Microarray and RASopathy-disorder testing in fetuses with increased nuchal translucency

Area of Science:

• Prenatal diagnosis
• Medical genetics
• Fetal medicine

Background:

• Increased nuchal translucency (NT) thickness (≥3.5 mm) is associated with a higher risk of chromosomal abnormalities and adverse pregnancy outcomes.
• Current diagnostic protocols may not fully capture the spectrum of genetic and structural anomalies in these pregnancies.

Purpose of the Study:

• To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities, and RASopathy-disorder (RD) pathogenic variants in pregnancies with NT ≥3.5 mm.
• To propose an optimized clinical protocol for the surveillance of this high-risk group.

Main Methods:

• Retrospective chart review of 226 pregnancies with NT ≥3.5 mm undergoing invasive genetic testing (chorionic villus sampling or amniocentesis).
• Utilized quantitative fluorescence polymerase chain reaction (QF-PCR), karyotyping, chromosomal microarray analysis (CMA), and targeted gene sequencing for RD pathogenic variants.
• Integrated detailed fetal ultrasound examinations and echocardiography for structural anomaly detection.

Main Results:

• Chromosomal aneuploidy detected in 51.3% of cases by QF-PCR.
• CMA identified abnormal/pathogenic cytogenetic results in 8.2% of remaining cases.
• RD testing revealed pathogenic variants in 2.9% of cases; optimal NT cut-off for RD screening was 7.9 mm.
• Genetic investigations were normal in 83.6% of cases, yet detailed ultrasounds identified structural abnormalities in 26.1% and cardiac issues in 9.8%.

Conclusions:

• Chromosomal microarray analysis (CMA) and molecular testing for RASopathy disorders (RD) are essential in pregnancies with increased NT (≥3.5 mm).
• Combining genetic testing with detailed fetal ultrasound and echocardiography provides critical information for pregnancy management and recurrence risk assessment.
• The proposed integrated approach enhances diagnostic yield and aids in counseling for pregnancies with thickened nuchal translucency.