title: The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study.
abstract: 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.
authors.affiliation: Department of Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Paula D
authors.initials: PD
authors.lastname: James
authors.forename: Colleen
authors.initials: C
authors.lastname: Notley
authors.forename: Carol
authors.initials: C
authors.lastname: Hegadorn
authors.forename: Jayne
authors.initials: J
authors.lastname: Leggo
authors.forename: Angie
authors.initials: A
authors.lastname: Tuttle
authors.forename: Shawn
authors.initials: S
authors.lastname: Tinlin
authors.forename: Christine
authors.initials: C
authors.lastname: Brown
authors.forename: Chandler
authors.initials: C
authors.lastname: Andrews
authors.forename: Andrea
authors.initials: A
authors.lastname: Labelle
authors.forename: Yvette
authors.initials: Y
authors.lastname: Chirinian
authors.forename: Lee
authors.initials: L
authors.lastname: O'Brien
authors.forename: Maha
authors.initials: M
authors.lastname: Othman
authors.forename: Georges
authors.initials: G
authors.lastname: Rivard
authors.forename: Dilys
authors.initials: D
authors.lastname: Rapson
authors.forename: Christine
authors.initials: C
authors.lastname: Hough
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: 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*
chemical_list: D000017:ABO Blood-Group System; D014841:von Willebrand Factor