Novel Mechanisms of Genetic Errors of Immunity

Inborn Errors of Immunity (IEI) collectively comprise more than 500 different monogenic disorders of the immune system. Primary Immune Regulation Disorders (PIRD) represent a subset of IEI, that are characterized clinically by a lack of regulation of the immune response resulting in overlapping features of infectious susceptibility, autoimmunity, lymphoproliferation, inflammation, and/or atopy. While tremendous advances in patient diagnosis and disease mechanisms understanding have been made, significant gaps in the field remain. First, the molecular diagnostic rate for all IEI remains only 30-40%, even in multiplex families with high likelihood of genetic inheritance. Second, most diseases of immune dysregulation have variable penetrance (i.e, have or don’t have disease) and have variable expressivity (i.e, have mild vs severe disease). This phenomenon is by and large unexplained. Our emerging data suggests three evolving genetic concepts of disease including epigenetic, somatic mutations, and genetic modifiers. We propose to use the term Genetic Errors of Immunity (GEIs) to encompass these broad and novel molecular mechanisms. In Project 1 we will tackle a novel epigenetic mechanism, where despite heterozygosity on DNA level, transcriptionally only one allele is expressed in select cell lineages, a phenomenon termed autosomal random monoallelic expression (aRMAE). We propose to map genes that are prone to aRMAE in the immune system, define epigenetic marks governing this process, and validate these findings in individuals with identified genetic lesions within families with known incomplete penetrance. This will allow us to document discrepant genotype to “transcriptotype” and measure functional implication of this epigenetic phenomenon. In Project 2 we will investigate somatic mutations as a cause of GEIs, a concept in its infancy. Herein we propose to perform high-depth targeted sequencing to identify genetic mosaicism in patients with suspected GEI who were negative by standard genetic testing, and to develop single cell technologies for evaluating their functional impact on the immune response. Our preliminary data suggests that a mutation causative of PIRD can be both somatic and in a gene undergoing aRMAE, suggesting clear synergy among Project 1 and Project 2. Finally in Project 3, we will address known genetic risk variants in tandem with polygenic risk score (both of which would otherwise be clinically silent). This concept is of great interest in the IEI field. Understanding these modifier genes, whether germline, somatic or epigenetically regulated (undergoing aRMAE) forms a clear cohesive connection between Projects 1-3. To support this set of integrated yet distinct projects we propose: 1) an administrative core charged with coordination of meetings, regulatory compliance, and grant management; 2) Sequencing and sample core: tasked with patient and control sample WEG, WGS, Targeted Deep Sequencing, RNA Seq, and scRNASeq and 3) Bioinformatics and computational biology Core tasked with development and integration of bioinformatic pipelines. Combined, these 3 projects and 3 cores will synergize in defining novel disease mechanisms in GEI. Project Number: 5P01AI186771-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: MEGAN COOPER (+1 co-PI) | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $2,483,910 | Activity Code: P01 | Study Section: ZAI1-MR-I(S2) View on NIH RePORTER: https://reporter.nih.gov/project-details/5P01AI18677102