title: Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene.
abstract: Haemophillia A (HA) is an X-linked bleeding disorder caused by mutations in the F8 gene. While the disease affects 1 in 5000 males, phenotypic expression of haemophilia A is rare in females, similar to other X-linked recessive disorders. We describe a 5-year-old female with severe haemophilia A. We determined the underlying molecular defect in the F8 genes of the proband and her closest family members by direct DNA sequencing, marker analysis and quantitative real-time polymerase chain reaction. The patient showed two different mutations in the F8 gene: the paternal copy of the F8 gene had a de novo p.Phe652/653 deletion in exon 13 while the maternally inherited gene showed a large deletion encompassing exons 1 to 22. The structural analysis of residues Phe652/Phe653 based on a three-dimensional model of activated factor VIII provides evidence of the impact of the mutant factor VIII protein in the clinical manifestations of the patient. This unusual finding highlights the need to perform a thorough molecular analysis including sequencing, marker and quantitative analyses to identify compound heterozygous females with HA.
authors.affiliation: Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Venceslá
authors.forename: P
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: M
authors.initials: M
authors.lastname: Baena
authors.forename: M
authors.initials: M
authors.lastname: Quintana
authors.forename: M
authors.initials: M
authors.lastname: Baiget
authors.forename: E F
authors.initials: EF
authors.lastname: Tizzano
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D003062:Codon; D005169:Factor VIII