Rare Autosomal Trisomies Detected by Noninvasive Prenatal Testing: Performance, Outcomes, and Exploratory Analysis of...

To characterize rare autosomal trisomies (RATs) detected by genome-wide noninvasive prenatal testing (GW-NIPT), evaluate their clinical significance, and explore whether sequencing-derived parameters are associated with adverse pregnancy outcomes.

This single-center retrospective cohort study included 64,889 singleton pregnancies undergoing GW-NIPT (March 2021-July 2024). RATs-positive cases were evaluated using invasive diagnostics, pregnancy outcomes, and sequence-derived markers, including a platform-specific theoretical mosaicism ratio (TMR).

Of 112 RATs-positive pregnancies (0.17%), 79 underwent invasive diagnosis. Positive predictive value (PPV) for fetal confirmation was 5.1% (4/79) and diagnostic yield was 8.9% (7/79) when uniparental disomy/runs of homozygosity (UPD/ROH) findings were included. Follow-up of 104 pregnancies included 63 uncomplicated pregnancies, 34 adverse pregnancy outcomes, and 7 terminations of pregnancy (TOP). In the primary analysis of 93 pregnancies, the TMR showed poor discrimination for adverse outcomes (AUC 0.643, 95% CI 0.531-0.756). TMR ≥ 0.63 was associated with adverse outcomes after adjustment (adjusted OR 3.66, 95% CI 1.33-10.05; p = 0.012).

RATs-positive NIPT results carried clinically meaningful pregnancy risk despite low fetal confirmation rates. TMR was higher with adverse pregnancy outcomes, but overlap and poor receiver operating characteristic (ROC) performance limit standalone use. TMR should be supplementary, interpreted in the context of chromosome, diagnostic, ultrasound, and obstetric findings.