Performance of Cell-Free DNA Screening for Fetal Common Aneuploidies and Sex Chromosomal Abnormalities: A Prospective Study from a Less Developed Autonomous Region in Mainland China

To evaluate the performance of noninvasive prenatal screening (NIPS) in the detection of common aneuploidies in a population-based study, a total of 86,262 single pregnancies referred for NIPS were prospectively recruited. Among 86,193 pregnancies with reportable results, follow-up was successfully conducted in 1160 fetuses reported with a high-risk result by NIPS and 82,511 cases (95.7%) with a low-risk result. The screen-positive rate (SPR) of common aneuploidies and sex chromosome abnormalities (SCAs) provided by NIPS were 0.7% (586/83,671) and 0.6% (505/83,671), respectively. The positive predictive values (PPVs) for Trisomy 21, Trisomy 18, Trisomy 13 and SCAs were calculated as 89.7%, 84.0%, 52.6% and 38.0%, respectively. In addition, less rare chromosomal abnormalities, including copy number variants (CNVs), were detected, compared with those reported by NIPS with higher read-depth. Among these rare abnormalities, only 23.2% (13/56) were confirmed by prenatal diagnosis. In total, four common trisomy cases were found to be false negative, resulting in a rate of 0.48/10,000 (4/83,671). In summary, this study conducted in an underdeveloped region with limited support for the new technology development and lack of cost-effective prenatal testing demonstrates the importance of implementing routine aneuploidy screening in the public sector for providing early detection and precise prognostic information.

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Cell-free DNA screening for aneuploidies in 7113 pregnancies: single Italian centre study

Genetics Research ◽

10.1017/s001667232000004x ◽

2020 ◽

Vol 102 ◽

Cited By ~ 1

Author(s):

Alvaro Mesoraca ◽

Katia Margiotti ◽

Claudio Dello Russo ◽

Anthony Cesta ◽

Antonella Cima ◽

...

Keyword(s):

Sex Chromosome ◽

Clinical Performance ◽

False Negative ◽

Prenatal Testing ◽

High Sensitivity ◽

Trisomy 13 ◽

Sequencing Platform ◽

Non Invasive ◽

Negative Results ◽

False Negative Results

Abstract Introduction Non-invasive prenatal testing (NIPT) using cell-free foetal DNA has been widely accepted in recent years for detecting common foetal chromosome aneuploidies, such as trisomies 13, 18 and 21, and sex chromosome aneuploidies. In this study, the practical clinical performance of our foetal DNA testing was evaluated for analysing all chromosome aberrations among 7113 pregnancies in Italy. Methods This study was a retrospective analysis of collected NIPT data from the Ion S5 next-generation sequencing platform obtained from Altamedica Medical Centre in Rome, Italy. Results In this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomies 13, 18 and 21. Out of the 7113 samples analysed, 74 cases (1%) were positive by NIPT testing; foetal karyotyping and follow-up results validated 2 trisomy 13 cases, 5 trisomy 18 cases, 58 trisomy 21 cases and 10 sex chromosome aneuploidy cases. There were no false-negative results. Conclusion In our hands, NIPT had high sensitivity and specificity for common chromosomal aneuploidies such as trisomies 13, 18 and 21.

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Performance of non-invasive prenatal testing for foetal chromosomal abnormalities in 1048 twin pregnancies

Molecular Cytogenetics ◽

10.1186/s13039-021-00551-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yuan Cheng ◽

Xinran Lu ◽

Junxiang Tang ◽

Jingran Li ◽

Yuxiu Sun ◽

...

Keyword(s):

Sex Chromosome ◽

Chromosomal Abnormalities ◽

False Negative ◽

Prenatal Testing ◽

Maternal Plasma ◽

Clinical Value ◽

Non Invasive ◽

Negative Results ◽

Negative Case ◽

Twin Pregnancies

Abstract Objective To investigate the clinical value of non-invasive prenatal testing (NIPT) to screen for chromosomal abnormalities in twin pregnancies and to provide further data on NIPT manifestations in twin pregnancies. Materials and methods In a 4-year period, 1048 women with twin pregnancies were voluntarily prospectively tested by NIPT to screen for chromosomal abnormalities by sequencing cell-free foetal DNA (cffDNA) in maternal plasma. Positive NIPT results were confirmed by karyotyping, while negative results were followed up 42 days after delivery. Results Thirteen women had positive NIPT results as follows: 2 cases of trisomy 21 (T21), 1 of trisomy 18 (T18), 7 of sex chromosome aneuploidy (SCA), 1 of microdeletion, and 2 of microduplication. Of these 13 cases, 2 were true-positive cases confirmed by foetal karyotype analysis, namely, 1 case of T21 and 1 of microdeletion. Furthermore, the remaining 11 high-risk pregnant women were confirmed as false positive by foetal karyotyping. Thus, the combined positive predictive value (PPV) of NIPT screening for chromosomal abnormalities in twin pregnancies was 15.4% (2/13). There were no false-negative case via our follow-up results. Conclusion Safe and rapid NIPT has a certain clinical application value; however, the PPV is limited, and the screening efficiency is not stable. Careful use should be made in the screening of chromosomal abnormalities in twin pregnancies.

