Positive cell-free fetal DNA testing for trisomy 13 reveals confined placental mosaicism

Hall, April; Drendel, Holli M.; Verbrugge, Jennifer; Reese, Angela; Schumacher, Katherine L.; Griffith, Christopher B.; Weaver, David D.; Abernathy, Mary Pell; Litton, Christian; Vance, Gail H.

doi:10.1038/gim.2013.26

Cited by 76 publications

(62 citation statements)

References 20 publications

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“…The CV (i.e., CV Ui ϭ Ui /R Ui ) relates Ui to the ratio of tags in an unaffected sample being measured and thus provides a relative measure that can be compared among chromosomes with different numbers of tags. Table 2 lists the CVs obtained for chromosomes 13,18,21, and X, as well as the FFs at an NCV of 3 for each of the individual chromosomes. An NCV of 3 is a typical cutoff value for classifying a sample as aneuploid.…”

Section: Melissa Study Samplesmentioning

confidence: 99%

Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X

et al. 2014

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BACKGROUND:Noninvasive prenatal testing based on massively parallel sequencing (MPS) of cell-free DNA in maternal plasma has become rapidly integrated into clinical practice for detecting fetal chromosomal aneuploidy. We directly determined the fetal fraction (FF) from results obtained with MPS tag counting and examined the relationships of FF to such biological parameters as fetal karyotype and maternal demographics.

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Section: Melissa Study Samplesmentioning

confidence: 99%

Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X

et al. 2014

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“…(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%

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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“…Such recombination events can lead to misdiagnosis if care is not taken to ensure that the same haplotype flanks the assayed mutation in both upstream and downstream DNA sequences. Another potential pitfall for NIPD of monogenic disorders is the phenomenon (which has already led to cases of misdiagnosis in the field of noninvasive fetal aneuploidy testing) of placental mosaicism (22)(23)(24)(25)(26)(27)(28). Given that maternal circulating fetal DNA is derived from the placenta (29), theoretically, the presence of two distinct maternal and/or paternal haplotypes in the placenta could lead to misinterpretation of cell-free fetal haplotypes.…”

Section: Discussionmentioning

confidence: 99%

Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

Zeevi¹,

Altarescu²,

Weinberg‐Shukron³

et al. 2015

Journal of Clinical Investigation

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BACKGROUND.Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population. METHODS.Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease-associated founder mutation-flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods. RESULTS.Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation-flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles. CONCLUSIONS.The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations. FUNDING. SZMC,

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Positive cell-free fetal DNA testing for trisomy 13 reveals confined placental mosaicism

Cited by 76 publications

References 20 publications

Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X

Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X

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

Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

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