Novel STAT1 gain-of-function variants and treatment monitoring in a Chilean cohort

Introduction: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) cause an autosomal dominant immune disorder characterized by a variable clinical phenotype, including disseminated or recurrent infections, chronic mucocutaneous candidiasis, and autoimmunity. Janus kinase inhibitors (JAKi) and prophylactic anti-fungals are the main pharmacologic treatments. Some patients may require higher doses of JAKi. However, there are no clear biomarkers for proper dosing and indications are mainly based on clinical improvement. Objective disease biomarkers should be established. We describe the first STAT1 GOF Chilean cohort including three novel variants and describe their STAT1 phosphorylation and interferon signature (IFNsg) status.
Methods: In vitro assay in STAT1 deficient cells was used to confirm GOF of novel variants. STAT1 phosphorylation was determined by flow cytometry and type I IFNsg by RT-qPCR using blood samples from patients. These parameters were longitudinally assessed in one patient receiving increasing doses of a JAKi.
Results: Three STAT1 variants were novel and confirmed in vitro. IFNsg and STAT1 phosphorylation was elevated in all patients for whom samples were available: 5/6 patients for IFNsg and 3/6 patients for STAT1 phosphorylation. In one patient with STAT1 c.820C>T variant we observed the highest IFNsg during macrophage activation syndrome that prompted increasing dose of a JAKi. Despite clinical improvement on escalating JAKi dose, IFNsg remained elevated for this patient, suggesting the need for alternative biomarkers to guide clinical management. Two patients of the cohort underwent hematopoietic stem-cell transplantation (HSCT) and died.
Conclusion: Unfortunately, we found that the IFNsg was not a reliable biomarker for tracking disease progression or treatment response in STAT1 GOF. Overall, this work underscores the complexities of managing STAT1 GOF and emphasizes the importance of further research to implement reliable biomarkers in complicated clinical scenarios (including HSCT) in which clinical assessment may be confounding.

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Scroll to Top