A newly identified pathology of Episodic Angioedema with Hypereosinophilia (Gleich's Syndrome) revealed by Multi-Omics Analysis

Episodic Angioedema with Eosinophilia (Gleich syndrome) is a rare disease characterized by periodic angioedema, fever, and marked eosinophilia. This study aimed to elucidate the pathogenic factors of severe Gleich syndrome through comprehensive multi-omics analysis, including whole genome sequencing (WGS) and RNA sequencing (RNA-seq). A young female patient (age: 16-20 years old) presenting with periodic high fever, extensive urticaria/eczema, and marked eosinophilia was diagnosed with Gleich syndrome. The symptoms were severe, with no spontaneous remission, but responded well to oral steroids, showing mild resolution. WGS analysis of the patient's blood samples identified high-impact pathogenic mutations in 16 genes, including PRDM16. RNA-seq analysis revealed differentially expressed genes (DEGs) associated with immune response regulation and viral defense. Combined z-score analysis of WGS and RNA-seq data identified ACE as a key gene. ACE expression was markedly downregulated during disease progression and recovered with treatment. IFNG was also identified. The results of this study suggest that a marked decrease in ACE, driven by genetic mutations in PRDM16 and altered expression of IFNG, leading to increased bradykinin and enhanced activation of the arachidonic acid cascade, may have caused the clinical presentation of Gleich syndrome, including dramatic inflammation and angioedema. This study underscores the importance of integrating WGS and RNA-seq data to elucidate the molecular basis of rare diseases and provides a foundation for developing therapeutic strategies for hypereosinophilic conditions.