Document Detail


The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles.
MedLine Citation:
PMID:  23311757     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion.
OBJECTIVES: The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients.
PATIENTS AND 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:
M Bowman; A Tuttle; C Notley; C Brown; S Tinlin; M Deforest; J Leggo; V S Blanchette; D Lillicrap; P James;
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  11     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-08-30     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  512-20     Citation Subset:  IM    
Copyright Information:
© 2013 International Society on Thrombosis and Haemostasis.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aged, 80 and over
Blood Coagulation / genetics*
Canada / epidemiology
Child
Child, Preschool
Cohort Studies
Female
Genes, Dominant*
Genetic Predisposition to Disease
HEK293 Cells
Heredity
Heterozygote
Homozygote
Humans
Infant
Isoantibodies / blood
Male
Middle Aged
Mutation*
Phenotype
Questionnaires
Severity of Illness Index
Transfection
Young Adult
von Willebrand Disease, Type 3 / blood,  diagnosis,  epidemiology,  genetics*
von Willebrand Factor / genetics*,  immunology,  metabolism
Grant Support
ID/Acronym/Agency:
HL081588/HL/NHLBI NIH HHS; P01 HL081588/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Isoantibodies; 0/von Willebrand Factor
Comments/Corrections
Comment In:
J Thromb Haemost. 2013 Sep;11(9):1786-7   [PMID:  23844668 ]
J Thromb Haemost. 2013 Sep;11(9):1784-5   [PMID:  23773799 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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