The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study.
In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of type 1 von Willebrand disease (VWD), a large multicenter Canadian study was undertaken. We present data from the sequence analysis of the VWF gene in 123 type 1 VWD index cases and their families. We have identified putative mutations within the VWF gene in 63% (n = 78) of index cases, leaving 37% (n = 45) with no identified changes. These changes comprise 50 different putative mutations: 31 (62%) missense mutations, 8 (16%) changes involving the VWF transcriptional regulatory region, 5 (10%) small deletions/insertions, 5 (10%) splicing consensus sequence mutations, and 1 nonsense mutation. Twenty-one of the index cases had more than one putative VWF mutation identified. We were somewhat more likely to identify putative mutations in cases with lower VWF levels, and the contribution of other factors, such as ABO blood group, seems more important in milder cases. Taken as a whole, our data support a complex spectrum of molecular pathology resulting in type 1 VWD. In more severe cases, genetic changes are common within the VWF gene and are highly penetrant. In milder cases, the genetic determinants are more complex and involve factors outside of the VWF gene.
James
Paula D
PD
Department of Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
Notley
Colleen
C
Hegadorn
Carol
C
Leggo
Jayne
J
Tuttle
Angie
A
Tinlin
Shawn
S
Brown
Christine
C
Andrews
Chandler
C
Labelle
Andrea
A
Chirinian
Yvette
Y
O'Brien
Lee
L
Othman
Maha
M
Rivard
Georges
G
Rapson
Dilys
D
Hough
Christine
C
Lillicrap
David
D
D000017:ABO Blood-Group System / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002170:Canada / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D014842:von Willebrand Diseases / Q000097:blood / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics*
D000017:ABO Blood-Group System; D014841:von Willebrand Factor