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Phenotypic and Genotypic Characterization of Hereditary Angioedema in Saudi Arabia

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Abstract

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder affecting roughly 1:50,000 individuals. It is commonly characterized by swelling of the larynx, gastrointestinal tract, extremities, and skin. There is growing genetic heterogeneity associated with this disease but more than 95% of mutations are found in SERPING1, the gene which encodes complement 1 inhibitor (C1-INH). HAE cohorts from several populations have been published but no large scale study has been reported from the Arab world to date. Here we document the clinical and genetic findings of HAE patients from a single Saudi institution, which is a major referral center at the national level. A total of 51 patients across 17 unrelated families were recruited including two large multi-generational families, of which one contained an in-frame exonic deletion that was resolved through MLPA. Two cases were negative for all the genes we tested (including F12, PLG, ANGPT1, MYOF, KNG1, and HS3ST6). The predominant HAE subtype in our cohort was type I, at 76%. We were able to uncover a mutation in 49 patients (96%). No type III (normal C1-INH) patients were encountered in the clinic, suggesting that this subtype does not play a major role in HAE pathogenesis in Saudi Arabia. Additionally, the existence of four patients with consistently normal complement 4 (C4) levels alongside abnormal C1-INH profiles highlights the utility of dual screening for both proteins in suspected patients.

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Data Availability

All the sequence data are available upon request.

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References

  1. Zuraw BL. Clinical practice Hereditary angioedema. N Engl J Med. 2008;359(10):1027–36.

    Article  CAS  Google Scholar 

  2. Bork K, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267–74.

    Article  Google Scholar 

  3. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Med (Baltimore). 1992;71(4):206–15.

    Article  CAS  Google Scholar 

  4. Bowen T, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24.

    Article  Google Scholar 

  5. Roche O, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol. 2005;94(4):498–503.

    Article  Google Scholar 

  6. Zanichelli A, et al. A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy. Orphanet J Rare Dis. 2015;10:11.

    Article  Google Scholar 

  7. Faiyaz-Ul-Haque M, et al. Novel and recurrent mutations in the C1NH gene of Arab patients affected with hereditary angioedema. Int Arch Allergy Immunol. 2010;151(2):149–54.

    Article  CAS  Google Scholar 

  8. Jaradat SA, et al. Hereditary angioedema in a Jordanian family with a novel missense mutation in the C1-inhibitor N-terminal domain. Mol Immunol. 2016;71:123–30.

    Article  CAS  Google Scholar 

  9. Levi M, Cohn DM, Zeerleder S. Hereditary angioedema: linking complement regulation to the coagulation system. Res Pract Thromb Haemost. 2019;3(1):38–43.

    Article  Google Scholar 

  10. Banday AZ, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2020;7(1):75–83.

    Article  CAS  Google Scholar 

  11. Pappalardo E, et al. Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: functional and structural correlates. Mol Immunol. 2008;45(13):3536–44.

    Article  CAS  Google Scholar 

  12. Gosswein T, et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res. 2008;121(3–4):181–8.

    CAS  Google Scholar 

  13. Zahedi R, et al. Characterization of C1 inhibitor-Ta. A dysfunctional C1INH with deletion of lysine 251. J Biol Chem. 1996;271(39):24307–12.

    Article  CAS  Google Scholar 

  14. Bork K, et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immunol. 2021;148(4):1041–8.

    Article  CAS  Google Scholar 

  15. Sharma J, et al. Pathophysiology of hereditary angioedema (HAE) beyond the SERPING1 gene. Clin Rev Allergy Immunol. 2021;60(3):305–15.

    Article  CAS  Google Scholar 

  16. Zotter Z, et al. Frequency of the virilising effects of attenuated androgens reported by women with hereditary angioedema. Orphanet J Rare Dis. 2014;9:205.

    Article  Google Scholar 

  17. Itan Y, et al. HGCS: an online tool for prioritizing disease-causing gene variants by biological distance. BMC Genomics. 2014;15:256.

    Article  Google Scholar 

  18. Bygum A, et al. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. Allergy. 2011;66(1):76–84.

    Article  CAS  Google Scholar 

  19. Speletas M, et al. Hereditary angioedema: molecular and clinical differences among European populations. J Allergy Clin Immunol. 2015;135(2):570–3.

    Article  Google Scholar 

  20. Banerji A, et al. Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol. 2020;124(6):600–7.

    Article  Google Scholar 

  21. Liu S, et al. Hereditary angioedema: a Chinese perspective. Eur J Dermatol. 2019;29(1):14–20.

    CAS  Google Scholar 

  22. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391–8.

