doi: 10.1111/j.1469-1809.2011.00652.x Variation in the VWF Gene in Swedish Patients with Type 1 von Willebrand Disease Anna M. Johansson 1 , Christer Halld ´ en 2,3 , Torbj ¨ orn S ¨ all 4 ∗ and Stefan Lethagen 5,6,7 1 Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden 2 Department of Laboratory Medicine, Lund University, Malm¨ o, Sweden 3 Kristianstad University, Section Biomedicine, Kristianstad, Sweden 4 Department of Biology, Lund University, Lund, Sweden 5 Department for Coagulation Disorders, University Hospital, Malm¨ o, Sweden 6 Copenhagen Haemophilia Center, Copenhagen University Hospital, Copenhagen, Denmark 7 Medical & Science, Haemostasis, Global Development, Novo Nordisk A/S, Copenhagen, Denmark Summary The spectrum of mutations in the von Willebrand factor (VWF) gene in a Swedish type 1 von Willebrand disease (VWD) population was investigated. To gain more knowledge about the dynamics of VWD mutations, the data were analyzed from a population genetics perspective. The VWF gene was resequenced in 54 Swedish patients diagnosed with type 1 VWD. Fifty-five variable sites were located in exons, 10 in the promoter and 38 in introns. The spectrum of mutations was similar to a European study, but included 10 new candidate mutations. The synonymous sites were evenly distributed along the coding sequence, whereas nonsynonymous sites were located into three clusters. Overall, 44% of patients had no mutations or candidate mutations and no promoter haplotype was significantly associated with disease. In 11 patients (20%), more than one mutation or candidate mutation was detected. The allelic identity for the putative disease-causing mutations was approximately 0.1, compatible with an overall disease frequency of 1%. VWF sequences for exon 28 from eight monkey species were compared with the variable positions found in our patients. Positions classified as mutations were overrepresented among sites that were fixed in all eight monkey species. No general increase of the mutation rate was found for the pseudogene region. Keywords: DNA sequencing, mutation, type 1 VWD, VWF Introduction von Willebrand factor (VWF) is a protein that is essential for blood coagulation and acts as a carrier for factor VIII (FVIII) (Rodeghiero, 2002). The VWF gene, coding for VWF, re- sides on chromosome 12, spans 178 kb, and has 52 exons (Mancuso et al., 1989). A highly homologous VWF pseudo- gene is located on chromosome 22 and encompasses exons 23–34 of the VWF gene (including intron sequences). Muta- tions in the VWF gene or in a regulatory element may cause von Willebrand disease (VWD), which is the most common bleeding disorder. Depending on the nature of the change, ∗ Corresponding author: Torbj¨ orn S¨ all, Department of Biology, Lund University, SE-223 62 Lund, Sweden. Tel.: +46-46-222-78-58; Fax: +46-46-222-41-13; E-mail: Torbjorn.Sall@cob.lu.se VWD may take several forms and can be described as a com- plex of diseases including both quantitative and qualitative defects of the VWF gene. The current classification consists of six distinct types (Sadler et al., 2006). Type 1 and type 3 are quantitative defects, with type 1 displaying a reduction and type 3 a total absence of the VWF protein. In contrast, the four type 2 variants are all qualitative VWF defects (Keeney & Cumming, 2001). Type 1 is both the most benign and common subtype, comprising about 70% of patients. The genetic background to type 1 has until recently been largely unknown and the diagnostic criteria are under debate among experts. Type 1 VWD typically displays autosomal dominant inheritance, although diagnosis is complicated by reduced penetrance. In some families, the disease normally cosegregates with markers in the VWF gene whereas in others cosegregation Annals of Human Genetics (2011) 75,447–455 447 C  2011 The Authors Annals of Human Genetics C  2011 Blackwell Publishing Ltd/University College London