Landscape of Somatic Mutations in a Large Cohort of Chinese Patients With Immune Dysregulations

作者：Jiemin Fu, Qiang Fu, Jun Wang, Qintao Wang, Liang Zhang, Huihui Chi, Lei Zhang, Li Sun, Ying Huang, Tingyan He, Yuhao Yao, Xu Han, Shuangyue Ma, Changli Liu, Lin Liu, Xiang Chen, Shihao Wang, Hong Jiang, Wenjie Zheng, Shusen Zheng, Qiao Ye, Yang Du, Li Guo, Jing Zhu, Guomin Li, M. Zhang, Zhimiao Lin, Xiuli Ju, Yongmei Han, W. Chen, Jin Lin, Jing Xue, Hao Cheng, Caiqing Xu, Lin Huang, Longyan Qin, Jiashun Zeng, Yifang Mei, Tingting Yan, Qianying Lv, Yaoyao Shangguan, Cuifang Zheng, Xiaoliang He, Hongfei Liu, Xiaoli Chen, Hua Xie, Xiaodong Li, Ying Jin, Jiahui Peng, Bo Lin, Yao Huang, Xiuli Wang, Xiaoxi Yang, Nan Jiang, Wei Wang, Tong Wu, Dongze Wu, Yun Zhu, Yakai Fu, Jie Chen, Ran Wang, Xiaojun Liu, Dongbin Jiang, Huijie Xiao, Baige Su, Benshan Zhang, Fengqi Wu, Qiongyi Hu, Chengde Yang, Meiping Lu, S. Ye, Min Shen, Hongmei Song, Jun Cheng, Jun Yang, Zhihong Liu, Xiaomin Yu, Qing Zhou · 发表于：Arthritis & Rheumatology · 年份：2026 · DOI：10.1002/art.70126 · 被引用次数：2 · 研究领域：Immunodeficiency and Autoimmune Disorders、Inflammasome and immune disorders、Otitis Media and Relapsing Polychondritis

OBJECTIVE: This study aims to characterize pathogenic somatic mutations in patients with autoinflammatory or autoimmune diseases lacking disease-causing germline mutations, explore their contribution to disease pathogenesis and progression, and evaluate their implications for diagnosis and targeted therapy. METHODS: We performed a systematic analysis of somatic mutations in a selected panel of 185 immune-related genes in 2,912 patients with autoinflammatory or autoimmune diseases, recruited from 41 medical centers across China, who were previously negative for germline mutations based on whole-exome sequencing. RESULTS: We identified both previously reported and novel somatic mutations in genes such as UBA1, KRAS, and NLRP3. Pathogenic somatic mutations in TNFAIP3 were discovered first in patients with autoinflammatory diseases. The pathogenic somatic mutation detection rate was 1.35% in adults and 0.97% in children, emphasizing the importance of genetic diagnosis and novel gene discovery for somatic mutations. In addition, somatic mutations in Ras-related genes were identified in seven patients, and 39 clonal hematopoiesis-associated mutations were identified in 36 adult patients. Moreover, myeloid cells harboring somatic mutations expanded during disease flare and reduced during remission. Disregarding the dynamic elevation of the variant allele fraction during disease progression led to therapeutic failure. CONCLUSION: This study delineated the genetic landscape of pathoge...