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Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-020-01977-2 ◽

2020 ◽

Vol 37 (12) ◽

pp. 3143-3150

Author(s):

Wan Lu ◽

Ting Huang ◽

Xin-Rong Wang ◽

Ji-Hui Zhou ◽

Hui-Zhen Yuan ◽

...

Keyword(s):

High Risk ◽

Sex Chromosome ◽

Chromosomal Abnormalities ◽

False Positive Rate ◽

Prenatal Testing ◽

Central China ◽

Jiangxi Province ◽

Noninvasive Prenatal Testing ◽

Predictive Values ◽

Risk Pregnancy

Abstract Purpose To evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis. Methods This retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview. Results A total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively. Conclusion NIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.

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The Clinical Application of Non-invasive Prenatal Genetic Testing in the Screening of Fetal Chromosomal Diseases

10.21203/rs.3.rs-297925/v1 ◽

2021 ◽

Author(s):

Yu Pang ◽

chaohong wang ◽

Junxiang Tang ◽

Jiansheng Zhu

Keyword(s):

High Risk ◽

Clinical Application ◽

Trisomy 21 ◽

Sex Chromosome ◽

Chromosomal Abnormalities ◽

Reference Value ◽

Prenatal Testing ◽

Trisomy 13 ◽

Non Invasive ◽

Chromosome Aneuploidy

Abstract Objective：To explore the efficacy and clinical application value of non-invasive prenatal testing (non-invasive prenatal testing, NIPT) for screening fetal chromosomal abnormalities. Methods: NIPT was performed on 25,517 pregnant women. The high-risk samples were compared with amniotic fluid and cord blood chromosome karyotype analysis. Some samples were further verified by microarray (CMA), and pregnancy outcomes were followed up. Results: Of all the cases examined, 25502 cases were detected successfully, and a total of 294 high-risk samples (1.15%) were detected, of which further diagnosis was made in 208 cases, true positive samples were detected in 96 cases, and further tests were refused in 86 cases.71 cases (0.28%) of autosomal aneuploid high-risk samples were detected and 51 cases were diagnosed, including 44 cases of trisomy 21 (T21), 5 cases of trisomy 18 (T18), and 2 cases of trisomy 13 (T13). The PPV was 90.90%, 45.45% and 33.33%, respectively. Thirteen high-risk samples of trisomy 21, 18, and 13 were detected, and 1 case was confirmed as T21 mosaic PPV was 8.33% NPV was 100%. High-risk samples of sex chromosome aneuploidy (SCA) were detected in 72 cases (0.28%), 23 cases were diagnosed, and the PPV was 40.07%. The PPV was 12.00%, 50.00%, 72.73% and 75.00%, respectively, and the PPV was 12.00%, 50.00%, 72.73% and 75.00%, respectively. High-risk samples of copy number variation (CNV) were detected in 104 cases (0.41%), and 18 cases were diagnosed, with a PPV of 32.14%. Other high-risk samples of chromosome aneuploidy were detected in 34 cases (0.13%), and 3 cases were diagnosed as T2, T9, and T16, respectively. PPV is 8.70%.Conclusion: NIPT is suitable for trisomy 21, 18, and 13 screening, especially for T21. It also has a certain reference value for SCA and microdeletion and microduplication syndromes（MMS）, and it is not recommended for screening for other chromosomal 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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Expanded noninvasive prenatal testing for fetal aneuploidy and copy number variations and parental willingness for invasive diagnosis in a cohort of 18,516 cases

BMC Medical Genomics ◽

10.1186/s12920-021-00955-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yunsheng Ge ◽

Jia Li ◽

Jianlong Zhuang ◽

Jian Zhang ◽

Yanru Huang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

High Risk ◽

Pregnant Women ◽

Copy Number ◽

Prenatal Testing ◽

Copy Number Variations ◽

Trisomy 13 ◽

Noninvasive Prenatal Testing ◽

Predictive Values ◽

Parental Willingness

Abstract Background Noninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center. Methods A total of 24,702 pregnant women were retrospectively analyzed at the Women and Children’s Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes. Results Of the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38–100%), 96.67%(95%CI, 82.78–99.92%), and 100%(95%CI, 66.37–100.00%), and the specificity was 99.92%(95%CI, 99.87–99.96%), 99.96%(95%CI, 99.91–99.98%), and 99.88% (95%CI, 99.82–99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs. Conclusions Our study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

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

Human Genomics ◽

10.1186/s40246-019-0250-2 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 17

Author(s):

Yibo Chen ◽

Qi Yu ◽

Xiongying Mao ◽

Wei Lei ◽

Miaonan He ◽

...

