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Published on: August 20, 2019
Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis
Oded Breuer1, Hagit Daum2, Malena Cohen-Cymberknoh1
1Department of Pediatrics and Pediatric Pulmonary Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Background:
In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown.
Objective:
To investigate the cause and mechanism predisposing a patient to severe bronchiectasis.
Methods:
A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping.
Results:
The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen.
Conclusions:
Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.
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