Chromosomal microarray as primary diagnostic genomic tool for pregnancies at increased risk within a population-based...

Area of Science:

• Prenatal diagnostics
• Genomic medicine
• Medical genetics

Background:

• Combined first-trimester screening (cFTS) identifies pregnancies at increased risk for genomic abnormalities.
• Invasive testing is often pursued for definitive diagnosis in high-risk pregnancies.
• Conventional cytogenetic analysis has limitations in detecting smaller genomic variations.

Purpose of the Study:

• To assess the diagnostic performance of chromosomal microarray (CMA) for detecting genomic imbalances.
• To compare CMA's effectiveness against conventional methods in pregnancies with elevated cFTS risk.
• To evaluate the impact of modified screening thresholds on diagnostic yield.

Main Methods:

• Retrospective analysis of 575 pregnancies with cFTS risk ≥ 1:300 undergoing invasive testing.
• Exclusion of pregnancies with specific nuchal translucency or those opting for NIPT.
• High-resolution 180-K oligonucleotide array comparative genomic hybridization (aCGH) on fetal DNA samples.

Main Results:

• CMA identified 8.9% of genomic aberrations, significantly higher than conventional cytogenetic analysis (6.8%).
• Pathogenic copy number variants (CNVs) were detected in 2.6% of cases, with 12 likely missed by standard methods.
• Reducing cFTS thresholds to 1:100 or 1:50 would have missed 60% or 100% of pathogenic CNVs, respectively.

Conclusions:

• CMA is a superior diagnostic tool for identifying a greater number of genomic aberrations in at-risk pregnancies.
• Current contingent screening models risk missing significant pathogenic CNVs by setting higher risk thresholds.
• Optimizing prenatal screening requires careful consideration of diagnostic technology and risk stratification.