Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Heterozygous STAT1 gain-of-function (GOF) mutations were discovered in 2011.
• These mutations are increasingly identified globally in patients with autosomal dominant chronic mucocutaneous candidiasis (AD CMC).
• The full clinical spectrum of STAT1 GOF mutations requires delineation.

Purpose of the Study:

• To delineate the clinical spectrum associated with heterozygous STAT1 gain-of-function (GOF) mutations.
• To record demographic data, clinical features, immunological parameters, treatment, and outcomes in affected individuals.

Main Methods:

• Enrolled 274 patients from 167 kindreds across 40 countries.
• Collected comprehensive demographic, clinical, immunological, treatment, and outcome data.
• Analyzed patient data to identify correlations and predictors of prognosis.

Main Results:

• 98% of patients presented with CMC, with a median onset at 1 year.
• High prevalence of bacterial (74%), viral (38%), invasive fungal (10%), and mycobacterial (6%) infections.
• Significant autoimmune manifestations (37%) including hypothyroidism and type 1 diabetes.
• Invasive infections, cerebral aneurysms, and cancers were key predictors of poor outcome.
• Low circulating interleukin-17A-producing T-cell counts were observed in most patients (82%).

Conclusions:

• STAT1 GOF mutations are the genetic basis for AD CMC.
• These mutations are associated with a broad spectrum of clinical features beyond CMC, including infections, autoimmune diseases, cerebral aneurysms, and carcinomas.
• STAT1 GOF mutations can confer a poor prognosis, emphasizing the need for comprehensive patient management and further research.