STAT2 R148 variant: A 16th-century founder mutation and clinical response to high-dose JAK inhibitor therapy.

Source: PubMed, NCBI / U.S. National Library of Medicine

STAT2 R148 variants cause severe type I interferonopathy by disrupting USP18-mediated negative feedback regulation. We studied two new Iranian patients homozygous forp.R148Q variant presenting with life-threatening neuroinflammation and respiratory failure. Patient 1 developed seizures, brain calcifications, and severe pneumonia, achieving dramatic improvement with high-dose ruxolitinib. Patient 2 presented with lymphadenopathy, encephalitis, and recurrent infections and died from respiratory failure at 8.5 years. Haplotype and principal component analysis (PCA) analysis revealed a founder variant originating ∼491 years ago in the Middle East/North African region. A review of five published cases and these two patients demonstrated constant neurological involvement and a high mortality rate. Early recognition and high-dose JAK inhibitor therapy may improve outcomes in this devastating but potentially treatable interferonopathy.