Mutation of the angiopoietin‐1 gene (ANGPT1) associates with a new type of hereditary angioedema

Background: Hereditary angioedema (HAE) is a rare genetic disease usually caused by mutation in the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE, no causative variants have been described, and the pathophysiology of the disease remains unknown (hereditary angioedema with yet unknown genetic defect [U‐HAE]). Identification of causative genes in patients with U‐HAE is valuable for understanding the cause of the disease. Objective: We conducted genetic studies in Italian patients with U‐HAE to identify novel causative genes. Methods: Among patients belonging to 10 independent families and unrelated index patients with U‐HAE recruited from the Italian Network for C1‐INH‐HAE (ITACA), we selected a large multiplex family with U‐HAE and performed whole‐exome sequencing. The angiopoietin‐1 gene (ANGPT1) was investigated in all patients with familial or sporadic U‐HAE. The effect of ANGPT1 variants was investigated by using in silico prediction and plasma and transfected cells from both patients and control subjects. Results: We identified a missense mutation (ANGPT1, c.807G>T, p.A119S) in a family with U‐HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U‐HAE but not in asymptomatic family members or an additional 20 patients with familial U‐HAE, 22 patients with sporadic U‐HAE, and 200 control subjects. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor tunica interna endothelial cell kinase 2 of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed reduced binding capability to its receptor. Conclusion: ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.