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Am J Perinatol 2014; 31(07): 577-582
DOI: 10.1055/s-0034-1371706
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Antenatal Noninvasive DNA Testing: Clinical Experience and Impact

Millie A. Ferres
1   Mother Infant Research Institute, Tufts Medical Center and Floating Hospital for Children, Tufts University School of Medicine, Boston, Massachusetts
2   Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts
3   Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, Massachusetts
,
Lisa Hui
4   Mercy Hospital for Women, Heidelberg, Victoria, Australia
5   Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
,
Diana W. Bianchi
1   Mother Infant Research Institute, Tufts Medical Center and Floating Hospital for Children, Tufts University School of Medicine, Boston, Massachusetts
2   Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts
3   Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

22 November 2013

23 January 2014

Publication Date:
28 March 2014 (online)

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Abstract

Background Nearly two decades ago, the discovery of circulating cell-free fetal DNA in maternal blood created a paradigm shift in prenatal testing. Recent advances in DNA sequencing technology have facilitated the rapid translation of DNA-based testing into clinical antenatal care.

Content In this review, we summarize the technical approaches and current clinical applications of noninvasive testing using cell-free DNA in maternal plasma. We discuss the impact of these tests on clinical care, outline proposed integration models, and suggest future directions for the field.

Summary The use of cell-free DNA in maternal blood for the detection of fetal rhesus D antigen status, fetal sex, and common whole chromosomal aneuploidies is now well established, although testing for aneuploidy is still considered screening and not diagnostic. Further advances in technology and bioinformatics may see future clinical applications extend to the noninvasive detection of fetal subchromosomal aneuploidy, single gene disorders, and the entire fetal genome.

Keywords

cell-free fetal DNA - prenatal screening - noninvasive prenatal testing - NIPD - NIDT - pregnancy

Note

Dr. Bianchi is the chair of the Clinical Advisory Board of Verinata Health, an Illumina company, for which she receives an honorarium. She also receives sponsored research funding from Verinata Health; this is administered through Tufts Medical Center.


 

