Unveiling the Genetic and Epidemiological Patterns of Primary Immunodeficiency Diseases (PIDs) in a Cohort of Eastern Iranian Patients

Background and Aim Primary immunodeficiency diseases (PIDs) are monogenic inborn immune disorders, grouped into 10 categories by IUIS, with 555 identified IEIs causing conditions ranging from life-threatening severe combined immunodeficiency (SCID) to milder common variable immunodeficiency (CVID). Affecting over 6 million globally, PIDs increase mortality risk and demand genetic/immunological testing. In Iran, high consanguinity rates may warrant influence of genetic factors. Diagnostic challenges due to heterogeneity necessitate application of advanced tools like exome sequencing (ES). This study was carried out on Eastern Iran's PIDs to help enhancing both local and global required interventions. Methods This study focused on 99 patients from Eastern Iran clinically diagnosed with PIDs who were referred for genetic evaluations between 2016 and 2025. Genetic analyses involved DNA extraction from blood samples, exome sequencing with Illumina platforms, and in-house bioinformatic pipelines for variant identification and classification. Sanger sequencing and co-segregation studies further validated findings. Medical records, family histories, and pedigrees were thoroughly analyzed. We also meticulously delineated syndromic and non-syndromic PID disorders. Results The significant findings were as follows: discovery of 47 novel IEIs; High consanguinity rates (76%) correlated with an 82.8% diagnostic yield and a mortality rate of 8% amongst patients. SCID-associated mutations, as the most common PID, were accounted for 16.1% of cases; other common disorders were CVID8, AT, and VICIS. Additionally, certain mutations may link to pregnancy loss which may need further functional studies. Around 70% of unresolved cases were syndromic. Class I immunodeficiencies (affecting cellular/humoral immunity) were most frequent (26.8%). The most common genetic mutations in Eastern Iranian PID patients involved the EPG5 gene, with four novel variant of uncertain significance (VUS), missense mutations (c.T6368G; p.Met2123Arg, c.3892G>C; p.Ala1298Pro, c.5057G>A; p.Arg1686His, c.5714G>A; p.Arg1905Gln) were associated with Vici syndrome (VICIS). Conclusion Current findings with significant number of novel IEIs enhanced understanding of PID diagnosis. Localized PID clusters may have been influenced by genetic isolation and cultural practices. Findings also urge early diagnosis to reduce morbidity and mortality. Additionally, pregnancy loss may link to certain mutations. Predominant syndromic unresolved cases reflect the complexity of diagnosis and the need for continuous genetic data reassessment.