Novel SERPING1 Variant Traced Through Four Generations of Chinese Family With Hereditary Angioedema

Researchers in China have identified a previously unreported SERPING1 variant in a four-generation family affected by hereditary angioedema with C1-inhibitor deficiency, a rare autosomal dominant disorder in which pathogenic variants in SERPING1 cause recurrent swelling attacks. The finding, reported as a case study in Frontiers in Allergy, documents a 19-base-pair complex insertion-deletion in the gene that co-segregated with C1-inhibitor deficiency across seven carriers in the four-generation pedigree, while also revealing that two carriers of the variant show no symptoms at all.

The investigation began with nine family members, who underwent clinical evaluation, biochemical testing of complement C4, C1-inhibitor concentration and functional activity, whole-exome sequencing, and Sanger validation of the sequencing results. The variant, designated c.204_205delinsCCGGCCAAGAACACCAACA, produces a frameshift in the protein sequence, annotated as p.Asn69ArgfsTer16, meaning the reading frame is disrupted at position 69 and a premature stop codon appears 16 residues later.

Sanger sequencing confirmed that the variant co-segregated perfectly with C1-inhibitor deficiency across seven carriers in the family, five of whom were symptomatic and two of whom were asymptomatic. Two unaffected relatives tested wild-type at this locus. Hereditary angioedema with C1-inhibitor deficiency is described as a rare autosomal dominant disorder caused by pathogenic variants in SERPING1.

To classify the variant, the researchers applied the ACMG/AMP guidelines with updated ClinGen SVI specifications, a standardized framework used by clinical genetics laboratories worldwide. The variant was classified as pathogenic based on a combination of criteria: PVS1, indicating a predicted loss-of-function mechanism; PP1_Strong, reflecting strong evidence from segregation within the family; PP4, indicating the phenotype is highly specific for the disorder; and PM2_Supporting, reflecting absence from population databases. The variant was absent from the 1000 Genomes, gnomAD, ClinVar, and HGMD databases, supporting its novelty.

The two asymptomatic carriers demonstrate incomplete clinical penetrance, a phenomenon in which individuals carrying a disease-causing variant do not manifest the associated condition. The authors conclude that family-based screening identifies asymptomatic carriers who may benefit from preventive counseling.

The identification of this novel complex indel expands the global spectrum of known SERPING1 variants associated with hereditary angioedema type 1.

The researchers emphasize that family-based screening identifies asymptomatic carriers who may benefit from preventive counseling.

Subject of Research: A novel SERPING1 complex indel causing hereditary angioedema with C1-inhibitor deficiency type 1 in a four-generation Chinese pedigree

Article Title: Case Report: A novel SERPING1 variant in a four-generation Chinese pedigree with hereditary angioedema with C1-inhibitor deficiency type 1

Article References: Zhu, P., Luo, Y., Dai, S., JIANG, C., & Zhang, W. (2026). Case Report: A Novel SERPING1 Variant in a Four-Generation Chinese Pedigree with Hereditary Angioedema with C1-Inhibitor Deficiency Type 1. Frontiers in Allergy, 7, 1961416. https://doi.org/10.3389/falgy.2026.1961416

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1961416

Keywords: SERPING1, hereditary angioedema, C1-inhibitor deficiency, whole-exome sequencing, incomplete penetrance, genetics, case report, Chinese pedigree, ACMG/AMP classification, complement C4, autosomal dominant, variant spectrum