Chromosomal microarray as a primary diagnostic genomic tool for pregnancies defined as being at increased risk within a population based combined first-trimester screening program
OBJECTIVE: To evaluate the impact of using high-resolution chromosomal microarray (CMA) as the standard diagnostic approach to examine for genomic imbalances in pregnancies with increased risk (risk higher than 1:300) defined through combined first trimester screening (cFTS). METHODS: A cohort of 575 consecutive pregnancies that had cFTS risk higher than 1:300 through a publicly funded population based screening program in the Central and Northern Regions of Denmark between September 2015 and September 2016. Women with an NT larger than 3.5 mm or opting for NIPT were excluded. Comparative genomic hybridization was performed using a 180 K oligonucleotide array on DNA extracted directly from samples. Genomic outcomes are reported in relation to cFTS findings. RESULTS: 22 cases (22/575, 3.8%; 95% CI: 2.5-5.7%) of trisomy 21, 18 and 13 were detected. A further 14 cases (14/575, 2.4%; 95% CI: 1.4-4.0%) of other types of aneuploidy were detected as well as 15 (15/575, 2.6%: 95% CI: 1.5-4.3%) cases with a pathogenic or likely pathogenic copy number variant (CNV). 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. CONCLUSION: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk after cFTS. Limiting diagnostic testing to pregnancies with a risk above 1:100 or 1:50, as proposed in contingent NIPT/invasive testing models, will lead to a significant proportion of pathogenic CNVs being missed at first trimester screening.