Non-invasive prenatal testing for trisomy 13: more harm than good?

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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Implementation of cell-free DNA-based non-invasive prenatal testing in a National Health Service Regional Genetics Laboratory

Genetics Research ◽

10.1017/s0016672319000119 ◽

2019 ◽

Vol 101 ◽

Cited By ~ 1

Author(s):

Fiona S. Togneri ◽

Mark D. Kilby ◽

Elizabeth Young ◽

Samantha Court ◽

Denise Williams ◽

...

Keyword(s):

National Health Service ◽

High Risk ◽

Health Service ◽

National Health ◽

Prenatal Testing ◽

Low Risk ◽

Trisomy 13 ◽

Cell Free Dna ◽

Non Invasive ◽

Free Dna

Abstract Background Non-invasive prenatal testing (NIPT) for the detection of foetal aneuploidy through analysis of cell-free DNA (cfDNA) in maternal blood is offered routinely by many healthcare providers across the developed world. This testing has recently been recommended for evaluative implementation in the UK National Health Service (NHS) foetal anomaly screening pathway as a contingent screen following an increased risk of trisomy 21, 18 or 13. In preparation for delivering a national service, we have implemented cfDNA-based NIPT in our Regional Genetics Laboratory. Here, we describe our validation and verification processes and initial experiences of the technology prior to rollout of a national screening service. Methods Data are presented from more than 1000 patients (215 retrospective and 840 prospective) from ‘high- and low-risk pregnancies’ with outcome data following birth or confirmatory invasive prenatal sampling. NIPT was by the Illumina Verifi® test. Results Our data confirm a high-fidelity service with a failure rate of ~0.24% and a high sensitivity and specificity for the detection of foetal trisomy 13, 18 and 21. Secondly, the data show that a significant proportion of patients continue their pregnancies without prenatal invasive testing or intervention after receiving a high-risk cfDNA-based result. A total of 46.5% of patients referred to date were referred for reasons other than high screen risk. Ten percent (76/840 clinical service referrals) of patients were referred with ultrasonographic finding of a foetal structural anomaly, and data analysis indicates high- and low-risk scan indications for NIPT. Conclusions NIPT can be successfully implemented into NHS regional genetics laboratories to provide high-quality services. NHS provision of NIPT in patients with high-risk screen results will allow for a reduction of invasive testing and partially improve equality of access to cfDNA-based NIPT in the pregnant population. Patients at low risk for a classic trisomy or with other clinical indications are likely to continue to access cfDNA-based NIPT as a private test.

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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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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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Cytogenomic results following high-chance non-invasive prenatal testing: a UK national audit

Genetics Research ◽

10.1017/s0016672320000087 ◽

2020 ◽

Vol 102 ◽

Author(s):

Fiona S. Togneri ◽

Stephanie K. Allen ◽

Kathy Mann ◽

Elaine Holgado ◽

Sian Morgan

Keyword(s):

Trisomy 21 ◽

Prenatal Testing ◽

Healthcare Systems ◽

Trisomy 13 ◽

National Audit ◽

Private Provision ◽

Non Invasive ◽

The Uk ◽

High Chance ◽

Singleton Pregnancies

Abstract Objective Non-invasive prenatal testing (NIPT) is increasingly being adopted as a screening test in the UK and is currently accessed through certain National Health Service healthcare systems or by private provision. This audit aims to describe reasons for and results of cytogenomic investigations carried out within UK genetic laboratories following an NIPT result indicating increased chance of cytogenomic abnormality (‘high-chance NIPT result’). Method A questionnaire was sent out to 24 genetics laboratories in the UK and completed by 18/24 (75%). Results Data were returned representing 1831 singleton pregnancies. A total of 1329 (73%) invasive samples were taken following NIPT results showing a high chance of trisomy 21; this was confirmed in 1305 (98%) of these by invasive sampling. Trisomy 21 was confirmed in >99% of patients who also had high-screen risk results or abnormal scan findings. Amongst invasive samples taken due to NIPT results indicating a high chance of trisomy 18, 84% yielded a compatible result, and this number dropped to 49% for trisomy 13 and 51% for sex chromosomes. Conclusion In the UK, the majority of patients having invasive sampling for high-chance NIPT results are doing so following an NIPT result indicating an increased chance of common trisomies (92%). In this population, NIPT performs particularly well for trisomy 21, but less well for other indications.

