title: Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD.
abstract: BACKGROUND
  von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported.
  
  
  OBJECTIVE
  To estimate the proportion of type 1 VWD that is linked to the VWF gene.
  
  
  METHODS
  Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed.
  
  
  RESULTS
  Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene.
  
  
  CONCLUSIONS
  We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.
authors.affiliation: Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands. h.c.j.eikenboom@lumc.nl
authors.forename: J
authors.initials: J
authors.lastname: Eikenboom
authors.forename: V
authors.initials: V
authors.lastname: Van Marion
authors.forename: H
authors.initials: H
authors.lastname: Putter
authors.forename: A
authors.initials: A
authors.lastname: Goodeve
authors.forename: F
authors.initials: F
authors.lastname: Rodeghiero
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.forename: A B
authors.initials: AB
authors.lastname: Federici
authors.forename: J
authors.initials: J
authors.lastname: Batlle
authors.forename: D
authors.initials: D
authors.lastname: Meyer
authors.forename: C
authors.initials: C
authors.lastname: Mazurier
authors.forename: J
authors.initials: J
authors.lastname: Goudemand
authors.forename: R
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: U
authors.initials: U
authors.lastname: Budde
authors.forename: J
authors.initials: J
authors.lastname: Ingerslev
authors.forename: Z
authors.initials: Z
authors.lastname: Vorlova
authors.forename: D
authors.initials: D
authors.lastname: Habart
authors.forename: L
authors.initials: L
authors.lastname: Holmberg
authors.forename: S
authors.initials: S
authors.lastname: Lethagen
authors.forename: J
authors.initials: J
authors.lastname: Pasi
authors.forename: F
authors.initials: F
authors.lastname: Hill
authors.forename: I
authors.initials: I
authors.lastname: Peake
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D012307:Risk Factors; D014842:von Willebrand Diseases / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D014841:von Willebrand Factor