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

Hassan Abolhassani; Janet Chou; Wayne Bainter; Craig D. Platt; Mahmood Tavassoli; Tooba Momen; Marzieh Tavakol; Mohammad Hossein Eslamian; Mohammad Gharagozlou; Masoud Movahedi; Mohsen Ghadami; Amir Ali Hamidieh; Gholamreza Azizi; Reza Yazdani; Mohsen Afarideh; Alireza Ghajar; Arash Havaei; Zahra Chavoshzadeh; Seyed Alireza Mahdaviani; Taher Cheraghi; Nasrin Behniafard; Reza Amin; Soheila Aleyasin; Reza Faridhosseini; Farahzad Jabbari-Azad; Mohammamd Nabavi; Mohammad Hassan Bemanian; Saba Arshi; Rasol Molatefi; Roya Sherkat; Mahboubeh Mansouri; Mehrnaz Mesdaghi; Delara Babaie; Iraj Mohammadzadeh; Javad Ghaffari; Alireza Shafiei; Najmeddin Kalantari; Hamid Ahanchian; Maryam Khoshkhui; Habib Soheili; Abbas Dabbaghzadeh; Afshin Shirkani; Rasoul Nasiri Kalmarzi; Seyed Hamidreza Mortazavi; Javad Tafaroji; Abbas Khalili; Javad Mohammadi; Babak Negahdari; Mohammad Taghi Joghataei; Basel K. al-Ramadi; Capucine Picard; Nima Parvaneh; Nima Rezaei; Talal A. Chatila; Michel J. Massaad; Sevgi Keles; Lennart Hammarström; Raif S. Geha; Asghar Aghamohammadi

doi:10.1016/j.jaci.2017.06.049

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

Hassan Abolhassani, Janet Chou, Wayne Bainter, Craig D. Platt, Mahmood Tavassoli, Tooba Momen, Marzieh Tavakol, Mohammad Hossein Eslamian, Mohammad Gharagozlou, Masoud Movahedi, Mohsen Ghadami, Amir Ali Hamidieh, Gholamreza Azizi, Reza Yazdani, Mohsen Afarideh, Alireza Ghajar, Arash Havaei, Zahra Chavoshzadeh, Seyed Alireza Mahdaviani, Taher CheraghiNasrin Behniafard, Reza Amin, Soheila Aleyasin, Reza Faridhosseini, Farahzad Jabbari-Azad, Mohammamd Nabavi, Mohammad Hassan Bemanian, Saba Arshi, Rasol Molatefi, Roya Sherkat, Mahboubeh Mansouri, Mehrnaz Mesdaghi, Delara Babaie, Iraj Mohammadzadeh, Javad Ghaffari, Alireza Shafiei, Najmeddin Kalantari, Hamid Ahanchian, Maryam Khoshkhui, Habib Soheili, Abbas Dabbaghzadeh, Afshin Shirkani, Rasoul Nasiri Kalmarzi, Seyed Hamidreza Mortazavi, Javad Tafaroji, Abbas Khalili, Javad Mohammadi, Babak Negahdari, Mohammad Taghi Joghataei, Basel K. al-Ramadi, Capucine Picard, Nima Parvaneh, Nima Rezaei, Talal A. Chatila, Michel J. Massaad, Sevgi Keles, Lennart Hammarström, Raif S. Geha, Asghar Aghamohammadi

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1450-1458
Number of pages	9
Journal	Journal of Allergy and Clinical Immunology
Volume	141
Issue number	4
DOIs	https://doi.org/10.1016/j.jaci.2017.06.049
Publication status	Published - Apr 2018

Keywords

Combined immunodeficiencies
next-generation DNA sequencing
targeted gene panel sequencing
whole-exome sequencing

