The long-term goal of this project is to determine the cause of birth defects in critically-ill undiagnosed infants, using the embryonic phenotyping pipeline within the Knockout Mouse Phenotyping Program (KOMP2), with focus on post-implantation developmental lethality and sub-viability. Genes in this category are intuitively predicted to be associated with congenital anomalies, with likely enrichment for dominant disorders. The haplo-essential genes in mice that cannot go beyond the founder stage are likely enriched for human haploinsufficient genes responsible for Mendelian diseases and developmental disorders. Through this proposal, the investigator will prioritize de novo, LoF and other variants in genes with high pLI score from exome sequencing (ES) studies of the deceased children from her previously published study (PMID: 28973083). The genes with putative dominant null alleles will then be intersected with the known developmental essential and subviable genes in the International Mouse Phenotyping Consortium (IMPC) dataset to find phenotypic correlations. The investigator will use the embryonic lethal data to particularly analyze undiagnosed human cardiovascular phenotypes with early lethality. Through this opportunity for career enhancement in genomics, the applicant who is primarily a clinician, will learn to compare the mouse and human phenotypes using standardized phenotype terms and to utilize automated tools designed by IMPC to accelerate discovery of rare diseases. The investigator anticipates acquiring skills and hands-on experience to evaluate morphological abnormalities in developmental essential mouse embryos under the supervision of Dr. Dickinson's team. The scope of work, using mouse embryonic data to find clinical utility for patients with undiagnosed genetic conditions is in complete alignment with the project goals of KOMP2. The proposed work will also prepare the investigator to accelerate her existing efforts on rare disease diagnoses in children.
Many infants born with serious birth defects who are suspected to have a genetic condition, succumb to their malformations without ever getting a molecular diagnosis. For these families of undiagnosed children, there is often no resolution of the cause of suffering of their loved ones and no way of addressing the risks to future progeny. The proposed research would use the knowledge about genes that cause early lethality in mice to understand the genetic basis of severe congenital anomalies including congenital heart disease in children.
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