A two-year prospective study assessing the performance of fetal chromosomal microarray analysis and next-generation sequencing in high-risk pregnancies.

BACKGROUND: Introduction of cell-free fetal DNA (cff-DNA) testing in maternal blood opened possibilities to improve the performance of combined first-trimester screening (cFTS) in terms of better detection of trisomies and lowering invasive testing rate. The use of new molecular methods, such as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS), has shown benefits in prenatal diagnosis of chromosomal and genetic diseases, which are not detectable with cff-DNA screening, but require an invasive procedure. METHODS: The objective of this study was to evaluate prospectively during two years performance of CMA and NGS in high-risk pregnancies. Initially, we investigated 14,566 singleton pregnancies with cFTS. A total of 334 high-risk pregnancies were selected for CMA diagnostic performance evaluation and 28 cases of highly dysmorphic fetuses for NGS analysis. CMA study group was divided into two groups based on the indications for testing; group A patients with high-risk for trisomies after cFTS, but normal ultrasound and group B patients who met criteria for CMA as a first-tier diagnostic test. RESULTS: The diagnostic yield of CMA was overall 3.6% (1.6% in Group A and 6.0% in Group B). In NGS analysis group, we report diagnostic yield of 17.9%. CONCLUSION: The use of CMA in high-risk pregnancies is justified and provides relevant clinical information in 3.6% of the cases. NGS analysis in fetuses with multiple anomalies shows promising results, but more investigations are needed for a better understanding of practical applications of this molecular diagnosis method in prenatal settings.