Objectives Still's Disease represents a prototypical polygenic systemic autoinflammatory diseases (SAIDs), characterized by recurrent systemic inflammation and dysregulation of innate immunity. Despite extensive clinical characterization, familial clustering Still's disease remains unreported. This study investigates a novel variant underlying a distinct Still's disease‐like autoinflammatory syndrome. Methods Whole‐exome sequencing was performed in a three‐generation family with three affected individuals. Functional analyses were conducted to assess the impact of the RIPK3 p.Q134K variant on kinase activity, necroptosis and inflammatory signaling. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and in vitro cytokine assays were used to characterize inflammatory responses. Results A heterozygous RIPK3 p.Q134K variant was identified in all affected individuals. Functional analyses demonstrated that this variant exhibits gain‐of‐function activity, characterized by enhanced RIPK3 kinase activity and increased RIPK3 self‐association, which in turn promote MLKL phosphorylation and necroptosis. RNA sequencing of PBMCs from one patient revealed marked upregulation of NF‐κB and MAPK signaling pathways and elevated expression of IL‐6, and TNF‐α, which was effectively suppressed by pharmacological inhibition of RIPK3. Conclusions This study describes a familial Still's disease‐like autoinflammatory syndrome caused by a gain‐of‐function RIPK3 variant. Our findings establish aberrant RIPK3 activation as a driver of autoinflammation and expand the spectrum of human RIPK3‐associated diseases.
Chen et al. (Thu,) studied this question.