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

Background Hereditary angioedema with C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal dominant disorder caused by pathogenic variants in SERPING1. We report a four-generation Chinese pedigree with a novel SERPING1 variant. Methods Nine family members underwent clinical evaluation, biochemical testing (complement C4, C1-INH concentration and functional activity), whole-exome sequencing (WES), and Sanger validation. Pathogenicity was classified according to ACMG/AMP guidelines with updated ClinGen SVI specifications. Results A novel 19-bp complex indel in SERPING1 (c.204_205delinsCCGGCCAAGAACACCAACA; p.Asn69ArgfsTer16) was identified. Sanger sequencing confirmed perfect co-segregation with C1-INH deficiency across seven carriers (five symptomatic, two asymptomatic), while two unaffected relatives were wild-type. The variant was classified as pathogenic (PVS1 + PP1_Strong+PP4 + PM2_Supporting) and absent from 1,000 Genomes, gnomAD, ClinVar, and HGMD. Two asymptomatic carriers demonstrated incomplete clinical penetrance. Conclusion This novel SERPING1 complex indel causes HAE-C1INH type 1 in this Chinese pedigree, expanding the global variant spectrum. Family-based screening identifies asymptomatic carriers who may benefit from preventive counseling.