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Thromb Haemost 2006; 96(05): 630-641
DOI: 10.1160/TH06-07-0383
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease

Anthony Cumming
1   University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
Pamela Grundy
1   University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
Stephen Keeney
1   University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
William Lester
2   Department of Haematology, Birmingham Children’s Hospital, Birmingham, UK
,
Said Enayat
2   Department of Haematology, Birmingham Children’s Hospital, Birmingham, UK
,
Andrea Guilliatt
2   Department of Haematology, Birmingham Children’s Hospital, Birmingham, UK
,
Derrick Bowen
3   Department of Haematology, University of Wales College of Medicine, Cardiff, UK
,
John Pasi
4   Department of Haematology, Royal London Hospital, London, UK
,
David Keeling
5   Oxford Haemophilia Centre, Churchill Hospital, Oxford, UK
,
Frank Hill
2   Department of Haematology, Birmingham Children’s Hospital, Birmingham, UK
,
Paula H. B. Bolton-Maggs
1   University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
Charles Hay
1   University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
Peter Collins
3   Department of Haematology, University of Wales College of Medicine, Cardiff, UK
,
on behalf of the UK Haemophilia Centre Doctors’ Organisation › Author AffiliationsFinancial support: This work was supported in part by a grant from the UK Haemophilia Society.
Further Information

Publication History

Received 11 July 2006

Accepted after revision 15 September 2006

Publication Date:
01 December 2017 (online)

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Summary

Forty families diagnosed by UK centres to have type 1 VWD were recruited. Following review, six families were re-diagnosed to have type 2 VWD, one to have a platelet storage pool disorder, and one family was determined to be unaffected. Direct DNA sequencing of the promoter region and all exons and intronic boundaries of the VWF gene identified six mutations likely to be causative of VWD in index cases of nine of the 32 (28%) confirmed type 1 VWD families. These included R1205H (3614G>A) VWD Vicenza, P1648fsX45 (4944delT), D141G (422A>G) and three splice site mutations: 3108+5G>A, 7437+1G>A and 3379+1G>A. The Y1584C (4751A>G) polymorphism was present in eight additional families. No significant VWF gene mutation or polymorphism was identified in 15 of the32 type 1VWD index cases (47%). Haplotype studies were performed using a panel of VWF polymorphisms to investigate the segregation in families of VWD phenotype with the VWF gene. In 13 of the 32 families it was likely that VWD segregated with the VWF gene. In eight families (25%) VWD clearly did not segregate with the VWF gene. We suggest that mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in type 1 VWD. If genetic studies are performed, the incomplete penetrance and variable expressivity of type 1 VWD must be taken into account. Unless linkage of VWD phenotype with the VWF gene can be clearly demonstrated, the results of any genetic family studies should be interpreted with caution.

Keywords

Type 1VWD, VWF gene mutations - inherited bleeding disorders - molecular pathogenesis
 

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