Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 42,910 single pregnancies with different clinical features

Abstract Background Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. Methods A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. Results A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5–10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. Conclusion Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

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Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

Gynecologic and Obstetric Investigation ◽

10.1159/000518002 ◽

2021 ◽

pp. 1-9

Author(s):

Yunfang Shi ◽

Xiaozhou Li ◽

Duan Ju ◽

Yan Li ◽

Xiuling Zhang ◽

...

Keyword(s):

Screening Tool ◽

Sex Chromosome ◽

Diagnostic Testing ◽

Prenatal Testing ◽

Maternal Plasma ◽

Chromosome Abnormalities ◽

Noninvasive Prenatal Testing ◽

Sex Chromosome Abnormalities ◽

Sex Chromosome Aneuploidies ◽

Mosaic Karyotype

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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Cell-free DNA screening for sex chromosome aneuploidies by non-invasive prenatal testing in maternal plasma

Molecular Cytogenetics ◽

10.1186/s13039-020-0478-5 ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Yipeng Wang ◽

Shanshan Li ◽

Wei Wang ◽

Yuan Dong ◽

Meng Zhang ◽

...

Keyword(s):

Sex Chromosome ◽

Prenatal Testing ◽

Maternal Plasma ◽

Cell Free Dna ◽

Non Invasive ◽

Free Dna ◽

Sex Chromosome Aneuploidies

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Non-invasive Prenatal Testing (NIPT)

10.2310/obg.19129 ◽

2019 ◽

Author(s):

Courtney Manning ◽

Mary-Alice Abbott

Keyword(s):

High Risk ◽

Screening Test ◽

Sex Chromosome ◽

Diagnostic Testing ◽

Prenatal Testing ◽

Trisomy 18 ◽

Trisomy 13 ◽

Non Invasive ◽

Risk Result ◽

Cell Free Fetal Dna

Non-invasive prenatal testing (NIPT) is a screening test that can determine if a pregnancy is at high risk for the common aneuploidies by analyzing cell-free fetal DNA in the maternal bloodstream. The screening includes trisomy 21, trisomy 18, and trisomy 13, with the option of screening for sex chromosome aneuploidy and fetal sex. Traditionally this testing is offered to women that are at high risk for these aneuploidies, most commonly women of advanced maternal age. Individuals that receive a high risk result on NIPT should be offered diagnostic testing to confirm the result. New forms of NIPT have recently emerged, however the use of this technology as a screening test for other genetic conditions is not currently recommended by national professional society guidelines. Patients should be counseled and consented for NIPT, as this is an optional screening test. This review contains 2 tables, and 39 references. Keywords: NIPT, non-invasive prenatal testing, aneuploidy, Down syndrome, trisomy 18, trisomy 13, Turner syndrome, microdeletions, diagnostic testing

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Maternal Mosaicism Is a Significant Contributor to Discordant Sex Chromosomal Aneuploidies Associated with Noninvasive Prenatal Testing

Clinical Chemistry ◽

10.1373/clinchem.2013.215145 ◽

2014 ◽

Vol 60 (1) ◽

pp. 251-259 ◽

Cited By ~ 156

Author(s):

Yanlin Wang ◽

Yan Chen ◽

Feng Tian ◽

Jianguang Zhang ◽

Zhuo Song ◽

...

Keyword(s):

Sex Chromosome ◽

Massively Parallel Sequencing ◽

Prenatal Testing ◽

Maternal Plasma ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Noninvasive Prenatal Testing ◽

The Common ◽

Chromosomal Aneuploidies ◽

Sex Chromosome Aneuploidies

Abstract BACKGROUND In the human fetus, sex chromosome aneuploidies (SCAs) are as prevalent as the common autosomal trisomies 21, 18, and 13. Currently, most noninvasive prenatal tests (NIPTs) offer screening only for chromosomes 21, 18, and 13, because the sensitivity and specificity are markedly higher than for the sex chromosomes. Limited studies suggest that the reduced accuracy associated with detecting SCAs is due to confined placental, placental, or true fetal mosaicism. We hypothesized that an altered maternal karyotype may also be an important contributor to discordant SCA NIPT results. METHODS We developed a rapid karyotyping method that uses massively parallel sequencing to measure the degree of chromosome mosaicism. The method was validated with DNA models mimicking XXX and XO mosaicism and then applied to maternal white blood cell (WBC) DNA from patients with discordant SCA NIPT results. RESULTS Sequencing karyotyping detected chromosome X (ChrX) mosaicism as low as 5%, allowing an accurate assignment of the maternal X karyotype. In a prospective NIPT study, we showed that 16 (8.6%) of 181 positive SCAs were due to an abnormal maternal ChrX karyotype that masked the true contribution of the fetal ChrX DNA fraction. CONCLUSIONS The accuracy of NIPT for ChrX and ChrY can be improved substantially by integrating the results of maternal-plasma sequencing with those for maternal-WBC sequencing. The relatively high frequency of maternal mosaicism warrants mandatory WBC testing in both shotgun sequencing– and single-nucleotide polymorphism–based clinical NIPT after the finding of a potential fetal SCA.

