Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Fabre, Alexandre; Marchal, Sarah; Barlogis, Vincent; Mari, Bernard; Barbry, Pascal; Rohrlich, Pierre‐Simon; Forbes, Lisa R.; Vogel, Tiphanie P.; Giovannini‐Chami, Lisa

doi:10.1016/j.jaip.2019.02.018

Cited by 153 publications

(174 citation statements)

References 34 publications

(247 reference statements)

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“…The third patient had underlying CAEBV and developed Grade IV GVHD six months post‐transplant and died from complications of intensive immunosuppression. Of note, all three patients that died had HLH associated with conditions that have been associated with poor outcomes after HSCT, namely STAT3 GOF, systemic JIA and CAEBV (Snowden et al , ; Snowden et al , ; Sawada & Inoue, ; Fabre et al , ).…”

Section: Patient Characteristics and Outcomementioning

confidence: 99%

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH

et al. 2020

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Section: Patient Characteristics and Outcomementioning

confidence: 99%

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH

et al. 2020

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“…In this study, we performed WES on a selected subgroup of CVID patients with a classical infectious phenotype combined with autoimmunity, inflammation, and/or malignancy and identified probable and possible disease-causing candidate gene variants through a targeted bioinformatics analysis, focusing on 564 primary immunodeficiency-related genes. This approach resulted in the identification of two previously described gene variants in NFKB1 (21,32), nine novel variants, including variants in STAT3, TNFAIP3, IL-17F, IRAK4, TTC37, DDX41, NLRC3, TNFRSF1A, and PLCG2 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(34)(35)(36) associated with different states of immune dysregulation but not previously associated with CVID, and with possible probable diseasecausing impact according to bioinformatics. Altogether, we identified probable/possible disease-causing variants in nine of 20 patients in this CVID subpopulation.…”

Section: Discussionmentioning

confidence: 99%

“…It is localized in the N-terminal domain, in which gain-of-function (GOF) STAT3 variants have been described (22). A recent overview of patients with STAT3 GOF describes the general phenotype of the patients, including autoimmune cytopenias, lymphadenopathy, enteropathy, and interstitial lung disease, while immunodeficiency is not predominant (34). Patient 10 was diagnosed with CVID 10 years ago and experienced severe disease with significant hepatosplenomegaly, pancytopenia with persistent CD4 lymphopenia, and pneumonias.…”

Section: Identified Variantsmentioning

confidence: 99%

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

et al. 2020

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Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

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“…Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent two sides of the same coin [1] . Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency [2][3][4][5] . Systemic lupus erythematosus (SLE; OMIM 152700) is a prototype autoimmune disease with a strong genetic component, characterized by differences in autoantibody profile, serum cytokines, and a multisystem involvement commonly affecting the skin, renal, musculoskeletal, and hematopoietic systems [6] .…”

Section: Introductionmentioning

confidence: 99%

“…On the molecular level, RALD is defined by somatic mutations of either NRAS or KRAS gene in a subset of hematopoietic cells [3,9] . Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (OMIM 615952) is a new clinical entity characterized by early-onset poly-autoimmunity, lymphoproliferation, and growth failure [4] . Cell-surface interleukin-2 receptor α (IL-2RA, CD25) expression is critical for maintaining immune function and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Liu

et al. 2019

Preprint

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Purpose: Systemic lupus erythematosus (SLE) is a rare autoimmune disease, which is more severe in case of pediatric onset. This may be due to greater involvement of genetic factors compared with adult forms. In recent years, multiple monogenic diseases with early-onset autoimmunity and lymphoproliferation have been identified, such as Autoimmune lymphoproliferative syndrome (ALPS), RAS-associated autoimmune leukoproliferative disease (RALD), Signal transducer and activator of transcription 3 (STAT3) Gain-of-Function (GOF) syndrome and Interleukin-2 receptor α (IL2RA) deficiency. Therefore, we performed whole exome sequencing in SLE children with lymphoproliferation to identify genes associated with these conditions. Methods: We enrolled seven SLE patients with lymphoproliferation, which are from different families. Demographic data, clinical manifestations, laboratory and histopathological findings, treatment, and outcome were documented. WES was performed in seven cases and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by Western blot. Results: Four patients were male, and three were female. No consanguinity was reported within the seven families. The average age at onset was 5.0 years (range from 1.2 to 10.0 years). The most common features were renal (7/7 patients), hematological (6/7 patients) involvement, and recurrent fever (6/7patients) while only two patients presented with skin involvement. Antinuclear antibodies ( ANA) at a titer of ≥1:320 was positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from four patients, at levels ranging from 8.8% to 42.8% in variant tissues, that was absent from their parents. BCL-2-Interacting Mediator of Cell Death (BIM) levels in peripheral blood mononuclear cells (PBMCs) from four patients were markedly reduced, whereas those in control was normal. Another two mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in PIK3CD gene, were detected in two patients, respectively. Conclusion: SLE is a novel phenotype of germline mutation in PI3CKD gene and somatic mutation in NRAS gene. These genes, NRAS , TNFAIP3 and PIK3CD , should be considered as candidates for SLE children with lymphoproliferation. If patients with SLE and lymphoproliferation presented with renal and hematological involvement, and recurrent fever, they need gene testing, especially in male patient.

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Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Cited by 153 publications

References 34 publications

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

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