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

doi:10.1016/j.jaci.2017.06.049

. 2018 Apr;141(4):1450-1458.

doi: 10.1016/j.jaci.2017.06.049. Epub 2017 Sep 12.

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

Hassan Abolhassani¹, Janet Chou², Wayne Bainter², Craig D Platt², Mahmood Tavassoli³, Tooba Momen³, Marzieh Tavakol⁴, Mohammad Hossein Eslamian⁵, Mohammad Gharagozlou⁶, Masoud Movahedi⁶, Mohsen Ghadami⁷, Amir Ali Hamidieh⁸, Gholamreza Azizi⁹, Reza Yazdani¹⁰, Mohsen Afarideh¹¹, Alireza Ghajar¹¹, Arash Havaei¹¹, Zahra Chavoshzadeh¹², Seyed Alireza Mahdaviani¹³, Taher Cheraghi¹⁴, Nasrin Behniafard¹⁵, Reza Amin¹⁶, Soheila Aleyasin¹⁶, Reza Faridhosseini¹⁷, Farahzad Jabbari-Azad¹⁷, Mohammamd Nabavi¹⁸, Mohammad Hassan Bemanian¹⁸, Saba Arshi¹⁸, Rasol Molatefi¹⁹, Roya Sherkat²⁰, Mahboubeh Mansouri²¹, Mehrnaz Mesdaghi¹², Delara Babaie¹², Iraj Mohammadzadeh²², Javad Ghaffari²³, Alireza Shafiei²⁴, Najmeddin Kalantari²⁵, Hamid Ahanchian¹⁷, Maryam Khoshkhui¹⁷, Habib Soheili²⁶, Abbas Dabbaghzadeh²², Afshin Shirkani²⁷, Rasoul Nasiri Kalmarzi²⁸, Seyed Hamidreza Mortazavi²⁹, Javad Tafaroji³⁰, Abbas Khalili³¹, Javad Mohammadi³², Babak Negahdari³³, Mohammad-Taghi Joghataei³⁴, Basel K Al-Ramadi³⁵, Capucine Picard³⁶, Nima Parvaneh¹¹, Nima Rezaei³⁷, Talal A Chatila², Michel J Massaad², Sevgi Keles², Lennart Hammarström³⁸, Raif S Geha³⁹, Asghar Aghamohammadi⁴⁰

Affiliations

¹ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
² Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
³ Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute of Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
⁴ Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
⁵ Department of Pediatrics, Hamadan University of Medical Sciences, Hamadan, Iran.
⁶ Department of Immunology, Asthma and Allergy Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Sciences, Tehran, Iran.
⁷ Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
⁸ Hematology, Oncology and Stem Cell Transplantation Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
⁹ Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran.
¹⁰ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
¹¹ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran.
¹² Pediatric Infections Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹³ Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁴ Department of Pediatrics, 17th Shahrivar Children's Hospital, Guilan University of Medical Sciences, Rasht, Iran.
¹⁵ Department of Allergy and Clinical Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
¹⁶ Department of Pediatric Immunology and Allergy, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
¹⁷ Department of Allergy and Clinical Immunology, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁸ Department of Allergy and Clinical Immunology, Rasool e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
¹⁹ Department of Allergy and Clinical Immunology, Rasool e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran; Department of Pediatrics, Bo-Ali children's Hospital of Ardabil University of Medical Sciences, Ardabil, Iran.
²⁰ Acquired Immunodeficiency Research Center, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
²¹ Immunology and Allergy Department, Mofid Children's Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran.
²² Noncommunicable Pediatric Diseases Research Center, Amirkola Hospital, Babol University of Medical Sciences, Babol, Iran.
²³ Department of Pediatrics, Mazandaran University of Medical Sciences, Sari, Iran.
²⁴ Department of Immunology, Bahrami Hospital, Tehran University of Medical Sciences, Tehran, Iran.
²⁵ Department of Immunology and Allergy, Golestan University of Medical Sciences, Gorgan, Iran.
²⁶ Department of Pediatrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
²⁷ Allergy and Clinical Immunology Department, Bushehr University of Medical Science, School of Medicine, Bushehr, Iran.
²⁸ Cellular & Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
²⁹ Department of Pediatrics, Kermanshah University of Medical Sciences, Kermanshah, Iran.
³⁰ Department of Pediatrics, Qom University of Medical Sciences, Qom, Iran.
³¹ Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
³² Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
³³ School of Advanced Technologies in Medicine, Department of Medical Biotechnology, Tehran University of Medical Sciences, Tehran, Iran.
³⁴ Cellular and Molecular Research Center & Department of Anatomy and Neuroscience, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
³⁵ Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates.
³⁶ Study Center for Primary Immunodeficiencies, AP-HP, Necker Enfants Malades Hospital, Paris, France.
³⁷ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
³⁸ Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
³⁹ Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
⁴⁰ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran. Electronic address: aghamohammadi@tums.ac.ir.

