Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing

Guseh, Stephanie H.; Wilkins‐Haug, Louise; Kaimal, Anjali J; Dunn-Albanese, Lisa; Adams, Sophie; Carroll, Sarah B.; Discenza, Marie; Dobson, Lori J.; Brillinger, Marney; Foster, J. W.; Gbur, Samantha; Green, Hayley; Herrig, Nancy; Mandigo, Chelsea; Pacione, Michelle; Roberts, Penelope; Sassaman, Abigail; Steinberg, Kathleen; Studwell, Courtney; Gray, Kathryn J.

doi:10.1038/s41436-021-01147-4

Cited by 5 publications

(7 citation statements)

References 20 publications

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“…20,831 titles were assessed for relevance, of which 19,563 were excluded and 1268 underwent abstract or full text screening. Ultimately, after applying the exclusion criteria as outlined in the methods, 21 articles were included in the final meta‐analysis 30–50 (Figure 1). Characteristics of included studies are shown in Table 1.…”

Section: Resultsmentioning

confidence: 99%

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A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

et al. 2023

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Objectives The aim was to determine the accuracy of cell‐free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies. Methods A systematic review and meta‐analysis was performed to assess cfDNA accuracy for prenatal detection of 45,X, 47,XXY, 47,XXX and 47,XYY. Inclusion was restricted to studies published between January 2010 and December 2021 reporting both cfDNA and confirmatory diagnostic test results. Results For 45,X, the sensitivity was 98.8% (95%CI 94.6%–100%), specificity 99.4% (95%CI 98.7%–99.9%) and positive predictive value (PPV) 14.5% (95%CI 7.0%–43.8%). For 47,XXY, the sensitivity was 100% (95%CI 99.6%–100%), specificity 100% (95%CI 99.9%–100%) and PPV 97.7% (95%CI 78.6%–100%). For 47,XXX, the sensitivity was 100% (95%CI 96.9%–100%), specificity 99.9% (95%CI 99.7%–100%) and PPV 61.6% (95%CI 37.6%–95.4%). For 47,XYY, the sensitivity was 100% (95%CI 91.3%–100%), specificity 100% (95% CI 100%–100%) and PPV 100% (95%CI 76.5%–100%). All four SCAs had estimated negative predictive values (NPV) exceeding 99.99%, though false negatives were reported. Conclusions This analysis suggests that cfDNA is a reliable screening test for SCA, though both false negatives and false positives were reported. These estimates of test performance are derived from pregnancies at high pretest risk for aneuploidy, limiting the generalisability to average risk pregnancies.

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Section: Resultsmentioning

confidence: 99%

“…A total of 16 included studies reported cfDNA results for Klinefelter Syndrome (47,XXY) 30,32–39,41,44,46,48–50 . This represented 11,248 cell‐free DNA tests with 62 confirmed affected pregnancies, 10 false positive tests and 10 false negative tests (Supplemental Table 2).…”

Section: Resultsmentioning

confidence: 99%

A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

et al. 2023

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“…Performance of NIPS varies by type of genetic changes being assessed. For example, NIPS for CNVs and sex chromosome aneuploidy has both poor positive and negative predictive values in comparison to NIPS for common autosomal trisomes 19–22 . Our findings suggest that PPV of NIPS‐SGD exceeds that of NIPS for CNVs, sex chromosome aneuploidy, and common autosomal trisomies.…”

Section: Discussionmentioning

confidence: 71%

Single gene non‐invasive prenatal screening for autosomal dominant conditions in a high‐risk cohort

et al. 2023

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PurposeTo determine the utility of single gene non‐invasive prenatal screening (NIPS‐SGD) in a high‐risk reproductive genetics clinic.MethodsA clinical pilot for NIPS‐SGD was conducted from March 2020 to November 2021. A NIPS‐SGD panel assessing pathogenic variants in 30 genes was offered to pregnant individuals for the following indications: (1) advanced sperm age ≥40 years, (2) nuchal translucency (NT) ≥ 3.5 mm, (3) fetal anomaly, or (4) family history of a condition covered by the panel. Diagnostic testing was offered concurrently.ResultsNIPS‐SGD was ordered for 253 individuals: 88 (34.8%) for fetal anomalies, 96 (37.9%) for advanced sperm age, 37 (14.6%) for increased NT, and 5 (2.0%) for family history. Among 228 (90.1%) completed tests, 8 (3.5%) were positive. Diagnostic testing for 78 individuals revealed no false positive or negative results. Of 41 (25.9%) individuals who received a molecular diagnosis, 34 (82.9%) were outside the scope of NIPS‐SGD. Positive NIPS‐SGD altered medical management in five cases.ConclusionsNIPS‐SGD in a high‐risk population can lead to earlier prenatal diagnosis, enhanced surveillance, and targeted genetic analysis, but should not replace clinically indicated diagnostic testing. Potential incidental findings include parental diagnoses and misattributed parentage.

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“…All the above studies failed to distinguish the presence or absence of ultrasound anomalies among the true positive population. Stephanie Guseh et al (2021) . Assessed the concordance of genome-wide screening and diagnostic testing, indicating that the major limitation of genome-wide screening compared with diagnostic testing is in the population with abnormal ultrasound with κ = 0.38 (95% CI, 0.08–0.67), including 5 concordant positives, 4 false positives, 7 false negatives, and 48 concordant negative results, indicating a high residual risk in a false negative population.…”

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confidence: 99%

Potentials and challenges of chromosomal microarray analysis in prenatal diagnosis

Liu

Wang

et al. 2022

Front. Genet.

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Introduction: For decades, conventional karyotyping analysis has been the gold standard for detecting chromosomal abnormalities during prenatal diagnosis. With the development of molecular cytogenetic methods, this situation has dramatically changed. Chromosomal microarray analysis (CMA), a method of genome-wide detection with high resolution, has been recommended as a first-tier test for prenatal diagnosis, especially for fetuses with structural abnormalities.Methods: Based on the primary literature, this review provides an updated summary of the application of CMA for prenatal diagnosis. In addition, this review addresses the challenges that CMA faces with the emergence of genome sequencing techniques, such as copy number variation sequencing, genome-wide cell-free DNA testing, and whole exome sequencing.Conclusion: The CMA platform is still suggested as priority testing methodology in the prenatal setting currently. However, pregnant women may benefit from genome sequencing, which enables the simultaneous detection of copy number variations, regions of homozygosity and single-nucleotide variations, in near future.

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Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing

Cited by 5 publications

References 20 publications

A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

Single gene non‐invasive prenatal screening for autosomal dominant conditions in a high‐risk cohort

Potentials and challenges of chromosomal microarray analysis in prenatal diagnosis

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