title: Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations.
abstract: Severe von Willebrand's disease (VWD) type 3 is a rare autosomal-recessively inherited bleeding disorder, showing considerable genotypic heterogeneity. We investigated the phenotype in correlation with the genotype in Finnish type 3 VWD patients. Ten patients previously diagnosed with VWD type 3 treated at the Coagulation Disorder Unit in Helsinki University Hospital were re-evaluated for bleeding tendency and treatment. Phenotypic characterization included coagulation and platelet function testing confirming the diagnosis. The genotype was assessed by initial screening for the common c.2435delC mutation and subsequently if needed, by analysing all 51 coding exons of the von Willebrand factor gene. Our result confirmed the diagnosis of type 3 VWD for all 10 patients. We discovered two common mutations: nine of the 20 alleles (45%) were found to carry the c.2435delC frameshift mutation, previously described to be frequent in countries surrounding the Baltic Sea. The nonsense mutation c.4975C>T (p.R1659X) was found on 8/20 (40%) of the alleles. In addition, three novel mutations, a potential splice site mutation (c.874+2T>C) and two frameshift mutations (c.1668delC and c.2072delCCinsG) were found. Seven patients were homozygous and three compound heterozygous for the reported mutations. This study indicates that mainly two mutations (c.2435delC and p.R1659X) cause the majority of type 3 VWD in Finland. This result sets future standards for the genetic testing among the Finnish type 3 VWD population.
authors.affiliation: Coagulation Disorders Unit, Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Jokela
authors.forename: R
authors.initials: R
authors.lastname: Lassila
authors.forename: T
authors.initials: T
authors.lastname: Szanto
authors.forename: L
authors.initials: L
authors.lastname: Joutsi-Korhonen
authors.forename: E
authors.initials: E
authors.lastname: Armstrong
authors.forename: F
authors.initials: F
authors.lastname: Oyen
authors.forename: S
authors.initials: S
authors.lastname: Schneppenheim
authors.forename: R
authors.initials: R
authors.lastname: Schneppenheim
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D018389:Codon, Nonsense; D005260:Female; D005387:Finland; D016368:Frameshift Mutation; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D056729:von Willebrand Disease, Type 3 / Q000175:diagnosis / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D014841:von Willebrand Factor
keywords: genetic defect; inherited bleeding disorder; type 3; von Willebrand's disease