The Common Fund Knockout Mouse Phenotyping Program (KOMP2) is a valuable resource for functionally characterizing mammalian genes. We propose to increase the utility of KOMP2 by curating and annotating genomic information in the dataset by collecting and curating human clinical data to match human patients to KOMP2 mice with severe phenotypes. The goal of this project is to assess pediatric patient cohorts with exome sequencing data and no molecular diagnosis for variants of uncertain significance in genes that correspond to a lethal phenotype in KOMP2 mouse mutant lines. Mouse lines categorized as cellular lethal, developmental lethal or subviable are targeted as relevant for early and severe pediatric phenotypes. For this reason, we will consider four human patient cohorts. The first cohort consists of patients who died within the first year of life. The second cohort consists of patients admitted to the pediatric intensive care units (ICUs) within the first 100 days of life. The third cohort is a recent sample of pediatric patients with trio exome data available. The fourth cohort is a pediatric cohort with likely Mendelian disease genes of unknown function. With each cohort we will identify variants of uncertain significance in human orthologues corresponding to mouse genes classified as cellular lethal, developmental lethal or sub-viable. Then, we will compare the mouse and human phenotypes using standardized phenotype terms to prioritize follow up of genes with variants in our human cohorts and with similar phenotypes in mice and humans.

This project will assess pediatric patient cohorts with exome sequencing data and no molecular diagnosis for variants of uncertain significance in genes that correspond to KOMP2 mouse mutant lines. Mouse lines categorized as cellular lethal, developmental lethal or sub-viable are targeted as relevant for early and severe pediatric phenotypes. We will compare variants identified in human orthologues corresponding to mouse genes and compare the mouse and human phenotypes using standardized phenotype terms to prioritize follow up of pairs with similar phenotypes.