Neonatologist, Associate Professor University of Utah School of Medicine Sandy, Utah, United States
Background: Genome sequencing (GS) has been increasingly utilized as a first-tier test for acutely ill infants in intensive care units (ICUs) to improve clinical outcomes. Yet, there remains significant uncertainty about the timing and selection of infants to test. Therefore, it has been difficult to optimize the implementation of GS and some payers remain reluctant to cover costs. To overcome these challenges, we postulated that infants’ illness severity may serve as a primary selection criterion for GS regardless of a clinical suspicion for genetic disease. In ICUs, infants on extracorporeal membrane oxygenation (ECMO) are among the most acutely ill and suffer some of the highest mortality rates. Thus, we explored the utilization of first-tier GS in all infants on ECMO. Objective: To assess whether universal, first-tier GS of ICU infants on ECMO is effective in identifying a primary diagnosis and the risk of coagulopathy. Design/Methods: We designed a prospective, multicenter non-interventional pilot study involving eight ICUs belonging to the Children’s Hospitals Neonatal Consortium (CHNC) and we used single IRB reliance. Target enrollment was 25 infants between 0-12 months. The need for ECMO was the primary selection criterion; blood samples were collected before cannulation. Parents provided consent and a blood sample within a week of cannulation. GS and variant analysis were performed according to standard research procedures with no plans for timely return of results to clinicians. Results: We collected all samples of 25 duos/trios (infant and one or two parents). To date, we completed the analysis of nine cases. In two infants the findings explained their phenotype: an infant was diagnosed with trisomy 21 and another one with autosomal dominant capillary malformation-arteriovenous malformation-2 (heterozygous variant in EPHB4). A third infant had compound heterozygous variants in ZNFX1 which may cause immunodeficiency-91 and hyperinflammation, a disease associated with the need for pediatric ECMO, as well as a heterozygous variant in KCNH2, consistent with long QT syndrome. A fourth infant carried a heterozygous variant in VWF (von Willebrand factor), possibly increasing bleeding risks on ECMO. A fifth child with congenital diaphragmatic hernia (CDH) carried compound heterozygous variants in XIRP2, a gene associated with CDH.
Conclusion(s): These findings suggest the clinical benefit of universal, first-tier GS in pediatric ECMO. We are also completing a pharmacogenomics analysis. We plan a future multicenter randomized trial to assess the clinical utility of universal ultra-rapid GS in pediatric ECMO.
