Abstract

BACKGROUND Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. OBJECTIVES This study aims to characterize the categories of CID patients in Iran clinically and genetically. METHODS Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and non-syndromic CIDs (352 patients). Targeted DNA sequencing was performed on 243 patients (34.9%). RESULTS The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of HIES (p<0.001), onset of disease > 5y (p=0.02), and the absence of multiple affected family members (p=0.04), were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ATM, autosomal dominant mutations in STAT3 and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower five-year survival rate rather than those with non-syndromic CIDs. CONCLUSIONS This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The impact of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.