Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Hereditary angioedema (HAE) is a rare genetic condition that is inherited in an autosomal dominant pattern. It is defined by recurrent episodes of fluid accumulation outside blood vessels, resulting in the rapid swelling of tissues in the hands, feet, limbs, face, intestinal system, and airways.1,2 HAE is classified into 2 types: HAE with a deficiency of C1-esterase inhibitor protein (C1-INH HAE) and HAE with normal levels of C1-INH protein (nC1-INH-HAE). C1-INH HAE is further subdivided into 2 variants. Type 1, which accounts for approximately 90% of cases, is characterized by low levels or the absence of C1-INH, caused by failure to synthesize C1-INH. Type 2 HAE, which accounts for the remaining 10% of cases, is characterized by normal or increased levels of dysfunctional C1-INH. In this type, an abnormal, nonfunctional protein is synthesized.1,3 In nC1-INH-HAE, C1-INH is quantitatively and qualitatively normal; up to 25% to 30% of individuals with this rare variant have an alteration in the F12 gene (FXII-HAE). The genetic basis for the remaining 70% to 75% of cases is unknown (unknown-HAE or U-HAE).1,3
Mutations in the SERPING1 Gene
C1-INH HAE is caused by mutations in the genes that code for C1-INH protease, which belongs to the serine superfamily of proteins.4 Mutations in the serine protease inhibitor G1 gene (SERPING1) account for most cases of HAE. C1-INH is a key regulator of important enzymes involved in the production of bradykinin, which causes angioedema by increasing vascular permeability and allowing fluid to flow into the extracellular space. Bradykinin is released and overproduced due to loss of the inhibitory activity of C1-INH.1
SERPING1 gene mutations (which cause type 1 and type 2 HAE) account for more than 95% of all cases of HAE.5 The SERPING1 gene comprises 8 exons and 7 introns located on the long arm of chromosome 11 (11q12-q13.1) and has an odd promoter that lacks the TATA box. TdT-like initiator and polypurine pyrimindine tract are present instead. SERPING1 has a number of exonic mutations as well as mutations at intron/exon junctions, which are inherited in an autosomal-dominant manner. However, approximately 25% of all cases of HAE with C1-INH deficiency are sporadic (ie, they are the consequence of de novo mutations in SERPING1).2,5 The clinical signs of HAE with CI-INH deficiency vary widely according to the location of the SERPING1 mutation. This gene displays remarkable allelic heterogeneity, with roughly 450 distinct mutations recorded in the Human Gene Mutation Database (HGMD) and a similar database specifically dedicated to HAE (HAEdb, hae.enzim.hu).5
The mutations that cause type 1 HAE are very diverse and dispersed across the gene. Up to 20% of cases are the consequence of large rearrangements (partial deletions and, less commonly, partial duplications). Missense mutations (34%), frameshift modifications, and small indels (31%) are the most common mutations, followed by splice site mutations (10%), nonsense mutations (7%), and regulatory mutations (1%).3
In type 2 HAE, inactive C1-INH is caused by point mutations in or near the reactive center loop. A mutation at Arg444 (the P1 residue) is responsible for dysfunctional C1-INH in up to 70% of patients with type 2 HAE.3
Mutations in the Factor XII (F12) Gene
No mutations have been detected in the SERPING1 gene in individuals with nC1-INH-HAE. The F12 gene encodes coagulation factor XII. This 12-kb gene comprises 14 exons. One F12 gene mutation associated with HAE is a gain-of-function mutation and is transmitted in an autosomal-dominant pattern with incomplete penetrance. The mutation occurs at exon 9 of F12, which encodes a highly glycosylated region of the protein, and enhances the production of activated factor XII (factor XIIa) via plasmin activation. C1-INH regulates the contact system through coagulation factor FXIIa and inhibition of plasma kallikrein. The 4 most common pathogenic mutations in this gene are the following: 2 missense variants in exon 9 (p.Thr328Lys and p.Thr328Arg) in 6 of 20 German families with nC1-INH-HAE; an exon 9/intron 9 boundary large deletion of 72 bp (c.971_1018 + 24del72) in 2 unrelated families from Turkey; a mutation at the exon 9/intron 9 junction; and a duplication of 18 bp (c.892_909dup) in a Hungarian family resulting in repetition of 6 amino acids (p.298e303) at the same locus.1,5
Mutations in Other Genes
Plasminogen (PLG) Gene
A newly discovered missense mutation in exon 9 of the plasminogen (PLG) gene (c.988A>G or c.1100A>G, depending on the assembly used)) results in the substitution of glutamic acid for lysine at position 330 (p.Lys330Glu or p.Lys311Glu, depending on the numbering scheme used). This mutation affects the structure of the wild-type protein by changing the kringle 3 domain. HAE occurs when a mutated protein causes an increase in bradykinin production.5
Angiopoietin 1 (ANGPT1) Gene
All of the 3 previously mentioned genetic mutations result in increased bradykinin 2 receptor-mediated signaling due to increased bradykinin production. However, mutations in the angiopoietin 1 (ANGPT1) gene decrease the plasma levels of angiopoietin 1 protein and disrupt the cytoskeletal organization of vascular endothelial cells. This newly discovered genetic mutation (missense mutation c.807G>T, p.Ala119Ser) was identified by means of whole-exome sequencing (WES) in patients with nC1-INH HAE.The discovery of formerly unknown pathways in the pathophysiology of HAE has ushered in a new era in the management of this disorder.5
- Santacroce R, D’Andrea G, Maffione AB, Margaglione M, d’Apolito M. The genetics of hereditary angioedema: a review. J Clin Med. 2021;10(9):2023. doi:10.3390/jcm10092023
- Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 8, 2022.
- Piñero-Saavedra M, González-Quevedo T. The genetics of hereditary angioedema: a review. J Rare Dis Res Treat. 2017;2(4):14-19. doi:10.29245/2572-9411/2017/4.1105
- Siles R. Hereditary angioedema. Cleveland Clinic Center for Continuing Education. Published April 2017. Last reviewed December 2017. Accessed June 8, 2022.
- Banday AZ, Kaur A, Jindal AK, Rawat A, Singh S. An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2019;7(1):75-83. doi:10.1016/j.gendis.2019.07.002
Reviewed by Debjyoti Talukdar, MD, on 6/23/2022.