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

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, Mohammad; 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; Kalmarzi, Rasoul Nasiri; Mortazavi, Seyed Hamidreza; Tafaroji, Javad; Khalili, Abbas; Mohammadi, Javad; Negahdari, Babak; Joghataei, Mohammad-Taghi; al-Ramadi, Basel K.; Pïcard, Capucine; Parvaneh, Nima; Rezaei, Nima; Chatila, Talal A.; Massaad, Michel J.; Keleş, Sevgi; Hammarström, Lennart; Geha, Raif S.; Aghamohammadi, Asghar

doi:10.1016/j.jaci.2017.06.049

Cited by 78 publications

(88 citation statements)

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“…The mean target coverage resulted of 529 ± 169X (panel 1), 361 ± 97X (panel 2) and 417 ± 117X (panel 3) for Ion Torrent and 229 ± 25X for Haloplex panels (Supplementary Figure 2A). The mean target coverage for Ion Torrent panels was optimal as compared to recently published works in which a coverage of 335X was obtained (34). Indeed, the Ion Torrent expected coverage of the coding regions was 95.43% for panel 1 (SCID-CID), 94.13% for panel 2 (rare CID) and 97.2% for the panel 3 (Supplementary Tables 1-3).…”

Section: Target Enrichment Performance and Gene Coveragementioning

confidence: 67%

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

et al. 2019

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Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs . The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% ( n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

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Section: Target Enrichment Performance and Gene Coveragementioning

confidence: 67%

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

et al. 2019

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“…In this study, we reported characteristics of 19 patients with STAT3 and 16 with DOCK8 gene defects, among 129 patients with HIES. Although stepwise genetic evaluation using Sanger sequencing and TGS showed 58.3% diagnostic yield in the evaluated HIES patients (compared to 87.1% in other syndromic combined immunodeficiency), the recently discovered autosomal recessive gene ZNF34 was not included in our gene panel. Moreover, due to the possibility of the presence of novel gene defects in this group, they should undergo whole exome or whole genome sequencing.…”

Section: Discussionmentioning

confidence: 96%

“…26 the recently discovered autosomal recessive gene ZNF34 was not included in our gene panel. Moreover, due to the possibility of the presence of novel gene defects in this group, they should undergo whole exome or whole genome sequencing.…”

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confidence: 99%

The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long‐term follow‐up and genetic analysis

Tavassoli

Abolhassani

Yazdani

et al. 2019

Pediatric Allergy Immunology

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Background Hyper‐IgE syndromes (HIES) are distinct diseases characterized by recurrent cutaneous and lung infections, eczema, and elevated serum IgE level. Methods In this study, clinical manifestations, immunologic findings, and genetic studies of all patients with HIES in the Iranian national registry database were evaluated. Results A total of 129 HIES patients with a median age of 14.0 (9.0‐24.0) years were followed up for a total of 307.8 patient‐years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3‐deficient patients was higher than in patients with DOCK8 mutation (P = 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3‐deficient cases compared to patients with DOCK8 deficiency (P = 0.001 and P = 0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than in patients with DOCK8 gene mutation (P = 0.02). The eosinophils’ count was enhanced in patients with DOCK8 deficiency than in patients with STAT3 gene defects (P = 0.02). Conclusion Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency, investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities.

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“…However, no stop-gain mutations have been proven to cause Job’s syndrome, suggesting that the underlying mechanism in Job’s syndrome is not one of haploinsufficiency. Three individuals are heterozygous for a mutation that creates a premature stop, which has however not been proven to underlie haploinsufficiency and Job’s syndrome [78]. Interestingly, three families with mosaic mutations in multiple tissues have been described.…”

Section: Job’s Syndromementioning

confidence: 99%

Human hyper-IgE syndrome: singular or plural?

et al. 2018

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Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

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

Abstract: 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.

Cited by 78 publications

References 49 publications

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long‐term follow‐up and genetic analysis

Human hyper-IgE syndrome: singular or plural?

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