The Impact of Rapid Exome Sequencing on Medical Management of Critically Ill Children.

OBJECTIVES: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population. STUDY DESIGN: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES. RESULTS: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days. CONCLUSIONS: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.

Rapid clinical exome sequencing in a pediatric ICU: Genetic counselor impacts and challenges.

Exome sequencing (ES) has revolutionized molecular diagnosis in children with genetic disease over the past decade. However, exome sequencing in the inpatient setting has traditionally been discouraged, in part due to an increased risk of providers failing to retrieve and act upon results, as many patients are discharged before results return. The development of rapid turn-around-times (TATs) for genomic testing has begun to shift this paradigm. Rapid exome sequencing (rES) is increasingly being used as a diagnostic tool for critically ill infants with likely genetic disease and presents significant challenges to execute. We implemented a program, entitled the Rapid Inpatient Genomic Testing (RIGhT) project, to identify critically ill children for whom a molecular diagnosis is likely to change inpatient management. Two important goals of the RIGhT project were to provide appropriate genetic counseling, and to develop protocols to ensure efficient test coordination- both of which relied heavily on laboratory and clinic-based genetic counselors (GCs). Here, rES was performed on 27 inpatient trios from October 2016 to August 2018; laboratory and clinical GCs encountered significant challenges in the coordination of this testing. The GCs involved retrospectively reviewed these cases and identified three common challenges encountered during pretest counseling and coordination. The aim of this paper is to define these challenges using illustrative case examples that highlight the importance of including GCs to support rES programs.