An Immunodeficiency Tale: Same Mutation, Different Phenotype

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is an autosomal-recessive inborn error of immunity resulting in impaired actin cytoskeletal function. This condition presents with similar features to Wiskott-Aldrich Syndrome, including leukocytoclastic vasculitis, thrombocytopenia, eczema and colitis. An absence of ARPC1B protein leads to impaired actin filament formation, which is critical for leukocyte activity in mediating cytoskeletal processes, including migration, adhesion, endocytosis, and phagocytosis. We present two index cases from different families, who despite sharing an identical homozygous ARPC1B splice-site variant, had distinct clinical phenotypes including age of onset of symptoms and clinical manifestations. In addition, differences were observed in their immunological profiles including neutrophil chemotaxis, upregulation of complement receptor expression as well as the B cell responses to EBV transformation. We postulate that the observed phenotypic differences are likely due to reversion mosaicism, which restores or maintains a level of residual function in particular immune compartments.