Screening for Fetal Aneuploidy and Sex Chromosomal Anomalies in a Pregnant Woman With Mosaicism for Turner Syndrome—Applications and Advantages of Cell-Based NIPT

Abstract

Background: Cell-free NIPT and cell-based NIPT are risk-free testing options using maternal blood samples to screen for fetal aneuploidies, but the methods differ. For cell-free NIPT, the fetal fraction of cell-free DNA in plasma is analyzed with a high background of maternal DNA. In contrast, for cell-based NIPT, a limited number of the rare, intact fetal cells are isolated for the genetic analysis. This case demonstrates the differences regarding testing for fetal sex-chromosomes anomalies (SCAs) between these two tests.Materials and Methods: A pregnant woman with mosaicism for Turner syndrome opted for NIPT in first trimester. For the cell-free NIPT analysis, DNA extraction, genome-wide massive parallel sequencing, and data analysis were carried out as described by the kit manufacturer (Illumina©, San Diego, CA, USA). For cell-based NIPT, the first sample gave no result, but the woman consented to repeat cell-based NIPT. After whole genome amplification and STR analysis, fetal DNA from three individual fetal cells was subjected to chromosomal microarray (aCGH, Agilent oligoarray, 180 kb).Results: Fetal fraction was 7%, and cell-free NIPT showed 2 copies of chromosomes 13, 18, and 21 and a decreased proportion of chromosome X, suggestive of fetal Turner syndrome. In contrast, the cell-based NIPT result showed no aneuploidy and two X-chromosomes in the fetus.Conclusion: cell-based NIPT may provide a non-invasive testing option to screen for SCAs in women with mosaicism for monosomy-X in blood, where cell-free NIPT cannot discriminate whether the X-loss is maternal or fetal.

Cell-Free DNA Screening for Sex Chromosome Abnormalities and Pregnancy Outcomes, 2018–2020: A Retrospective Analysis

“…They include 45, X, 47, XXX, 47, XXY, 47, XYY, and their mosaic types [23]. SCA incidence in newborns is 1/400-1/500, which is higher than that the incidence of common trisomies, such as T21 (12.6/10,000), T18 (1.2-2.3/10,000), and T13 (1.4/10,000) [16,17,20]. Hence, the clinical presentation of SCAs should be identified.…”

“…This could be due to the lower guanosine-cytosine content of X chromosome and the age-related loss of X chromosome in male [15]. After prenatal diagnostic testing, the results were inconsistent with NIPT, which were probably due to the low fetal DNA fraction, maternal obesity, maternal copy number variations or mosaicism, abnormal maternal karyotype, confined placental mosaicism, a vanishing twin, and maternal neoplasm [16]. Among the inconsistent results, the following seven cases with other karyotype results were detected: 46, XN, 9qh+; 46, XN, 21pss; 46, XN, inv (9) (p12q13); 46, XN, del (8) (q24.13-24.22); 47, XN, +21 (n = 2); and 47, XN, +18.…”

“…Since the PPV of NIPT for sex chromosome abnormalities was low, couples can feel pressurized to undergo further prenatal diagnosis with sex chromosome abnormalities [6]. Abnormal sex chromosomes in pregnant women are an important reason for false-positive results of sex chromosome abnormality detection by NIPT [16]. Therefore, all NIPT cases should be examined by maternal peripheral blood karyotyping.…”

“…No obvious abnormality in the fetus was observed at birth. The clinical phenotype and severity of mosaic karyotype in the fetus after birth depend on the proportion of mosaic and normal cells [16]. The birth of fetuses with sex chromosome abnormalities may be affected by the information and guidance provided by the genetic counselor and age, education, economic status, pregnancy history, and acceptance by the parents.…”

Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

“…Importantly, cell-based NIPT is not affected by maternal factors known to influence the analysis of cffDNA. This was recently demonstrated in a case with a pregnant woman who was mosaic for monosomy X where cell-based NIPT showed an euploid 46,XX female fetus, while cell-free NIPT showed increased risk of 46,X associated with Turner syndrome (Jeppesen et al, 2021). However, more data is needed to determine the sensitivity and specificity before the test is ready for routine clinical use (Vossaert et al, 2019).…”