5.

    CAS  PubMed  Google Scholar 

  99. Brar H, Wang E, Struble C, Musci TJ, Norton ME. The fetal fraction of cell-free DNA in maternal plasma is not affected by a priori risk of fetal trisomy. J Matern Fetal Neonatal Med. 2013;26(2):143–5.

    CAS  PubMed  Google Scholar 

  100. 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.

    Google Scholar 

  101. Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. 2013;33(6):575–9.

    CAS  PubMed  Google Scholar 

  102. Palomaki GE, Kloza EM, O'Brien BM, Eklund EE, Lambert-Messerlian GM. The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population. Genet Med. 2017;19(7):778–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Benn P, Curnow KJ, Chapman S, Michalopoulos SN, Hornberger J, Rabinowitz M. An economic analysis of cell-free DNA non-invasive prenatal testing in the US general pregnancy population. PLoS One. 2015;10(7):e0132313.

    PubMed  PubMed Central  Google Scholar 

  104. Agarwal A, Sayres LC, Cho MK, Cook-Deegan R, Chandrasekharan S. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33(6):521–31.

    PubMed  PubMed Central  Google Scholar 

  105. Deans Z, Khawaja F, Hastings R, Rack K, Patton S, Gutowska-Ding W, Allen S, Jenkins L, Chitty L, Sistermans E. Measuring the quality of NIPT for aneuploidies – results from the first pilot EQA. Prenat Diagn. 2017;37(Suppl 1):6–7. (Abstract)

    Google Scholar 

  106. Skotko BG. With new prenatal testing, will babies with Down syndrome slowly disappear? Arch Dis Child. 2009;94(11):823–6.

    PubMed  Google Scholar 

  107. Mozersky J, Ravitsky V, Rapp R, Michie M, Chandrasekharan S, Allyse M. Toward an ethically sensitive implementation of noninvasive prenatal screening in the global context. Hast Cent Rep. 2017;47(2):41–9.

    Google Scholar 

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Authors and Affiliations

  1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women and Infants Hospital/Alpert Medical School of Brown University, Providence, RI, USA

    Glenn E. Palomaki

  2. Savjani Institute for Health Research, Windham, ME, USA

    Glenn E. Palomaki

  3. Biomedical Sciences, University of South Carolina School of Medicine/Greenville Health System, Greenville, SC, USA

    Robert G. Best

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  1. Glenn E. Palomaki
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  2. Robert G. Best
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Correspondence to Glenn E. Palomaki .

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Editors and Affiliations

  1. Professor and Chair of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    George Jabboure Netto

  2. Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, Clinical Professor of Pathology, University of Chicago Pritzker School of Medicine, Evanston, IL, USA

    Karen L. Kaul

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Palomaki, G.E., Best, R.G. (2019). Sequencing Cell-Free DNA in the Maternal Circulation to Screen for Down Syndrome, Other Common Trisomies, and Selected Genetic Disorders. In: Netto, G., Kaul, K. (eds) Genomic Applications in Pathology. Springer, Cham. https://doi.org/10.1007/978-3-319-96830-8_36

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  • DOI: https://doi.org/10.1007/978-3-319-96830-8_36

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