High false‐positive non‐invasive prenatal screening results for sex chromosome abnormalities: Are maternal factors the culprit?

Zhang, Bin; Zhou, Qin; Chen, Ying-ping; Shi, Ye; Zheng, Fangxiu; Li, Jianbing; Yu, Bin

doi:10.1002/pd.5529

Cited by 29 publications

(26 citation statements)

References 26 publications

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“…In our previous study (Zhang et al, 2020), we stated that the prediction of SCAs by NIPS may be interfered by maternal factors, and finding a way to deal with discordant SCA results caused by maternal sex chromosome abnormalities is the largest challenge remaining for NIPS.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, the values of Z-scores had increased in some false-positive cases for XXX and XXY, which may be associated with maternal X chromosome aneuploids. In our previous study ( Zhang et al, 2020 ), we stated that the prediction of SCAs by NIPS may be interfered by maternal factors, and finding a way to deal with discordant SCA results caused by maternal sex chromosome abnormalities is the largest challenge remaining for NIPS.…”

Section: Discussionmentioning

confidence: 99%

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The Optimal Cutoff Value of Z-scores Enhances the Judgment Accuracy of Noninvasive Prenatal Screening

Zhou

Zhang

et al. 2021

Front. Genet.

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ObjectiveTo evaluate the accuracy of Z-scores of noninvasive prenatal screening (NIPS) in predicting 21, 18 trisomy, and X chromosome aneuploidy.MethodsA total of 39,310 prenatal women were recruited for NIPS from September 2015 to September 2020. Interventional prenatal diagnosis was applied to verify the diagnosis of NIPS-positive results. Logistic regression analysis was employed to relate the Z-scores to the positive predictive value (PPV) of NIPS-positive results. Using receiver operating characteristic (ROC) curves, we calculated the optimal cutoff value of Z-scores to predict fetal chromosome aneuploidy. According to the cutoff value, NIPS-positive results were divided into the medium Z-value (MZ) and high Z-value (HZ) groups, and PPV was calculated to access the accuracy of Z-scores.ResultsA total of 288 effective values of Z-scores were used as the final data set. The logistics regression analysis revealed that Z-scores were significantly associated with true-positive results for 21 trisomy (T21) and 18 trisomy (T18) (P < 0.05), whereas the same was not observed for X chromosome aneuploids (P > 0.05). The optimal cutoff value of the Z-score for T21, T18, XO, XXX, and XXY indicated by ROC curve analysis were 5.79, 6.05, −9.56, 5.89, and 4.47, and the area under the curve (AUC) were 0.89, 0.80, 0.48, 0.42, and 0.45, respectively. PPV in the HZ group was higher than that in the MZ group, and the application of the cutoff value reduced the false discovery rate (FDR), which was only 2.9% in the HZ group compared with 61.1% in the MZ group for T21 and T18. The difference in total PPV between the MZ and HZ groups for X chromosome aneuploids was statistically significant. Moreover, the PPV for XXX and XXY seemed to increase with Z-scores but not for XO.ConclusionThe Z-score is helpful for the accurate judgment of NIPS results and for clinical prenatal counseling. Especially for T21 and T18, Z-scores have an excellent clinical association, which is superior to that seen with X chromosome aneuploids. In addition, using Z-scores to judge NIPS results offers a certain reference value for XXX and XXY but not for XO.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Optimal Cutoff Value of Z-scores Enhances the Judgment Accuracy of Noninvasive Prenatal Screening

Zhou

Zhang

et al. 2021

Front. Genet.

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“…Pseudoautosomal region consisted of 2 short segments at both termini of sex chromosomes. There would be errors in sequencing of these locations on X and Y chromosomes because of a short sequencing length of 36 bases [19,20,22]. This may be related to a highly variable amplification of chromosome X due to lower guanosine-cytosine content and loss of X chromosome in aging women, which required further investigation [22,24,30].…”

Section: Discussionmentioning

confidence: 99%

“…Yao et al [40] demonstrated for the first time that maternal genomic materials could affect NIPT accuracy. Afterward, many studies demonstrated that maternal factors could significantly affect the accuracy of NIPT for fetal SCAs [8, [16][17][18][19][20][21][22][23][24]41]. Wang et al [8] reported that maternal X chromosome aneuploidy and mosaicism were responsible for approximately 8.6% of discordant NIPT results for SCAs.…”

Section: Discussionmentioning

confidence: 99%

“…The positive predictive value (PPV) of SCAs screening was consistently lower in respect of autosomal trisomies. This could be related to confined placental mosaicism (CPM), abnormal maternal SCAs, including full maternal SCA, mosaic maternal SCA, and maternal copy number variants, as well as loss of an X chromosome from maternal cells as a natural part of aging [16][17][18][19][20][21][22]. Therefore, there is a lack of reliable data on SCA rates.…”

Section: Introductionmentioning

confidence: 99%

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Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

Shi

et al. 2021

Gynecol Obstet Invest

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Objective: This study was designed to investigate the efficiency of noninvasive prenatal testing (NIPT) for screening fetal sex chromosome aneuploidies (SCAs) through sequencing of cell-free DNA in maternal plasma. Methods: This is a retrospective study on the positive NIPT results for SCAs collected from our hospital between January 2012 and December 2018. Samples with positive NIPT results for SCAs were then confirmed by prenatal or postnatal karyotyping analysis. Results: After cytogenetic analysis, abnormal karyotypes were confirmed in 104 cases and the overall positive predictive value (PPV) of NIPT for SCAs was 43.40% (102/235). The most frequently detected karyotypes included 47,XXY (n = 42), 47,XXX (n = 20), 47,XYY (n = 16), and 45,X (n = 2). Meanwhile, 10 cases were confirmed with mosaic karyotype 45,X/46,XX and 14 cases with numerical or structural chromosome abnormalities, including a double trisomy 48,XXX,+18. Cytogenetic results from the other 131 cases showed normal XX or XY, which were discordant with NIPT results. Upon analysis of parental karyotypes, 29 (12.34%) showed false positivity in NIPT results that were caused by maternal sex chromosome abnormalities. Conclusion: NIPT is an effective screening tool for SCA with a PPV of 43.40%. Maternal karyotype abnormalities occurred in 12.34% of the cases with abnormal NIPT. Diagnostic testing of the fetus and the mother are recommended.

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Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence

Xie

Tan

et al. 2020

Molec Gen & Gen Med

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BackgroundFollow‐up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA.MethodsFollowing positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus‐specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow‐up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA.ResultsOf the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow‐up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%–20% and 3% of SCA cases, respectively.ConclusionThese five cases further demonstrated the necessity to pursue follow‐up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence‐based approach to guide prenatal diagnosis of SCA.

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High false‐positive non‐invasive prenatal screening results for sex chromosome abnormalities: Are maternal factors the culprit?

Cited by 29 publications

References 26 publications

The Optimal Cutoff Value of Z-scores Enhances the Judgment Accuracy of Noninvasive Prenatal Screening

The Optimal Cutoff Value of Z-scores Enhances the Judgment Accuracy of Noninvasive Prenatal Screening

Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence

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