Analyzing false-negative results detected in low-risk non-invasive prenatal screening cases

The non-invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false-negative results are inevitable and important, limited false-negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false-negative results detected in the NIPS cases with a low-risk result.

NIPS was performed using whole-genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low-risk result performed in our center in 2017 were followed-up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies.

By following-up 10,975 low-risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false-negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases.

Our results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false-negative results.