Enrichment of Variants of Known and Unknown Significance in Specific Inborn Error of Immunity Categories in Children with Autoimmune Cytopenia

Autoimmune cytopenias (AIC) are characterized by immune-mediated destruction of platelets (immune thrombocytopenia [ITP]), red blood cells (autoimmune hemolytic anemia [AIHA]), neutrophils (autoimmune neutropenia [AIN]), or multiple lineages (Evans Syndrome [ES]). Although AIC are a common first presentation for IEI, the majority of patients with AIC remain without a genetic diagnosis. Utilization of clinical genetic testing is increasing in the evaluation of patients with AIC, but it is challenging to assess the contribution of certain variants, particularly variants of unknown significance (VUS) and monoallelic variants in recessive genes, to AIC development. Even if these variants do not lead to an IEI diagnosis, their role in the development of an AIC remains unclear. To investigate this question, we aimed to assess whether variants in specific IEI categories were more frequent in patients with AIC than the expected occurrence. In collaboration with Labcorp (formerly Invitae), we obtained results of clinical genetic testing in children under 21 years with AIC who had sequencing with one of six available IEI next-generation sequencing panels. We included 912 patients (ITP, n = 430; AIHA, n = 119; AIN, n = 197; and ES, n = 166). In these patients, there were a total of 2,953 variants identified, including 2,459 VUS. We analyzed the enrichment in specific IEI categories based on the International Union of Immunological Societies (IUIS) classification by comparing the proportion of variants found in each category to the number of genes within this category. We found that three categories were overrepresented: complement deficiency, immune dysregulation, and phagocyte defects (Figure 1 A). The direction of enrichment remained the same whether we considered only VUS, only likely pathogenic/pathogenic variants, or both. In the phagocyte subcategory, we found a significant enrichment in respiratory burst defect genes, both for VUS and likely pathogenic/pathogenic variants (Figure 1 B). No subcategory of immune dysregulation was significantly overrepresented (Figure 1 C), and there are no complement deficiency subcategories in the IUIS classification. Our data suggest that variants in specific IEI categories are overrepresented in patients with AIC and that VUS may contribute to AIC occurrence, specifically those in respiratory burst genes. Figure 1.