Diagnostic and Clinical Outcomes of Sex Chromosome Abnormalities Detected on Noninvasive Prenatal Screening

Noninvasive prenatal screening (NIPS) screens for aneuploidy, but its positive predictive value for sex chromosome aneuploidies (SCA) is variable. NIPS reports include "atypical sex chromosome findings," which may indicate fetal/maternal SCAs or mosaicism, although sensitivity is unknown. Previous studies are limited by small cohorts and insufficient maternal testing and ultrasound data. This study evaluates confirmation rates and outcomes for screen-positive SCAs, including "atypical sex chromosome" on NIPS.

This retrospective study included singleton pregnancies that underwent diagnostic testing for screen-positive SCAs or atypical sex chromosome findings on NIPS from 2019 to 2024. Data collected included demographics, ultrasound findings, cytogenetics, maternal karyotype, and perinatal outcomes. The primary outcome was diagnostic confirmation, defined as proportion of NIPS screen-positive SCA and "atypical sex chromosome" confirmed by diagnostic testing. Secondary outcomes included fetal/placental mosaicism, incidental genetic findings, and maternal genetic results. Chi-squared and Kruskal-Wallis tests were used for categorical and continuous variables, respectively.

Of 510 patients who underwent diagnostic testing, 91 met inclusion criteria. Overall, 41.8% (n = 38) of NIPS-predicted SCAs were confirmed. Confirmation rates varied by SCA type: monosomy X (32.1%), XXY (80%), XYY (100%), XXX (66.7%), and atypical findings (26.2%) (p < 0.001). Mosaicism was present in 31.6% of confirmed cases. Incidental genetic findings, including fetal copy number variants, occurred in 11 cases. Maternal karyotype was normal in 100% of confirmed cases versus 54.2% of nonconfirmed (p = 0.033). Perinatal outcomes were generally favorable.

Fewer than half of NIPS-predicted SCAs were confirmed, with low confirmation rates for monosomy X and atypical findings. Mosaicism accounted for nearly one-third of confirmed cases. False-positive results often included incidental fetal and maternal findings, which may contribute to high false-positive rates. These findings emphasize the need for comprehensive pretest counseling and standardized testing guidelines, given the risk of unexpected maternal SCAs and fetal copy number variants.

· Less than half of NIPS-predicted SCAs were true-positive.. · Nearly one-third of confirmed SCAs involved mosaicism.. · Abnormal maternal karyotype may drive false-positive rates..