Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy

Abstract

Genome-wide noninvasive prenatal testing identifies several rare autosomal trisomies in the general obstetrical population, but its use is questioned by its low positive predictive value. Furthermore, the origin of rare autosomal trisomies and the clinical effect of reporting them has not been sufficiently investigated. In addition, professional societies express their need for data assessing the clinical use of genome-wide noninvasive prenatal testing for rare autosomal trisomies for years. This study aimed to investigate the origin of rare autosomal trisomies and the clinical effect of disclosing rare autosomal trisomies in clinical settings. Women who received noninvasive prenatal testing between March 2021 and March 2022 were prospectively enrolled. Clinical follow-up and cytogenetic and molecular investigations were performed. Posthoc analysis was performed to investigate the association between placental mosaicism and clinical outcomes. Overall, 154 rare autosomal trisomies were identified in 89,242 pregnancies (0.17%) through noninvasive prenatal testing. In the 120 cases in which cytogenetic and molecular investigations were carried out, the rare autosomal trisomies were found to originate from true fetal mosaicism (n=5), uniparental disomy (n=5), maternal mosaic trisomy (n=3), maternal malignancy (n=1), and confined placental mosaicism (n=106). Clinical follow-up showed that 40% of all rare autosomal trisomy cases had adverse perinatal outcomes. In women with false-positive noninvasive prenatal testing results originating from confined placental mosaicism, the frequency of adverse perinatal outcomes was 26%. More importantly, the placental mosaicism ratio revealed by noninvasive prenatal testing was significantly higher in women who experienced adverse perinatal outcomes than those who did not (0.688 vs 0.332; P<.001). Women with noninvasive prenatal testing results indicative of rare autosomal trisomies are at risk of adverse perinatal outcomes, and that risk can be stratified using chromosomes and the mosaicism ratio revealed by noninvasive prenatal testing. Our data are valuable for obstetrical caregivers advising a patient with a noninvasive prenatal testing result indicative of a rare autosomal trisomy and a false-positive diagnosis and for managing risks during pregnancy.