J Vis Exp. 2026 Jun 16;(232). doi: 10.3791/71279.
ABSTRACT
Pediatric vasculitis is traditionally diagnosed by histopathological evaluation; however, increasingly, less invasive imaging-based approaches are used in clinical practice. Despite these advances, identification of an underlying monogenic etiology remains essential for understanding disease mechanisms, predicting prognosis, and guiding targeted therapeutic strategies. Type I interferonopathies comprise a heterogeneous group of immune-mediated disorders characterized by constitutive interferon signaling and frequent vasculitic or vasculopathic manifestations. Persistent activation of nucleic acid-sensing pathways and impaired intracellular homeostasis contribute to endothelial dysfunction and chronic vascular inflammation. This study presents a comprehensive genetic analysis workflow for detecting vasculitis-associated variants in interferonopathy-related genes within a pediatric autoinflammatory disease cohort. Whole-exome sequencing was performed in 1,204 patients with suspected autoinflammatory disorders. Variants affecting coding regions and splice sites were analyzed using a bioinformatic pipeline based on American College of Medical Genetics and Genomics guidelines, integrating statistical filtering and signal processing techniques inspired by discrete Fourier transforms (DFT) and statistical distributions to improve variant prioritization and interpretation. Interferonopathy-associated variants were identified in 132 pediatric patients evaluated through a rheumatology clinic database. Overall, 92 unique variants were detected, including 13 previously reported pathogenic or likely pathogenic variants and 79 novel variants that were not present in public databases as of February 2026. The clinical manifestations mostly included recurrent fever, vasculitic manifestations, and complex autoinflammatory presentations. Variants involved genes associated with dysregulated interferon signaling and innate immune activation, including pathways linked to STING activation, nucleic acid metabolism, and intracellular trafficking dysfunction. This interdisciplinary workflow demonstrates the potential diagnostic utility of genomic analysis in pediatric vasculitis and highlights the importance of sustained interferon signaling in vascular injury and autoinflammatory disease pathogenesis.
PMID:42406817 | DOI:10.3791/71279