Inborn Errors of Immunity Genotype: A Retrospective Study from the United Arab Emirates

Abstract

Inborn errors of immunity (IEI) contribute substantially to morbidity in the Middle East and North Africa (MENA), particularly in the United Arab Emirates (UAE), where high consanguinity increases the prevalence of autosomal-recessive and complex genetic disorders. Regional IEI genomic data remain limited, and population-specific variants are underrepresented in global databases, limiting diagnostic accuracy and precision-medicine implementation. We retrospectively reviewed 2,500 patients assigned immunodeficiency-related ICD codes over ten years at two tertiary centers in Al Ain, UAE. Based on the availability of genetic testing reports for inborn errors of immunity, 232 patients (~ 9%) were included in the analysis. Variants were annotated using American College of Medical Genetics and Genomics guidelines and open-access resources, including Ensembl and ClinVar, and genes were classified according to the International Union of Immunological Societies framework. Allele frequencies were reported based on gnomAD and the Emirati Genome Project. Reported variants were systematically reclassified using Franklin, VarSome, ClinGen, and HGMD, where available. Based on original reports, 245 IEI-related variant observations were identified across 107 genes: 99 (40.4%) pathogenic/likely pathogenic, 68 (27.8%) benign/likely benign, and 78 (31.8%) variants of uncertain significance (VUS). Following reclassification, pathogenic/likely pathogenic variants increased to 107 (43.7%), VUS decreased to 54 (22.0%), and benign/likely benign variants increased to 76 (31.0%). Recurrent genes included ATM , DOCK8 , RAG1 , RAG2 , UNC13D , LRBA , MEFV , and NLRP3 , and 7.8% of patients carried multiple IEI-related variants. This study provides one of the largest genomic characterizations of IEI in the UAE and demonstrates that systematic variant reinterpretation improves diagnostic accuracy, underscoring the importance of population-specific genomic resources for precision medicine. Genomic characterization of a UAE cohort with suspected inborn errors of immunity (IEI). Review of 2,500 immunology-related clinical records identified 232 genetically tested patients, yielding 245 variant observations across 107 genes. Variant reassessment reduced variants of uncertain significance from 78 (31.8%) to 54 (22.0%), highlighting the importance of regional genomic resources, prospective IEI registries, and segregation and functional studies.