  • References

  • 1 Lo YM, Corbetta N, Chamberlain PF , et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350 (9076) 485-487
    CrossrefPubMedGoogle Scholar
  • 2 Fan HC, Quake SR. Detection of aneuploidy with digital polymerase chain reaction. Anal Chem 2007; 79 (19) 7576-7579
    CrossrefPubMedGoogle Scholar
  • 3 Lo YM, Lun FM, Chan KC , et al. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc Natl Acad Sci U S A 2007; 104 (32) 13116-13121
    CrossrefPubMedGoogle Scholar
  • 4 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) 16266-16271
    CrossrefPubMedGoogle Scholar
  • 5 Chiu RW, Chan KC, Gao Y , 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) 20458-20463
    CrossrefPubMedGoogle Scholar
  • 6 Chiu RW, Akolekar R, Zheng YW , et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011; 342: c7401
    CrossrefPubMedGoogle Scholar
  • 7 Ehrich M, Deciu C, Zwiefelhofer T , 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) e1-e11
    PubMedGoogle Scholar
  • 8 Sehnert AJ, Rhees B, Comstock D , 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) 1042-1049
    CrossrefPubMedGoogle Scholar
  • 9 Palomaki GE, Kloza EM, Lambert-Messerlian GM , et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011; 13 (11) 913-920
    CrossrefPubMedGoogle Scholar
  • 10 Sparks AB, Wang ET, Struble CA , et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 2012; 32 (1) 3-9
    CrossrefPubMedGoogle Scholar
  • 11 Palomaki GE, Deciu C, Kloza EM , et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med 2012; 14 (3) 296-305
    CrossrefPubMedGoogle Scholar
  • 12 Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP ; MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012; 119 (5) 890-901
    CrossrefPubMedGoogle Scholar
  • 13 Ashoor G, Syngelaki A, Wagner M, Birdir C, Nicolaides KH. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012; 206 (4) e1-e5
    CrossrefPubMedGoogle Scholar
  • 14 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) e1-e9
    CrossrefPubMedGoogle Scholar
  • 15 Norton ME, Brar H, Weiss J , et al. 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 2012; 207 (2) e1-e8
    PubMedGoogle Scholar
  • 16 Dan S, Wang W, Ren J , et al. Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat Diagn 2012; 32 (13) 1225-1232
    CrossrefPubMedGoogle Scholar
  • 17 Bianchi DW. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges. Nat Med 2012; 18 (7) 1041-1051
    CrossrefPubMedGoogle Scholar
  • 18 Scheffer PG, van der Schoot CE, Page-Christiaens GC, de Haas M. Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7-year clinical experience. BJOG 2011; 118 (11) 1340-1348
    CrossrefPubMedGoogle Scholar
  • 19 Clausen FB, Christiansen M, Steffensen R , 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) 752-758
    CrossrefPubMedGoogle Scholar
  • 20 Wikman AT, Tiblad E, Karlsson A, Olsson ML, Westgren M, Reilly M. Noninvasive single-exon fetal RHD determination in a routine screening program in early pregnancy. Obstet Gynecol 2012; 120 (2 Pt 1) 227-234
    CrossrefPubMedGoogle Scholar
  • 21 Rijnders RJ, van der Schoot CE, Bossers B, de Vroede MA, Christiaens GC. Fetal sex determination from maternal plasma in pregnancies at risk for congenital adrenal hyperplasia. Obstet Gynecol 2001; 98 (3) 374-378
    CrossrefPubMedGoogle Scholar
  • 22 Santacroce R, Vecchione G, Tomaiyolo M , et al. Identification of fetal gender in maternal blood is a helpful tool in the prenatal diagnosis of haemophilia. Haemophilia 2006; 12 (4) 417-422
    CrossrefPubMedGoogle Scholar
  • 23 Hill M, Lewis C, Jenkins L, Allen S, Elles RG, Chitty LS. Implementing noninvasive prenatal fetal sex determination using cell-free fetal DNA in the United Kingdom. Expert Opin Biol Ther 2012; 12 (Suppl. 01) S119-S126
    CrossrefPubMedGoogle Scholar
  • 24 Lo YM, Chan KC, Sun H , et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010; 2 (61) 61ra91
    CrossrefPubMedGoogle Scholar
  • 25 Srinivasan A, Bianchi DW, Huang H, Sehnert AJ, Rava RP. Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. Am J Hum Genet 2013; 92 (2) 167-176
    CrossrefPubMedGoogle Scholar
  • 26 Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X and Y using targeted sequencing of polymorphic loci. Prenat Diagn 2013; 33: 575-579
    CrossrefPubMedGoogle Scholar
