3 research outputs found
Phenomic analysis of chronic granulomatous disease reveals more severe integumentary infections in X-Linked compared with autosomal recessive chronic granulomatous disease
BACKGROUND : Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI),
characterised by recurrent bacterial and fungal infections. It is inherited either in an Xlinked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of
phenotypes expressed, and its study allows us to generate new knowledge of the
disease. The objective of the study is to reveal the phenomic differences between XL
and AR-CGD by using Human Phenotype Ontology (HPO) terms. METHODS : We collected data on 117 patients with genetically diagnosed CGD from Asia
and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only
90 patients with sufficient clinical information were included for phenomic analysis. We
used HPO terms to describe all phenotypes manifested in the patients.
RESULTS : XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and
genetic diagnosis compared with AR-CGD patients. The integument and central nervous
system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal
abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with
XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as
their first manifestation. Among our CGD patients, lung was the most frequently infected
organ, with gastrointestinal system and skin ranking second and third, respectively.
Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the
most frequent pathogens to be found.
CONCLUSION : Phenomic analysis confirmed that XL-CGD patients have more recurrent
and aggressive infections compared with AR-CGD patients. Various phenotypic
differences listed out can be used as clinical handles to distinguish XL or AR-CGD
based on clinical features.The Society for Relief of Disabled Children and Jeffrey Modell Foundation.https://www.frontiersin.org/journals/immunologydm2022Paediatrics and Child Healt
Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease
STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder
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Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease
STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder