Genotype–Phenotype Correlations in Patients with STAT1 Gain-of-Function Mutations: A Case Series
Abstract
STAT1 gain-of-function (GOF) mutations result in a broad clinical spectrum characterized by complex phenotypic manifestations. In addition to the hallmark chronic mucocutaneous candidiasis (CMC), patients are predisposed to bacterial and viral infections, autoimmunity, endocrinopathies, lymphoproliferative disorders, and malignancies. Severe complications, including invasive infections, cerebral aneurysms, and malignancies, are significant predictors of poor outcomes. Understanding genotype–phenotype correlations is critical for optimizing management in this challenging patient population.
We conducted a retrospective review of electronic medical records for five patients diagnosed with STAT1 GOF mutations at Mayo Clinic, Rochester, MN. This case series included data on demographics, clinical history, immunologic evaluations, genetic testing results, disease manifestations, treatments, and outcomes.
The cohort included five patients (1 male, 4 females; mean age at diagnosis: 21.7 years) with heterozygous STAT1 GOF mutations. Three patients had c.1154C>T (p.Thr385Met), one had c.1310C>T (p.Thr437Ile) in the DNA-binding domain (DBD), and one had c.856A>G (p.Lys286Glu) in the coiled-coil domain (CCD). Universal features included CMC and recurrent sinopulmonary infections. Patients with c.1154C>T presented with early-onset infections, severe autoimmunity (e.g., pancytopenia and enteropathy), and bronchiectasis, requiring ruxolitinib in all three cases. The patient with c.1310C>T…
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