Expanding the Genetic and Clinical Spectrum of Hereditary Angioedema with Normal C1 Inhibitor: Novel Variants and...

Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema.