A Novel Molecular Indicator for Inhibitor Development in Haemophilia A

INTRODUCTION: Inhibitor development(ID) risk in the patients with haemophilia A(HA) having missense mutations has been reported to be 3-10% in other studies. We investigated the association between ID risk and various features of missense mutations including aminoacid group change caused by.
METHODS: Missense mutations in the F8 gene, patients’ clinical findings including severity of HA and ID status were obtained from the F8 gene variant database(http: //www.factorviii-db.org/). Twenty aminoacids are classified into groups according to their side chains. All information about each mutation and whether the mutation caused aminoacid group change were recorded. Additionally, localisation (at which domain) of the changed aminoacid in the F8 protein was recorded. In this study, we used CADD, REVEL, M-CAP, and DANN scores to find a significant cut-off value indicating ID.
RESULTS: We found three features that could be predicted to ID in mild HA: First, Among mild HA patients, 7.9% (n=70/883) of patients with mutations causing no aminoacid group changes showed ID, this rate was only 2.9% in patients with mutations leading to aminoacid group changes. Second, patients with mutations causing no aminoacid group changes effecting A2, A3 and C2 domains, ID risk was found to be higher than the patients with mutations leading to aminoacid group changes. Third, CADD and REVEL scores have been found to be associated with ID.
DISCUSSION AND CONCLUSION: In mild haemophilia A patients, the ability of aminoacid group changes of missense mutations, and CADD and REVEL scores could be suggested to use for predicting ID risk.