Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU

Abstract

Objectives: Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing 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: Rapid whole genome sequencing 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 rapid whole genome sequencing 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 rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.

Figures

Figure 1.

Number of probands nominated for rWGS by specialty

Figure 2:

Flow diagram of the proportion of PICU patients who were enrolled, received genetic disease diagnoses by rWGS, and had consequent changes in management (precision medicine)

Figure 3.

Characteristics of PICU cohort. A, Age of 38 probands receiving rWGS. B, Time from diagnosis to change in clinical management. C, Primary indication for PICU admission in 18 patients in whom a diagnosis was made. D, Presence or absence of developmental delay and/or dysmorphic features at the time of PICU admission.