Contribution of chromosomal microarray analysis and next‐generation sequencing to genetic diagnosis in fetuses with normal karyotype

Abstract

Aim:The aim of this study was to investigate the contribution of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) to genetic diagnosis in fetuses with normal karyotype who underwent invasive testing for different indications. Methods: The results of invasive genetic testing performed at a tertiary center between September 2020 and March 2022 were retrospectively analyzed. Indications for invasive tests were classified as fetal structural malformation, presence of soft markers, and high risk in screening tests. CMA results were classified as pathogenic or likely pathogenic (pCNVs), benign (bCNVs), and variants of unknown clinical significance (VOUS). Results: A total of 830 invasive tests were performed and aneuploidy was detected in 11.2% of the fetuses. CMA was performed in 465 fetuses with normal karyotype, and pCNVs were detected in 6.9%. pCNVs were detected in 8.2% of fetuses with structural malformations, 6.5% in soft markers, and 4.7% in high risk in screening tests. Pathogenic variants were detected by NGS in 33.8% of fetuses with bCNVs. Conclusions: pCNVs can be significantly detected not only in fetuses with structural malformations, but also in invasive testing with other indications. NGS significantly contributes to genetic diagnosis in fetuses with structural malformations.

Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?

“…It is surprising that the rates of TOPFA remained stable despite the improvement in diagnostic tools, which would logically lead to an expected increase in the identification of fetal abnormalities. CMA has now become the primary method for cytogenetic analysis in prenatal testing and has significantly enhanced diagnostic yield 8,11,28 . As expected we did observe an elevated identification of deletions, duplications, and single nucleotide variations as the indication for TOPFA, but without significantly affecting the overall number of pregnancy terminations.…”

“…CMA has now become the primary method for cytogenetic analysis in prenatal testing and has significantly enhanced diagnostic yield. 8,11,28 As expected we did observe an elevated identification of deletions, duplications, and single nucleotide variations as the indication for TOPFA, but without significantly affecting the overall number of pregnancy terminations. -285…”

“…Over the investigated time period, there was a small increase in the number of cases with genetic deletions, duplications and single nucleotide variations, which may reflect the more recent introductions of CMA, WES and WGS, whereas all other subgroups were stable. 11,28,29 The number of cases with genetic aberrations in the present study seems higher compared to other studies, but this may reflect increased access to genetic testing in Denmark compared to other countries. [30][31][32] It is surprising that the rates of TOPFA remained stable despite the improvement in diagnostic tools, which would logically lead to an expected increase in the identification of fetal abnormalities.…”

Absent or hypoplastic nasal bone: What to tell the prospective parents?

“…Although our study did not find any CNVs, studies have found significant CNVs on CMA in cases of AHNB (Gu et al, 2019; Zhang et al, 2021). CMA has also increased yield in euploid fetuses on karyotyping (Akalın et al, 2023).…”

The Role of Preprocedure Genetic Counseling in Pregnancies Interrupted for Fetal Abnormalities

“…These tests alone or in combination can identify an underlying genetic etiology in up to 75% of structurally abnormal fetuses, though still leaving cases without a diagnosis. 13 Research has examined the positive association between prenatal genetic counseling and uptake of diagnostic testing; 14 however, this has not been explored at the time of pregnancy termination for fetal indications that include suspected aneuploidy or congenital birth defects. 15,16 The purpose of this study was to identify predictors and utility of diagnostic genetic testing at the time of interruption of pregnancy.…”