DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: An international collaborative study

Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 03/2012; 14(3):296-305. DOI: 10.1038/gim.2011.73
Source: PubMed


To determine whether maternal plasma cell-free DNA sequencing can effectively identify trisomy 18 and 13.
Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias.
Among the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset.
Among high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.

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Available from: Stanley F Nelson, Jul 30, 2014
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    • "Evaluating the impact of new technologies and policies on the birth rates of infants with Down syndrome is important [Skotko, 2009]. Since October 2011, noninvasive prenatal screening (NIPS) using cell-free DNA has been commercially available, offering expectant women the option to determine with near 99% sensitivity and specificity whether their fetus might have Down syndrome (DS) [Bianchi et al., 2012; Norton et al., 2012; Palomaki et al., 2012; Zimmermann et al., 2012]. Prior to NIPS, approximately 72% of all pregnant women in the U.S. pursued traditional prenatal screens [Palomaki et al., 2013], and an estimated maximum of 2% of all pregnant women elected to have a chorionic villus sampling (CVS) or amniocentesis, diagnostic invasive procedures that carry small risks of procedure-related miscarriages [Greely, 2011]. "
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    ABSTRACT: The present and future live birth prevalence of Down syndrome (DS) is of practical importance for planning services and prioritizing research to support people living with the condition. Live birth prevalence is influenced by changes in prenatal screening technologies and policies. To predict the future impact of these changes, a model for estimating the live births of people with DS is required. In this study, we combine diverse and robust datasets with validated estimation techniques to describe the non-selective and live birth prevalence of DS in the United States from 1900-2010. Additionally, for the period 1974-2010, we estimate the impact of DS-related elective pregnancy terminations (following a prenatal diagnosis of DS) on the live births with DS. The live birth prevalence for DS in the most recent years (2006-2010) was estimated at 12.6 per 10,000 (95% CI 12.4-12.8), with around 5,300 births annually. During this period, an estimated 3,100 DS-related elective pregnancy terminations were performed in the U.S. annually. As of 2007, the estimated rates at which live births with DS were reduced as a consequence of DS-related elective pregnancy terminations were 30% (95% CI: 27.3-31.9) for the U.S. as a whole. Our results and our model provide data on the impact of elective pregnancy terminations on live births with DS and may provide a baseline from which future trends for live births with DS can be estimated. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · American Journal of Medical Genetics Part A
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    • "Nonetheless, it remains critical that the data is analyzed and interpreted properly. Both directed and whole genome approaches have shown that there is a general separation between euploid and aneuploid samples in their analyses and, for the most part, a case clearly falls into one category (Negative), or the other (Positive), making the reporting of such a case straightforward [1], [2], [4], [5], [16]. The challenge lies in how to assess and report out the cases that hover between these two distinct groupings. "
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    ABSTRACT: Objective As the first laboratory to offer massively parallel sequencing-based noninvasive prenatal testing (NIPT) for fetal aneuploidies, Sequenom Laboratories has been able to collect the largest clinical population experience data to date, including >100,000 clinical samples from all 50 U.S. states and 13 other countries. The objective of this study is to give a robust clinical picture of the current laboratory performance of the MaterniT21 PLUS LDT. Study Design The study includes plasma samples collected from patients with high-risk pregnancies in our CLIA–licensed, CAP-accredited laboratory between August 2012 to June 2013. Samples were assessed for trisomies 13, 18, 21 and for the presence of chromosome Y-specific DNA. Sample data and ad hoc outcome information provided by the clinician was compiled and reviewed to determine the characteristics of this patient population, as well as estimate the assay performance in a clinical setting. Results NIPT patients most commonly undergo testing at an average of 15 weeks, 3 days gestation; and average 35.1 years of age. The average turnaround time is 4.54 business days and an overall 1.3% not reportable rate. The positivity rate for Trisomy 21 was 1.51%, followed by 0.45% and 0.21% rate for Trisomies 18 and 13, respectively. NIPT positivity rates are similar to previous large clinical studies of aneuploidy in women of maternal age ≥35 undergoing amniocentesis. In this population 3519 patients had multifetal gestations (3.5%) with 2.61% yielding a positive NIPT result. Conclusion NIPT has been commercially offered for just over 2 years and the clinical use by patients and clinicians has increased significantly. The risks associated with invasive testing have been substantially reduced by providing another assessment of aneuploidy status in high-risk patients. The accuracy and NIPT assay positivity rate are as predicted by clinical validations and the test demonstrates improvement in the current standard of care.
    Full-text · Article · Oct 2014 · PLoS ONE
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    • "In trisomic pregnancies, the quantity of molecules derived from the trisomic chromosome, as compared with an assumed disomic reference chromosome, is higher than in euploid pregnancies. In addition to random massively parallel shotgun sequencing (MPSS) technology [1] [2] [3] [7] [12] [13] [14] [15] [16] [17], targeted massively parallel sequencing (t-MPS) has been successfully applied, reducing costs and increasing efficiency [4] [5] [6] [8] [18] [19] [20]. In contrast, SNP-based methods determine the number of chromosomal copies by looking for specific patterns in allelic measurements [21] [22]. "
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    ABSTRACT: Abstract Objective: To evaluate non-invasive prenatal testing (NIPT) of cell-free DNA (cfDNA) as a screening method for major chromosomal anomalies (CA) in a clinical setting. Methods: From January to December 2013, Panorama™ Test (Natera) or Harmony™ Prenatal Test (Ariosa Diagnostics) were offered as advanced NIPT, in addition to first trimester combined screening in singleton pregnancies. Results: The cohort included 333 pregnant women with a mean maternal age (MA) of 37 years who underwent testing at a mean gestational age (GA) of 14.6 weeks. Eighty-four percent were low-risk pregnancies. Results were provided in 97.3% of patients at a mean reporting time of 12.9 calendar days. Repeat sampling was performed in 6 cases and results were obtained in 5 of them. No results were provided in 4 cases. Four cases of Down syndrome were detected and there was one discordant result of Turner syndrome. We found no statistical differences between commercial tests except in reporting time, fetal fraction and MA. The cfDNA fraction was statistically associated with test type, maternal weight, BMI, and log βhCG levels. Conclusions: NIPT has the potential to be a highly effective screening method for major CA in a clinical setting.
    Full-text · Article · Jul 2014 · Journal of Maternal-Fetal and Neonatal Medicine
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