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.
Retrospective cohort study.
Single-center PICU in a tertiary children’s hospital.
Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018.
Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available.
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.
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.
1Department of Pediatrics, University of California at San Diego, La Jolla, CA.
2Rady Children’s Hospital San Diego, San Diego, CA.
3Rady Children’s Institute for Genomic Medicine, San Diego, CA.
4Department of Neuroscience, University of California at San Diego, La Jolla, CA.
*See also p 1085.
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Supported, in part, by grant U19HD077693 from National Institute of Child Health and Human Development and National Human Genome Research Institute.
Drs. Sanford’s, Briggs’s, Watkins’s, and Dimmock’s institution received funding from Grant U19HD077693 from National Institute of Child Health and Human Development and National Human Genome Research Institute (NHGRI). Drs. Sanford, Clark, Farnaes, Bainbridge, Watkins, Chowdhury, Dimmock, and Kingsmore received support for article research from the National Institutes of Health (NIH). Dr. Sanford also received support for article research from NHGRI. Dr. Briggs disclosed that he is employed by the U.S. Navy. Drs. Bainbridge’s and Kingsmore’s institutions received funding from the NIH. Dr. Bainbridge disclosed that he is a founder of Codified Genomics LLC. Dr. Dimmock received funding from Biomarin (consultant for Pegvaliase trials), Audentes Therapeutics (Scientific Advisory Board), and Ichorion Therapeutics (consultant for mitochondrial disease drugs). The remaining authors have disclosed that they do not have any potential conflicts of interest.
The RCIGM investigators are: Sergey Batalov, Sara Caylor, Katarzyna Ellsworth, Jennifer Friedman, Lisa Salz, Mari Tokita, Kristen Wigby, and Terence Wong.
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