Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies

Abstract

Objective We evaluated the effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray (CMA) on the detection of copy number variants (CNVs) and uniparental disomy (UPD) in prenatal diagnosis. Methods Five thousand twenty‐six consecutive prenatal specimens (>98% high‐risk pregnancy) were studied by high‐resolution CMA, with cutoffs of 50 kb for losses and 200 kb for gains in nontargeted regions and 20 kb for losses and 100 kb for gains in targeted regions. We assessed actual detection rates using the current assay as well as hypothetical detection rates using platforms with the same or lower resolution and smaller or larger cutoffs. Results The detection rate of our current assay was 11.2% (562 of 5026), including abnormal findings in 543 cases and likely pathogenic variants in 19. The hypothetical decrease in the overall detection of variants (excluding likely benign) and UPD ranged from 3.8% to 23.0%. For the subgroup of pathogenic and likely pathogenic CNVs < 1 Mb, the decrease of detection ranged from 2.7% to 24.3%. Conclusions These findings underscore the significant effects of chosen CMA platform, as well as size filter cutoffs and targeted regions used in data analysis, on detection of CNVs and UPDs in a cohort of prenatal cases.

Prenatal chromosomal microarray testing of fetuses with ultrasound structural anomalies: A prospective cohort study of over 1000 consecutive cases

“…This has important implications for current practice suggesting that CMA may only be diagnostically efficient in significantly elevated NTs . Heterogeneity in relation to the incidence of CNVs may be explained by differences in the CMA platform used and its coverage, differing study populations, the timing of analysis, and variations in microarray platforms and reporting policies . It is likely that this difference in VUS rates between our study and the EACH study may be explained by increasing experience in variant interpretation using internationally agreed classifications, more sophisticated bioinformatic pathways, and further development of in silico tools and larger cohorts of samples in internal and public population and patient databases such as ClinVar, DECIPHER, and the Database of Genomic Variants .…”

“…The cohort was composed of a well characterised group in which the ultrasound phenotypes were confirmed by nationally accredited fetal medicine sub‐specialists. Study limitations included the use of a lower resolution aCGH than is currently utilised, meaning that some smaller CNVs may not have been detected . Also, the NT group only captured subjects who requested screening and/or did not have a miscarriage prior to testing, introducing an element of bias.…”

Are all chromosome microarrays the same? What clinicians need to know

“…In this issue, Wang et al assessed how array design and laboratory established thresholds affect diagnostic yield . They looked at the CMA results from 5026 consecutive prenatal tests performed in their laboratory using their standard laboratory settings and reporting criteria.…”

“…In this issue, Wang et al report prenatal microarray findings for 5026 pregnancies . They look at the diagnostic yield generated using a high‐resolution single nucleotide polymorphism (SNP) microarray platform, coupled with their in‐house laboratory‐established detection thresholds and reporting criteria.…”

“…They look at the diagnostic yield generated using a high‐resolution single nucleotide polymorphism (SNP) microarray platform, coupled with their in‐house laboratory‐established detection thresholds and reporting criteria. They then compare those findings against other vendors' platforms and published reporting thresholds to determine the changes in potentially reportable results . To appreciate the context of these findings, we provide a detailed introduction for clinicians to the technical and diagnostic aspects of microarray testing in the prenatal setting.…”