Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma


  • Funding sources: Sequenom, Inc. and Sequenom Center for Molecular Medicine (SCMM). The sponsors participated in the design of the study, data collection, data management, data analysis, decision to submit the report for publication, manuscript preparation, and review.

  • Conflicts of interest: Mazloom, Džakula, Wang, Oeth, Jensen, Tynan, McCullough, Saldivar, Bombard, and Deciu are employees of Sequenom Center for Molecular Medicine and Sequenom shareholders. Ehrich, van den Boom, Maeder, and McLennan are employees of Sequenom, Inc. and Sequenom shareholders. Palomaki and Canick 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-Principal Investigators for a Women & Infants Hospital of Rhode Island project fully funded to through a grant from Sequenom, Inc., between October 2008 and February 2012.



Whole-genome sequencing of circulating cell free (ccf) DNA from maternal plasma has enabled noninvasive prenatal testing for common autosomal aneuploidies. The purpose of this study was to extend the detection to include common sex chromosome aneuploidies (SCAs): [47,XXX], [45,X], [47,XXY], and [47,XYY] syndromes.


Massively parallel sequencing was performed on ccf DNA isolated from the plasma of 1564 pregnant women with known fetal karyotype. A classification algorithm for SCA detection was constructed and trained on this cohort. Another study of 411 maternal samples from women with blinded-to-laboratory fetal karyotypes was then performed to determine the accuracy of the classification algorithm.


In the training cohort, the new algorithm had a detection rate (DR) of 100% (95%CI: 82.3%, 100%), a false positive rate (FPR) of 0.1% (95%CI: 0%, 0.3%), and nonreportable rate of 6% (95%CI: 4.9%, 7.4%) for SCA determination. The blinded validation yielded similar results: DR of 96.2% (95%CI: 78.4%, 99.8%), FPR of 0.3% (95%CI: 0%, 1.8%), and nonreportable rate of 5% (95%CI: 3.2%, 7.7%) for SCA determination


Noninvasive prenatal identification of the most common sex chromosome aneuploidies is possible using ccf DNA and massively parallel sequencing with a high DR and a low FPR. © 2013 John Wiley & Sons, Ltd.