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

Katherine M Rodriguez; Jordan Vaught; Lisa Salz; Jennifer Foley; Zaineb Boulil; Heather M Van Dongen-Trimmer; Drewann Whalen; Okonkwo Oluchukwu; Kuang Chuen Liu; Jennifer Burton; Prachi Syngal; Ofelia Vargas-Shiraishi; Stephen F Kingsmore; Erica Sanford Kobayashi; Nicole G Coufal

doi:10.1097/PCC.0000000000003522

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

Pediatr Crit Care Med. 2024 Apr 26. doi: 10.1097/PCC.0000000000003522. Online ahead of print.

Authors

Katherine M Rodriguez^{1

2

3}, Jordan Vaught^{1

2}, Lisa Salz³, Jennifer Foley¹, Zaineb Boulil¹, Heather M Van Dongen-Trimmer⁴, Drewann Whalen⁵, Okonkwo Oluchukwu^{5

6}, Kuang Chuen Liu^{5

6}, Jennifer Burton^{5

6}, Prachi Syngal^{4

6}, Ofelia Vargas-Shiraishi⁷, Stephen F Kingsmore³, Erica Sanford Kobayashi^{3

4

7}, Nicole G Coufal^{1

2

3}

Affiliations

¹ Rady Children's Hospital, San Diego, CA.
² Department of Pediatrics, University of California, San Diego, CA.
³ Rady Children's Institute for Genomic Medicine, San Diego, CA.
⁴ OSF Children's Hospital of Illinois, Peoria, IL.
⁵ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA.
⁶ Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL.
⁷ Department of Pediatrics, Children's Hospital of Orange County, Orange, CA.

PMID: 38668387
DOI: 10.1097/PCC.0000000000003522

Abstract

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.