  • 27 Nicolaides KH, Syngelaki A, Gil MM, Quezada MS, Zinevich Y. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Fetal Diagn Ther 2013; (e-pub ahead of print). doi: 10.1159/000355655
    PubMedGoogle Scholar
  • 28 Futch T, Spinosa J, Bhatt S, de Feo E, Rava RP, Sehnert AJ. Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn 2013; 33 (6) 569-574
    CrossrefPubMedGoogle Scholar
  • 29 Malone FD, Canick JA, Ball RH , et al; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005; 353 (19) 2001-2011
    CrossrefPubMedGoogle Scholar
  • 30 Benn P, Borell A, Chiu RW , et al. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2013; 33 (7) 622-629
    CrossrefPubMedGoogle Scholar
  • 31 The American College of Obstetricians and Gynecologists Committee of Genetics; The Society for Maternal Fetal Medicine Publications Committee. Committee Opinion. No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012; Dec; 120 (6) 1532-1534 . doi: 10.1097/01.AOG.0000423819.85283.f4
    CrossrefPubMedGoogle Scholar
  • 32 Fairbrother G, Johnson S, Musci TJ, Song K. Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population. Prenat Diagn 2013; 33 (6) 580-583
    CrossrefPubMedGoogle Scholar
  • 33 Song Y, Liu C, Qi H, Zhang Y, Bian X, Liu J. Noninvasive prenatal testing of fetal aneuploidies by massively parallel sequencing in a prospective Chinese population. Prenat Diagn 2013; 33 (7) 700-706
    CrossrefPubMedGoogle Scholar
  • 34 Walsh JM, Goldberg JD. Fetal aneuploidy detection by maternal plasma DNA sequencing: a technology assessment. Prenat Diagn 2013; 33 (6) 514-520
    CrossrefPubMedGoogle Scholar
  • 35 Srinivasan A, Bianchi DW, Liao W, Sehnert AJ, Rava RP. 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: S31
    CrossrefPubMedGoogle Scholar
  • 36 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) e1-e6
    PubMedGoogle Scholar
  • 37 Nicolaides KH, Wright D, Poon LC, Syngelaki A, Gil MM. First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell-free DNA testing. Ultrasound Obstet Gynecol 2013; 42 (1) 41-50
    CrossrefPubMedGoogle Scholar
  • 38 Chetty S, Garabedian MJ, Norton ME. Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening. Prenat Diagn 2013; 33 (6) 542-546
    CrossrefPubMedGoogle Scholar
  • 39 Bianchi D, Wilkins-Haug L. Integration of noninvasive DNA testing for aneuploidy into prenatal care: what has happened since the rubber met the road?. Clin Chem 2014; 60 (1) 78-87
    CrossrefPubMedGoogle Scholar
  • 40 Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chorionic villus sampling (CVS)—diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992. Prenat Diagn 1997; 17 (9) 801-820
    CrossrefPubMedGoogle Scholar
  • 41 Faas BH, de Ligt J, Janssen I , et al. Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells. Expert Opin Biol Ther 2012; 12 (Suppl. 01) S19-S26
    CrossrefPubMedGoogle Scholar
  • 42 Osborne CM, Hardisty E, Devers P , et al. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn 2013; 33 (6) 609-611
    CrossrefPubMedGoogle Scholar
  • 43 Bianchi DW, Prosen T, Platt LD , et al; MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Massively parallel sequencing of maternal plasma DNA in 113 cases of fetal nuchal cystic hygroma. Obstet Gynecol 2013; 121 (5) 1057-1062
    CrossrefPubMedGoogle Scholar
  • 44 Mazloom AR, Džakula Z, Oeth P , et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn 2013; 33 (6) 591-597
    CrossrefPubMedGoogle Scholar
  • 45 Samango-Sprouse C, Banjevic M, Ryan A , et al. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat Diagn 2013; 33 (7) 643-649
    CrossrefPubMedGoogle Scholar
  • 46 Guex N, Iseli C, Syngelaki A , et al. A robust second-generation genome-wide test for fetal aneuploidy based on shotgun sequencing cell-free DNA in maternal blood. Prenat Diagn 2013; 33 (7) 707-710
    CrossrefPubMedGoogle Scholar
  • 47 Yu SC, Jiang P, Choy KW , et al. Noninvasive prenatal molecular karyotyping from maternal plasma. PLoS ONE 2013; 8 (4) e60968
    CrossrefPubMedGoogle Scholar
  • 48 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) 1148-1151
    CrossrefPubMedGoogle Scholar
  • 49 Lench N, Barrett A, Fielding S , et al. The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: challenges and progress made. Prenat Diagn 2013; 33 (6) 555-562
    CrossrefPubMedGoogle Scholar
  • 50 Snyder MW, Simmons LE, Kitzman JO , et al. Noninvasive fetal genome sequencing: a primer. Prenat Diagn 2013; 33 (6) 547-554
    CrossrefPubMedGoogle Scholar