Washington University School of Medicine Undiagnosed Diseases Network Clinical Site

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PROJECT SUMMARY Clinical whole genome sequencing (cWGS) is increasingly being used as a diagnostic tool for critically ill infants and children. Multiple clinical trials in neonatal and pediatric intensive care units (NICUs, PICUs) have demonstrated a diagnostic success rate of ~30-40% for cWGS among critically ill infants and children. However, because genetic diseases in critically ill infants and children may reduce reproductive fitness, pathogenic variants are likely to be enriched in novel genes not previously associated with human diseases and not detected by clinical reanalysis. In addition, use of pathogenicity prediction tools for noncoding variants identified with cWGS including deep intronic and untranslated regions (UTR) remains limited. Thus, the majority of critically ill infants and children with suspected genetic diseases who have been carefully phenotyped during their ICU hospitalizations remain undiagnosed after cWGS. Confirmation of pathogenicity among novel ‘candidate’ genes or variants of uncertain significance (VUS) is limited to enrollment in research studies with limited capacity and accessibility. We propose systematically reviewing, consenting, and enrolling critically ill infants and children from the intensive care units at St. Louis Children’s Hospital with non-diagnostic cWGS into the UDN to increase the throughput and diversity of participants who will benefit from Undiagnosed Diseases Network (UDN) research reanalysis and from use of additional tools (e.g., transcriptomic analysis, long-read DNA genomic sequencing, in vitro functional studies, model organism screening) offered through the UDN and not covered by third party payers. In addition, we will prioritize enrollment of critically ill infants and children from underrepresented minorities and underserved communities for UDN enrollment. To increase diagnostic success of Washington University in St. Louis (WUSTL) UDN Phase 2 participants with non-diagnostic clinical and genomic evaluations, we propose performing RNA-Seq transcriptomic analyses, long-read DNA genomic sequencing, and functional studies of noncoding variants in deep intronic or untranslated (5 and 3’ UTR) regions.