LITTLE FALCON: A rapid whole genome sequencing program for critically ill patients in a Middle Eastern healthcare system

We report LITTLE FALCON, a citywide rapid whole genome sequencing (rWGS) program implemented across neonatal and pediatric intensive care units within Dubai healthcare system. One hundred critically ill patients, representing 18 Middle Eastern and Asian countries, underwent trio rWGS with a mean turnaround time of 3.4 days. The overall diagnostic yield was 53% (95% CI, 43.3-62.5%), increasing to 80% among patients from consanguineous families (P < 0.001) or those with suspected metabolic disorders. Multiple molecular diagnoses were identified in 11% of the cases, including complex dual diagnoses (6%), and additional actionable findings outside the primary indication, comprising newborn screening–relevant results (3%) and ACMG-designated secondary findings (2%). Beyond diagnostic clarification, rWGS was associated with clinically meaningful shifts in care trajectory in 53% of patients (95% CI, 43.3-62.5%) including those with (n=45) or without (n=8) molecular diagnoses; rWGS informed time-sensitive therapeutic, procedural, and prognostic decisions during periods of significant physiologic instability in the critical care setting. Compared with a matched historical cohort of critically ill patients referred to standard-of-care genetic testing, rWGS significantly shortened diagnostic timelines (median 3.4 vs 38 days; P < 0.001), increased diagnostic yield (53% vs 30%; 95% CI for controls, 21.3-40.2%; P < 0.01), and increased the likelihood of clinical management change (53% vs 18%; 95% CI for controls, 11.1-27.4%; P < 0.001). These findings demonstrate the feasibility and clinical utility of rWGS and support its integration into routine NICU/PICU care within a citywide healthcare system in the Middle East.