    Article  Google Scholar 

  23. Jindal AK, et al. Novel SERPING1 gene mutations and clinical experience of type 1 hereditary angioedema from North India. Pediatr Allergy Immunol. 2021;32(3):599–611.

    Article  CAS  Google Scholar 

  24. Ozkars MY, et al. A hereditary angioedema screening in two villages, based on an index case, and identification of a novel mutation, “1033G>T”, at the SERPING1 gene. Postepy Dermatol Alergol. 2019;36(4):403–11.

    Article  Google Scholar 

  25. Karim Y, Griffiths H, Deacock S. Normal complement C4 values do not exclude hereditary angioedema. J Clin Pathol. 2004;57(2):213–4.

    Article  CAS  Google Scholar 

  26. Tarzi MD, et al. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol. 2007;149(3):513–6.

    Article  CAS  Google Scholar 

  27. Pitts JS, et al. Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the forth and second components of complement. J Lab Clin Med. 1978;92(4):501–7.

    CAS  Google Scholar 

  28. Cicardi M, et al. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. 1991;87(4):768–73.

    Article  CAS  Google Scholar 

  29. Gelfand JA, et al. Treatment of hereditary angioedema with danazol Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976;295(26):1444–8.

    Article  CAS  Google Scholar 

  30. Alswat K, et al. Nonalcoholic fatty liver disease burden - Saudi Arabia and United Arab Emirates, 2017–2030. Saudi J Gastroenterol. 2018;24(4):211–9.

    Article  Google Scholar 

  31. Al-Qahtani AH, et al. Hereditary angioedema may be associated with the development of fatty liver. J Allergy Clin Immunol Pract. 2019;7(6):2082–3.

    Article  Google Scholar 

  32. Riedl MA. Critical appraisal of androgen use in hereditary angioedema: a systematic review. Ann Allergy Asthma Immunol. 2015;114(4):281-288 e7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all our patients and their family members for their gracious and enthusiastic participation. We are also grateful to Salma M Wakil, Dorota Monies, and to all members of the sequencing and genomics core facilities at the Centre for Genomic Medicine, KFSH&RC for their invaluable assistance. We also thank Qasim A Sheikh for his help with data analysis and Samer Alkhateeb for his generous support with logistics.

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Authors and Affiliations

  1. Department of Medicine, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Farrukh Sheikh, Maram Albanyan, Fatimah Alawami, Safia Sumayli, Sulaiman Al Gazlan, Rand Arnaout, Hassan Alrayes & Saad AlShareef

  2. Translational Genomics Department, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, MBC 3, P.O. Box 3354, Riyadh, 11211, Saudi Arabia

    Huda Alajlan, Hibah Alruwaili & Anas M. Alazami

  3. Department of Pediatrics, Allergy and Immunology Section, Faisal Specialist Hospital and Research Centre, Riyadh, King, Saudi Arabia

    Sawsan Abu Awwad, Hasan Al-Dhekri, Bandar Al-Saud & Hamoud Al-Mousa

  4. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Bandar Al-Saud & Hamoud Al-Mousa

  5. Department of Medicine, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia

    Najla Sayes

  6. Clinical Genomics Department, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Mohamed H. Al-Hamed

  7. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia

    Hamoud Al-Mousa & Anas M. Alazami

Authors
  1. Farrukh Sheikh
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  2. Huda Alajlan
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  3. Maram Albanyan
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  9. Hasan Al-Dhekri
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  17. Anas M. Alazami
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Contributions

FS and AA designed the study, analyzed the data, and prepared the manuscript; FA and SA tabulated the clinical data and prepared the manuscript; HuA and HiA performed the experiments and assisted in the data analysis; FS, MA, FA, RA, SS, HaA, BA-S, HA-D, NS, and SA cared for patients and contributed the clinical data; SAA and HA-M coordinated and documented patient recruitment and data; MA participated in manuscript writing; MHA-H conducted experiments and assisted in manuscript preparation.

Corresponding author

Correspondence to Anas M. Alazami.

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Ethics Approval

All research involving patient materials was approved by the King Faisal Specialist Hospital & Research Centre (Riyadh) institutional review board, RAC # 2080 025.

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Obtained.

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The authors declare no competing interests.

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Sheikh, F., Alajlan, H., Albanyan, M. et al. Phenotypic and Genotypic Characterization of Hereditary Angioedema in Saudi Arabia. J Clin Immunol 43, 479–484 (2023). https://doi.org/10.1007/s10875-022-01399-y

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  • DOI: https://doi.org/10.1007/s10875-022-01399-y

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