Characterisation of a large complex intragenic re-arrangement in the FVII gene (F7) avoiding misdiagnosis in inherited factor VII deficiency.
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.
Giansily-Blaizot
Muriel
M
Inserm, U827, Laboratoire de Génétique de Maladies Rares: Pathologie Moléculaire, Etudes Fonctionnelles et Banques de Données Génétiques, Montpellier, France. m-giansily@chu-montpellier.fr
Thorel
Delphine
D
Khau Van Kien
Philippe
P
Behar
Catherine
C
Romey
Marie-Catherine
MC
Mugneret
Francine
F
Schved
Jean-François
JF
Claustres
Mireille
M
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
D005167:Factor VII