Skip to main content

Main menu

  • Home
  • About
    • Clinical Chemistry
    • Editorial Board
    • Most Read
    • Most Cited
    • Alerts
    • CE Credits
  • Articles
    • Current Issue
    • Early Release
    • Future Table of Contents
    • Archive
    • Browse by Subject
  • Info for
    • Authors
    • Reviewers
    • Subscribers
    • Advertisers
    • Permissions & Reprints
  • Resources
    • AACC Learning Lab
    • Clinical Chemistry Trainee Council
    • Clinical Case Studies
    • Clinical Chemistry Guide to Scientific Writing
    • Clinical Chemistry Guide to Manuscript Review
    • Journal Club
    • Podcasts
    • Q&A
    • Translated Content
  • Abstracts
  • Submit
  • Contact
  • Other Publications
    • The Journal of Applied Laboratory Medicine

User menu

  • Subscribe
  • My alerts
  • Log in

Search

  • Advanced search
Clinical Chemistry
  • Other Publications
    • The Journal of Applied Laboratory Medicine
  • Subscribe
  • My alerts
  • Log in
Clinical Chemistry

Advanced Search

  • Home
  • About
    • Clinical Chemistry
    • Editorial Board
    • Most Read
    • Most Cited
    • Alerts
    • CE Credits
  • Articles
    • Current Issue
    • Early Release
    • Future Table of Contents
    • Archive
    • Browse by Subject
  • Info for
    • Authors
    • Reviewers
    • Subscribers
    • Advertisers
    • Permissions & Reprints
  • Resources
    • AACC Learning Lab
    • Clinical Chemistry Trainee Council
    • Clinical Case Studies
    • Clinical Chemistry Guide to Scientific Writing
    • Clinical Chemistry Guide to Manuscript Review
    • Journal Club
    • Podcasts
    • Q&A
    • Translated Content
  • Abstracts
  • Submit
  • Contact
Review ArticleCitation Classic

The Quest for Accurate Measurement of Fetal DNA in Maternal Plasma

Y.M. Dennis Lo
DOI: 10.1373/clinchem.2010.149757 Published February 2011
Y.M. Dennis Lo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: loym@cuhk.edu.hk
  • Article
  • Info & Metrics
  • PDF
Loading

Featured Article: Lo YMD, Tein MSC, Lau TK, Haines CJ, Leung TN, Poon PMK, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 1998;62:768–75.3

There has been a multidecade search for noninvasive methods of prenatal diagnosis. In 1997, my group reported the presence of cell-free fetal DNA in maternal plasma and serum (1), opening up exciting possibilities that this new noninvasive source of fetal genetic materials might be used for prenatal testing. Much remained unknown, however, regarding this newly discovered phenomenon. For example, it was unclear when fetal DNA first entered into the maternal circulation and whether its concentration would be sufficient for robust diagnostic assays to be developed.

The 1998 report featured here represented the first attempt to address these and other issues. I decided to use the then-new real-time quantitative PCR (2) as a tool for measuring fetal and total DNA in maternal plasma and serum. I was fortunate that my department head at the time, Professor Magnus Hjelm, had kindly provided me with the funding to purchase a real-time PCR instrument, one of the first in Asia. Armed with this new equipment, I was able to rapidly develop a set of protocols that would allow the robust detection and measurement of fetal DNA and total DNA in maternal plasma and serum. These protocols and their variants have since become the standard techniques in the field of noninvasive prenatal diagnosis and are used in other fields with a need to measure nucleic acids in plasma (3).

With this technique, I was able to document that fetal DNA was detectable in maternal serum from the seventh week of gestation, with the absolute concentration of fetal DNA increasing as the gestational age progressed. These data also provided a set of normative values to compare with the concentrations occurring in pathologic conditions, such as preeclampsia, preterm labor, fetal trisomy 21, and so forth. Indeed, subsequent work has demonstrated that these pathologic conditions are associated with an increase in the concentrations of circulating fetal DNA.

