Implementation of genetic diagnosis and personalized management of hereditary angioedema in a Chinese regional center: a community case study of three families.

Background: Hereditary angioedema (HAE) remains significantly underdiagnosed and misdiagnosed in China, with laryngeal involvement leading to high mortality rates, creating an urgent need for exploring feasible diagnostic and management approaches in resource-limited settings. Objectives: To establish and evaluate a community-oriented comprehensive HAE diagnosis and management program at a regional center in central China; characterize the clinical and biochemical phenotypes of three unrelated families; identify SERPING1 variants; implement personalized treatment and family cascade screening; and evaluate key program elements as a proof-of-concept model. Methods: From September 2022 to August 2025, we established a systematic workflow for suspected HAE cases at Henan Provincial People's Hospital, integrating clinical assessment, biochemical testing, and genetic analysis. Three unrelated families (45 subjects total) were enrolled. The program included standardized clinical assessment and real-time biochemical screening (C4, C1 inhibitor concentration/function), targeted SERPING1 sequencing and variant classification American College of Medical Genetics and Genomics (ACMG), family cascade screening and genetic counseling, stratified personalized treatment (on-demand icatibant and lanadelumab prophylaxis), electronic follow-up Angioedema Control Test (AECT)/Angioedema Quality of Life Questionnaire (AE-QoL), and quality management [Standard Operating Procedures (SOPs) and provincial External Quality Assessment (EQA) planning)]. Results: Family 1: A heterozygous missense variant c.1034G > A (p.Gly345Glu) was detected in exon 7 of SERPING1 in the proband, absent in 13 unaffected family members. Laboratory tests showed decreased serum C4 and C1INH levels with reduced functional activity, consistent with HAE type 1. Family 2: Three affected members carried the same heterozygous missense variant c.1396C > T (p.Arg466Cys) in exon 8 of SERPING1, absent in 8 unaffected members. Despite elevated C1INH antigen levels, functional activity was markedly reduced, establishing HAE type 2 diagnosis. Family 3: Three affected members carried the same heterozygous missense variant c.1483G > A (p.Val495Ile) in exon 8 of SERPING1, absent in 17 unaffected members. Laboratory tests showed decreased serum C4 and C1INH levels with reduced functional activity, consistent with HAE type 1. Personalized treatment strategies achieved good disease control: mild cases with on-demand icatibant; severe phenotypes with lanadelumab prophylaxis. During 12-25 months of follow-up, the four symptomatic patients showed markedly reduced attack frequency with no life-threatening events. Discussion & conclusion: This community program represents a proof-of-concept demonstrating what is possible in establishing specialized HAE services in resource-limited settings. Key facilitating factors included cascade screening and genetic counseling, standardized testing pathways and variant classification, flexible prophylactic strategies adapted to economic conditions, and electronic quality and outcome monitoring. This program has expanded the domestic SERPING1 variant spectrum and provides preliminary insights and references for the future development of HAE services.