Factor 8 Gene Mutation Spectrum of 270 Patients with Haemophilia A: Identification of 36 Novel Mutations

Objective: Haemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the F8 gene. The aim of this study is to determine mutation spectrum of F8 gene in a large HA cohort from Turkey, and then to establish a phenotype-genotype correlation. Materials and Methods: All HA patients (270 patients), analyzed molecularly in Ege University Pediatric Genetics Molecular Laboratory between March 2017 and March 2018, were included in this study. To identify "intron 22 inversion" (Inv22), "intron 1 inversion" (Inv1), "small deletion/insertions" and "point mutations", molecular analyses of F8 were performed using a sequential application of molecular techniques. Results: The mutation detection success rate was 95.2%. A positive Inv22 was found in 106 patients (39.3%), Inv1 was found in 4 patients (1.5%), and 106 different disease-causing sequence variants were identified in 137 patients (50.6%). In 10 patients (3.7%), amplification failures involving one or more exonic regions, considered to be large intragenic deletions, were identified. Of 106 different F8 mutations, 36 were novel. The relationship between F8 genotype and inhibitor development was considered significant. Conclusion: A high mutation detection rate was achieved via the broad molecular techniques performed in this study; including 36 novel mutations. With regard to mutation types, mutation distribution and their impact on clinical severity and inhibitor development were found to be similar to those previously reported in different haemophilia population studies.