Genetic alterations and pathways in patients with Hereditary Angioedema of Unknown Cause (U-HAE)

Abstract

Objective: Hereditary angioedema ( HAE) with normal C1 inhibitor (HAE-nC1-INH), is a genetically complex, rare disease andmutations in F12, ANGPT1, PLG, MYOF genes are found in some families with HAE-nC1-INH. However, often a specific mutationcannot be identified and this type is called as hereditary angioedema of unknown cause (U-HAE). Our aim was to identify putativecausative genetic alterations and/or pathways by whole exome sequencing in patients with U-HAE.Patients and Methods: Nine patients from 8 families between the ages of 3 to 63 years with U-HAE and 6 controls were enrolled forthe study and whole exome sequencing were performed.Results: No significant difference was found between the case and control group for the a priori suspected set of genes. Variants in thegenes; RAMP2, IL6, GP1BA, C1QBP were significantly different between U-HAE and control group. Downstream functional analysisfound that blood coagulation pathways were enriched in these genes.Conclusion: Proteins that are not involved in contact pathways may also play a role in U-HAE. These variants need to be replicated inlarger cohorts and studied at the functional level to verify our findings.