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.
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%.
Eikenboom
J
J
Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands. h.c.j.eikenboom@lumc.nl
Van Marion
V
V
Putter
H
H
Goodeve
A
A
Rodeghiero
F
F
Castaman
G
G
Federici
A B
AB
Batlle
J
J
Meyer
D
D
Mazurier
C
C
Goudemand
J
J
Schneppenheim
R
R
Budde
U
U
Ingerslev
J
J
Vorlova
Z
Z
Habart
D
D
Holmberg
L
L
Lethagen
S
S
Pasi
J
J
Hill
F
F
Peake
I
I
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
D014841:von Willebrand Factor