Sex chromosome aneuploidy detection by noninvasive prenatal testing: helpful or hazardous?

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Abstract
To assess the incidence of sex chromosome aneuploidy (SCA) predicted by non-invasive prenatal testing (NIPT), assess test performance, and compare it with nuchal translucency (NT) screening among patients seen in our prenatal diagnosis center. We identified suspected cases of SCA by reviewing results from all NIPT samples sent from our center to commercial laboratories offering analysis by cell-free DNA between December 1, 2012 to July 31, 2015. Records of pregnancies positive for SCA were reviewed for ultrasound findings, NIPT indications, and karyotype results on maternal, fetal and postnatal samples. Other SCA cases presenting during this period regardless of NIPT status, were identified from genetic counseling and cytogenetics laboratory logbooks. NIPT predicted sex chromosome aneuploidy in 18/2851 patients (0.63%). All had diagnostic testing of fetal or newborn samples. No patients terminated pregnancies based on NIPT. NIPT suggested triple X in 5 cases, 2 with elevated NT: all were confirmed on karyotype. Two Klinefelter syndrome cases were also accurately predicted by NIPT. NIPT indicated monosomy X in 11 cases. Only 1 was a true positive. Ten were false positives, with 46,XX found on fetal or newborn karyotype. Maternal karyotype was mosaic (45,X[4], 46,XX[26]) in one case. Over the same time period, 4 additional cases of 45,X were confirmed on fetal samples, all with cystic hygromas. One of these had had a false negative NIPT result. The remaining patients pursued only direct testing via CVS or amniocentesis. SCA was frequently suspected on NIPT. False positive rate for monosomy X was surprisingly high (91%). Prediction of other SCA was more accurate. Diagnostic fetal chromosome analysis should be offered after abnormal NIPT, or in the presence of cystic hygromas despite normal NIPT. NIPT limitations should be explained in pretest counseling.