A gradual change of chromosome mosaicism from placenta to fetus leading to T18 false negative result by NIPS

Abstract

Background: Noninvasive prenatal screening (NIPS) has higher sensitivity and specificity compared to traditional prenatal screening. Nevertheless, the discordant results between the NIPS and prenatal diagnosis were occasionally reported. In current study, we investigated the genetic basis of a T18 fetus with a discordant trisomy 5 (T5) positive and trisomy 18 (T18) negative NIPS result.

Methods: NIPS was used to detect fetal DNA in maternal circulating plasma based on semiconductor sequencing platform. The aneuploidies of the fetus and different part of placental tissues were investigated by copy number variation sequencing (CNV-seq) and chromosome microarray analysis (CMA).

Results: The positive result of T5 was detected for the pregnant woman in NIPS, while T18 was found in the fetal karyotyping analysis after amniocentesis. Furthermore, placental mosaicism of T5 and T18 was found by CNV-seq and CMA, which revealed the mosaic ratio of T5 was gradually increased from umbilical cord to the placenta center, while that of T18 was gradually decreased.

Conclusion: For the reason of cell-free fetal DNA (cff DNA) in the maternal circulation originates from trophoblast cells of placenta, the level of placental mosaicism could cause false negative NIPS result in multiple aneuploidies. The present study proved that a discordant T5 positive and T18 negative NIPS result was caused by placental mosaicism. This study highlights placental mosaicism as a significant risk factor for discordant NIPS results. The result will be helpful for genetic counseling and clinical management of such pregnant woman.

Keywords: False-negative result; Non-invasive prenatal screening; Placental mosaicism; Trisomy 18.