Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023.

Objectives: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions.
Design: Ambidirectional multisite cohort study.
Setting: Four tertiary children's hospitals.
Patients: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023.
Interventions: None.
Measurements and Main Results: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication ( p < 0.0001) and contributed to a decision to consult palliative care ( p < 0.02).
Conclusions: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.
Competing Interests: Drs. Rodriguez and Coufal’s institution received funding from the National Institutes of Health (NIH). Drs. Rodriguez, Kingsmore (grants U19HD077693, UL1TR002550, and 1UM1TR004407), and Coufal received support for article research from the NIH. Dr. Kingsmore received funding from Ultragenyx, Amgen, Horizon, Sanofi, Takeda, Alexion, Sarepta, Ionis, Inozyme, Travere, and Orchard. Dr. Coufal received funding from Rady Children’s Hospital. The remaining authors have disclosed that they do not have any potential conflicts of interest.
(Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)