Exploration of Clusters of Rare Disease: ARPC1B Deficiency with Founder Effect in Nepal

BackgroundMore than one-fourth of the world’s burden of ARPC1B deficiency (ARPC1BD), a rare immune-actinopathy, is reported from Nepal, a resource-constrained Himalayan country with a single trained immunologist. The discovery of clusters indicates a potentially large, undiagnosed population. We conduct extensive immunophenotyping, functional, and genetic studies for ARPC1BD in a prospective cohort.MethodsWe established the core area of diagnosed cases with a c.64+2T>A splice site mutation of the ARPC1B gene. All cases are diagnosed by the lead author and enrolled after genetic evidence only. Investigations were performed at local labs or with the help of collaborators. A mixed-methods approach, involving both quantitative and qualitative data collection, will be continued over the next year.ResultThe study is in its initial phase. We have identified 20 ARPC1BD cases, of whom four died due to complications. Five patients have undergone hematopoietic stem cell transplantation, and two are preparing for it. Most cases are from Koshi, Gandaki, Lumbini, and Madhesh provinces of Nepal, with sporadic cases across peripheral regions. To date, 36 symptomatic siblings, relatives, or individuals from the same clan or kindred—presenting with recurrent allergy, infections, inflammatory or autoinflammatory features, bleeding, or combinations thereof—have been enrolled for initial evaluation. Genetic confirmation of ARPC1BD was achieved in three siblings of the probands and one child from the same kindred. Homozygosity mapping and haplotype analysis in eight patients identified the c.64+2T>A intronic splice-site mutation as a founder variant (of Nepalese origin), an analysis being extended to all new cases.Sampling, immunophenotyping, and genetic analyses are ongoing. Planned next steps include expanded genetic screening of symptomatic family members and nearby individuals, analysis across clans and kindred, and detailed genotype–phenotype correlation, haplotype, linkage, and polymorphism studies to define the genetic landscape of ARPC1BD. This work contributes valuable data to the global understanding of ARPC1BD.ConclusionThe findings from this research will provide comprehensive insights into the genetic and clinical features of ARPC1BD. This study will directly impact global immune-actinopathy literature, patient care, and serve as a foundation for future research on rare genetic disorders in similar settings.