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Prenatal Diagnosis

Cover image for Vol. 33 Issue 6

Special Issue: Noninvasive Prenatal Testing Using Maternal Plasma DNA: Part I

June 2013

Volume 33, Issue 6

Pages 511–618

Issue edited by: Lyn S. Chitty, Diana W. Bianchi

  1. Editorial

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
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      Noninvasive prenatal testing: the paradigm is shifting rapidly (pages 511–513)

      Lyn S. Chitty and Diana W. Bianchi

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4136

  2. Reviews

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
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      Fetal aneuploidy detection by maternal plasma DNA sequencing: a technology assessment (pages 514–520)

      Judith M. E. Walsh and James D. Goldberg

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4109

      What's already known about this topic?

      • Noninvasive prenatal testing by analysis of cell-free DNA has the potential to accurately diagnose common fetal aneuploidies, although how best to use this test in the context of other available prenatal tests has not yet been determined.

      What does this study add?

      • This study critically assesses the published literature on the use of maternal plasma DNA sequencing for fetal aneuploidy detection and compares it with the established alternatives. Finally, it provides guidelines for evidence-based use of maternal plasma DNA sequencing for the detection of fetal aneuploidy
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      Commercial landscape of noninvasive prenatal testing in the United States (pages 521–531)

      Ashwin Agarwal, Lauren C. Sayres, Mildred K. Cho, Robert Cook-Deegan and Subhashini Chandrasekharan

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4101

      What's already known about this topic?

      • Data about technologies underlying cell-free fetal DNA-based noninvasive prenatal tests and their clinical validity are available in scientific publications. Several papers have detailed ethical and practical concerns surrounding noninvasive prenatal testing.
      • Information about the costs, reimbursement, and intellectual property associated with recently launched tests are available but not readily accessible to stakeholders.
      • There has been limited discussion of issues surrounding patenting and commercialization and their effects on clinical translation of noninvasive prenatal testing.

      What does this study add?

      • We detail the intellectual property and business landscape of current and emerging noninvasive prenatal tests by bringing together information from trade press, news, legal business, and scientific publications.
      • We also discuss potential effects of patenting and commercialization on the clinical implementation of noninvasive prenatal testing and patient access.
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      Factors affecting the clinical use of non-invasive prenatal testing: a mixed methods systematic review (pages 532–541)

      Heather Skirton and Christine Patch

      Article first published online: 4 APR 2013 | DOI: 10.1002/pd.4094

      What's already known about this topic?

      • Non-invasive prenatal testing (NIPT) is available for foetal sex determination in pregnancies at high risk of sex-linked disorders and for diagnosis of a limited number of genetic conditions.
      • There is limited use of NIPT for aneuploidy detection, albeit currently only in the private sector.
      • This method eliminates the risks to the foetus inherent in invasive procedures and can be performed earlier in the pregnancy.

      What does this study add?

      • Users and potential users of NIPT regard it positively, but there are wider ethical and societal concerns about the impact of easier access to prenatal testing.
  3. Original Articles

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have free access to this content
      Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening (pages 542–546)

      Shilpa Chetty, Matthew J. Garabedian and Mary E. Norton

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4125

      What's already known about this topic?

      • NIPT now offers an alternative to invasive diagnostic testing in the setting of positive screening results, with high sensitivity and specificity for trisomies 18 and 21.

      What does this study add?

      • The introduction of NIPT in our population has influenced the prenatal diagnostic choices made by women with abnormal aneuploidy screening. We found that rates of invasive testing decreased significantly following the introduction of NIPT. Additionally, fewer women declined follow-up testing when NIPT was an option.
  4. Reviews

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
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      Noninvasive fetal genome sequencing: a primer (pages 547–554)

      Matthew W. Snyder, LaVone E. Simmons, Jacob O. Kitzman, Donna A. Santillan, Mark K. Santillan, Hilary S. Gammill and Jay Shendure

      Article first published online: 1 APR 2013 | DOI: 10.1002/pd.4097

      What's already known about this topic?

      • Noninvasive fetal genome sequencing was recently demonstrated to be technically achievable, yielding an accurate and substantially complete result. Genome-wide inherited and de novo variation can be determined during pregnancy without risk to the mother or fetus. However, technical, ethical, and translational challenges must be addressed before this technique can be introduced in the clinic.

      What does this study add?

      • We present an overview of noninvasive fetal genome sequencing for a clinical audience. We discuss the methodology in an accessible format and consider the key challenges along the path to clinical adoption.
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      The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: challenges and progress made (pages 555–562)

      Nicholas Lench, Angela Barrett, Sarah Fielding, Fiona McKay, Melissa Hill, Lucy Jenkins, Helen White and Lyn S. Chitty

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4124

      What's already known about this topic?

      • Non-invasive prenatal testing of cell-free fetal DNA in maternal plasma is widely used for aneuploidy detection, fetal RHD typing and fetal sex determination in pregnancies at high risk of sex-linked disorders.

