Rapid genomic sequencing in the NICU: Who to test and why

Accessibility of rapid genomic sequencing (rGS), including rapid whole-exome sequencing (rWES) and rapid whole-genome sequencing (rWGS), is transforming care in neonatal intensive care units (NICUs) by enabling timely and precise diagnoses of genetic disorders with high diagnostic yield and significant impact on clinical management. However, determining which infants should undergo sequencing remains a major challenge, particularly in settings with limited genetic expertise and poor access to genomic resources. Currently, no single strategy optimizes diagnostic yield, equity, feasibility, and cost across all settings. We conducted a structured literature review to evaluate patient selection approaches for genomic sequencing in the NICU and synthesized findings from major studies comparing various inclusion-based and exclusion-based approaches. Across 39 included studies, all except one utilized phenotype-driven inclusion criteria based on, for example, congenital anomalies, neurological manifestations, multisystem disease, or unexplained critical illness, while only one study employed a predominantly exclusion-based, genotype first strategy. Studies were conducted primarily in tertiary or high-resource NICUs, highlighting ongoing disparities in access to genomic testing and specialist expertise. Future research should focus on prospective comparisons of selection frameworks and the development of scalable implementation models that support equitable genomic care in NICU populations.