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Original Investigation
June 23/30, 2020

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Australian Genomics Health Alliance Acute Care Flagship
JAMA. 2020;323(24):2503-2511. doi:10.1001/jama.2020.7671
Key Points

Question  Can ultra-rapid genomic testing be performed for critically ill pediatric patients in a public health care system?

Findings  This multisite descriptive feasibility study included 12 Australian hospitals and 2 laboratories. Among the 108 critically ill infants and children with suspected monogenic conditions who had ultra-rapid genomic testing, the mean time to genomic test report was 3.3 days and the molecular diagnostic yield was 51%.

Meaning  This study suggests feasibility of ultra-rapid genomic testing in a public setting for critically ill pediatric patients. However, further research is needed to understand its clinical value.

Abstract

Importance  Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.

Objective  To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.

Design, Setting, and Participants  Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.

Exposures  Ultra-rapid exome sequencing.

Main Outcomes and Measures  The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.

Results  The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing–based copy number analysis, use of international databases to identify novel gene–disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).

Conclusions and Relevance  This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

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