EP450: Effectiveness and utility of noninvasive prenatal screening (NIPS) for sex chromosome aneuploidies

Abstract

Noninvasive prenatal screening (NIPS) has high sensitivity and specificity for the common autosomal aneuploidies. However, compared to these autosomal trisomies, the few studies assessing NIPS for detecting sex chromosome aneuploidy (SCA) have shown higher false positive rates; particularly for monosomy X. The primary goal of this study was to determine the effectiveness and utility of NIPS as a tool for recognizing SCA; we also discuss uptake of diagnostic testing. Over 39 months (August 2018-October 2021), we performed NIPS for 1438 specimens. Overall, the proportion of specimens with any high-risk result was 2.6% (37/1438). Of those, autosomal aneuploidy was prognosticated in 2.09% (30/1438), while SCA was suspected in 0.49% (7/1438) of patients, with similar frequencies of abnormal results being published among other laboratories performing this test. Of the seven pregnancies at high risk for SCA, three were high risk for Turner syndrome (45,X); three for Klinefelter syndrome (47,XXY); and one for Triple X (47,XXX). None of the patients with high-risk results for SCA elected to have additional prenatal diagnostic testing. Also, no patients elected to terminate pregnancies based on NIPS SCA results. Follow-up karyotype analysis was available for four of these seven cases: three newborns and one product of conception (POC) specimen. Of the three pregnancies at high risk for monosomy X, two resulted in miscarriage; with one having follow-up genetic testing that confirmed monosomy X (true positive). The third high-risk monosomy X case resulted in a liveborn. Subsequent testing of the newborn including FISH, karyotype and microarray yielded results consistent with a normal female complement (false positive). Of the three pregnancies at high risk for 47,XXY, all resulted in live births, with two confirmed as true positives in the newborns (the third did not pursue testing). The case at high risk for 47,XXX was reported as phenotypically normal but no diagnostic testing was performed. Seven patients received high-risk results for SCA; however, none elected to pursue diagnostic testing prenatally via amniocentesis or CVS. Follow-up testing was available in four of the seven cases. Three were true positive (two 47,XXY and one 45,X) and one was a false positive (45,X). Calculation of the test specifications (sensitivity, specificity, PPV, NPV) for SCAs is limited due to lack of confirmatory genetic testing and limited phenotypes observed in the newborn period (and beyond) for some conditions. NIPS allows for earlier diagnosis of SCA, which could aid in behavioral interventions or fertility concerns/management for people with SCAs.