Amanda S Freed1, Sarah V Clowes Candadai2, Megan C Sikes3, Jenny Thies3, Heather M Byers1, Jennifer N Dines1, Mesaki Kenneth Ndugga-Kabuye1, Mallory B Smith4, Katie Fogus3, Heather C Mefford5, Christina Lam6, Margaret P Adam7, Angela Sun7, John K McGuire4, Robert DiGeronimo8, Katrina M Dipple9, Gail H Deutsch10, Zeenia C Billimoria8, James T Bennett11. 1. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA. 2. Department of Laboratories, Seattle Children's Hospital, Seattle, WA; Patient-centered Laboratory Utilization Guidance Services (PLUGS), Seattle Children's Hospital, Seattle, WA. 3. Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA. 4. Division of Pediatric Critical Care, Department of Pediatrics, University of Washington, Seattle, WA. 5. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA. 6. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA. 7. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA. 8. Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA. 9. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA. 10. Department of Pathology, University of Washington and Seattle Children's Hospital, Seattle, WA. 11. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA. Electronic address: jtbenn@uw.edu.
Abstract
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.
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.
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