title: The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles.
abstract: BACKGROUND
  Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion.
  
  
  OBJECTIVE
  The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients.
  
  
  METHODS
  Thirty-four families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values and anti-VWF inhibitor status were included as well as sequence analysis.
  
  
  RESULTS
  We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS = 22) than those with mutations elsewhere in VWF (BS = 13). Sixty-two out of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified.
  
  
  CONCLUSIONS
  We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In approximately 50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.
authors: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors: M
authors: M
authors: Bowman
authors: A
authors: A
authors: Tuttle
authors: C
authors: C
authors: Notley
authors: C
authors: C
authors: Brown
authors: S
authors: S
authors: Tinlin
authors: M
authors: M
authors: Deforest
authors: J
authors: J
authors: Leggo
authors: V S
authors: VS
authors: Blanchette
authors: D
authors: D
authors: Lillicrap
authors: P
authors: P
authors: James
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D014162:Transfection; D055815:Young Adult; D056729:von Willebrand Disease, Type 3 / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D007518:Isoantibodies; D014841:von Willebrand Factor