PMID: 28916186
DOI: 10.1016/j.jaci.2017.06.049

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

Hassan Abolhassani et al. J Allergy Clin Immunol. 2018 Apr.

. 2018 Apr;141(4):1450-1458.

doi: 10.1016/j.jaci.2017.06.049. Epub 2017 Sep 12.

Authors

Affiliations

¹ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
² Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
³ Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute of Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
⁴ Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
⁵ Department of Pediatrics, Hamadan University of Medical Sciences, Hamadan, Iran.
⁶ Department of Immunology, Asthma and Allergy Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Sciences, Tehran, Iran.
⁷ Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
⁸ Hematology, Oncology and Stem Cell Transplantation Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
⁹ Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran.
¹⁰ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
¹¹ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran.
¹² Pediatric Infections Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹³ Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁴ Department of Pediatrics, 17th Shahrivar Children's Hospital, Guilan University of Medical Sciences, Rasht, Iran.
¹⁵ Department of Allergy and Clinical Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
¹⁶ Department of Pediatric Immunology and Allergy, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
¹⁷ Department of Allergy and Clinical Immunology, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁸ Department of Allergy and Clinical Immunology, Rasool e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.
¹⁹ Department of Allergy and Clinical Immunology, Rasool e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran; Department of Pediatrics, Bo-Ali children's Hospital of Ardabil University of Medical Sciences, Ardabil, Iran.
²⁰ Acquired Immunodeficiency Research Center, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
²¹ Immunology and Allergy Department, Mofid Children's Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran.
²² Noncommunicable Pediatric Diseases Research Center, Amirkola Hospital, Babol University of Medical Sciences, Babol, Iran.
²³ Department of Pediatrics, Mazandaran University of Medical Sciences, Sari, Iran.
²⁴ Department of Immunology, Bahrami Hospital, Tehran University of Medical Sciences, Tehran, Iran.
²⁵ Department of Immunology and Allergy, Golestan University of Medical Sciences, Gorgan, Iran.
²⁶ Department of Pediatrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
²⁷ Allergy and Clinical Immunology Department, Bushehr University of Medical Science, School of Medicine, Bushehr, Iran.
²⁸ Cellular & Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
²⁹ Department of Pediatrics, Kermanshah University of Medical Sciences, Kermanshah, Iran.
³⁰ Department of Pediatrics, Qom University of Medical Sciences, Qom, Iran.
³¹ Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
³² Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
³³ School of Advanced Technologies in Medicine, Department of Medical Biotechnology, Tehran University of Medical Sciences, Tehran, Iran.
³⁴ Cellular and Molecular Research Center & Department of Anatomy and Neuroscience, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
³⁵ Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates.
³⁶ Study Center for Primary Immunodeficiencies, AP-HP, Necker Enfants Malades Hospital, Paris, France.
³⁷ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
³⁸ Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
³⁹ Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
⁴⁰ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran, and the University of Medical Science, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran. Electronic address: aghamohammadi@tums.ac.ir.

PMID: 28916186
DOI: 10.1016/j.jaci.2017.06.049

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 patients with CIDs 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 nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients.

Results: 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.

Conclusions: 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.

Keywords: Combined immunodeficiencies; next-generation DNA sequencing; targeted gene panel sequencing; whole-exome sequencing.

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

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

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