title: Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population.
abstract: The 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.
authors.affiliation: Department of Haematology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. j.boekhorst@hemat.umcn.nl
authors.forename: Jorien
authors.initials: J
authors.lastname: Boekhorst
authors.forename: Bert
authors.initials: B
authors.lastname: Verbruggen
authors.forename: Jean Maurice
authors.initials: JM
authors.lastname: Lavergne
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Costa
authors.forename: Selene C M
authors.initials: SC
authors.lastname: Schoormans
authors.forename: Paul P T
authors.initials: PP
authors.lastname: Brons
authors.forename: Marian G J
authors.initials: MG
authors.lastname: van Kraaij
authors.forename: Irena R O
authors.initials: IR
authors.lastname: Nováková
authors.forename: Waander L
authors.initials: WL
authors.lastname: van Heerde
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019774:Blood Coagulation Factor Inhibitors / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D018570:Risk Assessment
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII