Expanded Phenotype, Outcome, and New Insights from the Largest Single-Country Cohort of ARPC1B Deficiency

Genetic alteration of the genes of cytoskeletal regulatory proteins (e.g., actin-related protein complex-1 [ARPC1]) results in severe immune and hematological defects. ARPC1B deficiency (ARPC1BD) is an immune-actinopathy with combined immunodeficiency, allergy, inflammation, and bleeding tendency. Only a few dozen cases have been reported worldwide. A single Nepalese center has diagnosed 20 cases (including 14 previously reported cases and 6 new cases) of ARPC1B deficiency so far. As far as published evidence shows, this is the largest single-country or single-center cohort. Eighteen cases had the same homozygous splice-site founder variant c.64+2T>A in intron 2 of the ARPC1B gene. Two cases had compound heterozygous mutation (c.64+2T>A and c.784-1G>A). This cohort proves this variant to be the most prevalent pathogenic variant resulting in ARPC1BD to date. Most of the cases were from 4 provinces. Haplotype analysis and homozygosity mapping proved this variant to be situated within a unique shared region of homozygosity, and all cases had similar haplotype around the variant, suggesting a founder gene effect. All of our cases had severe infective, allergic, autoimmune, and autoinflammatory features. Our cases (with the same founder variant) manifested a peculiar set of features, including frontal protuberance, a higher incidence of otitis, arthritis (including Rheumatoid factor positivity), recurrent skin vasculitis, severe skin hyperpigmentation, hyperkeratosis, distal phalangeal enlargement, inflammatory bowel disease-like features, gastroenteritis, elevated anti-tissue transglutaminase antibodies, immunoglobulin (Ig) A, and very high IgE. A lesser proportion had low IgG & CD3+ cells, but none had natural killer (NK) cell lymphopenia. A wide spectrum of microbial infections was noted. Four patients did not receive specific therapy, and 5 underwent hematopoietic stem cell transplantation. Among these 5, 4 are doing well, whereas one died of vasculitis, pneumonia, and bowel obstruction. Among 20, a total of 4 patients died. Long-term morbidity in surviving patients included retinitis and severe pulmonary consequences. Nepal has a glaring lack of awareness, a nationalized healthcare system, and government support for complex immunological diseases, especially for their diagnostic, therapeutic, and research avenues. Comparatively soaring diagnosis of the cases with the same pathogenic variant of ARPC1BD in a small geographic area has provided many scientific insights about rare immune-actinopathy.