Mosaic maternal 10qter deletions are associated with FRA10B expansions and may cause false-positive noninvasive prenatal screening results

Amsterdam, Karin Huijsdens-van; Straver, Roy; Maarle, Merel C. van; Knegt, Alida C.; Opstal, Diane Van; Sleutels, Frank; Smeets, Dominique; Sistermans, Erik A.

doi:10.1038/gim.2018.32

Cited by 15 publications

(11 citation statements)

References 15 publications

(18 reference statements)

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“…This finding has been seen several times before from cfDNA screening, and has not been associated with clinical phenotype. 12 Four cases involved CNVs that may be associated with myelodysplastic syndromes (i.e., del[5q], del[7q], and del[20q]), raising the possibility of an underlying, previously undiagnosed maternal condition. [13][14][15] These cases were reported as positive for the CNV identified and the ordering clinician was contacted by a laboratory genetic counselor to discuss the potential etiology of these findings.…”

Section: Review Of Discordant Resultsmentioning

confidence: 99%

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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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Section: Review Of Discordant Resultsmentioning

confidence: 99%

“…This finding has been seen several times before from cfDNA screening, and has not been associated with clinical phenotype. 12 …”

Section: Discussionmentioning

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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“…Finally, WISECONDOR (26) specifically addresses untraceable between-sample variation. Here, a reference set is required to both normalize bins directly, using the first three components of a principle component analysis (PCA) (27), and for defining sets of within-sample reference bins, each of which represent another window that is thought to behave the same. The search for sets of within-sample reference bins is executed by the Euclidean distance, which scans all samples of the pooled reference.…”

Section: Introductionmentioning

confidence: 99%

WisecondorX: improved copy number detection for routine shallow whole-genome sequencing

Raman

Dheedene

Smet

et al. 2018

Nucleic Acids Research

108

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Shallow whole-genome sequencing to infer copy number alterations (CNAs) in the human genome is rapidly becoming the method par excellence for routine diagnostic use. Numerous tools exist to deduce aberrations from massive parallel sequencing data, yet most are optimized for research and often fail to redeem paramount needs in a clinical setting. Optimally, a read depth-based analytical software should be able to deal with single-end and low-coverage data—this to make sequencing costs feasible. Other important factors include runtime, applicability to a variety of analyses and overall performance. We compared the most important aspect, being normalization, across six different CNA tools, selected for their assumed ability to satisfy the latter needs. In conclusion, WISECONDOR, which uses a within-sample normalization technique, undoubtedly produced the best results concerning variance, distributional assumptions and basic ability to detect true variations. Nonetheless, as is the case with every tool, WISECONDOR has limitations, which arise through its exclusiveness for non-invasive prenatal testing. Therefore, this work presents WisecondorX in addition, an improved WISECONDOR that enables its use for varying types of applications. WisecondorX is freely available at https://github.com/CenterForMedicalGeneticsGhent/WisecondorX .

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“…For instance, 10qter is such a problematic region in that it may be deleted because of the presence of a fragile site in maternal DNA, which will complicate the detection of a fetal chromosome 10 aberration. 22 Another example is that a 3-Mb terminal loss at 6qter (case 8) was reliably detected in Nexus, but it was impossible to detect a 4-Mb gain of 22q11, which is known to be highly variable (case 12). It has to be noted that the algorithm that detects such small CNVs also produces significant noise, and therefore potentially produces many false-positive findings.…”

Section: Discussionmentioning

confidence: 99%