176 - The Utah NeoSeq Project: Developing and Implementing Genomic Sequencing in Acute Neonatal Care

Our goal is to improve genetic diagnosis in critically ill infants. The use of rapid whole genome sequencing (rWGS) is limited by diagnostic rates of 35-45%. We combine rWGS with novel diagnostic workflows and emerging technologies to maximize diagnostic utility.

Design/Methods: The Utah NeoSeq Project, developed at the University of Utah NICU (neonatal intensive care unit), enrolls neonates with clinical symptoms suggestive of a genetic disorder with the availability for inclusion of patients prenatally. Short read rWGS is completed at ARUP Laboratories with automated variant calling and analysis performed by the Utah Center for Genetic Discovery. A multidisciplinary team meets weekly to complete variant review. Mosaic, a secure genomic data management platform and Calypso, a team-based genomic diagnostic platform support data analysis, data quality control, phenotype analysis, and clinical presentation discussions. Research results are returned to the clinical care team and family and confirmed with CLIA validated testing. Non-diagnostic rWGS cases are assessed for utility of RNA sequencing, long-read sequencing, and/or functional analysis studies. All non-diagnostic cases undergo reanalysis annually. Provider surveys at the time of result return assess clinical utility and change in management.

Results: We have enrolled 51 NICU infants with 49% having a diagnostic or likely diagnostic result. Subsequent analyses on 9 non-diagnostic results include: 1 patient diagnosed after RNA sequencing; 2 diagnosed at their one-year reanalysis; and 6 who had trio long-read DNA sequencing but no new diagnoses. Forty-one provider surveys were completed; the most common reported outcomes included increased clarity for the primary care team (63%) and improved communication of outcome/prognosis with the family (39%).

Conclusion(s): The strategy of the Utah NeoSeq Project demonstrates a feasible expansion of the approach to diagnosis for critically ill infants and suggests higher diagnostic yields.  This generalizable protocol addresses the need for expedited and comprehensive genetic evaluation with the benefits of emerging genomic technologies, and functional analysis pathways framed around the appreciation that a multidisciplinary approach is necessary to maximize the benefit to our patients.