关键词: 系统性红斑狼疮, 狼疮肾炎, 外显不全, DNA 甲基化

Abstract: Objective:To investigate the epigenetic mechanisms underlying phenotypic discordance in monozygotic twins carrying the identical pathogenic DDX58 p.R109C (c.325C>T) mutation. Methods:Following the collection of peripheral blood from the discordant twins and subsequent DNA extraction,whole-genome bisulfite sequencing (WGBS) was employed to identify differentially methylated regions (DMR). Subsequently,pathway enrichment and functional analysis were performed on genes associated with promoter DMR (DAG). Results:Compared with her unaffected sister,the proband with lupus nephritis (LN) exhibited 47054 DMR in peripheral blood,consisting of 29058 hypermethylated and 17996 hypomethylated DMR.Functional analysis revealed that genes associated with the 1659 hypermethylated DMRs in promoters were primarily involved in ubiquitin-mediated proteolysis and leukocyte transendothelial migration.In contrast,genes associated with 1922 hypomethylated DMRs were enriched in immune and inflammatory pathways,including cAMP signaling,T/B cell receptor activation,and Th17 cell differentiation. Conclusion:This study reveals that DNA methylation modification may be a key factor mediating clinical phenotypic heterogeneity,thereby providing mechanistic insights into the incomplete penetrance of monogenic lupus from an epigenetic perspective.

Key words: systemic lupus erythematosus,lupus nephritis,incomplete penetrance,DNA methylation