Hereditary angioedema with a mutation in the plasminogen gene

Abstract

Hereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene. The study comprised analysis of whole exome sequencing, Sanger sequencing, and clinical data of patients. We detected a mutation in the plasminogen gene in patients with HAEnCI. The mutation c.9886A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the plasminogen protein. The mutation was identified by next generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The plasminogen gene mutation was present in all studied symptomatic patients and was also found in 9 out of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). 331 out of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling. HAE with a mutation in the plasminogen gene is a novel type of HAE. It is associated with a high risk of tongue swellings.