Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly ...unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.
We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.
Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.
This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.
Genet Med 2013:15(6):478–481
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This multicenter study compared a prenatal assay of cell-free DNA with a standard method of screening for trisomies among women at average risk. The positive predictive values of cfDNA testing and ...standard screening for trisomy 21 were 80.9% and 3.4%, respectively.
Screening for fetal aneuploidy with the use of cell-free DNA (cfDNA) obtained from maternal plasma was introduced in 2011. Such screening has been reported to have a detection rate for trisomy 21 (Down's syndrome) of more than 99%, with a false positive rate as low as 0.1%.
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Thus, cfDNA testing appears to represent a substantial improvement over traditional multiple-marker screening. In practice, the use of this test could result in a significant reduction in diagnostic procedures.
Although several large proof-of-principle studies have confirmed the high sensitivity and specificity of cfDNA testing for the detection of trisomy 21, most of these . . .
Background
There is a significant variability in reported fetal fraction (FF), a common cause for no‐calls in cell‐free (cf)DNA based non‐invasive prenatal screening. We examine the effect of ...imprecision in FF measurement on the performance of cfDNA screening for Down syndrome, when low FF samples are classified as no‐calls.
Methods
A model for the reported FF was constructed from the FF measurement precision and the underlying true FF. The model was used to predict singleton Down syndrome detection rates (DRs) for various FF cut‐offs and underlying discriminatory powers of the test.
Results
Increasing the FF cut‐off led to slightly increased apparent DR, when no‐calls are excluded, and an associated larger decrease in effective DR, when no‐calls are included. These effects were smaller for tests with higher discriminatory power and larger as maternal weight increased.
Conclusions
Most no‐calls due to a low reported FF have a true FF above the cut‐off. The discriminatory power of a test limits its effective DR and FF precision determines the tradeoff between apparent and effective DR when low FF is used to discard samples. Tests with high discriminatory power do not benefit from current FF measurements.
Key points
What is already known about this topic?
Fetal fraction (FF) is often considered to be a crucial quality control parameter for interpretation of cell free DNA based non‐invasive prenatal testing (NIPT)
There is a large variability in the measurement of FF for single samples
A large fraction of test non‐reportable results (no‐calls) are due to a too low reported FF
What does this study add?
This article presents the consequences of the high variability in FF measurements in the context of screening NIPT test performance
For tests with a high discriminatory power, discarding samples based on too low reported FF leads to a slight apparent increase in NIPT performance metrics but at a relatively large expense of unnecessary anxiety, clinical and financial burden of additional counseling and follow‐up procedures
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to ...annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up. Methods Women aged 39–41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151. Findings Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8–18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74–1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58–0·97) but not thereafter (RR 1·02, 0·80–1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93–1·04). Interpretation Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40–49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis. Funding National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE:To estimate performance of a single-nucleotide polymorphism–based noninvasive prenatal screen for fetal aneuploidy in high-risk and low-risk populations on single venopuncture.
METHODS:One ...thousand sixty-four maternal blood samples from 7 weeks of gestation and beyond were included; 1,051 were within specifications and 518 (49.3%) were low risk. Cell-free DNA was amplified, sequenced, and analyzed using the Next-generation Aneuploidy Test Using SNPs algorithm. Samples were called as trisomies 21, 18, 13, or monosomy X, or euploid, and male or female.
RESULTS:Nine hundred sixty-six samples (91.9%) successfully generated a cell-free DNA result. Among these, sensitivity was 100% for trisomy 21 (58/58, confidence interval CI 93.8–100%), trisomy 13 (12/12, CI 73.5–100%), and fetal sex (358/358 female, CI 99.0–100%; 418/418 male, CI 99.1–100%), 96.0% for trisomy 18 (24/25, CI 79.7–99.9%), and 90% for monosomy X (9/10, CI 55.5–99.8%). Specificity for trisomies 21 and 13 was 100% (905/905, CI 99.6–100%; and 953/953, CI 99.6–100%, respectively) and for trisomy 18 and monosomy X was 99.9% (938/939, CI 99.4–100%; and 953/954, CI 99.4–100%, respectively). However, 16% (20/125) of aneuploid samples did not return a result; 50% (10/20) had a fetal fraction below the 1.5th percentile of euploid pregnancies. Aneuploidy rate was significantly higher in these samples (P<.001, odds ratio 9.2, CI 4.4–19.0). Sensitivity and specificity did not differ in low-risk and high-risk populations.
CONCLUSIONS:This noninvasive prenatal screen performed with high sensitivity and specificity in high-risk and low-risk cohorts. Aneuploid samples were significantly more likely to not return a result; the number of aneuploidy samples was especially increased among samples with low fetal fraction. This underscores the importance of redraws or, in rare cases, invasive procedures based on low fetal fraction.
LEVEL OF EVIDENCE:II
Abstract The first prenatal screening test to be introduced was based on a single maternal serum marker of neural tube defects. Since then various prenatal screening concepts have been developed, the ...most successful being Down syndrome risk estimation using multiple serum and ultrasound markers. Today a completely new approach to aneuploidy screening is available based on maternal plasma cell-free DNA testing. This has the potential to markedly improve screening performance but routine testing is currently too expensive in a public health setting. However, it can be cost-effective when used in combination with existing multi-maker tests. Some are beginning to broaden prenatal screening to include pregnancy complications such as pre-eclampsia that can be prevented using soluble low-dose aspirin treatment started before 16 weeks of gestation. Prenatal screening for cardiac abnormalities, fragile X syndrome and recessive genetic disorders is underutilized and public health planners should considered a more widespread application of available methods.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Maternal markers are widely used to screen for fetal neural tube defects (NTDs), chromosomal abnormalities and cardiac defects. Some are beginning to broaden prenatal screening to include pregnancy ...complications such as pre-eclampsia. The methods initially developed for NTDs using a single marker have since been built upon to develop high performance multi-maker tests for chromosomal abnormalities. Although cell-free DNA testing is still too expensive to be considered for routine application in public health settings, it can be cost-effective when used in combination with existing multi-maker marker tests. The established screening methods can be readily applied in the first trimester to identify pregnancies at high risk of pre-eclampsia and offer prevention though aspirin treatment. Prenatal screening for fragile X syndrome might be adopted more widely if the test was to be framed as a form of maternal marker screening.
Linked article: This is a mini commentary on David Wright eet al., pp. 1308–1317 in this issue. To view this article visit https://doi.org/10.1111/1471-0528.17096.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim was to describe and assess a new late pregnancy point-of-care urinary preeclampsia screening test. Urine samples were collected from a consecutive series of 1,532 pregnant women hospitalized ...at 20-41 weeks gestation in a Chinese single obstetric unit. A simple disposable Congo red based device was newly developed and employed to prospectively test misfolded proteins in pregnant women's urine. A total of 140 preeclampsia cases were clinically diagnosed, 101 severe and 87 pre-term. Detection and false positive rates were similar in the training and validation subsets with combined 74% and 3.0%. The detection rate was 83% in severe, 86% in pre-term, 49% and 50% in mild and term cases (P<0.0001) respectively. In conclusion, a simple point-of-care urinary test for misfolded proteins can be used to screen for preeclampsia in late pregnancy with very high screening performance. To the best of our knowledge, this is the first study to screen for preeclampsia using Congo red based device in Chinese pregnant population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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