Abstract | BACKGROUND: 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.
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Authors | M Bowman, A Tuttle, C Notley, C Brown, S Tinlin, M Deforest, J Leggo, V S Blanchette, D Lillicrap, P James, Association of Hemophilia Clinic Directors of Canada |
Journal | Journal of thrombosis and haemostasis : JTH
(J Thromb Haemost)
Vol. 11
Issue 3
Pg. 512-20
(Mar 2013)
ISSN: 1538-7836 [Electronic] England |
PMID | 23311757
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2013 International Society on Thrombosis and Haemostasis. |
Chemical References |
- Isoantibodies
- von Willebrand Factor
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Topics |
- 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
- Severity of Illness Index
- Surveys and Questionnaires
- Transfection
- Young Adult
- von Willebrand Disease, Type 3
(blood, diagnosis, epidemiology, genetics)
- von Willebrand Factor
(genetics, immunology, metabolism)
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