In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency


Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is caused by mutations affecting the SERPING1 gene. Adult patients (≥ 18 years old) diagnosed with C1-INH-HAE were clustered according to a modified SERPING1 gene mutation classification [5]. Demographic, clinical, and laboratory data were studied. Published manuscripts on the genotype/phenotype relationship were reviewed. Eighty-eight patients participated in the study, with 78 having a classifiable mutation. We compared the data in the 3 largest groups: class 0 only (n = 32), class II only (n = 18), class III only (n = 22). Antigenic C4 and C1 inhibitors were higher in class II (p = 0.008 and p = 0.02, respectively), and facial attacks in the last 6 months were more frequent in class III (p = 0.04)). All the other differences were non-significant. Twelve manuscripts on phenotype/genotype correlation were found: missense mutations in SERPING1 gene were associated with delay in disease onset and lower severity score in some studies, whereas the CC F12-C46T/C polymorphism produced earlier disease onset. Our study shows minimal differences regarding clinical phenotype in patients with class 0, II, and III SERPING1 gene mutations, with a tendency to class III having a more severe phenotype. The study should be performed in a larger sample to confirm if they are significant.

We propose that larger multicenter, international studies are performed, comparing different SERPING1 gene mutation classifications, combining polymorphisms in other involved genes (kallikrein-kinin system, regulation of vasculature, plasminogen activation) and using different variables and clinical scores to assess C1-INH-HAE disease activity and/or severity in order to study possible genotype/phenotype relationships.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.



Hereditary angioedema


C1 inhibitor


Hereditary angioedema due to C1 inhibitor deficiency


Reactive center loop


Plasma-derived human C1 inhibitor concentrate


Long-term prophylaxis


Interquartile range


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The authors would like to thank all the patients involved for giving consent and support to this study.


ALL is supported by the Centre for Biomedical Network Research on Rare Diseases. TC is a researcher from the IdiPaz program to promote research activities. This work was partially supported by grant PI15-00255 from Instituto de Salud Carlos III (ISCIII, Ministerio de Economía y Competitividad) and Fondos FEDER.

Author information




DLA, ALL and TC designed the study. ALL performed the genetic study. ALL and CD classified the SERPING1 gene mutations. RC, ML, EP, MP, TC collected the clinical data and passed the HAE-AS to patients. DLA and MP performed the statistical analysis. All the authors analyzed the results. DLA and TC wrote the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to David Loli-Ausejo.

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The authors certify that they have no affiliations with or involvement in any organization or entity in the subject matter or materials discussed in this manuscript.

Ethical Approval

The Ethics Review Panel of La Paz University Hospital reviewed and approved this study meeting the requirements of the 2013 Helsinki declaration and its later amendments (PI-1654, PI-2297).

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All patients included were duly informed and gave written consent to participate and have their samples biobanked.

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Loli-Ausejo, D., López-Lera, A., Drouet, C. et al. In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency. Clinic Rev Allerg Immunol (2021).

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  • Hereditary angioedema
  • Phenotype
  • Genotype
  • Association
  • SERPING1 gene