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2017.06.049

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Abolhassani, H., Chou, J., Bainter, W., Platt, C. D., Tavassoli, M., Momen, T., Tavakol, M., Eslamian, M. H., Gharagozlou, M., Movahedi, M., Ghadami, M., Hamidieh, A. A., Azizi, G., Yazdani, R., Afarideh, M., Ghajar, A., Havaei, A., Chavoshzadeh, Z., Mahdaviani, S. A., ... Aghamohammadi, A. (2018). Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. Journal of Allergy and Clinical Immunology, 141(4), 1450-1458. https://doi.org/10.1016/j.jaci.2017.06.049

Abolhassani, H, Chou, J, Bainter, W, Platt, CD, Tavassoli, M, Momen, T, Tavakol, M, Eslamian, MH, Gharagozlou, M, Movahedi, M, Ghadami, M, Hamidieh, AA, Azizi, G, Yazdani, R, Afarideh, M, Ghajar, A, Havaei, A, Chavoshzadeh, Z, Mahdaviani, SA, Cheraghi, T, Behniafard, N, Amin, R, Aleyasin, S, Faridhosseini, R, Jabbari-Azad, F, Nabavi, M, Bemanian, MH, Arshi, S, Molatefi, R, Sherkat, R, Mansouri, M, Mesdaghi, M, Babaie, D, Mohammadzadeh, I, Ghaffari, J, Shafiei, A, Kalantari, N, Ahanchian, H, Khoshkhui, M, Soheili, H, Dabbaghzadeh, A, Shirkani, A, Nasiri Kalmarzi, R, Mortazavi, SH, Tafaroji, J, Khalili, A, Mohammadi, J, Negahdari, B, Joghataei, MT, al-Ramadi, BK, Picard, C, Parvaneh, N, Rezaei, N, Chatila, TA, Massaad, MJ, Keles, S, Hammarström, L, Geha, RS & Aghamohammadi, A 2018, 'Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency', Journal of Allergy and Clinical Immunology, vol. 141, no. 4, pp. 1450-1458. https://doi.org/10.1016/j.jaci.2017.06.049

@article{46ca18a8ad37487c97d328743af050b3,

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

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",

author = "Hassan Abolhassani and Janet Chou and Wayne Bainter and Platt, {Craig D.} and Mahmood Tavassoli and Tooba Momen and Marzieh Tavakol and Eslamian, {Mohammad Hossein} and Mohammad Gharagozlou and Masoud Movahedi and Mohsen Ghadami and Hamidieh, {Amir Ali} and Gholamreza Azizi and Reza Yazdani and Mohsen Afarideh and Alireza Ghajar and Arash Havaei and Zahra Chavoshzadeh and Mahdaviani, {Seyed Alireza} and Taher Cheraghi and Nasrin Behniafard and Reza Amin and Soheila Aleyasin and Reza Faridhosseini and Farahzad Jabbari-Azad and Mohammamd Nabavi and Bemanian, {Mohammad Hassan} and Saba Arshi and Rasol Molatefi and Roya Sherkat and Mahboubeh Mansouri and Mehrnaz Mesdaghi and Delara Babaie and Iraj Mohammadzadeh and Javad Ghaffari and Alireza Shafiei and Najmeddin Kalantari and Hamid Ahanchian and Maryam Khoshkhui and Habib Soheili and Abbas Dabbaghzadeh and Afshin Shirkani and {Nasiri Kalmarzi}, Rasoul and Mortazavi, {Seyed Hamidreza} and Javad Tafaroji and Abbas Khalili and Javad Mohammadi and Babak Negahdari and Joghataei, {Mohammad Taghi} and al-Ramadi, {Basel K.} and Capucine Picard and Nima Parvaneh and Nima Rezaei and Chatila, {Talal A.} and Massaad, {Michel J.} and Sevgi Keles and Lennart Hammarstr{\"o}m and Geha, {Raif S.} and Asghar Aghamohammadi",

