ABSTRACT:
Advances in genome and exome sequencing have revolutionized the understanding and management of autoimmune and autoinflammatory diseases, enabling earlier and more accurate diagnosis, especially for rare disorders. Conditions such as retinal vasculopathy with cerebral leukoencephalopathy (RVCL), STING-associated vasculopathy with onset in infancy (SAVI), COPA syndrome, and VEXAS syndrome illustrate how genetic discoveries are reshaping rheumatology. Many of these disorders converge on the TREX1–cGAS–STING pathway, underscoring shared molecular mechanisms despite distinct clinical presentations. Next-generation sequencing, combined with careful clinical phenotyping, has revealed novel pathogenic variants, facilitated genetic counseling, and opened avenues for precision medicine, including targeted cytokine inhibitors, gene-editing tools, and small molecules modulating cGAS–STING signaling. However, therapeutic challenges persist due to incomplete understanding of disease mechanisms, small patient populations, and the limitations of current immunomodulatory treatments. Animal models and in vitro studies of patient-derived cells are proving essential for translating genetic insights into viable therapies. A shift from symptom-based to molecularly defined disease classification promises to improve treatment outcomes by addressing underlying genetic and immunological heterogeneity. The integration of genomic medicine into rheumatology not only benefits patients with ultra-rare syndromes but also offers potential breakthroughs for more common autoimmune and autoinflammatory conditions, advancing the broader vision of personalized medicine.