Immune dysregulation diseases caused by somatic mutations

Immune dysregulation diseases represent a heterogeneous group of disorders resulting from aberrant immune system function. Genetic research in this field has traditionally focused on germline mutations. However, advances in high-throughput sequencing have revealed that somatic mutations represent an important and previously underrecognized pathogenic mechanism in monogenic immune dysregulation disorders, including autoinflammatory diseases, autoimmune disorders, and immunodeficiencies. This insight expands our understanding of the genetic basis of immune dysregulation.To date, approximately 20 genes have been implicated as disease-causing through somatic mutations. These mutations are widely distributed across crucial pathways involved in immune responses and cell fate, including cell death, RAS signaling, inflammasome activation, type I interferon responses, Toll-like receptor pathways, and ubiquitin-mediated processes. Among these disorders, there is considerable variation in the variant allele frequency, molecular mechanisms, and affected immune cell populations. This heterogeneity underscores the exquisite precision and complexity inherent to the immune system’s regulatory networks. Furthermore, these somatic mutations provide insights into the mechanisms maintaining and disrupting immune homeostasis.The clinical detection and diagnosis of diseases caused by somatic mutations remain challenging. As these somatic mutations are present in only a fraction of cells, their allelic frequency may be low and often fall below the detection threshold of conventional genetic testing, increasing the risk of falsenegative results. In addition, limited clinical awareness of somatic mutations in monogenic disorders, together with a lack of standardized, efficient, and cost-effective detection workflows and interpretive guidelines, further complicates diagnosis. Collectively, these limitations hinder the ability to accurate molecular diagnosis in a substantial number of patients and consequently impede the development and implementation of precise, targeted treatment strategies.Somatic mutations provide critical insights into the pathogenesis of late-onset immune dysregulation, sporadic disease, atypical clinical phenotypes, and conditions with incomplete penetrance. Their recognition has substantially improved the genetic diagnostic yield and therapeutic outcomes in patients with immune dysregulation, while deepening our understanding of the precise regulatory mechanisms governing immune homeostasis. Moreover, the study of somatic mutations offers a valuable framework for identifying novel drug targets and advancing precision medicine–based therapeutic strategies.This review aims to summarize the recent advances in the study of somatic mutations in immune dysregulation diseases. We discuss the expanding spectrum of causative genes, insights into pathogenic mechanisms, emerging therapeutic strategies, and the critical challenges associated with detection technologies. This review aims to provide a conceptual and practical framework for understanding the role of somatic mutations in immune dysregulation. Continued advances in detection technologies, functional interpretation, and clinical integration are expected to further expand the diagnostic and therapeutic landscape of these complex disorders.