The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies

Authors

  • Jacob A. Canick,

    Corresponding author
    1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School of Brown University, Providence, RI, USA
    Search for more papers by this author
    • JAC and GEP contributed equally to this study.
  • Glenn E. Palomaki,

    1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School of Brown University, Providence, RI, USA
    Search for more papers by this author
    • JAC and GEP contributed equally to this study.
  • Edward M. Kloza,

    1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School of Brown University, Providence, RI, USA
    Search for more papers by this author
  • Geralyn M. Lambert-Messerlian,

    1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School of Brown University, Providence, RI, USA
    Search for more papers by this author
  • James E. Haddow

    1. Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital and Alpert Medical School of Brown University, Providence, RI, USA
    Search for more papers by this author

  • Funding sources: None
  • Conflicts of interest: Canick, Palomaki, Kloza, Lambert-Messerlian, and Haddow are employees of Women and Infants Hospital of Rhode Island. Canick and Palomaki were members of the Sequenom Clinical Advisory Board between November 2007 and October 2008, and resigned when they received study funding. Palomaki and Canick were Co-PIs for a Women & Infants Hospital of Rhode Island project fully funded through a grant from Sequenom, Inc., San Diego, CA between October 2008 and February 2012. Kloza, Lambert-Messerlian, and Haddow were also part of this funded project. Palomaki and Canick have received funding to create a study design from Natera, Inc., San Carlos, CA beginning in December 2012. Kloza was a member of the Natera Clinical Advisory Board between September 2013 and January 2013.

ABSTRACT

Maternal plasma contains circulating cell-free DNA fragments originating from both the mother and the placenta. The proportion derived from the placenta is known as the fetal fraction. When measured between 10 and 20 gestational weeks, the average fetal fraction in the maternal plasma is 10% to 15% but can range from under 3% to over 30%. Screening performance using next-generation sequencing of circulating cell-free DNA is better with increasing fetal fraction and, generally, samples whose values are less than 3% or 4% are unsuitable. Three examples of the clinical impact of fetal fraction are discussed. First, the distribution of test results for Down syndrome pregnancies improves as fetal fraction increases, and this can be exploited in reporting patient results. Second, the strongest factor associated with fetal fraction is maternal weight; the false negative rate and rate of low fetal fractions are highest for women with high maternal weights. Third, in a mosaic, the degree of mosaicism will impact the performance of the test because it will reduce the effective fetal fraction. By understanding these aspects of the role of fetal fraction in maternal plasma DNA testing for aneuploidy, we can better appreciate the power and the limitations of this impressive new methodology. © 2013 John Wiley & Sons, Ltd.

Ancillary