Guidelines for diagnosis of HAE-nC1INH include (i) a history of recurrent angioedema in the absence of concomitant hives or use of medication known to cause angioedema; (ii) documented normal or near normal C4, C1INH antigen, and C1INH function; and (iii) either a genetic variant associated with the disease or a family history of angioedema and documented lack of efficacy of chronic, high-dose antihistamine therapy (10). This evidence concerns the gene C4A and angioedema.