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.
