149: NIPT for sex chromosome aneuploidy: initial clinical laboratory experience and biologic reasons for discordant results

► To examine the performance of noninvasive prenatal testing for sex chromosome aneuploidy (SCA) and fetal sex using genome-wide massively parallel sequencing in a CLIA-licensed, CAP-accredited clinical laboratory. ► SCA testing became clinically available in July 2012. All US-based NIPT laboratories now offer testing for 45,X (monosomy X/Turner syndrome), 47,XXX (triple X syndrome), 47,XXY (Klinefelter syndrome), and 47,XYY (Jacobs syndrome). — Some labs automatically test for SCAs, while for others it is optional. — If NIPT does not identify a SCA, the fetal sex is reported as XX or XY. ► Limited studies have shown high accuracy with NIPT for sex chromosomes and SCAs; however, its accuracy is slightly lower than for autosomal aneuploidies [1-3]. ► Maternal mosaicism as an explanation for discordant results is likely to be more common for sex chromosomes than for autosomes [4]. ► Reports of discordance between fetal sex by NIPT and fetal sex by clinical determination (karyotype or ultrasound) present counseling and management dilemmas for which no medical guidelines currently exist. Study Objective and Background ► Data are included from verifi® prenatal test samples with the SCA test option. ► Clinical follow-up information was collected and documented according to standard laboratory practice and quality procedures. ► SCA “Detected” results were categorized in one of three ways based on follow-up information: — ‘Concordant’ if the NIPT SCA result matched the fetal/neonatal karyotype result. — ‘Discordant’ if the NIPT SCA result did not match the fetal/neonatal karyotype result. — ‘No Discordance Reported’ if no follow-up information was reported back to the laboratory. ► Fetal sex chromosome (XX or XY) results were categorized in one of four ways based on follow-up information: — ‘Concordant’ if the NIPT sex result matched the fetal/neonatal karyotype result. — ‘Discordant (karyotype)’ if the NIPT sex result did not match the fetal/neonatal karyotype result. — ‘Discordant (ultrasound)’ if the NIPT sex result did not match ultrasound or post-mortem examination determination of fetal sex. — ‘No Discordance Reported’ if no follow-up information was reported back to the laboratory. Results ► 18,161 samples were tested for SCAs during the study period. — No SCAs were detected in 17,957 cases (98.88%) (Figure 1). – In these cases, XX or XY was reported. – XY to XX ratio of 1.06, which is on par with 1.05 as reported in 2012 U.S. birth statistics [5]. – XX and XY performance is well within, or better than, previous performance parameters in a blinded clinical research trial [1]. — SCAs were detected in 204 cases (1.12%) (Figure 2). – A false positive rate of 0.26% is estimated based on available clinical follow-up information.                                               