note = "Funding Information: Supported by grant 91002997 from the Iranian National Science Foundation (to A.A.), the Alex and Eva Wallstr{\"o}m Foundation (to H.A.), the Division of Immunology at Boston Children's Hospital, and the Perkin Foundation (to R.S.G. and J.C.). Funding Information: Disclosure of potential conflict of interest: J. Chou is employed by Boston Children's Hospital and has grants/grants pending with the National Institute of Allergy and Infectious Diseases. B. K. al-Ramadi has received payment for lectures, including service on speakers' bureaus for MSD. T. Chatila has received a grant from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: {\textcopyright} 2017 American Academy of Allergy, Asthma & Immunology",

year = "2018",

month = apr,

doi = "10.1016/j.jaci.2017.06.049",

language = "English",

volume = "141",

pages = "1450--1458",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "4",

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TY - JOUR

T1 - Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency

AU - Abolhassani, Hassan

AU - Chou, Janet

AU - Bainter, Wayne

AU - Platt, Craig D.

AU - Tavassoli, Mahmood

AU - Momen, Tooba

AU - Tavakol, Marzieh

AU - Eslamian, Mohammad Hossein

AU - Gharagozlou, Mohammad

AU - Movahedi, Masoud

AU - Ghadami, Mohsen

AU - Hamidieh, Amir Ali

AU - Azizi, Gholamreza

AU - Yazdani, Reza

AU - Afarideh, Mohsen

AU - Ghajar, Alireza

AU - Havaei, Arash

AU - Chavoshzadeh, Zahra

AU - Mahdaviani, Seyed Alireza

AU - Cheraghi, Taher

AU - Behniafard, Nasrin

AU - Amin, Reza

AU - Aleyasin, Soheila

AU - Faridhosseini, Reza

AU - Jabbari-Azad, Farahzad

AU - Nabavi, Mohammamd

AU - Bemanian, Mohammad Hassan

AU - Arshi, Saba

AU - Molatefi, Rasol

AU - Sherkat, Roya

AU - Mansouri, Mahboubeh

AU - Mesdaghi, Mehrnaz

AU - Babaie, Delara

AU - Mohammadzadeh, Iraj

AU - Ghaffari, Javad

AU - Shafiei, Alireza

AU - Kalantari, Najmeddin

AU - Ahanchian, Hamid

AU - Khoshkhui, Maryam

AU - Soheili, Habib

AU - Dabbaghzadeh, Abbas

AU - Shirkani, Afshin

AU - Nasiri Kalmarzi, Rasoul

AU - Mortazavi, Seyed Hamidreza

AU - Tafaroji, Javad

AU - Khalili, Abbas

AU - Mohammadi, Javad

AU - Negahdari, Babak

AU - Joghataei, Mohammad Taghi

AU - al-Ramadi, Basel K.

AU - Picard, Capucine

AU - Parvaneh, Nima

AU - Rezaei, Nima

AU - Chatila, Talal A.

AU - Massaad, Michel J.

AU - Keles, Sevgi

AU - Hammarström, Lennart

AU - Geha, Raif S.

AU - Aghamohammadi, Asghar

N1 - Funding Information: Supported by grant 91002997 from the Iranian National Science Foundation (to A.A.), the Alex and Eva Wallström Foundation (to H.A.), the Division of Immunology at Boston Children's Hospital, and the Perkin Foundation (to R.S.G. and J.C.). Funding Information: Disclosure of potential conflict of interest: J. Chou is employed by Boston Children's Hospital and has grants/grants pending with the National Institute of Allergy and Infectious Diseases. B. K. al-Ramadi has received payment for lectures, including service on speakers' bureaus for MSD. T. Chatila has received a grant from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: © 2017 American Academy of Allergy, Asthma & Immunology

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Combined immunodeficiencies

KW - next-generation DNA sequencing

KW - targeted gene panel sequencing

KW - whole-exome sequencing

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DO - 10.1016/j.jaci.2017.06.049

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AN - SCOPUS:85031108441

SN - 0091-6749

VL - 141

SP - 1450

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JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 4

ER -

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

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