Abstract
Background: Non-invasive prenatal testing (NIPT) is a commonly employed clinical method to screen for fetal aneuploidy, while the Y chromosome-based NIPT method is regarded as the gold standard for the estimation of fetal fraction (FF) of male fetuses. However, when the fetus has a derivative Y chromosome thereby containing a partial Y chromosome, the Y chromosome-based NIPT method cannot accurately calculate FF. Therefore, alternative methods to precisely calculate FF are required.Methods: Two prenatal cases could not be detected effectively using the Y chromosome-based NIPT method because of low FF. According to the Y chromosome-based method, the FF of the fetuses were 1.730 ± 0.050% (average gestation week: 18+1) and 2.307 ± 0.191% (average gestation week: 20+0) for cases 1 and 2, respectively. Using various genetic diagnostic techniques, including the BoBs™ assay, karyotype analysis, improved nucleolus-organizing region (NOR)-banding analysis, Affymetrix CytoScan 750K Array, and fluorescence in situ hybridization (FISH) analysis, we determined the genetic defects of two fetuses with translocations of the SRY locus. Further, we reassessed the FF using FF-QuantSC and X chromosome-based methods. The distribution diagram of reads for chromosome Y was also analyzed.Results: The FF of the fetuses determined by FF-QuantSC were 10.330% (gestation week: 18+4) in case 1 and 9.470% (gestation week: 21+4) in case 2, while the FF of the fetuses determined using the X chromosome-based method were 8.889% (gestation week: 18+4) in case 1 and 2.296% (gestation week: 21+4) in case 2. Both the distribution diagrams of reads for chromosome Y of the two cases showed the deletion in the long arm of the Y chromosome.Conclusion: For repeatedly low FF samples detected using the Y chromosome-based NIPT method for a long gestational week, we believe that FF-QuantSC and distribution diagrams of reads could be used as a supplement to NIPT, especially for rare cases of sex reversal caused by SRY translocation.
Highlights
Since cell-free fetal DNA was detected in cell-free DNA obtained from the plasma of pregnant women (Lo et al, 1997), comparison of chromosome dosage distribution of cffDNA between patients and controls has played an increasingly important role in the diagnosis of fetal aneuploidy (Wang et al, 2006)
In order to assess the relationship between Y chromosome abnormalities and Fetal fraction (FF), we retrospectively analyzed pregnancies with available non-invasive prenatal testing (NIPT) data from our hospital (Shaoxing Maternity and Child Health Care Hospital) and found two cases with low FF determined by the traditional Y chromosome-based method
FF-QuantSC accounts for the characteristics of samples with moderate FF during artificial neural network training, avoiding the fluctuation caused by chromosome abnormality in the samples
Summary
Since cell-free fetal DNA (cffDNA) was detected in cell-free DNA (cfDNA) obtained from the plasma of pregnant women (Lo et al, 1997), comparison of chromosome dosage distribution of cffDNA between patients and controls has played an increasingly important role in the diagnosis of fetal aneuploidy (Wang et al, 2006). As an alternative screening method, non-invasive prenatal testing (NIPT) has proven to be highly sensitive and specific for the detection of common chromosomal aneuploidies, such as trisomy 21, trisomy 18, and trisomy 13, with low false-positive and false-negative rates (Song et al, 2013; Bianchi et al, 2014; Chandrasekharan et al, 2014; Liao et al, 2014). NIPT evaluates the risk of fetal chromosomal aneuploidies by detecting cffDNA circulating in maternal plasma via next-generation sequencing (NGS) technology (Chandrasekharan et al, 2014; Xue et al, 2019). Non-invasive prenatal testing (NIPT) is a commonly employed clinical method to screen for fetal aneuploidy, while the Y chromosome-based NIPT method is regarded as the gold standard for the estimation of fetal fraction (FF) of male fetuses.
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