Hereditary angioedema (HAE) [9 genes]

Hereditary angioedema (HAE) is an inflammatory disorder characterized by recurrent and unpredictable attacks of tissue inflammation and swelling involving the complement system and coagulation factors. Clasically, primary forms of angioedema have been associated with mutations in the SERPING1 gene (HAE types I and II) and in the F12 gene (HAE type III). However, different genetic factors have recently been described whose defects cause HAE, which are classified according to whether or not they cause a decrease in C1NH protein. SERPING1 encodes the inhibitory protein C1, a fundamental component of plasma that acts as an inhibitor of the complement system, the fibrinolytic system and the kallikrein-kinin system. In the kallikrein-kinin system, the inhibitory protein C1 blocks the activity of enzymes in the system that promote inflammation. When there is not enough functional C1 inhibitor, the kallikrein-kinin pathway is affected, and therefore bradykinin production becomes uncontrolled.

On the other hand, an excess of bradykinin leads to abnormal fluid accumulation in tissues and episodes of swelling. Mutations in the F12, MYOF, ANGTP1, PLG and KNG1 genes have a similar effect, regulating bradykinin production in the kallikrein-kinin system.

Finally, there are other genetic causes that do not depend on the above pathways, but are also involved in the development of edema, such as carboxypeptidase deficiency (CPN1), complement hyperactivation with angiopathic thrombosis and CD55 enteropathy, or defects in heparan sulphate glucosamine 3-sulfotransferase (HS3ST6).

• 1/10,000 – 1/150,000 individuals

The identification of a genetic cause of HAE allows a precise molecular diagnosis to be made and genetic counseling to be offered to the patient and family. The HAE management recommendations are reflected in the WAO/EAACI international clinical guideline (Maurer et al., 2021).

The HAE genetic diagnostic panel is indicated when there are recurrent episodes of non-pruritic swelling/edema of subcutaneous and/or submucosal tissues (extremities, face, or genitals) that may be accompanied by attacks of gastrointestinal pain or inflammation, especially, but not exclusively, when there is a positive family history of the disease since up to 25% of cases occur sporadically. 85% of HAE cases are due to pathogenic variants in the SERPING1 gene that leads to a deficiency of C1-INH with plasma levels below 50% compared to normal parameters. The remaining 15% are due to genetic defects in the F12, CD55, PLG and ANGPT1 genes. When HAE is suspected, there is a high percentage of cases in which a genetic cause is not identified, so biochemical tests are essential in these cases to evaluate the levels and function of C1-INH and C4.