The c.64 + 2 T > A Founder Variant Hits Home: Report on 14 Patients Expands the Phenotypic Landscape of Inherited ARPC1B Deficiency - a Comparative Analysis.

Abstract

Background: Inherited ARPC1B deficiency (ARPC1BD) is a rare autosomal recessive inborn error of immunity that manifests with allergic, infective, and autoimmune/inflammatory features. Only about three dozen patients with ARPC1BD have been reported in the literature thus far.

Methods: We describe 14 patients (ten families) with ARPC1BD from Nepal. Many of these patients have unique/rare clinical features that expand the phenotypic spectrum of ARPC1BD. The study included data on clinical-epidemiological features, immuno-hematological parameters, treatment, and outcome. Homozygosity mapping and haplotype analysis were used to evaluate the founder effect.

Results: We noted allergic/autoimmune and infective manifestations in all of our patients. Notable clinical features noted in our study include rheumatoid factor positive (RF+) chronic arthritis (mimicking RF+ juvenile idiopathic arthritis), significantly elevated anti-tissue transglutaminase antibody titers, generalized skin hyperpigmentation, distal phalangeal enlargement, frontal bone hypertrophy, hypertrophic skin scars, and hyperkeratosis. All cases harbored the founder splice-site variant c.64+2T>A in the ARPC1B gene. Long-term outcomes in our patients appeared worse than reported previously. Comparative phenotypic analysis showed significantly greater proportions of otitis, gastroenteritis, inflammatory bowel disease-like manifestations, and elevated IgA in patients with c.64+2T>A variant as compared to other variants. Homozygosity mapping (in eight probands) revealed that the gene/variant is contained within the only overlapping region of homozygosity (>1 Mb) across all autosomal chromosomes. Besides, the included probands share a similar haplotype around the said variant.

Conclusions: c.64+2T>A is a founder variant in Nepalese patients with ARPC1BD. This variant is associated with a severe clinical phenotype and diverse clinical complications.