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

ABSTRACT Objective 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. Method 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. Results 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 Conclusion 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. 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.