Polygenic contributors to disease expressivity in genetic errors of immunity

Project Summary—Project 3 Genetic errors of the immune system (GEIS) encompass monogenic Inborn Errors of Immunity (IEI) and other somatic disorders impacting immune functions. Over 500 such disorders have been described to date, leading to broad and diverse clinical phenotypes encompassing autoimmunity, inflammation, atopy and infection. A large proportion of GEIS have highly variable penetrance and expressivity, leading to difficulties in diagnosis and management-- but also opportunities to better understand “common” immune-mediated disease, which may manifest as a genetic disorder more frequently than previously understood. The importance in obtaining a molecular pathomechanistic diagnosis and predicting penetrance and expressivity is driven by a) the ever- increasing precision therapies targeted to genetically determined cellular pathways b) the increasing safety and efficacy of hematopoetic stem cell transplantation for defined immune disorders and, most importantly, c) the dramatic increase in efficacy of management outcomes when patients are treated *prior* to the emergence of severe symptoms. Our central hypothesis is that polygenic risk scores (PRS) and pathway-specific regulatory variants can help predict penetrance and expressivity of clinical phenotypes in genetic diseases of the immune system, and reveal biologically important, measurably impact immune-mediated disease pathomechanisms. To address this issue, we will capitalize on advances in the construction of PRS for many immune disorders, the ascertainment of rare and common variants impacting immune pathway function or immune gene expression (via quantitative trait loci, or QTL) and a novel genomic editing tool model the interaction between rare and common genetic determinants of disease. These tools will used in series of sizeable cohorts of otherwise rare individual GEIS—in particular those impacting JAK1/STAT3 signaling and PI3 Kinase/mTOR signaling. We will quantify the impact of existing immune disease-specific PRS and known eQTL on penetrance and expressivity within each GDIS. We will also functionally assess the impact of pathway-specific variation via flow cytometric assays which interrogate pathway component expression and activity in patient samples, and experimentally manipulate polygenic variants via a novel base editing tool. Finally, we will incorporate the genomic, eQTL and functional data to de novo construct PRS for enriched phenotypes within individual PIRD. These tools while hopefully help build the predictive models needed to determine management before life altering morbidities arise, and substantially contribute to our understanding of immune-mediated disease pathomechanisms and provide novel diagnostic opportunities for common immune-mediated diseases.