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Non-invasive prenatal testing for detection of trisomy 13, 18, 21 and sex chromosome aneuploidies in 8594 cases

Ginekologia Polska ◽

10.5603/gp.2019.0050 ◽

2019 ◽

Vol 90 (5) ◽

pp. 270-273 ◽

Cited By ~ 1

Author(s):

Yunyun Zheng ◽

Shanning Wan ◽

Yinghui Dang ◽

Tingting Song ◽

Biliang Chen ◽

...

Keyword(s):

Sex Chromosome ◽

Prenatal Testing ◽

Trisomy 13 ◽

Non Invasive ◽

Sex Chromosome Aneuploidies

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Non‐invasive prenatal testing for the prenatal screening of sex chromosome aneuploidies: A systematic review and meta‐analysis of diagnostic test accuracy studies

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1654 ◽

2021 ◽

Author(s):

Bounhome Soukkhaphone ◽

Carmen Lindsay ◽

Sylvie Langlois ◽

Julian Little ◽

Francois Rousseau ◽

...

Keyword(s):

Systematic Review ◽

Diagnostic Test ◽

Prenatal Screening ◽

Sex Chromosome ◽

Meta Analysis ◽

Prenatal Testing ◽

Diagnostic Test Accuracy ◽

Test Accuracy ◽

Non Invasive ◽

Sex Chromosome Aneuploidies

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A comment on “clinical experience with sex chromosome aneuploidies detected by noninvasive prenatal testing (NIPT): Accuracy and patient decision‐making”

Prenatal Diagnosis ◽

10.1002/pd.5382 ◽

2018 ◽

Vol 38 (13) ◽

pp. 1129-1130 ◽

Cited By ~ 2

Author(s):

Luisa Ronzoni ◽

Gaia Silibello ◽

Donatella Quagliarini ◽

Faustina Lalatta

Keyword(s):

Decision Making ◽

Clinical Experience ◽

Sex Chromosome ◽

Prenatal Testing ◽

Noninvasive Prenatal Testing ◽

Patient Decision Making ◽

Patient Decision ◽

Sex Chromosome Aneuploidies

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The Value of Non-Invasive Prenatal Testing in the Diagnosis of Birth Defects: Insights from a Large Multicentre Study in Southern China

10.21203/rs.3.rs-778395/v1 ◽

2021 ◽

Author(s):

Meiying Cai ◽

Na Lin ◽

Xuemei Chen ◽

Ying Li ◽

Min Lin ◽

...

Keyword(s):

Multicentre Study ◽

Pregnant Women ◽

Chromosomal Abnormalities ◽

Southern China ◽

Prenatal Testing ◽

Copy Number Variations ◽

Trisomy 13 ◽

Detection Rates ◽

Non Invasive ◽

Large Multicentre Study

Abstract Non-invasive prenatal testing (NIPT) is a fast, safe, and non-disruptive diagnostic method. At present, few studies have evaluated the screening efficiency of NIPT positive predictive value (PPV) in study subjects. Here, the results of NIPT in pregnant women were retrospectively analysed, and the detection rate, PPV and follow-up data were evaluated to determine its clinical value. A large multicentre study was conducted involving 52,855 pregnant women who received NIPT. Based on gestational age, amniotic fluid or umbilical cord blood were extracted for simultaneous karyotype and chromosome microarray analysis (CMA) in NIPT-positive patients. Among the 52,855 cases, 754 were NIPT-positive, with a positivity rate of 1.4%. Karyotype analysis and/or CMA confirmed 323 cases of chromosomal abnormalities, with a PPV of 45.1%. PPV of Trisomy 21 (T21), Trisomy 18 (T18), Trisomy 13 (T13), sex chromosomal aneuploidies (SCA) and copy number variations (CNV) were 78.9%, 35.3%, 22.2%, 36.9% and 32.9%, respectively. The PPV of T21, T18, and T13 increased with age whereas, the PPV of SCA and CNVs had little correlation with age. The PPV was significantly high in patients with advanced age along with an abnormal ultrasound.NIPT had a high PPV for T21, and a low PPV for T13 and T18, while screening for SCA and CNVs showed clinical significance. However, in case of NIPT screening for SCA and CNVs, simultaneous karyotype and CMA should be performed to increase the detection rates. Interventional prenatal diagnosis is still required in NIPT-positive cases to avoid false positives or unnecessary termination of pregnancy.

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