Perhaps the most surprising aspect of this first quantitative study was the demonstration that the mean fractional concentration of fetal DNA in maternal plasma was approximately 3%. This high fractional concentration suggested the possibility of using maternal plasma for relatively robust prenatal diagnostic applications. This prediction has subsequently been shown to be correct, as evidenced by the accuracy of this approach for determining the fetal sex for sex-linked disorders and for fetal RhD genotyping. Another important finding that came out of this first study was the fact that maternal serum had a much lower fractional fetal DNA concentration than plasma, possibly due to the liberation of DNA during the clotting process, suggesting that maternal plasma might be preferred over maternal serum for noninvasive prenatal diagnosis.

Another important consequence of having reference values for fractional fetal DNA concentrations is that it has provided a foundation for investigators to develop prenatal tests that aim at detecting quantitative aberrations in the fetal genome, e.g., trisomy 21. Indeed, the fractional concentration of fetal DNA is a crucial parameter in the latest generation of “molecular counting” assays, such as those involving digital PCR (4) and next-generation sequencing (5), for detecting fetal DNA in maternal plasma. In general, the lower the fractional concentration of fetal DNA is, the larger is the number of molecules that would need to be counted to detect a particular quantitative aberration in the fetal genome.

The last 13 years have been an exciting time for building the foundation for noninvasive prenatal diagnosis using circulating nucleic acids. It is hoped that the next 13 years might see this foundation transformed into clinical applications that will make prenatal testing safer for pregnant women and their fetuses.

Footnotes

  • ↵3 This article has been cited more than 530 times since publication.

  • Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

  • Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

  • Employment or Leadership: Y.M.D. Lo, Clinical Chemistry, AACC.

  • Consultant or Advisory Role: Y.M.D. Lo, Sequenom.

  • Stock Ownership: Y.M.D. Lo, Sequenom.

  • Honoraria: None declared.

  • Research Funding: Y.M.D. Lo, Sequenom.

  • Expert Testimony: None declared.

  • Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.

  • Received for publication June 11, 2010.
  • Accepted for publication June 21, 2010.
  • © 2010 The American Association for Clinical Chemistry

References

  1. 1.↵
    1. Lo YMD,
    2. Corbetta N,
    3. Chamberlain PF,
    4. Rai V,
    5. Sargent IL,
    6. Redman CW,
    7. Wainscoat JS
    . Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350:485–7.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  2. 2.↵
    1. Heid CA,
    2. Stevens J,
    3. Livak KJ,
    4. Williams PM
    . Real time quantitative PCR. Genome Res 1996;6:986–94.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Lo YMD,
    2. Chan LY,
    3. Lo KW,
    4. Leung SF,
    5. Zhang J,
    6. Chan AT,
    7. et al
    . Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 1999;59:1188–91.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Lo YMD,
    2. Lun FMF,
    3. Chan KCA,
    4. Tsui NBY,
    5. Chong KC,
    6. Lau TK,
    7. et al
    . Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc Natl Acad Sci U S A 2007;104:13116–21.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Chiu RWK,
    2. Chan KCA,
    3. Gao Y,
    4. Lau VYM,
    5. Zheng W,
    6. Leung TY,
    7. 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;105:20458–63.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top

In this issue

Clinical Chemistry: 57 (3)
Vol. 57, Issue 3
March 2011
  • Table of Contents
  • Index by author
  • Table of Contents (PDF)
  • Cover (PDF)
  • Advertising (PDF)
  • Ed Board (PDF)
Print
Share
The Quest for Accurate Measurement of Fetal DNA in Maternal Plasma
Y.M. Dennis Lo
Clinical Chemistry Mar 2011, 57 (3) 522-523; DOI: 10.1373/clinchem.2010.149757
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
The Quest for Accurate Measurement of Fetal DNA in Maternal Plasma
Y.M. Dennis Lo
Clinical Chemistry Mar 2011, 57 (3) 522-523; DOI: 10.1373/clinchem.2010.149757

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Atrial Natriuretic Peptide, Heart Failure and the Heart as an Endocrine Organ
  • Circulating microRNAs: In a Class of Their Own
  • Hyperglycemia and Adverse Pregnancy Outcomes
Show more Citation Classic

Similar Articles

Subjects

  • SECTIONS
    • Citation Classics

Options

  • Home
  • About
  • Articles
  • Information for Authors
  • Resources
  • Abstracts
  • Submit
  • Contact
  • RSS

Other Publications

  • The Journal of Applied Laboratory Medicine
Footer logo

© 2019 American Association for Clinical Chemistry

Powered by HighWire