Two cases of placental trisomy 21 mosaicism causing false-negative NIPT results.

Background: Non-invasive prenatal testing (NIPT) using cell-free DNA has been widely used for prenatal screening to detect the common fetal aneuploidies (such as trisomy 21, 18, and 13). NIPT has been shown to be highly sensitive and specific in previous studies, but false positives (FPs) and false negatives (FNs) occur. Although the prevalence of FN NIPT results for Down syndrome is rare, the impact on families and society is significant.

Case presentation: This article described two cases of foetuses that tested "negative" for trisomy 21 by NIPT technology using the semiconductor sequencing platform. However, the fetal karyotypes of amniotic fluid were 46,XY, + 21 der(21;21)(q10;q10) and 47,XY, + 21 karyotypes, respectively. Placental biopsies confirmed that, in the first case, the chromosome 21 placenta chimerism ratio ranged from 13 to 88% with the 46,XX, + 21,der(21;21)(q10;q10)[86]/46,XX[14] karyotype of placental chorionic cells (middle of fetal-side placental tissue). However, in the second case, of all the placental biopsies, percentage of total chimerism was less than 30%; and placental biopsies taken at the middle of maternal side and middle of fetal side, also had variable trisomy 2 mosaicism levels of 10% and 8%, respectively. Ultimately, the pregnancies were interrupted at 30 gestational age (GA) and 27GA, respectively.

Conclusions: In this study, we present two cases of FN NIPT results that might have been caused by biological mechanisms, as opposed to poor quality, technical errors, or negligence. Clinical geneticists and their patients must understand that NIPT is a screening procedure.