title: Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution.
abstract: Hemophilia A (HA) is an X-linked hereditary bleeding disorder defined by a qualitative and/or quantitative factor VIII (FVIII) deficiency. The molecular diagnosis of HA is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing HA. We identified 95 novel mutations out of 180 different mutations responsible for HA in 515 patients from 406 unrelated families followed up at a single hemophilia treatment center of the Bicêtre university hospital (Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin-Bicêtre). These 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. We therefore developed a mutation analysis based on a body of proof that combines the familial segregation of the mutation, the resulting biological and clinical HA phenotype, and the molecular consequences of the amino acid (AA) substitution. For the latter, we studied the putative biochemical modifications: its conservation status with cross-species FVIII and homologous proteins, its putative location in known FVIII functional regions, and its spatial position in the available FVIII 3D structures. The usefulness of such a strategy in interpreting the causality of novel F8 mutations is emphasized.
authors.affiliation: Centre de traitement des hémophiles, Laboratoire d'Hématologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France. benoit.guillet@chu-rennes.fr
authors.forename: Benoît
authors.initials: B
authors.lastname: Guillet
authors.forename: Thierry
authors.initials: T
authors.lastname: Lambert
authors.forename: Roseline
authors.initials: R
authors.lastname: d'Oiron
authors.forename: Valérie
authors.initials: V
authors.lastname: Proulle
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Plantier
authors.forename: Anne
authors.initials: A
authors.lastname: Rafowicz
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Peynet
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Costa
authors.forename: Laurence
authors.initials: L
authors.lastname: Bendelac
authors.forename: Yves
authors.initials: Y
authors.lastname: Laurian
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Lavergne
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics*; D006467:Hemophilia A / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein
chemical_list: D005169:Factor VIII