Population-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency

Background: Congenital anomalies are a leading cause of perinatal mortality, with many having a genetic basis. Exome sequencing (ES) has transformed the diagnostic approach in the prenatal and post-mortem work-up of fetal congenital anomalies. Despite its benefits, population-based implementation programs that address equity and clinical consistency are scarce. Objective: To analyze perinatal cases referred for funding from the state government clinical sequencing initiative for patient eligibility, diagnostic yield, and clinical utility of ES. Methods: A retrospective analysis was conducted on prospectively collected data for 195 cases referred for perinatal ES from 2018 to 2022 in Victoria, Australia. All cases underwent eligibility review against the published criteria for funding by one of 3 multidisciplinary teams (MDT) with members drawn from 4 tertiary fetal medicine units. Descriptive statistics of eligibility assessment, indication for referral, results, diagnostic yield, turn-around time, and pregnancy outcomes were performed. Subgroup analysis was performed for prenatal and post-mortem cases. Differences in proportions were analyzed with the z-test, with p<0.05 considered significant. Results: Of the 195 referred cases, 179 (93%) were deemed eligible for publicly funded ES. The most frequent indications for ES were multisystem anomalies, brain anomalies, and skeletal abnormalities. The overall diagnostic yield was 38% (95% Confidence Interval (CI) [0.31-0.45]), with causative genes identified in 37.5% (95% CI [0.27-0.49]) of prenatal and 38% (95% CI [0.30-0.48]) of post-mortem cases. Prenatal ES had demonstrable clinical utility: the termination of pregnancy rate was significantly higher in cases with a causative finding on ES compared with those without (67% vs 17%, P< 0.0001). The average turnaround time was 21 calendar days for prenatal cases and 125 days for post-mortem cases. Conclusion: In conclusion, this study provides a model for a multicenter, MDT-led framework for perinatal ES that achieves high consistency regarding referrals, clinical utility, and diagnostic yield. Supported by public funding, this model serves as a benchmark for integrating ES into maternal fetal medicine services, ensuring equitable access and informed reproductive decision-making. Future research should focus on the long-term impact of ES on subsequent pregnancies and refine strategies to reduce turnaround times.