Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

Abstract

Objective: Non-invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed.

Method: NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected.

Results: In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre-eclampsia, low birth weight, preterm delivery, and/or congenital malformations.

Conclusion: The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases.

Figure 1

B‐allele frequency (BAF) plots of chromosome 16 in different tissues of case 6: AF, amniotic fluid; CB, umbilical cord blood; CTB1, 2, and 3, cytotrophoblast of placental biopsies 1, 2, and 3; MC1, 2, and 3, mesenchymal core of placental biopsies 1, 2, and 3. These BAF profiles show a meiotic origin of trisomy 16 with additional BAF lines representing genotypes present in the trisomic cell line that are not present in the diploid cell line. Mosaicism of a trisomy 16 cell line with two different diploid cell lines, one with BPD, and one with UPD was found. AF and CB both show a normal BAF profile fitting a 100% BPD16. CTB1 and MC1 of placental biopsy 1, both with a normal LogR profile (data not shown), show UPD16/BPD16 mosaicism of different levels (approximately 90%/10% in CTB and approximately 50%/50% in MC) as shown by a region of mosaic loss of heterozygosity at the p‐arm telomere. It should be noted that the BAF profile in CTB1 may also fit a low mosaic trisomy 16 of approximately 10% (with UPD16 in 90%). CTB2 of biopsy 2 shows a 100% trisomy 16. MC2 shows approximately 20% trisomy 16 with BPD 16 in the diploid cell line based on absence of a mosaic region of homozygosity near the p‐arm telomere. CTB3 of biopsy 3 shows approximately 80% trisomy 16 with UPD16 in the diploid cell line shown by the altered pattern near the telomere of the p‐arm. MC3 shows approximately 40% trisomy 16 with BPD16 in the diploid cell line based on absence of a region of homozygosity in the p‐arm. Based on the BAF profile, and as compared with the BAF profile of MC2, especially at the p‐arm, it cannot be excluded that besides a trisomy 16 and BPD16, also a UPD16 cell line is present in MC3 [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

LogR (left) and B‐allele frequency (BAF) profiles of part of the long arm of chromosome 21 in four placental biopsies (1‐4) of case 9. For each biopsy, cytotrophoblast (CTB) and mesenchymal core (MC) were investigated separately, with the upper plot within biopsies 1 to 4 showing the result of CTB and the lower one of the MC. The LogR plots (left) show a normal diploid result in CTB and MC of biopsies 1, 2, and 4 and of the MC of biopsy 3. In the CTB of biopsy 3, a 100% trisomy 21 was found. The BAF profiles (right) show a normal BPD 21 in CTB and MC of biopsies 1 and 2 and in the MC of biopsies 3 and 4. A 100% trisomy 21 was found in the CTB of biopsy 3 whereas a UPiD21 was present in the CTB of biopsy 4, shown by a complete loss of heterozygosity [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

The B‐allele frequency (BAF) profiles of chromosome 22 in amniotic fluid (AF) and the mesenchymal core of biopsy 1 (MC1) of case 10. In AF, a low mosaic trisomy 22 of about 10% was found with UPhD in the diploid cell line, as shown by loss of heterozygosity at the telomeric end of the q‐arm. The UPhD originated from loss of the “green chromosome” as illustrated in the figure on the right; however, it should be noted that the BAF profile, with a normal LogR, could also fit a low mosaic BPD22 of about 10% with UPD22 in the remaining 90%. In MC1, a mosaic trisomy 22 was found of about 50% with a BPD22 in the diploid cell line based on absence of a region of homozygosity. This BPD originated through loss of another trisomic chromosome during early embryogenesis, namely, the pink one, as illustrated in the figure on the right [Colour figure can be viewed at http://wileyonlinelibrary.com]