Accelerating genetic diagnosis in the NICU: neonatologist-driven rapid whole genome sequencing

To establish a rapid whole-genome sequencing (rWGS) workflow applicable to the neonatal intensive care unit (NICU) setting and evaluate its diagnostic utility and clinical feasibility. Twenty critically ill neonates with suspected genetic disorders were included in this study. A workflow for rWGS encompassing neonate enrollment through to the return of genetic diagnosis results was established. A trio-based rWGS data analysis was performed using DRAGEN-GATK-Hail, with results reviewed and reported by a multidisciplinary team. The average turnaround time for the 20 NICU neonates was 5.5 working days. Genetic diagnoses were achieved in ten cases, resulting in a diagnostic yield of 50%, based on the clinical database and variant pathogenicity assessments. The identified diagnostic variants were located across nine genes, including AGT, ANK1, NSD1, SERPINC1, OTC (in two cases), INS, PKHD1, SAMD9, and LZTR1. The clinical implications were confirmed in all ten diagnosed neonates, with 'genetic counseling and recurrence risk management', 'early therapeutic decision-making' and 'enhancement of clinical outcomes and survival rates'. Notably, neonate rWGS-03 demonstrated the highest impact, as rWGS enabled the early identification of renal tubular dysgenesis before symptom onset. This study demonstrates the feasibility of rWGS for critically ill neonates with suspected genetic disorders admitted to the NICU. As the first implementation of neonatologist-driven rWGS in Korea, it highlights the meaningful clinical benefits of timely and accurate diagnosis. Our findings underscore its clinical value and support the integration of rWGS into routine clinical care, as well as the development of future studies within public healthcare systems.