Molecular genetic diagnosis of hereditary angioedema

Hereditary angioedema (HAE) is a rare genetic condition currently subdivided into two groups: HAE due to C1-inhibitor deficiency (Type I) or dysfunction (Type II) (C1-INH-HAE) and HAE with normal activity of C1‐INH (nC1- INH-HAE). C1-INH-HAE is estimated to occur in approximately 99 % of cases HAE and is caused by sequence variants in the SERPING1 gene. The prevalence of nC1-INH-HAE is extremely low and accounts for about 1 % of all cases of HAE. nC1-INH-HAE currently subdivided on HAE, due to mutations in factor XII (FXII-HAE), plasminogen (PLG-HAE), angiopoietin 1 (ANGPT1-HAE), kininogen 1 gene (KNG1-HAE), or angioedema of unknown origin (U-HAE).

The amplicons of the entire coding regions and splice-sites of 18 genes from 24 patients (18 female) belonging to 17 families were analyzed by Next Generation Sequencing (NGS). The median age of patients was 33.5, of onset ‒ 16 years. 15 patients had a family history of edema.

We identified seven C1-INH-HAE patients and variants were detected in the SERPING1 gene. For three patients (members of the same family), a heterozygous variant was found deep in the intron of the SERPING1 gene, which is likely to affect protein synthesis. We identified two patients with changes in the PLAUR gene, which may be associated with the manifestation of symptoms angioedema. Six patients showed abnormalities in the genes AGT and KNG1, which can probably explain their early hypertension, which could provoke the appearance of edema.

1. Piñero-Saavedra M., Ganzalez-Quevedo T. J. The genetics of hereditary angioedema: a review. Journal of Rare Diseases Research and Treatment, 2017, vol. 2, no. 4, pp. 14–19.

2. Mansi M., Zanichelli A., Coerezza A., Suffritti C., Wu M. A., Vacchini R., Stieber C., Cichon S., Cicardi M. Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients. Journal of Internal Medicine, 2015, vol. 277, no. 5, pp. 585–593. https://doi.org/10.1111/joim.12304

3. Zuberbier T., Aberer W., Asero R., Latiff A. H. A., Baker D., Ballmer-Weber B. [et al.]. The EAACI/GA LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2017 revision and update. Allergy, 2018, vol. 73, no. 7, pp. 1393–1414. https://doi.org/10.1111/all.13397

4. Huston D. P., Sabato V. Decoding the enigma of urticaria and angioedema. Journal of Allergy and Clinical Immunology: In Practice, 2018, vol. 6, no. 4, pp. 11718–1175. https://doi.org/10.1016/j.jaip.2018.06.001

5. Cicardi M., Aberer W., Banerji A., Bas M., Bernstein J. A., Bork K. [et al.]. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy, 2014, vol. 69, no. 5, pp. 602–616. https://doi.org/10.1111/all.12380

6. Beltrami L., Zanichelli A., Zingale L., Vacchini R., Carugo S., Cicardi M. Long-term follow-up of 111 patients with angiotensinconverting enzyme inhibitor-related angioedema. Journal of Hypertension, 2011, vol. 29, no. 11, pp. 2273–2277. https://doi.org/10.1097/HJH.0b013e32834b4b9b

7. Maas C., López-Lera A. Hereditary angioedema: insights into inflammation and allergy. Molecular Immunology, 2019, vol. 112, no. 4, pp. 378–386. https://doi.org/10.1016/j.molimm.2019.06.017

8. Nussberger J., Cugno M., Cicardi M., Agostoni A. Local bradykinin generation in hereditary angioedema. Journal of Allergy and Clinical Immunology, 1999, vol. 104, no. 6, pp. 1321–1322. https://doi.org/10.1016/s0091-6749(99)70030-8

9. Cugno M., Nussberger J., Cicardi M., Agostoni A. Bradykinin and the pathophysiology of angioedema. International Immunopharmacology, 2003, vol. 3, no. 3, pp. 311–317. https://doi.org/10.1016/S1567-5769(02)00162-5

10. Davis 3rd A. E. Mejia P., Lu F. Biological activities of C1 inhibitor. Molecular Immunology, 2008, vol. 45, no. 16, pp. 4057–4063. https://doi.org/10.1016/j.molimm.2008.06.028

11. Kaplan A. P., Joseph K. Kinin formation in C1 inhibitor deficiency. Journal of Allergy and Clinical Immunology, 2010, vol. 125, no. 6, pp. 1411–1412. https://doi.org/10.1016/j.jaci.2010.02.036

