Genetic and Clinical Spectrum of Inborn Errors of Immunity in the Pakistani Population: A Systematic Review

Abstract Background Inborn errors of immunity (IEIs), historically termed primary immunodeficiencies (PID), are a broad group of rare inherited diseases caused by genetic variants that impair the development or functioning of the immune system. Although IEIs are genetically determined, molecular diagnoses remain unavailable for a substantial proportion of patients worldwide, particularly in low- and middle-income countries. Clinically, IEIs can present with diverse manifestations ranging from persistent and severe infections to immune dysregulation, gastrointestinal disease, autoimmunity, and malignancy. Objective To systematically review the clinical and genetic spectrum of IEI patients reported from Pakistan. Methods We conducted a systematic review of published IEI cases from Pakistan using PubMed, Google Scholar, and national journals (until August 2025), querying terms related to inborn errors of immunity and primary immunodeficiency. Extracted information included clinical phenotype, genetic mutation, mode of inheritance, and diagnosis approach, with all cases classified according to the 2024 International Union of Immunological Societies (IUIS) classification. Results A total of 328 patients from 63 publications met the inclusion criteria. Combined Immunodeficiencies (CIDs) were the most frequently reported category (39%), followed by Phagocytic Disorders (23%) and syndromic CIDs (12%). Common clinical manifestations were frequent respiratory infections (57%), diarrhea (47%), skin lesions (43%), and failure to thrive (28%). Genetic data was available for 142 patients (43%); however, due to the literature-based nature of the dataset, this does not represent a true diagnostic yield, as genetically unsolved cases are underreported. Among them, the most implicated genes were RAG1 , RAG2 , ITGB2 , and CYBB , indicating a predominance of severe, early-onset autosomal recessive disease, which is consistent with Pakistan’s high consanguinity rates. The remaining 57% of patients had no molecular work-up, highlighting major diagnostic gaps. Conclusion These findings highlight a predominance of severe IEI phenotypes in Pakistan alongside significant underdiagnosis and limited access to genetic testing, emphasizing the need to strengthen diagnostic infrastructure, expand genomic testing, and establish a national IEI registry to improve early diagnosis and access to potentially curative therapies.