Diagnostic performance of chromosomal microarray and whole exome sequencing in fetal structural anomalies: a...

Fetal structural anomalies detected by prenatal ultrasound were reported in 3-5% of pregnancies, and they range from a single, minor anomaly to multiple systemic anomalies. Tests designed to identify the genetic factors (chromosomal or monogenic) responsible for the vast majority of fetal structural anomalies play a crucial role in prenatal diagnosis. A retrospective analysis was performed to assess the diagnostic yield and clinical efficiency of prenatal chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in diagnosis of fetuses with structural anomalies, and to explore genotype-phenotype correlations.

We retrospectively analyzed 391 fetuses referred for genetic testing due to sonographically detected structural anomalies. CMA was performed in 310 cases, and WES was conducted in 81 cases with prior negative CMA results. Detected copy number variants (CNVs) and sequence variants were classified according to ACMG guidelines. Cases were stratified into nine phenotypic categories based on ultrasonographic findings.

CMA identified pathogenic CNVs in 13/310 cases (4.2%) and variants of uncertain significance (VUS) in 13/310 (4.2%). WES revealed pathogenic or likely pathogenic variants in 18/81 cases (22.2%) and VUS in 9/81 cases (11.1%). The highest diagnostic yield for CMA was observed in fetuses with cardiovascular anomalies (12%), and for WES in those with central nervous system anomalies (46.1%) and skeletal system anomalies (38.8%). Notably, eight novel likely pathogenic variants were identified. Incidental findings were detected in 2 WES cases.

CMA and WES provide complementary value in the genetic evaluation of fetal structural anomalies. While CMA remains a robust first-tier test, WES significantly enhances diagnostic yield, especially in cases with negative CMA and specific phenotypic features. Accurate ultrasonographic phenotyping and appropriate test selection are crucial for maximizing diagnostic outcomes in prenatal settings.