12. Zuraw B. L., Christiansen S. C. HAE pathophysiology and underlying mechanisms. Clinical Reviews in Allergy & Immunology, 2016, vol. 51, no. 2, pp. 216–229. https://doi.org/10.1007/s12016-016-8561-8

13. Bossi F., Fischetti F., Regoli D. [et al.] Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. Journal of Allergy and Clinical Immunology, 2009, vol. 124, no. 6, pp. 1303–1310e4. https://doi.org/10.1016/j.jaci.2009.08.007

14. Agostoni A., Aygören-Pürsün E., Binkley K. E., Blanch A., Bork K., Bouillet L. [et al.]. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. Journal of Allergy and Clinical Immunology, 2004, vol. 114, no. 3 (suppl.), pp. S51–S131. https://doi.org/10.1016/j.jaci.2004.06.047

15. Zanichelli A., Magerl M., Longhurst H., Fabien V., Maurer M. Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe. Allergy, Asthma and Clinical Immunology, 2013, vol. 9, art. 29. https://doi.org/10.1186/1710-1492-9-29

16. Zuraw B. L. Clinical practice. Hereditary angioedema. New England Journal of Medicine, 2008, vol. 359, no. 10, pp. 1027–1036. https://doi.org/10.1056/NEJMcp0803977

17. Longhurst H., Cicardi M. Hereditary angio-oedema. Lancet, 2012, vol. 379, no. 9814, pp. 474–481. https://doi.org/10.1016/S0140-6736(11)60935-5

18. Cicardi M., Bork K., Caballero T., Craig T., Li H. H., Longhurst H., Reshef A., Zuraw B. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy, 2012, vol. 67, no. 2, pp. 147–157. https://doi.org/10.1111/j.1398-9995.2011.02751.x

19. Sabharwal G., Craig T. Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). Expert Review of Clinical Immunology, 2015, vol. 11, no. 3, pp. 319–327. https://doi.org/10.1586/1744666x.2015.1012502

20. Banerji A., Riedl M. A., Bernstein J. A., Cicardi M., Longhurst H. J., Zuraw B. L. [et al.]. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. Journal of the American Medical Association, 2018, vol. 320, no. 20, pp. 2108–2121. https://doi.org/10.1001/jama.2018.16773

21. Bork K., Barnstedt S. E., Koch P., Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet, 2000, vol. 356, no. 9225, pp. 213–217. https://doi.org/10.1016/s0140-6736(00)02483-1

22. Bork K., Wulff K., Steinmüller-Magin L., Braenne I., Staubach-Renz P., Witzke G., Hardt. J. Hereditary angioedema with a mutation in the plasminogen gene. Allergy, 2018, vol. 73, no. 2, pp. 442–459. https://doi.org/10.1111/all.13270

23. Bafunno V., Firin, D., D’Apolito M., Cordisco G., Loffredo S., Leccese A., Margaglione M. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. Journal of Allergy and Clinical Immunology, 2018, vol. 141, no. 3, pp. 1009–1017. https://doi.org/10.1016/j.jaci.2017.05.020

24. Bork K., Wulff K., Rossmann H., Steinmüller‐Magin L., Brænne I., Witzke G., Hardt, J. Hereditary angioedema cosegregating with a novel kininogen1 gene mutation changing the N‐terminal cleavage site of bradykinin. Allergy, 2019, vol. 74, no. 12, pp. 2479–2481. https://doi.org/10.1111/all.13869

25. Vitrat-Hincky V., Gompel A., Dumestre-Perard C., Boccon-Gibod I., Droue, C., Cesbron J. Y., Bouillet L. Type III hereditary angio-oedema: clinical and biological features in a French cohort. Allergy, 2010, vol. 65, no. 10, pp. 1331–1336. https://doi.org/10.1111/j.1398-9995.2010.02368.x

26. Björkqvist J., de Maat S, Lewandrowski U., Di Gennaro A., Oschatz C., Schönig K. [et al.] Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. Journal of Clinical Investigation, 2015, vol. 125, no. 8, pp. 3132–3146. https://doi.org/10.1172/jci77139

27. Ensembl genome browser 95. Available at: http://www.ensembl.org/index.html (accessed 13.01.2019).

28. GeneCards The Human Gene Databace. Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=KNG1 (accessed 01.07.2020).