Discordant results between fetal karyotyping and non‐invasive prenatal testing by maternal plasma sequencing in a case of uniparental disomy 21 due to trisomic rescue

Abstract

Uniparental disomy (UPD) is an uncommon chromosome condition, but UPD involving chromosome 21 is rarely reported. We reported here a case who had first trimester screening test for Down syndrome, chorionic villus sampling for fetal karyotyping, quantitative fluorescence polymerase chain reaction (QF-PCR), as well as non-invasive prenatal testing (NIPT) by maternal plasma sequencing. There were discordant results between fetal karyotyping and NIPT due to UPD 21combined with confined placental mosaicism of trisomy 21. This demonstrated that it is possible to detect placental mosaicism by NIPT, but further studies are required to confirm its sensitivity. Therefore, all positive NIPT results must be confirmed by conventional invasive test and karyotyping. QF-PCR has the additional benefit in diagnosing UPD.

Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results

“…Recently published case reports have suggested this to be a mechanism underlying some false/discordant NIPS results. 12,13 Our analysis, based on a large cytogenetic data set that incorporates both the cytotrophoblast and the mesenchymal core, allows the prediction of the potential contribution of CPM and TFM to the rates of FP and FN NIPS results, respectively. However, it is important to note that verification of these predicted results would require prospective data to be obtained.…”

“…Even using a conservative assumption that a high percentage of mosaicism ≥70% abnormal cells would be required to produce sufficient fetal fraction to generate a "positive" by NIPS, the FP rate for the common trisomies (13,18, and 21) would be 0.033% or 1 in 3,006 cases reported as normal (95% confidence interval (CI): 1/1,877-1/4,813); for common trisomies and monosomy X, the FP rate would be 0.08%, which is equivalent to 1 in 1,243 cases reported as normal (95% CI: 1/917-1/1,687); and for all targeted or potentially identifiable chromosome abnormalities, the FP rate would be 0.091%, which is equivalent to 1 in 1,105 cases reported as normal (95% CI: 1/829-1/1,474). Table 2).…”

A case of maternal uniparental disomy of chromosome 20 detected by noninvasive prenatal test of 1,000 high-risk pregnancies

“…To best of our knowledge, two cases of UPD were detected by following discordant NIPT and invasive testing. Of these, one was a case of UPD 21 [8], and the other was a case of UPD 15 with fetal mosaicism [1]. In this study, we showed the potential use of NIPT for the detection of UPD, especially when the trisomies of specific chromosomes with imprinting syndromes are detected.…”

“…In this study, we performed whole genome sequencingbased NIPT (G-NIPT TM ; Green Cross Genome, Yongin, Korea) of 1,000 high-risk Korean pregnancies, and detected five cases of chromosomal trisomies other than in chromosomes 21, 18, and 13: one case each of chromosome 7,8,16, and two cases of chromosome 20. All three trisomy cases involving chromosomes 7 and 20 were investigated invasively for the presence of UPD.…”

False Negative Cell Free DNA Screening Result in a Newborn with Trisomy 13

“…In several reported cases, followup amniocentesis based on positive cfDNA screening results has identified a normal karyotype, suggesting a false positive cfDNA screening result [3][4][5][6][7][8]. Even though the published data indicates high sensitivity (≥99% for trisomy 21, ≥92% for trisomy 18, and ≥87% for trisomy 13) and specificity (≥99% for trisomy 21, 18, and 13) for aneuploidy detection [9], false positive results have been reported for confined placental mosaicism, vanishing twin or cotwin demise, fetal chromosome rearrangement, and maternal chromosome abnormalities or malignancy [10][11][12][13][14]. Based on several reports, false negative results for fetal aneuploidy are much less common than false positive results [4-6, 15, 16].…”