Efficiency of Rapid Whole-Genome Sequencing in Pediatric Intensive Care Units: Experience in a Diverse Population

Single-gene disorders are a common cause of infant and young children's mortality in intensive care units. Many of these genetic disorders have available treatments that may slow disease progression and improve patients' quality of life. However, clinicians often identify the underlying genetic etiology late in the disease course, when available treatments cannot reverse disease progression. Rapid whole-genome sequencing (RWGS) is increasingly used for early diagnosis of patients with rare disorders. It remains unclear which clinical indications are most efficient for providing actionable genetic diagnoses. It is also not well studied how efficient RWGS is in diverse populations where population genomic data is less abundant. We present RWGS results over a three-year period from four medical centers within a large hospital system in the State of New Jersey, which has one of the most diverse populations in the United States. The patients were referred to RWGS testing from the NICU and PICU units for various severe/life-threatening manifestations. All patients were tested at one laboratory center using the same technology for genome sequencing and analysis, as described, to eliminate possible interlaboratory variation in test efficiency. We identified a causative genetic etiology in 19 (36.5%) of the 52 tested individuals. We observed the highest yield of positive diagnoses in patients with unexplained failure to thrive (FTT). The genetic diagnoses were actionable for disease-specific, supportive, or progression-slowing targeted treatments, better-informed genetic counseling, or modifying the level of care for most positive individuals. Our study provides information on the test efficiency of RWGS in diverse populations and compares testing efficiency across leading referral indications. The study may help guide referral decisions for such testing.