Two cases of placental T21 mosaicism: challenging the detection limits of non‐invasive prenatal testing

Wang, Yanlin; Zhu, Jiansheng; Chen, Yan; Lu, Sha; Chen, Biliang; Zhao, Xin; Wu, YingXing; Han, Xu; Ma, Ding; Liu, Zhongyin; Cram, David S.; Cheng, Weiwei

doi:10.1002/pd.4212

Cited by 57 publications

(53 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(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

View full text Add to dashboard Cite

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:

show abstract

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

View full text Add to dashboard Cite

show abstract

“…In the case presented here, the proportion of the 8.5% fetal fraction that derived from trisomy 13 positive extraembryonic tissues was likely less than half, thus decreasing the functional fetal fraction to less than the level required. Similar patterns of mosaicism have been reported in cases with false negative cfDNA screening results [3,13,18]. This type of fetoplacental mosaicism is different from CMP, which is more commonly reported etiology for discordant cfDNA and fetal/infant cytogenetic results.…”

Section: Discussionmentioning

confidence: 56%

“…For trisomies 18 and 21, this mechanism has been recently described. A false negative trisomy 18 cfDNA screening result due to 48, XXX, +18 placental mosaicism and two cases with false negative trisomy 21 due to placental mosaicism have been reported [3,13]. Potential contribution of fetoplacental mosaicism to discordant cfDNA screening results has been reported; this study suggested that the sensitivity or specificity of cfDNA screening will never reach 100% due to the nature of fetoplacental mosaicism.…”

Section: Discussionmentioning

confidence: 96%

“…Several published reports of false positive and false negative cfDNA screening cases have implicated fetoplacental mosaicism [3,8,13,18]. The most common type of fetal-placental mosaicism, confined placental mosaicism (CPM), is a conception with normal fetus and placenta mosaic for a chromosome abnormality [19].…”

Section: Discussionmentioning

confidence: 99%

“…Although the genetic component of placental and fetal tissue is identical in the vast majority of pregnancies, false positive or false negative results may be due to fetoplacental mosaicism. In several reported cases, followup amniocentesis based on positive cfDNA screening results has identified a normal karyotype, suggesting a false positive cfDNA screening result [3][4][5][6][7][8]. Even though the published data indicates high sensitivity (≥99% for trisomy 21, ≥92% for trisomy 18, and ≥87% for trisomy 13) and specificity (≥99% for trisomy 21, 18, and 13) for aneuploidy detection [9], false positive results have been reported for confined placental mosaicism, vanishing twin or cotwin demise, fetal chromosome rearrangement, and maternal chromosome abnormalities or malignancy [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

False Negative Cell Free DNA Screening Result in a Newborn with Trisomy 13

Cao¹,

Hoppman²

2016

J Clin Case Rep

View full text Add to dashboard Cite

Background. Noninvasive prenatal screening (NIPS) is revolutionizing prenatal screening as a result of its increased sensitivity, specificity. NIPS analyzes cell-free fetal DNA (cffDNA) circulating in maternal plasma to detect fetal chromosome abnormalities. However, cffDNA originates from apoptotic placental trophoblast; therefore cffDNA is not always representative of the fetus. Although the published data for NIPS testing states that the current technique ensures high sensitivity and specificity for aneuploidy detection, false positives are possible due to isolated placental mosaicism, vanishing twin or cotwin demise, and maternal chromosome abnormalities or malignancy. Results. We report a case of false negative cell-free DNA (cfDNA) screening due to fetoplacental mosaicism. An infant male with negative cfDNA screening result was born with multiple congenital abnormalities. Postnatal chromosome and FISH studies on a blood specimen revealed trisomy 13 in 20/20 metaphases and 100% interphase nuclei, respectively. FISH analysis on tissues collected after delivery revealed extraembryonic mosaicism. Conclusions. Extraembryonic tissue mosaicism is likely responsible for the false negative cfDNA screening result. This case illustrates that a negative result does not rule out the possibility of a fetus affected with a trisomy, as cffDNA is derived from the placenta and therefore may not accurately represent the fetal genetic information.

show abstract

A clinically feasible algorithm for the parallel detection of glioma‐associated copy number variation markers based on shallow whole genome sequencing

Wu,

Ma,

Cai

et al. 2024

The Journal of Pathology CR

View full text Add to dashboard Cite

Molecular features are incorporated into the integrated diagnostic system for adult diffuse gliomas. Of these, copy number variation (CNV) markers, including both arm‐level (1p/19q codeletion, +7/−10 signature) and gene‐level (EGFR gene amplification, CDKN2A/B homozygous deletion) changes, have revolutionized the diagnostic paradigm by updating the subtyping and grading schemes. Shallow whole genome sequencing (sWGS) has been widely used for CNV detection due to its cost‐effectiveness and versatility. However, the parallel detection of glioma‐associated CNV markers using sWGS has not been optimized in a clinical setting. Herein, we established a model‐based approach to classify the CNV status of glioma‐associated diagnostic markers with a single test. To enhance its clinical utility, we carried out hypothesis testing model‐based analysis through the estimation of copy ratio fluctuation level, which was implemented individually and independently and, thus, avoided the necessity for normal controls. Besides, the customization of required minimal tumor fraction (TF) was evaluated and recommended for each glioma‐associated marker to ensure robust classification. As a result, with 1× sequencing depth and 0.05 TF, arm‐level CNVs could be reliably detected with at least 99.5% sensitivity and specificity. For EGFR gene amplification and CDKN2A/B homozygous deletion, the corresponding TF limits were 0.15 and 0.45 to ensure the evaluation metrics were both higher than 97%. Furthermore, we applied the algorithm to an independent glioma cohort and observed the expected sample distribution and prognostic stratification patterns. In conclusion, we provide a clinically applicable algorithm to classify the CNV status of glioma‐associated markers in parallel.

show abstract

Two cases of placental T21 mosaicism: challenging the detection limits of non‐invasive prenatal testing

Cited by 57 publications

References 10 publications

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

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

False Negative Cell Free DNA Screening Result in a Newborn with Trisomy 13

A clinically feasible algorithm for the parallel detection of glioma‐associated copy number variation markers based on shallow whole genome sequencing

Contact Info

Product

Resources

About