Genetics of Hereditary Angioedema Revisited

Clin Rev Allergy Immunol. 2016 Oct;51(2):170-82. doi: 10.1007/s12016-016-8543-x.


Contemporary genetic research has provided evidences that angioedema represents a diverse family of disorders related to kinin metabolism, with a much greater genetic complexity than was initially considered. Convincing data have also recently been published indicating that the clinical heterogeneity of hereditary angioedema due to C1 inhibitor deficiency (classified as C1-INH-HAE) could be attributed at least in part, either to the type of SERPING1 mutations or to mutations in genes encoding for enzymes involved in the metabolism and function of bradykinin. Alterations detected in at least one more gene (F12) are nowadays considered responsible for 25 % of cases of hereditary angioedema with normal C1-INH (type III hereditary angioedema (HAE), nlC1-INH-HAE). Interesting data derived from genetic approaches of non-hereditary angioedemas indicate that other immune pathways might be implicated in the pathogenesis of HAE. More than 125 years after the recognition of the hereditary nature of HAE by Osler, the heterogeneity of clinical expressions, the genetics of this disorder, and the genotype-phenotype relationships, still presents a challenge that will be discussed in this review. Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis. Uncovering genetic biomarkers affecting the severity of the disease and/or the effectiveness of the various treatment modalities might lead to the prevention of attacks and the optimization of C1-INH-HAE management that is expected to provide a valuable benefit to the sufferers of angioedema.

Keywords: F12 gene; Genetics; Hereditary angioedema; SERPING1 gene.

Publication types

  • Review

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Angioedemas, Hereditary / genetics*
  • Angioedemas, Hereditary / immunology
  • Angioedemas, Hereditary / metabolism
  • Angiotensin-Converting Enzyme Inhibitors
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmunity
  • Complement C1 Inactivator Proteins / chemistry
  • Complement C1 Inactivator Proteins / genetics
  • Complement C1 Inhibitor Protein / chemistry
  • Complement C1 Inhibitor Protein / genetics
  • Factor XII / genetics
  • Genetic Association Studies*
  • Genetic Heterogeneity
  • Humans
  • Kinins / metabolism
  • Mutation


  • Angiotensin-Converting Enzyme Inhibitors
  • Complement C1 Inactivator Proteins
  • Complement C1 Inhibitor Protein
  • Kinins
  • SERPING1 protein, human
  • Factor XII