Prenatal Whole-exome Sequencing in a Russian Clinical Cohort: Diagnostic Yield, Indications, and Spectrum of Molecular Findings

Abstract Objective: Prenatal whole-exome sequencing (prWES) is a promising molecular diagnostic tool that can be used to clarify the genetic etiology of prenatally detected abnormalities, including cases in which standard genetic testing fails to establish their cause. However, data on its diagnostic yield and the spectrum of detectable abnormalities in Russian clinical practice remain limited. Objective: To perform a retrospective analysis of the indications for prWES, its diagnostic yield, and the spectrum of molecular findings in a Russian clinical cohort. Materials and methods: This retrospective cohort study included 485 pregnancies in which prWES was performed. Results: The most common indications for testing were fetal structural anomalies (43.71%), ultrasound markers of chromosomal abnormalities (24.74%), and adverse family history (21.65%). Pathogenic and likely pathogenic variants were identified in 73 of 485 cases (15.05%), variants of uncertain significance in 104 cases (21.24%), and secondary findings in 3 cases (0.62%). The highest diagnostic yield was observed in fetuses with structural anomalies, in whom pathogenic and likely pathogenic variants were detected in 17.92% of cases. In the group with ultrasound markers of chromosomal abnormalities, the diagnostic yield was 12.5%, whereas in cases with adverse family history it was 11.43%. Among the confirmed molecular disorders, skeletal dysplasias and connective tissue disorders (27.4%), Noonan syndrome and Noonan-related disorders (19.18%), and neurodevelopmental disorders (17.81%) predominated. Conclusion: prWES demonstrates high clinical utility in the diagnosis of fetal monogenic disorders and shows the greatest effectiveness in fetuses with structural anomalies and in families at high genetic risk. These findings may contribute to the optimization of prenatal diagnostic algorithms and genetic counseling strategies.