Association of IgG4-related disease with human inborn errors of immunity

Objectives IgG4-related disease (IgG4-RD) is considered a complex multifactorial condition because immunological, environmental and genetic factors contribute to its pathogenesis and protean clinical manifestations. While immunological and environmental factors have been extensively investigated, the contribution of genetic factors remains poorly understood. We sought to investigate a predisposing genetic background associated with IgG4-RD.Methods Eighteen patients with IgG4-RD were Whole Exome Sequenced (WES) to assess germline variants in genes associated with human inborn errors of immunity (HIEI). Rare and ultra-rare variants with potential impact on protein structure were called and analysed. Fifty age-sex matched healthy individuals were used as controls.Results Germline ultra-rare variants in HIEI genes were enriched in IgG4-RD patients compared with the controls (P = 0.0025). Up to 10 rare gene variants were observed in a single patient. The most frequently mutated genes were PRKDC and LRBA. All variants were heterozygous, of uncertain significance and not per se causative of a reported monogenic disorder. Incomplete phenotype of monogenic diseases associated with HIEI was observed in some patients. These variants were unique to IgG4-RD patients and were not observed in the controls.Conclusions Patients with IgG4-RD carry an increased frequency of ultra-rare germline variants in HIEI genes. This genetic background might predispose to IgG4-RD and to its variable manifestations while additional genetic or environmental triggers may be required to establish the complete clinical phenotype.