c.1681-7 G>A Variant in the Factor XII Gene in a Family Diagnosed with HAE-FXII Does Not Affect Splice Site

Abstract

Abstract

Introduction: Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic condition characterized by recurrent episodes of localized tissue swelling, often affecting the skin, upper respiratory tract, and gastrointestinal system. HAE-FXII, also known as HAE with normal C1 inhibitor ( C1INH ), has been associated with mutations in only one of several genes, including FXII encoding coagulation factor XII (FXII). The aim of the study was to investigate the pathogenicity and functional consequences of the c.1681-7G>A intronic variant in the FXII gene according to ACMG guidelines in familial cases of HAE-FXII. Materials and Methods: Genetic analysis was performed using Sanger sequencing on affected individuals. To assess whether the variant affects splicing, in silico analysis and Messenger RNA (mRNA) studies were conducted on patient-derived samples. Results: The c.1681-7G>A variant was identified in multiple individuals from affected families. However, splicing analysis revealed that this intronic variant did not cause any alteration in mRNA processing. No aberrant transcripts were detected, and expression levels were comparable to controls, indicating that the variant does not have an effect on splicing or gene function. Discussion: The c.1681-7G>A variant in the FXII gene is unlikely to be a pathogenic alteration in HAE type III. Contribution to the Literature: These findings support its classification as a benign variant, emphasizing the importance of functional validation when interpreting intronic changes in genetic diagnostics.