Secondary findings from non‐invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service

Lau, Tze Kin; Jiang, F.; Stevenson, Robert J.; Lo, Tsz Kin; Chan, Lin Wai; Chan, M; Lo, Pui Shan Salome; Wang, Wei; Zhang, Hongyun; Chen, Fang; Choy, Kwong Wai

doi:10.1002/pd.4076

Cited by 120 publications

(99 citation statements)

References 18 publications

(35 reference statements)

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“…The ability to detect noninvasively other fetal aneuploidies has already been demonstrated. 5,29 In this study, trisomies other than 13, 18 and 21 were identified by NIPT in 4/1350 samples or 0.3% of all pregnancies. Trisomies were identified for chromosomes 7, 15 and 16.…”

Section: Discussionmentioning

confidence: 99%

“…A number of case reports, as well as retrospective and prospective validation studies of novel algorithms, have recently been reported on the ability to detect segmental imbalances and even submicroscopic CNVs. 5,13,20,29,[43][44][45][46][47][48] Lau et al 29,47 reported on the use of the FCAPS pipeline detecting a fetal duplication of 18p, which is 14 Mb in size. Here, we show the detection of a segmental trisomy 18, which is 29 Mb in size, demonstrating the power of this genome-wide profiling approach.…”

Section: Discussionmentioning

confidence: 99%

“…(1) maternal CNVs, maternal mosaicism, 21 maternal cancers or haematological malignancies, 22 and confined placental mosaicism (CPM) [23][24][25][26][27][28][29][30][31][32][33][34] may cause variability of the sequence read count statistics, which could mask or mimic true aneuploidy-related variation, and may, in turn, result in false-positive or false-negative results; (2) the degradation and/or apoptosis of maternal cells following maternal blood sampling would increase the maternal fraction in the plasma and as a consequence reduce the fetal fraction. A low fetal fraction could cause false-negative results and maternal cell degradation may result in low-quality experiments, which can cause false-positive or false-negative results.…”

Section: Introductionmentioning

confidence: 99%

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Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management

et al. 2015

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Noninvasive prenatal testing by massive parallel sequencing of maternal plasma DNA has rapidly been adopted as a mainstream method for detection of fetal trisomy 21, 18 and 13. Despite the relative high accuracy of current NIPT testing, a substantial number of false-positive and false-negative test results remain. Here, we present an analysis pipeline, which addresses some of the technical as well as the biologically derived causes of error. Most importantly, it differentiates high z-scores due to fetal trisomies from those due to local maternal CNVs causing false positives. This pipeline was retrospectively validated for trisomy 18 and 21 detection on 296 samples demonstrating a sensitivity and specificity of 100%, and applied prospectively to 1350 pregnant women in the clinical diagnostic setting with a result reported in 99.9% of cases. In addition, values indicative for trisomy were observed two times for chromosome 7 and once each for chromosomes 15 and 16, and once for a segmental trisomy 18. Two of the trisomies were confirmed to be mosaic, one of which contained a uniparental disomy cell line. As placental trisomies pose a risk for low-grade fetal mosaicism as well as uniparental disomy, genome-wide noninvasive aneuploidy detection is improving prenatal management. INTRODUCTIONThe presence of circulating cell-free fetal DNA in the maternal plasma of the pregnant woman, 1 in combination with recent advances in massively parallel sequencing (MPS) technologies, has made noninvasive prenatal testing (NIPT) of fetal aneuploidy a reality. NIPT reduces the need for invasive sampling and the associated risk of procedure-related pregnancy loss. In 2008, it was demonstrated that noninvasive fetal aneuploidy detection by MPS was feasible. 2,3 Multiple clinical validation studies using either targeted or whole-genome sequencing demonstrated the high sensitivity and specificity of NIPT. [4][5][6][7][8][9][10][11][12][13][14][15] Although most validation studies were predominantly evaluating the clinical validity in pregnancies at increased risk of the most common aneuploidies, it was recently shown that screening all pregnant women has positive predictive values of 45.5% and 40% for detection of trisomies 21 and 18, respectively. 16 MPS for aneuploidy detection applies counting statistics to millions of sequencing reads to identify subtle changes in the small percentage of fetal DNA present in the total cell-free DNA isolated from maternal plasma. 17,18 An increase or decrease in the number of normalized sequencing reads, typically converted to a 'z-score', 18 a 'normalized chromosome value', 13 genome-wide normalized score 19 or by 'withinsample copy number aberration detector' 20 is indicative of aneuploidy for the respective chromosome. Despite the high accuracy of current NIPT testing, a baseline false-positive and false-negative rate remains. Those incorrect results may have both biological and technical causes:

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management

et al. 2015

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“…While the improvement in screening performance is small, with suitable interpretive software this can readily be implemented without additional cost. A source of false positives associated with the DNA test arises from maternal mosaicism, 15 confined placental mosaicism, 16 and maternal copy-number variation. 17 Though they are rare occurrences, this problem is mitigated in reflex DNA screening.…”

Section: Discussionmentioning

confidence: 99%

Prenatal reflex DNA screening for trisomies 21, 18, and 13

Wald

Huttly

Bestwick

et al. 2018

Genetics in Medicine

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Purpose: The purpose of the study was to determine the screening performance of prenatal reflex DNA screening for trisomies 21 (T21), 18 (T18), and 13 (T13) as part of a routine service at five hospitals.Methods: Women who accepted screening had a first-trimester combined test (pregnancy-associated plasma protein A, free β-human chorionic gonadotropin, nuchal translucency interpreted with maternal age). Those with a risk of having an affected pregnancy ≥ 1 in 800 were reflexed to a DNA sequencing test using stored plasma from the original blood sample, thereby avoiding the need to recall them.Results: Of 22,812 women screened (including 106 with affected pregnancies), 2,480 (10.9%) were reflexed to DNA testing; 101/106 were detected (69/73 T21, 24/25 T18, and 8/8 T13), a 95% detection rate (95% confidence interval 89-98%) with four false positives (0.02%, 95% confidence interval 0.00-0.05%). The odds of being affected given a positive result were 25:1. Of the 105 screen-positive pregnancies, 91 (87%) had an invasive diagnostic test. Reflex DNA screening avoided up to 530 invasive diagnostic tests compared with using the combined test.Conclusion: Reflex DNA screening was successfully implemented in routine care, achieving a high detection rate, low false-positive rate, and, consequently, greater safety with fewer invasive diagnostic tests than other methods of screening.

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“…More recently, noninvasive screening for a few selected deletion syndromes is being investigated (Lau et al 2013(Lau et al , 2014Srinivasan et al 2013) and has been added by some providers (Bianchi and Wilkins-Haug 2014), but the performance of noninvasive detection of such microdeletions is still being evaluated. Diagnostic procedures, such as amniocentesis and chorionic villus sampling (CVS), followed by karyotype analysis, are available for detection of all trisomies and large chromosomal rearrangements.…”

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confidence: 99%