Genetic variants linked to type I interferonopathies identified in 132 pediatric vasculitis patients

Diagnosing the underlying monogenic etiology in pediatric vasculitis is crucial for understanding disease mechanisms, predicting prognosis, and guiding targeted therapies, yet traditional histopathological or imaging-based approaches often fall short in identifying these specific genetic drivers. Type I interferonopathies represent a diverse group of immune-mediated disorders characterized by constitutive interferon signaling, frequently manifesting with vasculitic or vasculopathic features. Persistent activation of nucleic acid-sensing pathways and impaired intracellular homeostasis contribute significantly to endothelial dysfunction and chronic vascular inflammation, highlighting a critical gap in precise genetic diagnosis for these complex conditions.

Researchers conducted a comprehensive genetic analysis workflow on 1,204 pediatric patients with suspected autoinflammatory disorders, recruited from a rheumatology clinic database. Whole-exome sequencing was performed to identify variants affecting coding regions and splice sites. A bioinformatic pipeline, based on American College of Medical Genetics and Genomics (ACMG) guidelines, was employed for variant analysis. This pipeline integrated statistical filtering and signal processing techniques, including methods inspired by discrete Fourier transforms (DFT) and statistical distributions, to enhance variant prioritization and interpretation, focusing on interferonopathy-related genes.

Interferonopathy-associated genetic variants were identified in 132 pediatric patients within the cohort. Overall, 92 unique variants were detected across these patients. This included 13 previously reported pathogenic or likely pathogenic variants, confirming known disease associations. Significantly, 79 novel variants were discovered that had not been present in public databases as of February 2026, expanding the known genetic landscape of these disorders. The clinical manifestations observed in these patients predominantly included recurrent fever, various vasculitic manifestations, and complex autoinflammatory presentations. Variants primarily involved genes associated with dysregulated interferon signaling and innate immune activation, specifically highlighting pathways linked to STING activation.