Citywide implementation of a rapid whole-genome sequencing program for critically ill pediatric patients.

Rapid whole-genome sequencing (rWGS) enables timely diagnosis and management of critically ill patients, particularly in consanguineous populations with a high burden of recessive diseases. Here we report Little Falcon, a citywide rWGS program implemented within centralized neonatal and pediatric intensive care units in Dubai. In total, 100 critically ill patients from 18 Middle Eastern and Asian countries underwent trio rWGS with a median turnaround time of 3.4 days. The overall diagnostic yield was 53% (95% CI 43.3-62.5%), rising to 80% in consanguineous families (P < 0.001). Multiple molecular findings were identified in 12% of patients, including dual diagnoses (5%), while additional actionable findings included newborn screening-relevant variants (4%) and American College of Medical Genetics secondary or incidental findings (3%). rWGS led to clinically meaningful management changes in 53% of patients including those with (n = 45) or without (n = 8) molecular diagnoses, altering disease trajectories in 16%. Compared with a matched historical cohort of critically ill patients receiving standard genetic testing, rWGS significantly reduced diagnostic time (3.4 versus 38 days, P < 0.001), increased diagnostic yield (53% versus 30%, P < 0.01) and improved clinical management (53% versus 18%, P < 0.001). These findings support integrating rWGS into routine neonatal and pediatric intensive care units within a citywide healthcare system.