Although the first descriptions of HAE appeared as early as in the XVIII century (3), the first cause of the disease was only identified in 1963 (4) as the deficiency of the inhibitor of C1 esterase (C1-INH) in plasma (HAE-C1-INH) (OMIM #106100), initiating a new era of the complement biochemical analysis in HAE patients, establishing low C1-INH and low C4 plasma levels as biomarkers of HAE-C1-INH (5). The gene discussed is C1S; the disease is hereditary angioedema.