Researchers identified novel pathogenic variants of SERPING1, the gene encoding C1 inhibitor (C1-INH), in patients with hereditary angioedema (HAE) using genomic sequencing approaches. Moreover, they showed that at least some of these variants might have consequences on C1-INH protein folding, glycosylation, and function.

“We anticipate our approach to defining the disease will allow for further informative insights into its pathophysiology and treatment,” the researchers wrote in the Journal of Allergy and Clinical Immunology.

The researchers identified 11 heterozygous variants in the SERPING1 gene of 15 participants, including 6 single-nucleotide variants, 2 nonframeshift deletions, and 3 frameshift variants. Five variants were classified as pathogenic (E85Dfs*63, N166Qfs*91, K201Qfs*56, P399A, and R466H), and 6 were classified as variants of uncertain significance (C130W, I224S, N272del, K273del, L349F, and F471C).

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One single-nucleotide variant, F471C, and 2 frameshift variants, N166Qfs*91 and E85Dfs*63, were identified for the first time. The remaining 5 single-nucleotide variants were rare variants (minor allele frequency of less than 0.01%).

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One patient had a compound variant, P399A/L349F, which may be associated with a more severe clinical phenotype.

Subsequent analysis suggested that C130W, N272del, P399A, and F471C were poorly synthesized. Furthermore, I224S could lead to C1-INH forming oligomers extracellularly, preventing proper C1-INH folding, whereas K273del might impair C1-INH function by adding an additional oligosaccharide.

The researchers analyzed genetic alterations in the SERPING1 gene of 20 patients from 14 families with HAE by whole-exome sequencing (WES). In addition, they performed whole-genome sequencing (WGS) in patients who did not demonstrate sequence alterations on WES. Five participants from 3 unrelated families did not show causative mutations on initial evaluation by WES, but WGS analysis identified 3 large deletions in the SERPING1 gene.


Ren Z, Zhao S, Li T, Wedner HJ, Atkinson JP. Insights into the pathogenesis of hereditary angioedema employing genetic sequencing and recombinant protein expression analyses. J Allergy Clin Immunol. Published online December 29, 2022. doi:10.1016/j.jaci.2022.11.027