Background: Biallelic loss-of-function mutations in the lipopolysaccharide-responsive and beige-like anchor (LRBA) gene lead to a severe syndrome of early-onset immune dysregulation called LRBA deficiency. Monoallelic CTLA4 mutations lead to a similar phenotype. In both conditions, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels are significantly decreased. In previously reported cases of symptomatic disease associated with LRBA pathogenic variants, patients usually have severely decreased or absent LRBA protein levels.

Objective: We describe 5 patients with biallelic missense variants in the LRBA gene presenting predominantly with Evans syndrome or colitis.

Methods: LRBA and CTLA-4 levels were investigated in LRBA missense, "classic" LRBA and in CTLA-4 insufficiency samples.

Results: Surprisingly, all 5 LRBA missense patients had normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in patients with CTLA-4 insufficiency at resting state. Lower levels of surface CTLA-4 are seen on cell activation, indicating that these LRBA variants lead to reduced CTLA-4 cell surface expression. Several of the missense variants are shared between unrelated patients in the cohort, suggesting a mutational hot spot or founder effect for those with shared ancestry.

Conclusion: Novel LRBA deficiency variants result in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.