title: Characterisation of a large complex intragenic re-arrangement in the FVII gene (F7) avoiding misdiagnosis in inherited factor VII deficiency.
abstract: Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder mostly caused by point mutations. Large genomic re-arrangements at F7 locus could account for a fraction of mutant alleles that remain unidentified after DNA sequencing, because they escape conventional polymerase chain reaction (PCR)-based techniques. We report the first systematic screening of F7 for large re-arrangements, by semi-quantitative multiplex PCR of fluorescent fragments targeting the 9 exons and the promoter region. A well-characterised cohort of 43 unrelated patients either apparently homozygous for a F7 point mutation or carrying at least one unidentified F7 mutant allele participated in this study. Two large F7 re-arrangements were identified in two FVII-deficient pedigrees, including a discontinuous deletion involving two distinct portions of F7 whose proximal and distal end junctions were characterised. A simple and efficient method for the routine detection of gross alterations of F7, which accounted for 2.3% of mutant alleles in our sample, is now available in inherited FVII deficiency. This test should complement conventional PCR-based techniques not only in unsolved cases, but also where inheritance pattern analysis is not achievable.
authors.affiliation: Inserm, U827, Laboratoire de Génétique de Maladies Rares: Pathologie Moléculaire, Etudes Fonctionnelles et Banques de Données Génétiques, Montpellier, France. m-giansily@chu-montpellier.fr
authors.forename: Muriel
authors.initials: M
authors.lastname: Giansily-Blaizot
authors.forename: Delphine
authors.initials: D
authors.lastname: Thorel
authors.forename: Philippe
authors.initials: P
authors.lastname: Khau Van Kien
authors.forename: Catherine
authors.initials: C
authors.lastname: Behar
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Romey
authors.forename: Francine
authors.initials: F
authors.lastname: Mugneret
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Schved
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005091:Exons; D005167:Factor VII / Q000235:genetics*; D005168:Factor VII Deficiency / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic
chemical_list: D005167:Factor VII