Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population

Abstract

SummaryThe development of neutralising antibodies to factor VIII (FVIII) is a major complication of haemophilia A (HA) therapy. We aimed to construct an individual risk profile for the development of inhibitors in HA and started by screening for the causative mutation in our HA patient population. A total of 109 patients and 28 carriers were screened. The analysis revealed 38 different mutations in the FVIII gene, of which 13 have not been described on the Haemophilia A Mutation, Search, Test and Resource Site (HAMSTeRS). Twenty-five mutations have been reported previously and all except two had a similar phenotype to what has been described. Three novel mutations were associated with severe HA: one non-missense mutation, a small insertion in the A2 domain, and two missense mutations, a H256R mutation in the A1 domain and a L2025P substitution in the C1 domain. One novel mutation, Y156C, was associated with moderate HA. Nine novel mutations caused mild HA. The P130R, D167E and V278M mutations are located in the A1 domain. R439C, Y511H, A544G and Q645H in the A2 domain, L1758F in the A3 domain and a S2157R mutation in the C1 domain. In conclusion, the genotypic profile of our HA population was not different from others described and is suitable to study inhibitor formation.

The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

“…The types of mutations found were in agreement with results reported in other settings (Table 2). [15][16][17][18][19][20][21][22][23][24] As expected, most of patients with severe HA carry a molecular defect predicting a null allele (large deletion, inversion, nonsense, and insertion/deletion mutations), whereas missense mutations have been found in the majority of patients with moderate (68%) and mild HA (80%).…”

Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia: Two Novel Mutations and Genotype-Phenotype Correlation

“…Genetic mutations in factor VIII cause deregulation of this protein leading to bleeding disorders [15][16][17][18][19]. Defects in factor VIII gene includes deletions, large DNA inversions, nonsense mutations, ins/ del-frame shifts, splice variants and a large number of missense point mutations, all of which can cause defects in the expression, secretion, and/or half-life of factor VIII protein in circulation [20][21][22][23][24][25].…”

“…Several studies are available in literature describing the mutations in factor VIII gene, from many ethnic groups and different populations [16,17,25,29,30]. Recently, some reports were published from Middle Eastern countries also describing factor VIII gene mutations [31][32][33][34].…”

Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

“…14 Promoter analysis was performed as previously described. 20 The amplified fragments were purified with QIAquick columns (Qiagen, Isaza, Barcelona, Spain), and analyzed by direct forward and reverse sequencing using a DNA sequencing kit (PerkinElmer-Applied Biosystems, Madrid, Spain) on an ABI PRISM 3100 Avant DNA automatic sequencer (Applied Biosystems, Madrid, Spain).…”