Characterisation of a Leaky Splice-Site Mutation Associated with Phenotypic Diversity in Two Unrelated Patients with ARPC1B Deficiency

TL;DR

Two unrelated patients with the same ARPC1B gene mutation show different symptoms due to partial protein expression from leaky splicing.

Contribution

The study identifies a leaky splice-site mutation in ARPC1B that explains phenotypic variability in patients with the same genetic defect.

Findings

Two unrelated patients with the same ARPC1B splice-site mutation exhibited distinct clinical and immunological profiles.

Leaky splicing from the mutation allows partial expression of functional ARPC1B, leading to milder symptoms in one patient.

Differential transcriptional activity of wildtype ARPC1B correlates with the severity of clinical manifestations.

Abstract

Autosomal-recessive pathogenic variants in Actin-related protein 2/3 complex subunit 1B (ARPC1B) result in an inborn error of immunity associated with eczema, thrombocytopenia, leukocytoclastic vasculitis and colitis. ARPC1B deficiency leads to impaired actin filament branching, affecting cytoskeletal processes in leukocytes, including migration, adhesion, endocytosis, and phagocytosis. This report presents two index cases from different families, who despite sharing an identical germline homozygous ARPC1B splice-site variant, ARPC1Bc.64+2T> A, 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 B cell maturation and responses to EBV transformation. Further molecular investigation suggests the downstream cryptic splice-site activated by the mutation permits ‘leaky splicing’, enabling trace expression of wildtype ARPC1B. This supports a less severe deficiency in ARPC1B activity, rendering a less severe phenotype in one case compared with the other due to differential transcriptional activity of wildtype ARPC1B.

The online version contains supplementary material available at 10.1007/s10875-026-02002-4.

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