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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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Assessment and clinical utility of a non-Next Generation Sequencing based Non-Invasive Prenatal Testing technology

10.1101/2021.06.21.21256776 ◽

2021 ◽

Author(s):

Uzay Gormus ◽

Alka Chaubey ◽

Suresh Shenoy ◽

Yong Wee Wong ◽

Lee Yin Chan ◽

...

Keyword(s):

Clinical Utility ◽

Prenatal Testing ◽

Trisomy 13 ◽

Rolling Circle Replication ◽

Rolling Circle ◽

Non Invasive ◽

Clinical Laboratories ◽

Testing Technology ◽

The Cost ◽

Fetal Aneuploidies

Background: Rolling circle replication (RCR) is a novel technology that has not been applied to cell-free DNA (cfDNA) testing until recently. Given the cost and simplicity advantages of this technology compared to other platforms currently used in cfDNA analysis, an assessment of RCR in clinical laboratories was performed. Here, we present the first validation study from clinical laboratories utilizing RCR technology. Methods: 831 samples from spontaneously pregnant women carrying a singleton fetus and 25 synthetic samples were analyzed for the fetal risk of Trisomy 21, Trisomy 18 and Trisomy 13 by three laboratories on three continents. All women who provided the samples were followed to birth, where evaluation for fetal aneuploidies was performed using newborn examinations and any suspected aneuploidies were confirmed with karyotyping. Results: The study found rolling circle replication to be a highly viable technology for clinical assessment of fetal aneuploidies with 100% sensitivity for T21 (95% CI:82.35% - 100.00%); 100.00% sensitivity for T18 (71.51% - 100.00%) and 100.00% sensitivity for T13 analyses (66.37% - 100.00%). The specificities were >99% for each trisomies [99.7% (99.01% - 99.97%) for T21; 99.5% (98.62% - 99.85%) for T18; 99.7% (99.03% - 99.97%) for T13], along with a first pass no-call rate of 0.93%. Conclusions: The study showed that using a rolling circle replication-based cfDNA system for the evaluation of the common aneuploidies would provide greater accuracy and clinical utility compared to conventional biochemical screening and comparable results to other reported cfDNA methodologies.

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Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009684 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1009684

Author(s):

Priit Paluoja ◽

Hindrek Teder ◽

Amin Ardeshirdavani ◽

Baran Bayindir ◽

Joris Vermeesch ◽

...

Keyword(s):

Screening Method ◽

Prenatal Testing ◽

Trisomy 13 ◽

Systematic Evaluation ◽

Advantages And Disadvantages ◽

Non Invasive ◽

Analysis Tools ◽

Patau Syndrome ◽

Edwards Syndrome ◽

Accuracy Comparison

Non-invasive prenatal testing (NIPT) is a powerful screening method for fetal aneuploidy detection, relying on laboratory and computational analysis of cell-free DNA. Although several published computational NIPT analysis tools are available, no prior comprehensive, head-to-head accuracy comparison of the various tools has been published. Here, we compared the outcome accuracies obtained for clinically validated samples with five commonly used computational NIPT aneuploidy analysis tools (WisecondorX, NIPTeR, NIPTmer, RAPIDR, and GIPseq) across various sequencing depths (coverage) and fetal DNA fractions. The sample set included cases of fetal trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome). We determined that all of the compared tools were considerably affected by lower sequencing depths, such that increasing proportions of undetected trisomy cases (false negatives) were observed as the sequencing depth decreased. We summarised our benchmarking results and highlighted the advantages and disadvantages of each computational NIPT software. To conclude, trisomy detection for lower coverage NIPT samples (e.g. 2.5M reads per sample) is technically possible but can, with some NIPT tools, produce troubling rates of inaccurate trisomy detection, especially in low-FF samples.

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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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