Variation in the VWF Gene in Swedish Patients with Type 1 von Willebrand Disease

Abstract

SummaryThe 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.

Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients

“…The p.R1379C mutation has been identified in Swedish patients as part of the European MCMDM-1VWD study 3 and in a separate study. 32 It has also been reported from Spain, 31 33 but no thorough investigation of its functional consequences has been reported. The p.P1413L and p.V1760I mutations have previously been reported in a European 3 and a Canadian study.…”

Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

“…In a strict sense, not all index cases fulfilled the modern definition of type 1 VWD, but at the time of diagnosis, their bleeding symptoms in combination with lowered VWF levels were interpreted as reflecting type 1 VWD. Two Swedish control populations were also analyzed: control population 1 (C 1 ) consisting of 192 individuals from the general population 9 and control population 2 (C 2 ) consisting of 288 unrelated male individuals with no history of bleeding from the general population. 10 This study was approved by the Ethics Committee of the Medical Faculty, Lund University, and the Swedish Data Inspection Board.…”

Update on Molecular Testing in von Willebrand Disease

“…34,39 Several studies of type 1 and type 3 VWD have employed the Sanger method using different whole VWF sequencing strategies to establish the underlying genotype. 4,[40][41][42][43][44] Considered together, optimized simplified procedures that amplify all regions under identical thermocycling parameters in a ready-to-use polymerase chain reaction (PCR) plate format reduces costs and facilitates complete Sanger sequencing of the VWF. This is suitable as a routine diagnostic tool for all types of VWD.…”