Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results

Grati, Francesca Romana; Malvestiti, Francesca; Ferreira, José Carlos; Bajaj, Komal; Gaetani, Elisa; Agrati, Cristina; Grimi, Beatrice; Dulcetti, Francesca; Ruggeri, Anna; Toffol, Simona De; Maggi, Federico; Wapner, Ronald J.; Gross, Susan J.; Simoni, Giuseppe

doi:10.1038/gim.2014.3

Cited by 188 publications

(205 citation statements)

References 24 publications

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“…It has been noted that feto-placental mosaicism can result in discordant findings between NIPT and fetal karyotyping (35 ). Chromosomal mosaicism in chorionic villus samples is detected in 1%-2% of cases, and can involve different numerical and structural chromosomal abnormalities and feto-placental lineages (36 ). True fetal mosaicism (TFM) is confirmed in only 13% of these cases, whereas in 87% the chromosomal abnormality is confined to the placenta [confined placental mosaicism (CPM)] (37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cases of mosaicism, in which the chromosomal constitution of the cytotrophoblast is different from that of the fetus, are potential sources of FP and FN results. CPM type I and III with an abnormal cytotrophoblast and normal amniocytes can cause FP results, whereas TFM type V with a normal cytotrophoblast and abnormal amniocytes can cause FN results (36 ). The largest monocentric study examining chromosomal mosaicism in relation to NIPT results includes a retrospective audit of 52673 chorionic villus samples in which cytogenetic analysis of the cytotrophoblast (direct) and villus mesenchyme (culture) was performed, followed by confirmatory amniocentesis in chorionic villi mosaic cases (36 ).…”

Section: Discussionmentioning

confidence: 99%

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Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non-Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex

Koumbaris¹,

Kypri²,

Tsangaras³

et al. 2016

Clinical Chemistry

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BACKGROUND There is great need for the development of highly accurate cost effective technologies that could facilitate the widespread adoption of noninvasive prenatal testing (NIPT). METHODS We developed an assay based on the targeted analysis of cell-free DNA for the detection of fetal aneuploidies of chromosomes 21, 18, and 13. This method enabled the capture and analysis of selected genomic regions of interest. An advanced fetal fraction estimation and aneuploidy determination algorithm was also developed. This assay allowed for accurate counting and assessment of chromosomal regions of interest. The analytical performance of the assay was evaluated in a blind study of 631 samples derived from pregnancies of at least 10 weeks of gestation that had also undergone invasive testing. RESULTS Our blind study exhibited 100% diagnostic sensitivity and specificity and correctly classified 52/52 (95% CI, 93.2%–100%) cases of trisomy 21, 16/16 (95% CI, 79.4%–100%) cases of trisomy 18, 5/5 (95% CI, 47.8%–100%) cases of trisomy 13, and 538/538 (95% CI, 99.3%–100%) normal cases. The test also correctly identified fetal sex in all cases (95% CI, 99.4%–100%). One sample failed prespecified assay quality control criteria, and 19 samples were nonreportable because of low fetal fraction. CONCLUSIONS The extent to which free fetal DNA testing can be applied as a universal screening tool for trisomy 21, 18, and 13 depends mainly on assay accuracy and cost. Cell-free DNA analysis of targeted genomic regions in maternal plasma enables accurate and cost-effective noninvasive fetal aneuploidy detection, which is critical for widespread adoption of NIPT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non-Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex

Koumbaris¹,

Kypri²,

Tsangaras³

et al. 2016

Clinical Chemistry

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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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“…Other reasons for discordant results from NIPS include the presence of cell-free DNA from a vanished twin, or karyotype anomalies in the mother which are assumed to represent abnormalities in the fetus [12]. These sources of false positive results are more likely when a counting methodology is used, rather than a SNP-based approach (detailed below).…”

Section: Will Nips Ever Be Considered a Diagnostic Test?mentioning

confidence: 99%

Current Concepts in Noninvasive Prenatal Screening (NIPS)

Leonard

2017

Journal of Fetal Medicine

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Noninvasive prenatal screening (NIPS) represents a significant advance in prenatal screening for trisomy 21 and other conditions. Like any new and rapidly developing technology, it is important for healthcare providers to keep up to date with current and developing issues to help ensure that users of tests such as NIPS are well informed. This review intends to outline and explain some of the main current issues with regards to NIPS and to look ahead to the future, in order to increase understanding and inform debate.

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Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results

Cited by 188 publications

References 24 publications

Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non-Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex

Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non-Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex

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

Current Concepts in Noninvasive Prenatal Screening (NIPS)

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