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, showing no spontaneous remission, but responded to oral steroid therapy with mild resolution. WGS of the patient’s blood 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 highlighted ACE as a key gene, with its expression significantly downregulated during disease progression and recovered with treatment. IFNG was also identified. The findings suggest that decreased ACE expression, driven by PRDM16 mutations and altered IFNG expression, likely contributed to increased bradykinin levels and activation of the arachidonic acid cascade, resulting in the severe inflammation and angioedema characteristic of Gleich syndrome. This study highlights the utility of integrating WGS and RNA-seq data to uncover the molecular basis of rare diseases and provides a foundation for developing therapeutic strategies for hypereosinophilic syndromes.