      What does this study add?

      • We describe the current limited use of cell-free fetal DNA analysis for prenatal diagnosis of single-gene disorders and discuss the application of new technologies to aid implementation.
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      Benefits and limitations of whole genome versus targeted approaches for noninvasive prenatal testing for fetal aneuploidies (pages 563–568)

      Elles M. J. Boon and Brigitte H. W. Faas

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4111

      What's already known about this topic?

      • Since the discovery of cell-free fetal DNA in maternal plasma, large progress has been made in the development of noninvasive prenatal tests.
      • The first applications in noninvasive prenatal diagnosis were single polymerase chain reaction-based.
      • Since 2008, a new era in the development of noninvasive aneuploidy testing was opened by the first successful application of massively parallel sequencing for this purpose.

      What does this study add?

      • For fetal aneuploidy testing, whole genome massively parallel sequencing is still rather expensive and to reduce costs, targeted sequencing approaches are being developed.
      • This review highlights benefits and limitations of both whole genome and targeted approaches for noninvasive prenatal testing for fetal aneuploidy detection for now and the near future as a shift in the most cost effective approach is anticipated in the near future.
  5. Original Articles

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have full text access to this OnlineOpen article
      Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples (pages 569–574)

      Tracy Futch, John Spinosa, Sucheta Bhatt, Eileen de Feo, Richard P. Rava and Amy J. Sehnert

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4123

      What's already known about this topic?

      • Results of clinical validation studies demonstrate a high degree of accuracy to detect fetal aneuploidy by massively parallel sequencing of cell-free DNA from maternal plasma.
      • Commercial laboratories now offer sequencing-based tests to detect fetal aneuploidy by using different proprietary analysis and reporting methods, but little is known about test performance in the clinical setting.

      What does this study add?

      • Analysis of commercial laboratory data obtained for nearly 6000 samples suggests that massively parallel sequencing of maternal cell-free DNA to detect fetal aneuploidy of chromosomes 21, 18, 13, and X meets or exceeds performance characteristics established by clinical validation studies.
      • Relevant biological correlations identified through clinical testing are discussed to increase provider awareness about this technology.
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      Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y (pages 575–579)

      K. H. Nicolaides, A. Syngelaki, M. Gil, V. Atanasova and D. Markova

      Article first published online: 24 APR 2013 | DOI: 10.1002/pd.4103

      What's already known about this topic?

      • A novel, effective method of screening for trisomies 21, 18, and 13 is derived from examination of cell-free DNA in maternal plasma.

      What does this study add?

      • Targeted sequencing of single-nucleotide polymorphisms at chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal autosomal aneuploidies, sex chromosome aneuploidies, and triploidy.
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      Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population (pages 580–583)

      Genevieve Fairbrother, Shayla Johnson, Thomas J. Musci and Ken Song

      Article first published online: 15 MAR 2013 | DOI: 10.1002/pd.4092

      What's already known about this topic?

      • Noninvasive prenatal testing (NIPT) with cell-free DNA has been shown to be highly accurate for detection of fetal autosomal trisomies.

      What does this study add?

      • This study shows the clinical use of NIPT for trisomies 21, 18, and 13 in a general screening population in the US including a comparison against first trimester combined screening.
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      A method for noninvasive detection of fetal large deletions/duplications by low coverage massively parallel sequencing (pages 584–590)

      Shengpei Chen, Tze Kin Lau, Chunlei Zhang, Chenming Xu, Zhengfeng Xu, Ping Hu, Jian Xu, Hefeng Huang, Ling Pan, Fuman Jiang, Fang Chen, Xiaoyu Pan, Weiwei Xie, Ping Liu, Xuchao Li, Lei Zhang, Songgang Li, Yingrui Li, Xun Xu, Wei Wang, Jun Wang, Hui Jiang and Xiuqing Zhang

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4110

      What's already known about this topic?

      • Sequencing-based noninvasive prenatal detection of fetal aneuploidy has been proven to be highly accurate. However, it is still a challenge to detect fetal deletion/duplication syndrome because of the interference from maternal DNA in maternal plasma.

      What does this study add?

      • Here, we developed a practical bioinformatic methodology to detect fetal chromosomal deletions/duplications of >10 Mb using low coverage whole genome sequencing of maternal plasma.
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      Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma (pages 591–597)

      Amin R. Mazloom, Željko Džakula, Paul Oeth, Huiquan Wang, Taylor Jensen, John Tynan, Ron McCullough, Juan-Sebastian Saldivar, Mathias Ehrich, Dirk van den Boom, Allan T. Bombard, Margo Maeder, Graham McLennan, Wendy Meschino, Glenn E. Palomaki, Jacob A. Canick and Cosmin Deciu

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4127

      What's already known about this topic?

