- D1.538 - First Report of the SERPING1 c.52-1G>A Variant in a Chinese HAE Pedigree: Severe Abdominal Phenotype Correlated with Attack-Phase Imaging

Hereditary angioedema (HAE) is often misdiagnosed when presenting with acute abdominal attacks. Although the SERPING1 c.52-1G>A splice-site variant is an established cause, its phenotypic expression and associated imaging findings during attacks remain uncharacterized in Chinese patients, limiting genotype-phenotype correlation and counseling.

We conducted a clinical-genetic analysis of a four-generation Han Chinese HAE pedigree. Diagnosis was confirmed biochemically (serum C4 and C1-INH antigen/function). Acute-phase abdominal imaging (CT/ultrasound) was reviewed for edema. Whole-exome sequencing was performed on the proband and two other affected family members, followed by Sanger sequencing for variant validation and co-segregation analysis within the pedigree.Pathogenicity was assessed per ACMG guidelines using splice prediction tools (SpliceAI, dbscSNV).

All three affected members had markedly reduced C4 and C1-INH, confirming HAE type I. Phenotypic heterogeneity was noted: two patients (66.7%) presented with recurrent severe abdominal pain and vomiting, while one had isolated cutaneous edema. Attack-phase CT in one patient demonstrated diffuse small-bowel wall thickening, mucosal enhancement, and mild ascites, consistent with intestinal angioedema. Genetic analysis identified the heterozygous SERPING1 c.52-1G>A variant in all symptomatic individuals, with complete disease co-segregation. The variant was classified as pathogenic (ACMG: PVS1, PM2).

This study describes the first Chinese HAE pedigree with the SERPING1 c.52-1G>A variant and delineates its association with a severe abdominal-predominant phenotype, which was objectively characterized by attack-phase imaging.Our findings expand the mutational spectrum of HAE in the Chinese population and suggest potential population-specific phenotypic patterns. We emphasize the necessity of including HAE in the differential diagnosis of unexplained recurrent abdominal pain and advocate for a combined diagnostic strategy integrating biochemical screening, attack-phase imaging, and confirmatory genetic testing to achieve precise diagnosis and guide family management.