Impact of mosaicism ratio on positive predictive value of <scp>cfDNA</scp> screening

Rafalko, Jill; Caldwell, Samantha; Tynan, John A.; Almasri, Eyad; Weinblatt, Vivian; McCullough, Ron

doi:10.1002/pd.5863

Cited by 16 publications

(20 citation statements)

References 14 publications

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“…Therefore, results from NIPT using cfDNA essentially reflect the genetic constitution of the cytotrophoblast and not the fetus itself. NIPT tests are not designed to detect mosaicism although it is sometimes apparent when the laboratory assessment of presence or absence of abnormality appears to be intermediate and incompatible with the level of fetal DNA in the sample 77 . Mosaicism can also be strongly suspected based on NIPT results that would be incompatible with viability, for example, for an autosomal monosomy or a RAT.…”

Section: Relevance Of Mosaicism To Nipt Using Cfdnamentioning

confidence: 99%

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

et al. 2021

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The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case‐by‐case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell‐free DNA.

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Section: Relevance Of Mosaicism To Nipt Using Cfdnamentioning

confidence: 99%

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

et al. 2021

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“…An algorithm is also applied to these results to determine the mosaicism ratio associated with the abnormal findings, which may help to identify which events could be fetal versus maternal in origin. 9,10 Of note, when a maternal event is suspected from cfDNA sequencing data, an assessment of fetal status for that particular region is precluded. However, for cases in which a maternal event is present, each pregnancy (current and future) is at 50% risk to inherit the maternal CNV, which allows for prenatal diagnosis in these high-risk pregnancies, and for informed reproductive planning.…”

Section: Type Of Abnormalities In True Positive Cohortmentioning

confidence: 99%

Genome-wide cell-free DNA screening: a focus on copy-number variants

Rafalko

Soster

Caldwell

et al. 2021

Genetics in Medicine

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Purpose Of 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. Methods Cases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. Results CNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1–79.5%) and 71.8% (95% CI: 65.5–77.4%) for “fetal-only” events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5–68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6–97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. Conclusion Genome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

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“…It may be noted that a wide range of MRs are seen for the true positive singleton cases included in this study population (Table 1). As discussed in a previous publication [1], this variability may exist for several reasons. For instance, lower MRs may be associated with placental mosaicism, which appears to occur more commonly in pregnancies affected with trisomy 13 and 18, compared to trisomy 21.…”

Section: Plos Onementioning

confidence: 90%

“…Once an 'affected fraction' is derived, mosaicism ratio can be calculated. As previously described, MR is derived by dividing the 'affected fraction' estimated for the aberrant chromosome or chromosomal segment over the fetal fraction estimated for all chromosomes [1,6,7].…”

Section: Cfdna Analysis and Calculation Of Mosaicism Ratiomentioning

confidence: 99%

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Application of mosaicism ratio to multifetal gestations

et al. 2021

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Mosaicism ratio, or MR, is a laboratory metric that can be calculated using massively parallel sequencing data from cell-free DNA (cfDNA) screening. MR compares the amount of cfDNA present from a particular chromosome or chromosomal region to the overall fetal fraction of the specimen. In singleton gestations, MR may be used to refine the positive predictive value of an abnormal cfDNA screening result by identifying cases that could be impacted by various biological factors, such as placental mosaicism or prior co-twin demise. The current study was designed to examine the behavior of mosaicism ratio (MR) in multifetal gestations. Multifetal cfDNA specimens with positive results for trisomies 21, 18, or 13 and confirmed diagnostic outcomes were compiled to examine MR of the aneuploid chromosome based on the number of affected fetuses/placentas. A second multifetal cohort was assembled to analyze the MR of the Y chromosome in cases with at least one male fetus. For aneuploid cases, the average MR of affected singletons (used as a biological proxy for two affected twins) was significantly higher than the average MR for twins in which one fetus was affected. The average MR of the aneuploid chromosome for one affected twin was 52%, 42%, and 48% of that of singleton gestations for trisomy 21, 18, and 13 cases, respectively. MR cutoffs of 0.7 for trisomy 21, and 0.5 for trisomies 18 and 13 may help predict whether one versus both twins are affected with aneuploidy when clinical concern arises. For male cases, the Y MR of XX/XY gestations was 48% of the Y MR for XY/XY gestations. Using a Y MR cutoff of 0.8 allowed determination of XX/XY versus XY/XY gestations with 92.3–94.9% accuracy. Based on the data presented, MR may have utility in the analysis and interpretation of cfDNA data from multifetal gestations.

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Impact of mosaicism ratio on positive predictive value of cfDNA screening

Cited by 16 publications

References 14 publications

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis

Genome-wide cell-free DNA screening: a focus on copy-number variants

Application of mosaicism ratio to multifetal gestations

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