Hereditary angioedema is a rare, autosomal dominant, genetic disorder characterized by recurrent episodes of angioedema. Over 800 SERPING1 gene variants have been reported, and their clinical profiles and causal genetic variants are highly heterogeneous. We report two cases of hereditary angioedema (HAE) in a Portuguese family: a 27-year-old male, under lanadelumab, and his 57-year-old father, kept on on-demand treatment. Genetic testing was performed following international guidelines. The Hereditary Angioedema Database Annotation highlighted a heterozygous insertion at exon 3 (c.336_337insC). This variant predicts a frameshift of the transcript, with the introduction of a premature STOP codon in C1-INH protein (p.Ser113LeufsTer20). We report the identification of a novel pathogenic SERPING1 variant in a family with HAE type 1, assisted by the Hereditary Angioedema Database Annotation variant prioritization tool. Our results may contribute to the identification of additional families with the same variant and can further enhance the knowledge about this condition.

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