Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases

Abstract

Autoinflammatory diseases (AIDs) comprise a heterogeneous group of disorders caused by dysregulated innate immune responses. Over the past decade, advances in next-generation sequencing have markedly expanded the spectrum of disease-associated genes and revealed novel genetic mechanisms, including somatic mosaicism and non-coding variation, while also highlighting the potential contribution of multilocus rare-variant burden and modifier effects. However, the rapid pace of gene discovery has also introduced new challenges in variant interpretation, disease classification, and clinical diagnosis. This review synthesizes findings from 100 publications published between 2014 and 2026 and summarizes recent genetic advances according to the major molecular pathways involved in autoinflammatory diseases. We review newly identified disease genes and pathogenic variants affecting ubiquitination and NF-κB regulation, inflammasome activation, type I interferon signaling, CDC42-mediated immune regulation, proteasome dysfunction, programmed cell death, cytokine signaling, and other emerging pathways. We further discuss recent insights into genotype–phenotype correlations, low-level somatic mosaicism, atypical gain- and loss-of-function variants, and multilocus rare-variant burden, including possible oligogenic or modifier effects. In addition, we summarize advances in genetic testing strategies, the increasing role of functional validation in interpreting variants of uncertain significance, and current challenges in establishing disease causality for newly proposed candidate genes. Finally, we compare the strength of evidence supporting recent genetic discoveries, highlight areas of ongoing controversy, and discuss future directions for improving molecular diagnosis and precision medicine in autoinflammatory diseases. By integrating recent discoveries within a pathway-based framework, this review provides an updated and clinically relevant overview of the rapidly evolving genetic landscape of AIDs.