Keyword(s):

Clinical Features ◽

Sex Chromosome ◽

Prenatal Testing ◽

Maternal Plasma ◽

Trisomy 13 ◽

Noninvasive Prenatal Testing ◽

Detection Rates ◽

Non Invasive ◽

Cell Free Fetal Dna ◽

Sex Chromosome Aneuploidies

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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Current status of non-invasive prenatal testing (NIPT): genetic counseling, dominant methods and overall performance

LaboratoriumsMedizin ◽

10.1515/labmed-2016-0038 ◽

2016 ◽

Vol 40 (5) ◽

Author(s):

Thomas Harasim ◽

Imma Rost ◽

Hanns-Georg Klein

Keyword(s):

Genetic Counseling ◽

Paradigm Shift ◽

Sex Chromosome ◽

Prenatal Testing ◽

Diagnostic Procedures ◽

Trisomy 13 ◽

Current Status ◽

Non Invasive ◽

Overall Performance ◽

Aneuploidy Testing

Abstract:The introduction of non-invasive prenatal testing (NIPT) into prenatal care represents a paradigm shift. With the absence of any intervention risk in contrast to invasive diagnostic procedures, NIPT has been widely adopted for the detection of fetal trisomy 13, 18 and 21. Additionally, fetal sex chromosome aneuploidy testing and sex determination are available, but can be compromised by both, medical and legal factors. Available validation studies were predominantly based on patients with a high

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Noninvasive Prenatal Screening Based on Second-Trimester Ultrasonographic Soft Markers in Low-Risk Pregnant Women

Frontiers in Genetics ◽

10.3389/fgene.2021.793894 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yunyun Liu ◽

Xiaosha Jing ◽

Lingling Xing ◽

Sha Liu ◽

Jianlong Liu ◽

...

Keyword(s):

Pregnant Women ◽

Prenatal Screening ◽

Sex Chromosome ◽

Nasal Bone ◽

Low Risk ◽

Trisomy 13 ◽

Second Trimester ◽

Predictive Values ◽

Noninvasive Prenatal Screening ◽

Hypoplastic Nasal Bone

Background: We aimed to assess the clinical application of noninvasive prenatal screening (NIPS) based on second-trimester ultrasonographic soft markers (USMs) in low-risk pregnant women.Methods: Data of pregnant women between April 2015 and December 2019 were retrospectively analyzed. Pregnant women [age at expected date of confinement (EDC) of <35 years; low risks for trisomy 21 (T21) and trisomy 18 (T18) based on maternal serum screening; presenting second-trimester USMs (7 types)] who successfully underwent NIPS and had available follow-up information were included in our study. Cases with positive NIPS results were prenatally diagnosed. All patients were followed up for 6 months to 2 years after NIPS, and their clinical outcomes were obtained. Subgroup analyses were performed according to the different USMs.Results: NIPS suggested that among a total of 10,023 cases, 37 (0.37%) were at high risk of aneuploidy, including 4 T21, 6 trisomy 13 (T13), and 27 sex chromosome abnormalities (SCA). Ten cases with aneuploidy (0.10%) were confirmed by prenatal diagnosis, consisting of two T21 and eight SCA. The eight fetuses with SCA consisted of one monosomy X, two XXY, one XXXY, one XXX, one XYY, and two mosaicisms. T21 was detected in one fetus with absent or hypoplastic nasal bone and one fetus with echogenic intracardiac focus (EICF). SCA was detected in five fetuses with EICF, two fetuses with multiple soft markers, and one fetus with echogenic bowel. The positive rate of chromosomal aneuploidy was significantly higher in fetuses with absent or hypoplastic nasal bone (6.25 vs. 0.10%, p = 0.017), echogenic bowel (3.7 vs. 0.10%, p = 0.029), and multiple soft markers (0.678 vs. 0.10%, p = 0.045) than in the total fetuses. The positive predictive values (PPVs) of NIPS in these three groups were 100%, 50%, and 100%, respectively. EICF accounted for 93.25% (9,346/10,023) of the study population, whereas the PPV of NIPS was only 20%.Conclusion: NIPS is an advanced screening test for low-risk pregnant women. In the 10,023 pregnant women sampled, SCA were more common than autosomal trisomy, and EICF was the most frequent USM but the least predictive aneuploidy. Further aneuploidy evaluation is suggested for low-risk pregnant women whose ultrasound indicates absent or hypoplastic nasal bone, echogenic bowel, or multiple soft markers. NIPS can serve as a second-line complementary screening for these women.

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