Five years of nationwide use of whole genome sequencing in ongoing pregnancies: Diagnostic yield, timing, and implementation

INTRODUCTION: We describe timing, diagnostic yield, secondary findings of prenatal whole genome sequencing (pWGS) in ongoing pregnancies during the first 5 years of implementation within a publicly funded healthcare system. Moreover, we discuss our collective clinical experiences implementing pWGS in prenatal care. MATERIAL AND METHODS: We conducted a historical cohort study, including all singleton pregnancies undergoing pWGS after a normal chromosomal microarray between 2019 and 2023. Data on sample type, gestational age at test ordering, turnaround time, diagnostic yield, and secondary findings were extracted from all four Danish clinical genetics laboratories. RESULTS: A total of 207 cases were analyzed, including 85 chorionic villus samples and 122 amniotic fluid samples; trio sequencing was performed in 204/207 (98.6%). Median gestational age at ordering was 20 weeks (IQR 17-21). Median turnaround time for ongoing pregnancies was 11 working days (IQR 8-17). Pathogenic or likely pathogenic variants explaining the phenotype were identified in 33/207 pregnancies (15.9%, 95% CI 11.6-21.5). Yield was highest in hydrops (25.0%, 95% CI 12.0-44.9) and multiple anomalies (24.3%, 95% CI 13.4-40.1), and lowest in isolated increased nuchal translucency (7.1%, 95% CI 2.0-22.6). Secondary findings were reported in 18/207 cases (8.7%, 95% CI 5.6-13.3). CONCLUSIONS: pWGS was delivered within clinically relevant turnaround times. Applied after normal chromosomal microarray, the yield represents incremental diagnostic value in a chromosomal microarray-negative population. In clinical practice, both normal and abnormal pWGS results form a central component of counseling in ongoing pregnancies with unresolved fetal risk. However, the impact of such results on parental decision-making or pregnancy outcomes was not assessed in this study.