POS0376 HUMAN INBORN ERRORS OF IMMUNITY IN IgG4 RELATED DISEASE
Authors: V. Batani, E. Benetti, J. Mahajne, F. Segala, C. Minici, M. Lanzillotta, D. Colavito, E. Della Torre
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> IgG4-related disease (IgG4-RD) is an immune-mediated condition of unknown etiology characterized by multiple clinical manifestations and by a prominent production of IgG4 antibodies possibly due to the perpetuation of an antigen driven immune response. Genetic background might contribute to disease immunopathology and predispose to patient-specific clinical picture thus explaining the protean nature of this condition. Data from previous genome wide association and single targeted gene studies were inconclusive. <h3>Objectives:</h3> In the present work we aimed to investigate the frequency of germline variants in genes associated to Human Inborn Errors of Immunity (HIEI) in patients with IgG4-RD and to compare it with healthy controls. <h3>Methods:</h3> Genomic DNA was extracted from the peripheral blood of IgG4-RD patients to perform whole exome sequencing (WES) analysis. Sex and age matched individuals not affected by immune-mediated disorders were used as controls. A filtering strategy was applied to select functional variants in genes of the HIEI panel of the latest available 2022 classification with moderate or high impact on protein structure/function using in silico predictive analyses. Enrichment in possibly harmful HIEI genes variants related to "immunodeficiencies", "autoinflammatory diseases" and "immune dysregulation" subgroups was compared between IgG4-RD patients and controls. <h3>Results:</h3> Genomic data of 18 IgG4-RD patients and 50 controls were collected. Analyzing the HIEI panel a total of 75 variants in 58 genes were found in IgG4-RD patients and 142 variants in 104 genes in controls. Mutations included missense mutations, splice site donor or acceptor sites, in frame insertions or deletions, frameshift insertions or deletions, stop-gain, and stop-loss mutations. Patients with IgG4-RD showed a significant enrichment (number of variants per subject) of impact variants in HIEI genes related to immunodeficiencies compared with controls (p = 0.0019) (<b>Figure 1).</b> Consistently, on disease-gene enrichment analysis, the condition most related with the genes observed mutated in IgG4-RD patients was common variable immunodeficiency. All mutations were heterozygous, of uncertain significance, and not per se causative of a reported immunological monogenic disorder. Accordingly, the full clinical phenotype of a monogenic diseases associated with HIEI was not observed in the cohort of patients with IgG4-RD but most of them showed incomplete clinical pictures. Subgroups of HIEI genes related to auto-inflammatory and immune dysregulation diseases did not show any difference in the degree of impact variants enrichment between patients and controls (<b>Figure 2).</b> <h3>Conclusion:</h3> This is the first study using a WES approach to investigate genetic predisposition in IgG4-RD. Patients with IgG4-RD carry an increased frequency of germline impact variants in HIEI genes related to immunodeficiency syndromes, but these mutations seem unable to generate per se an overt immunodeficiency phenotype. Our study does not provide any functional insight into the reported mutations but suggests that germline variants in HIEI immunodeficiency genes may serve as a first hit predisposing to IgG4-RD. Second genetic or environmental hits may therefore be required to the development of IgG4-RD. Although larger cohorts are needed to confirm these results, our study opens to novel perspectives to interpret the wider clinical and serological variability of patients affected by IgG4-RD. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>