Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 4; pp. 1450 - 1458
• Main Authors: Abolhassani, Hassan, Chou, Janet, Bainter, Wayne, Platt, Craig D., Tavassoli, Mahmood, Momen, Tooba, Tavakol, Marzieh, Eslamian, Mohammad Hossein, Gharagozlou, Mohammad, Movahedi, Masoud, Ghadami, Mohsen, Hamidieh, Amir Ali, Azizi, Gholamreza, Yazdani, Reza, Afarideh, Mohsen, Ghajar, Alireza, Havaei, Arash, Chavoshzadeh, Zahra, Mahdaviani, Seyed Alireza, Cheraghi, Taher, Behniafard, Nasrin, Amin, Reza, Aleyasin, Soheila, Faridhosseini, Reza, Jabbari-Azad, Farahzad, Nabavi, Mohammamd, Bemanian, Mohammad Hassan, Arshi, Saba, Molatefi, Rasol, Sherkat, Roya, Mansouri, Mahboubeh, Mesdaghi, Mehrnaz, Babaie, Delara, Mohammadzadeh, Iraj, Ghaffari, Javad, Shafiei, Alireza, Kalantari, Najmeddin, Ahanchian, Hamid, Khoshkhui, Maryam, Soheili, Habib, Dabbaghzadeh, Abbas, Shirkani, Afshin, Nasiri Kalmarzi, Rasoul, Mortazavi, Seyed Hamidreza, Tafaroji, Javad, Khalili, Abbas, Mohammadi, Javad, Negahdari, Babak, Joghataei, Mohammad-Taghi, al-Ramadi, Basel K., Picard, Capucine, Parvaneh, Nima, Rezaei, Nima, Chatila, Talal A., Massaad, Michel J., Keles, Sevgi, Hammarström, Lennart, Geha, Raif S., Aghamohammadi, Asghar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018; Elsevier Limited
• Subjects: Adaptive immunity; Adolescent; Age; Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Child; Child, Preschool; Combined immunodeficiencies; Consanguinity; Data processing; Defects; Deoxyribonucleic acid; Diagnosis; DNA; DNA repair; DNA sequencing; Female; Genes; Genes, Recessive - genetics; Genes, Recessive - immunology; Genetic Predisposition to Disease - genetics; Genetic screening; High-Throughput Nucleotide Sequencing - methods; Humans; Immunodeficiency; Immunoglobulin E; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - mortality; Infant; Iran; Job Syndrome - genetics; Job Syndrome - immunology; Job Syndrome - mortality; Job's syndrome; Laboratories; Male; Medicin och hälsovetenskap; Mortality; Mutation; Mutation - genetics; Mutation - immunology; next-generation DNA sequencing; Phenotype; Retrospective Studies; Sequence Analysis, DNA - methods; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - immunology; Survival Rate; targeted gene panel sequencing; Transcription; V(D)J recombination; whole-exome sequencing; Iran; Middle East; Saudi Arabia; United States > US; next-generation DNA sequencing; HIGM; BCG; WAS; targeted gene panel sequencing; PID; SCID; HIES; STAT; Combined immunodeficiencies; AT; BCGosis; NGS; whole-exome sequencing; HSCT; CID
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.06.049

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. This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .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 ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.