Chromosomal microarray as primary diagnostic genomic tool for pregnancies at increased risk within a population‐based combined first‐trimester screening program

• Published in: Ultrasound in obstetrics & gynecology 2018-04, Vol.51 (4), p.480-486
• Main Authors: Vogel, I., Petersen, O. B., Christensen, R., Hyett, J., Lou, S., Vestergaard, E. M.
• Format: Article
• Language: English
• Subjects: Amniocentesis; Aneuploidy; array comparative genomic hybridization; chromosomal microarray; Copy number; Deoxyribonucleic acid; Diagnostic software; Diagnostic systems; Diagnostic tests; DNA; DNA microarrays; Fetuses; genomic imbalance; Health risk assessment; Hybridization; Medical diagnosis; Medical screening; Oligonucleotides; pathogenic CNV; Pregnancy; Prenatal care; prenatal diagnosis; Risk; risk above 1:300; Villus
• ISSN: 0960-7692; 1469-0705
• DOI: 10.1002/uog.17548

ABSTRACT Objective To evaluate the performance of high‐resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first‐trimester screening (cFTS). Methods This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population‐based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non‐invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180‐K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings. Results Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5–5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4–4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5–4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8–11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0–9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed. Conclusions CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first‐trimester screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.