De novo mutations promote inflammation in children with STAT3 gain-of-function syndrome by affecting IL-1β expression

Abstract

Background STAT3 Gain-of-Function (GOF) syndrome characterized by early onset autoimmunity and primary immune regulatory disorder, the immunological mechanisms remain poorly understood. Employing whole-genome sequencing within familial trios, our study elucidated the pivotal role of de novo mutations in genetic diseases. Results We identified 37 high-risk pathogenic loci affecting 23 genes, notably including the novel STAT3c.508G>A mutation. Furthermore, significant downregulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c, was observed. Conclusion These findings not only contribute to our understanding of the pathogenesis but also highlight potential therapeutic strategies. Our study suggests that combined JAK inhibitors and IL-6R antagonists could offer promising avenues for mitigating the severity of these genetic disorders.