The epidemic of abnormal copy number variant cases missed because of reliance upon noninvasive prenatal screening

Evans, Mark I.; Andriole, Stephanie; Curtis, Jenifer; Evans, Slayton A.; Kessler, Alan; Rubenstein, Andrew F.

doi:10.1002/pd.5275

Cited by 31 publications

(33 citation statements)

References 22 publications

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“…While cfDNA had 100% sensitivity for the detection of the common autosomal trisomies, the risk of a subsequent diagnosis of any major chromosomal abnormality after a low-risk cfDNA result was not statistically different from that after a low-risk CFTS result. This finding may alleviate concerns regarding the loss of ascertainment of atypical abnormalities due to increasing uptake of cfDNA 9 . To our knowledge, our study is the first population-based report to reveal the actual, rather than modelled, set of selected abnormalities missed by CFTS and cfDNA screening up to 12 months after birth (notwithstanding the fact that some of those anomalies may not have a clinically detectable phenotype by that age).…”

Section: Discussionmentioning

confidence: 88%

State‐wide utilization and performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

Lindquist

Hui

Poulton

et al. 2020

Ultrasound in Obstet & Gyne

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Objectives To perform individual record linkage of women undergoing screening with cell‐free DNA (cfDNA), combined first‐trimester screening (CFTS), second‐trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population‐based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low‐risk aneuploidy screening result. Methods This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient‐funded cfDNA referrals from multiple providers were merged with state‐wide results for government‐subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false‐negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM. Results During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64–93.93%) for a screen‐positive rate (SPR) of 2.94%. There were 12 false‐negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00–100%) for a SPR of 1.21%. When high‐risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low‐risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low‐risk cfDNA result included pathogenic copy‐number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Conclusions Our state‐wide record‐linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low‐risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfD...

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Section: Discussionmentioning

confidence: 88%

State‐wide utilization and performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

Lindquist

Hui

Poulton

et al. 2020

Ultrasound in Obstet & Gyne

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show abstract

“…Currently, NIPT is applied globally as a prenatal screening test focusing on trisomies 13, 18, and 21, and on gonosomes [19]. This led to the secondary phenomenon that the incidence of children born with inborn disease-related copy number variations (CNVs), which were formerly picked up by GTG banding, FISH, and/or CMA, became epidemic [20,21]. In fact, this has had drastic consequences not only for individual families, insufficiently informed about the drawbacks of the NIPT test, but also for national health systems [19][20][21].…”

Section: Nonchromosome-directed Molecular Diagnostic Strategiesmentioning

confidence: 99%

Chromosomes in the DNA era: Perspectives in diagnostics and research

Weise

Mrasek

Pentzold

et al. 2019

Medizinische Genetik

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Chromosomes were discovered more than 130 years ago. The implementation of chromosomal investigations in clinical diagnostics was fueled by determining the correct number of human chromosomes to be 46 and the development of specific banding techniques. Subsequent technical improvements in the field of genetic diagnostics, such as fluorescence in situ hybridization (FISH), chromosomal microarrays (CMA, array CGH) or next-generation sequencing (NGS) techniques, partially succeeded in overcoming limitations of banding cytogenetics. Consequently, nowadays, higher diagnostic yields can be achieved if new approaches such as NGS, CMA or FISH are applied in

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“…Increasingly, women are seeking reassurance regarding all unbalanced chromosomal abnormalities (UBCA) that will have an impact on postnatal outcome, not only trisomies. Whilst cfDNA testing may increase the number of cases of trisomy detected, its exclusive use may reduce the detection of other types of abnormalitiy. A major reason for integrating cfDNA into screening strategies has been to avoid procedure‐related miscarriages, although the precise number of miscarriages avoided remains uncertain, and has not been taken into account systematically in economic models.…”

Section: Introductionmentioning

confidence: 99%

Cost‐effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model‐based analysis

Bras

Salomon

Bussières

et al. 2019

Ultrasound in Obstet & Gyne

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Objective To evaluate the cost‐effectiveness of five prenatal screening strategies for trisomies (13/18/21) and other unbalanced chromosomal abnormalities (UBCA), following the introduction of cell‐free DNA (cfDNA) analysis. Methods A model‐based cost‐effectiveness analysis was performed to estimate prevalence, safety, screening‐program costs and healthcare costs of five different prenatal screening strategies, using a virtual cohort of 652 653 pregnant women in France. Data were derived from the French Biomedicine Agency and published articles. Uncertainty was addressed using one‐way sensitivity analysis. The five strategies compared were: (i) cfDNA testing for women with a risk following first‐trimester screening of ≥ 1/250; (ii) cfDNA testing for women with a risk of ≥ 1/1000 (currently recommended); (iii) cfDNA testing in the general population (regardless of risk); (iv) invasive testing for women with a risk of ≥ 1/250 (historical strategy); and (v) invasive testing for women with a risk of ≥ 1/1000. Results In our virtual population, at similar risk thresholds, cfDNA testing compared with invasive testing was cheaper but less effective. Compared with the historical strategy, cfDNA testing at the ≥ 1/1000 risk threshold was a more expensive strategy that detected 158 additional trisomies, but also 175 fewer other UBCA. Implementation of cfDNA testing in the general population would give an incremental cost‐effectiveness ratio of €9 166 689 per additional anomaly detected compared with the historical strategy. Conclusion Extending cfDNA to lower risk thresholds or even to all pregnancies would detect more trisomies, but at greater expense and with lower detection rate of other UBCA, compared with the historical strategy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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The epidemic of abnormal copy number variant cases missed because of reliance upon noninvasive prenatal screening

Cited by 31 publications

References 22 publications

State‐wide utilization and performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

State‐wide utilization and performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

Chromosomes in the DNA era: Perspectives in diagnostics and research

Cost‐effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model‐based analysis

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