Abstract
Genetic diseases significantly contribute to morbidity and mortality in neonatal intensive care units (NICUs), with diagnoses often delayed due to clinical complexity. Rapid whole-exome sequencing (rWES) and transcriptomic analysis (RNA-seq) may improve diagnostic rates and clinical outcomes. Prospective study of neonates admitted to NICUs with suspected genetic diseases (n = 34) who underwent rWES, followed by RNA-seq applied in cases in which rWES failed to establish diagnosis. The primary outcome was the diagnostic rate. Secondary outcomes included time to diagnosis, clinical utility, parental stress, and cost-effectiveness. rWES achieved a 41% diagnostic rate with a mean turnaround time of 8.57 ± 2.62 days. RNA-seq increased the diagnostic yield by 6%, resulting in a total diagnostic rate of 47%. The use of rWES reduced unnecessary procedures by 15% and shortened hospital stays by 25% (p < 0.01). Cost-effectiveness analysis indicated that rWES was economically advantageous, with an ICER of < €9000. Relative to pre-diagnosis levels, parental anxiety decreased by 30% in cases in which diagnosis was achieved but increased by 15% in cases in which no diagnosis was established (p < 0.05).Conclusion: Implementing rWES in NICUs improves care for critically ill neonates by providing timely, accurate diagnosis, reducing healthcare costs, and alleviating parental anxiety. RNA-seq further enhances diagnostic accuracy.