Improving Diagnostic Yield in Critically Ill Children with Prior Negative Genetic Testing
Joshua Motelow, MD, PhD
BACKGROUND: For children with critical illness, a timely and accurate genetic diagnosis can aid prognostication and change management. Whole exome sequencing (WES) yields diagnoses in ~50% of cases. But WES examines only a limited range of variants in 1-2% of the genome suggesting that unrecognized pathogenic variants likely exist in critically ill children leading to missed diagnoses. GAP: In general, diagnostic rates may be increased by up to 30% beyond those achieved with WES using (1) whole genome sequencing (WGS) and (2) RNA-sequencing (RNA-seq). For a child with critical illness and suspected monogenic disease, the diagnostic yield of a testing strategy using WGS and RNA-sequencing after a negative WES is unknown. HYPOTHESIS: We hypothesize that an approach to genetic testing among children with critical illness using WGS and RNA-seq may improve diagnostic yield by 20% over an approach utilizing WES only. METHODS: In this study, we will use whole genome sequencing and RNA sequencing to improve the diagnostic rate among children with critical illness and prior negative whole exome sequencing. We will utilize the most clinically relevant tissue for RNA-seq when available. RESULTS: Pending. IMPACT: The results of this study have the potential to change the clinical management of children with critical illness, shed light onto the biologic basis of pediatric critical illness, and drive novel therapeutic development.