Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene
Sofia Vatsiou, Maria Zamanakou, Gedeon Loules, Teresa González-Quevedo, Grzegorz Porębski, Aldona Juchacz, Maria Bova, Chiara Suffritti, Davide Firinu, Dorottya Csuka, Emmanouil Manousakis, Anna Valerieva, Maria Staevska, Markus Magerl, Henriette Farkas, Anastasios E. Germenis
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
Keywords: F12 gene, F12 mutations, hereditary angioedema, next-generation