Biomarker for Hereditary AngioEdema Disease: An International, Multicenter, Longitudinal Monitoring Protocol

Hereditary Angioedema (HAE) is a rare autosomal dominant genetic disorder, characterized by recurrent episodes of angioedema of the face, larynx, lips, abdomen, and extremities.The most common types of HAE develop as result of mutations in the SERPING1 gene that encodes the C1 inhibitor (C1-INH), a protease involved in limiting bradykinin production. Excessive bradykinin due to low levels of C1-INH (HAE type 1) or dysfunctional C1-INH (HAE type 2) leads to capillary leakage and angioedema formation. The third type of HAE is not associated with a C1-INH deficiency, develops as a result of mutations in the Factor 12 gene (FXII) and affects almost exclusively women. Rare cases of HAE have also been described resulting from mutations in Plasminogen (PLG), Angiopoetin 1 (ANGPT1), and Kininogen 1 (KNG1).

The characteristic symptom of hereditary angioedema is recurrent episodes of swelling due to the accumulation of excessive body fluid. The most commonly affected areas of the body include the hands, feet, eyelids, lips, genitals, larynx and gastrointestinal tract. The most serious complication of HAE is laryngeal edema that can become life threatening; but it is a relatively rare event.

The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests.Clinical diagnosis is complicated because HAE is highly variable in the clinical phenotype and the majority of the physicians believe that they never seen a patient with that disorder. Laboratory diagnosis involves measurement of the C1-INH function, C1-INH and C4 levels. Both C1-INH protein level and function is low in HAE-1 patients, whereas in HAE-2 individuals the C1-INH concentrations is optimal or even elevated, however C1-INH function is impaired. Generally, C4 levels are low in both HAE-1/2 patients.

CENTOGENE utilizes Liquid Chromatography-Multiple Reaction Monitoring Mass Spectrometry (LC-MRM-MS) method to identify potential disease-specific biomarkers for HAE. Such biomarker/s may support the early diagnosis and treatment monitoring and personalization in the future.

Therefore, it is the goal of this study is to identify new biomarkers for HAE, validate the identified biomarkers, and monitor these biomarkers longitudinally to determine their clinical robustness, specificity, and predictive value.