      • Circulating cell-free fetal DNA present in maternal plasma enables noninvasive prenatal testing.
      • Using massively parallel sequencing (MPS), accurate detection of trisomies of chromosomes 21, 18, and 18 has been demonstrated and is now offered as a laboratory developed test.
      • Detection of monosomy X through MPS is also possible. Fewer data are available for other sex chromosome aneuploidies (SCAs).

      What does this study add?

      • By using a comprehensive bioinformatic model, we demonstrate that accurate detection of the most common SCAs through whole-genome MPS can be achieved.
      • The SCA detection algorithm will complement the already existing methods for detection of autosomal trisomy.
  6. Research Letters

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have free access to this content
      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 (pages 598–601)

      Min Pan, Fa Tao Li, Yan Li, Fu Man Jiang, Dong Zhi Li, Tze Kin Lau and Can Liao

      Article first published online: 27 MAR 2013 | DOI: 10.1002/pd.4069

      What's already known about this topic?

      • The non-invasive prenatal testing (NIPT) by maternal plasma sequencing has been proven to be a safe and highly efficient screening method for fetal aneuploidy. Some studies suggested that these cell-free DNAs are from the placenta. Therefore, an abnormal NIPT result could be due to confined placental mosaicism.

      What does this study add?

      • We reported here a case of UPD with confined placental mosaicism, which resulted in discordant results between fetal karyotyping and NIPT.
  7. Original Articles

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have free access to this content
      Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service (pages 602–608)

      Tze Kin Lau, Fu Man Jiang, Robert J. Stevenson, Tsz Kin Lo, Lin Wai Chan, Mei Ki Chan, Pui Shan Salome Lo, Wei Wang, Hong-Yun Zhang, Fang Chen and Kwong Wai Choy

      Article first published online: 2 APR 2013 | DOI: 10.1002/pd.4076

      What's already known about this topic?

      • Non-invasive prenatal testing (NIPT) by maternal plasma DNA sequencing is highly sensitive and specific in detecting fetal aneuploidies.

      What does this study add?

      • We report five cases of secondary findings of abnormal chromosome copy number when performing NIPT by maternal plasma sequencing for fetal aneuploidies.
  8. Research Letters

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have free access to this content
      Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease (pages 609–611)

      C. Michael Osborne, Emily Hardisty, Patricia Devers, Kathleen Kaiser-Rogers, Melissa A. Hayden, William Goodnight and Neeta L. Vora

      Article first published online: 4 APR 2013 | DOI: 10.1002/pd.4100

      What's already known about this topic?

      • Noninvasive prenatal testing for detection of trisomies 21, 18, and 13 is clinically available and is reported to have a false positive rate of 1% or less
      • This technology utilizes massively parallel shotgun sequencing of cell-free DNA, of maternal and placental origin, present in maternal plasma

      What does this study add?

      • Unexplained abnormal noninvasive prenatal testing results should prompt consideration of a maternal source of the abnormal cell-free DNA, such as malignancy
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      Cell-free fetal DNA sex determination identified a maternal SRY gene with a known X chromosome deletion (pages 612–613)

      C. J. Searle, K. Smith, G. Daniels, E. J. Maher and O. Quarrell

      Article first published online: 1 APR 2013 | DOI: 10.1002/pd.4078

      What's already known about this topic?

      • Cell-free fetal DNA testing is commonly used as a noninvasive method of determing fetal sex.
      • Presence of sex-determining region Y (SRY) on the X chromosome is associated with a variable sexual phenotype.

      What does this study add?

      • Details an unexpected cell-free fetal DNA sexing result.
      • Highlights the importance of using the technique of quantitative polymerase chain reaction in free fetal DNA testing.
      • If a similar result is found again, we would recommend further testing of the maternal chromosomes to look for a translocation encompassing the sex-determining region Y (SYR) gene.
  9. Reviews

    1. Top of page
    2. Editorial
    3. Reviews
    4. Original Articles
    5. Reviews
    6. Original Articles
    7. Research Letters
    8. Original Articles
    9. Research Letters
    10. Reviews
    1. You have free access to this content
      Noninvasive prenatal testing creates an opportunity for antenatal treatment of Down syndrome (pages 614–618)

      Faycal Guedj and Diana W. Bianchi

      Article first published online: 17 MAY 2013 | DOI: 10.1002/pd.4134

      What's already known about this topic?

      • DS is the most common autosomal aneuploidy associated with intellectual disability.
      • Worldwide, most screening programs focus on prenatal detection of DS.
      • Research to improve neurocognition in people with DS is almost exclusively focused on adults.
      • Pregnant women carrying affected fetuses with DS can choose to continue or terminate their pregnancies, but there is no fetal treatment available.

      What does this study add?

      • We present data to show that many pregnant women continue their pregnancies when their fetus is affected with DS.
      • We review the published literature on brain pathology in human fetuses with DS and embryonic mice affected with a model form of the disease.
      • We summarize the limited available information on prenatal treatment approaches for DS and make the case that there is an important window of opportunity to positively impact neurogenesis and brain morphogenesis by providing treatment during fetal life.

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