Novel Variants and Mechanisms in Atypical Hereditary Angioedema: A Chinese Multicenter Study

Background : Hereditary angioedema (HAE) is characterized by significant genetic heterogeneity. While rare variants in MYOF and HS3ST6 have been indicated in the Chinese population, their pathogenic spectrum, clinical phenotypes, and biochemical associations remain insufficiently elucidated. This study aimed to identify novel pathogenic variants and investigate genotype-phenotype correlations, specifically regarding atypical C1-inhibitor (C1-INH) levels in rare subtypes. Methods: We retrospectively enrolled 20 unrelated HAE probands from multiple centers in China. Detailed clinical data were collected, and whole-exome sequencing (WES) was performed on patients with normal C1-INH and a subset of HAE-1/2 patients (n=9). Candidate variants were validated by Sanger sequencing and co-segregation analysis. Results: The cohort encompassed HAE-1, HAE-2, HAE-FXII, and rare subtypes. WES identified four novel variants: SERPING1 c.23_26dup (p.Leu10AspfsTer11), F12 c.1751_1753del (p.Ile584del), MYOF c.4183G>A (p.Glu1395Lys), and HS3ST6 c.895del (p.Arg299AlafsTer36). Notably, patients carrying HS3ST6 and MYOF variants exhibited reduced C1-INH levels or function, mimicking the biochemical profile of HAE-1. Furthermore, the patient with the MYOF variant presented with urticaria and showed a partial response to omalizumab, suggesting potential mast cell involvement. Conclusion: This study provides the first multicenter validation of ultra-rare MYOF and HS3ST6 subtypes in China, expanding their genetic spectrum. The observation of secondary C1-INH deficiency in these subtypes challenges classifications relying solely on biochemical markers and supports the hypothesis of endothelial dysfunction-driven C1-INH consumption. These findings underscore the pivotal role of WES in diagnosing unexplained angioedema and lay a foundation for precision treatment strategies.