Abstract
Background: This study aims to evaluate prenatal diagnosis methods following positive noninvasive prenatal screening (NIPS) results. Methods: According to the positive noninvasive prenatal screening results, 926 pregnant women were divided into three groups: main target disease group (high risk for trisomy 21, trisomy 18, or trisomy 13), sex chromosome aneuploidy (SCA) group, and other chromosomal abnormalities group [abnormal Z-scores for chromosomes other than trisomy (T)21/T18/T13 or SCAs]. The verification methods and results were then retrospectively analysed. Results: In the main target disease group, the positive rate of chromosomal abnormalities confirmed by quantitative fluorescence polymerase chain reaction (QF-PCR) was 75.18% (212/282), which was not significantly different from that by karyotyping (79.36%, 173/218) and copy number variation (CNV) detection methods (71.43%, 65/91). The positive rate of additional findings confirmed by karyotyping and copy number variation detection methods in main target disease group was 0.46% (1/218) and 8.79% (8/91), respectively. The positive rate of chromosomal abnormalities confirmed by karyotyping and CNV detection methods were 27.11% (45/166) and 38.46% (95/247) in the SCA group and 4.17% (1/24) and 20% (36/180) in the other chromosomal abnormalities group, respectively. Fetal sex chromosome mosaicism was detected in 16.13% (20/124) of the confirmed SCA cases. There were no significant differences in the detection rates of chromosomal microarray analysis (CMA) and CNV sequencing (CNVseq) among the three groups (p > 0.05). Conclusion: QF-PCR can quickly and accurately identify aneuploidies following NIPS-positive results for common aneuploidy, and in combination with karyotyping and CNV detection techniques can provide more comprehensive results. With the NIPS-positive results for SCA or other abnormalities, CMA and CNVseq may have the same effect on increasing the detection rate. The addition of fluorescence in situ hybridization assay may help to identify true fetal mosaicism.
Highlights
Noninvasive prenatal screening (NIPS) based on cell-free DNA in maternal circulation is used primarily to screen for trisomies 21, 18, and13, that has been shown to outperform conventional screening methods (Norton et al, 2015)
The NIPS-positive results were classified into three categories: 1) “main target disease” if NIPS was positive for trisomy (T)21, T18, or T13; 2) “sex chromosome aneuploidy (SCA)” when NIPS was positive for SCA; and 3) “other chromosomal abnormalities” when NIPS presented abnormal Z-scores for chromosomes other than T21/T18/T13 or SCAs
In the SCAs group, 140/413 (33.90%) were confirmed as chromosome abnormalities including 115/140 (82.14%) with sex chromosome aneuploidy, 26/140 (18.57%) with only CNV and one with structural abnormality
Summary
Noninvasive prenatal screening (NIPS) based on cell-free DNA in maternal circulation is used primarily to screen for trisomies 21, 18, and, that has been shown to outperform conventional screening methods (Norton et al, 2015). Not all positive results detected by NIPS represent fetal aberrations because of certain biological factors, such as confined placental mosaicism (Grati, 2014; Grati, 2016), ‘vanishing’ twins (Grömminger et al, 2014), and maternal genomic contribution (Ji et al, 2018; Zhang et al, 2020). Cytogenetic karyotype testing enables the visual detection of chromosomal abnormalities such as full chromosome aneuploidies, polyploidy, mosaicism, and structural abnormalities of more than 5–10 million base pairs (Mb), including balanced and unbalanced rearrangements. Both quantitative fluorescence polymerase chain reaction (QF-PCR) and fluorescence in situ hybridization (FISH) provide a rapid prenatal diagnosis of chromosome aneuploidy, and FISH is a valuable complementary test for detecting mosaicism (Hultén et al, 2003; Su et al, 2015). This study aims to evaluate prenatal diagnosis methods following positive noninvasive prenatal screening (NIPS) results
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