| Description: |
STAT2 is a transcription factor activated by type I and III interferons. We report 23 patients with loss of function variants causing autosomal recessive (AR), complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells display impaired expression of interferon stimulated genes and impaired control of in-vitro viral infections. Clinical manifestations from early childhood onward include severe adverse reaction to live attenuated viral vaccines (LAV, 12/17 patients) and severe viral infections (10/23 patients), particularly critical influenza pneumonia (6 patients), critical COVID-19 pneumonia (1 patient), and herpes simplex encephalitis (1 patient). The patients display various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attests to unresolved viral infection in the absence of STAT2-dependent type I and III IFN immunity (7 patients). Transcriptomic analysis reveals that circulating monocytes, neutrophils, and CD8 memory T cells contribute to this inflammation. Eight patients died (35%, 2 months-7 years): one of HSV-1 encephalitis, one of fulminant hepatitis, and six of heart failure during a febrile illness with no identified etiology. 15 patients remain alive (5-40 years). AR complete STAT2 deficiency underlies severe viral diseases, with half of the patients surviving into teenage years or adulthood. |