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.

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.