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Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU
Erica F Sanford1,2,3, Michelle M Clark3, Lauge Farnaes3
1Department of Pediatrics, University of California at San Diego, La Jolla, CA.
Insights
Rapid whole genome sequencing diagnosed genetic disorders in 45% of critically ill children, guiding PICU care and post-discharge management. This genetic testing offers crucial insights for undiagnosed pediatric critical care patients.
Area of Science:
- Genetics
- Pediatric Critical Care
- Genomic Medicine
Background:
- Genetic disorders are a significant cause of mortality in neonatal and pediatric intensive care units (ICUs).
- Over 6,200 single-gene diseases exist, often undiagnosed before ICU admission.
- The clinical utility of rapid whole genome sequencing (WGS) in critically ill children remains under-evaluated.
Purpose of the Study:
- To evaluate the clinical utility of rapid whole genome sequencing (WGS) for diagnosing genetic conditions in critically ill children admitted to the pediatric intensive care unit (PICU).
- To assess the impact of WGS-guided diagnoses on patient management during and after PICU stay.
Main Methods:
- Retrospective cohort study conducted at a single-center PICU.
- Rapid whole genome sequencing (WGS) with phenotype-driven analysis was performed on 38 children (4 months to 18 years) and their parents.
- Analysis focused on identifying molecular diagnoses to inform clinical decisions.
Main Results:
- A molecular diagnosis was achieved in 17 of 38 children (45%) via rapid WGS.
- Genetic diagnoses led to changes in PICU management for 4 patients (24%), including pharmacotherapy adjustments and palliative care decisions.
- Diagnoses impacted post-PICU discharge management for 82% of identified cases, influencing treatment and surveillance strategies.
- Notably, 53% of diagnosed children lacked dysmorphic features or developmental delay, highlighting the need for genetic testing beyond physical அறிகுற.
Conclusions:
- Rapid whole genome sequencing (WGS) demonstrates clinical utility in diagnosing genetic diseases in a subset of critically ill children within the PICU.
- WGS can significantly influence clinical management both during PICU admission and after discharge.
- Further research is needed to optimize the early identification of PICU patients who would benefit most from rapid WGS when the etiology is unclear.
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.
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