DNA‐Binding domain mutations confer severe outcome at an early age among STAT1 gain‐of‐function patients

Abstract Background STAT1 gain‐of‐function (GOF) is an immune dysregulatory disorder with poorly studied genotype‐phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA‐binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains. Methods Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non‐DBD mutations. We subsequently re‐analyzed mortality data from a large, previously‐published 274‐patient cohort by the International STAT1 GOF Study Group. Results While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non‐DBD patients. Our re‐evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations. Conclusion We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early‐onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.