Multiomic Investigation of Sudden Unexplained Pediatric Deaths - PROJECT SUMMARY This proposal responds to the Notice of Special Interest “Understanding Sudden Death in the Young” (SDY) (NOT-HL-22-040) by building on our previous body of research in Robert’s Program on SUDP (Sudden Unexpected Death in Pediatrics) at Boston Children’s Hospital with additional phenotypic and genetic data collected in the NIH/CDC SDY Registry, to better define the molecular underpinnings of sudden and unexpected death in individuals 0-20 years of age (definition of SUDP and SDY). Sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC) (included in the definition of SUDP and SDY) are responsible for nearly one in ten deaths in US children. While public health efforts aim to minimize risk in the sleep environment for SIDS, the persistent mortality indicates that affected children may possess intrinsic vulnerabilities that increase their susceptibility to death. Robert’s Program on SUDP uses deep phenotyping, genetic analysis, and engagement of families to study SUDP as a constellation of undiagnosed diseases. Our premise is that intrinsic biological contributions to SUDP include neurodevelopmental, epilepsy- related, cardiac, metabolic, and respiratory factors that have a genetic basis. Our multidisciplinary approach mirrors undiagnosed disease programs, using deep phenotyping and comprehensive genomic analysis to identify unrecognized conditions. Our previous “proof of concept” study, funded in part as an R21, utilized exome sequencing and found evidence of genetically based susceptibilities in 11% of SUDP cases in genes related to neurological, cardiac, and systemic disease. For this proposal we hypothesize that we will identify contributions to SUDP through a multiomics approach, using GS and metabolomic data to identify potential underlying Mendelian disorders and to investigate genetic risk using polygenic scores (PGS) for phenotypes of interest in SUDP. In Aim 1 we will identify monogenic contributions to SUDP by phenotyping and performing genome sequencing (GS) in prospective cases from Robert’s Program trios (estimated 270 over the grant period) and analyzing these data together with GS and phenotype data from the SDY Registry (estimated 250 prospective cases over the grant period). When added to the existing cohort of nearly 1000 cases from the SDY Registry and Robert’s Program, total data will include over 1400 cases. We will also conduct long-read sequencing in Robert’s Program cases to identify monogenic contributions missed by GS alone. In Aim 2 we will explore risk for SUDP using validated PGS with phenotypic overlap to SUDP mechanisms (e.g., epilepsy and Brugada syndrome) in Robert’s Program and SDY Registry cases. In Aim 3 we will utilize metabolomics in Robert’s Program cases to uncover biochemical signatures of underlying metabolic disease. The impact of this research is the elucidation of genetic mechanisms in SUDP, advancing the forensic molecular autopsy in establishing a cause of mortality and assessing novel methods of identifying genetic and metabolomic underpinnings of SUDP.
