Early-onset systemic lupus erythematosus (SLE) is frequently associated with a more severe phenotype and may be linked to monogenic causes in at least 10% of all juvenile SLE cases. Recent advances in immunogenetics have identified Mendelian variants linked to inborn errors of immunity, underlying SLE. Toll-like receptor 7 (TLR7), an endosomal RNA sensor, has emerged as a key contributor to lupus pathogenesis through aberrant activation. We report a novel P435S gain-of-function (GOF) variant in TLR7 identified in a female patient presenting with early-onset SLE, recurrent infection, and neuroinflammatory features. Functional assays demonstrated the gain-of-function effect, confirming its pathogenicity and supporting its role in disease onset and progression. To further define the clinical spectrum of TLR7 GOF-associated disease, we conducted a systematic review of 11 additional reported cases, highlighting shared and divergent phenotypic features. These findings expand the understanding of TLR7-mediated autoimmunity and underscore the importance of genetic screening in early-onset SLE with atypical features.
Tusseau et al. (Tue,) studied this question.