Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene = Wybrane aspekty genotypowania wrodzonego obrzȩku naczynioruchowego w erze NGS: Gen F12

Objective. To screen a cohort of patients diagnosed with non-FXII angioedema for carriage of variants of F12 gene. Material and methods. DNA samples from 191 patients suffering from primary angioedema with normal C1-INH, 54 samples from non- -affected family members, and 161 samples from C1-INH-HAE (154 type I, 7 type II) patients were included in the study. The F12 gene was genotyped by targeted NGS (100% coverage of translated regions). Sanger sequencing was performed for the verification of all identified variants and family segregation studies. Results. The pathogenic F12 variant c.983C>A was detected in three patients from two unrelated families initially diagnosed as U-HAE. Six additional mutations were identified, four of which were characterized as benign (c.41T>C, c.418C>G, c.1025C>T, c.530C>T) and two of uncertain significance (c.1530G>C, c.1768T>G). Two synonymous variants (c.756C>T and c.711C>T), the common polymorphism c.619G>C, and the functional polymorphism c.-4T>C were detected in allele frequencies similar to those presented in the ExAC database for the European population. One more not yet reported synonymous variant (c. 1599A>G) was also found. Conclusion. Analyzing the entire translated region of F12 gene is important in order to identify new variants that possibly affect HAE expressivity. Interestingly, genetic analysis of F12 supports not only the diagnosis of FXII-HAE but also the correct exclusion diagnosis of U-HAE.