Rapid Whole Genome Sequencing and Fulfilling the Promise of Precision Pediatric Critical Care

OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal and pediatric intensive care unit (ICU) in the United States. Although individually rare, there are over 6200 single gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing (rWGS) is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN: Retrospective cohort study SETTING: Single-center PICU in a tertiary children’s hospital PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS: rWGS with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rWGS in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rWGS in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rWGS early in PICU admission when the underlying etiology is unclear.