Related Papers
Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD
David Habart
Type 1 von Willebrand disease (VWD) is characterized by a personal and family history of bleeding coincident with reduced levels of normal plasma von Wille-brand factor (VWF). The molecular basis of the disorder is poorly understood. The aims of this study were to determine phenotype and genotype and their relationship in patients historically diagnosed with type 1 VWD. Families were recruited in 9 European countries based on previous type 1 VWD diagnosis. Bleeding symptoms were recorded, plasma phenotype analyzed, and VWF mutation analysis performed in all index cases (ICs). Phenotypic and molecular analysis stratified patients into those with or without phenotypes suggestive of qualitative VWF defects (abnormal multimers) and with or without mutations. A total of 105 of 150 ICs (70%) had mutations identified. A subgroup with abnormal multimers (38% of ICs, 57 of 150) showed a high prevalence of VWF gene mutations (95% of ICs, 54 of 57), whereas in those with qualitatively normal VWF, fewer mutations were identified (55% of ICs, 51 of 93). About one third of the type 1 VWD cases recruited could be reconsidered as type 2. The remaining group could be considered "true" type 1 VWD, although mutations were found in only 55%. (Blood. 2007;109:112-121)
Journal of Thrombosis and Haemostasis
Expression of 14 von Willebrand factor mutations identified in patients with type1 von Willebrand disease from the MCMDM-1VWD study
2009 •
Anne C Goodeve
Elucidation of the genetic etiology of hemostasis and thrombosis through family-based studies
2013 •
Jesse Hinckley
Includes bibliographical references.296 p.Von Willebrand Factor (VWF) plays a key role in primary hemostasis by initiating platelet recruitment and adhesion and an indirect role in secondary hemostasis as the noncovalent chaperone of coagulation factor VIII (FVIII) in circulation. Larger blood components such as erythrocytes and leukocytes contribute to the etiology of hemostasis and thrombosis by displacing platelets and VWF toward the endothelium. I first characterized an Amish pedigree with VWD type 2. Genome-wide linkage analyses identified candidate quantitative trait loci (QTL) of VWF and FVIII levels on chromosomes 6p22, 9q34 (ABO), and 16q11. I also replicated previously reported associations confirming STXBP5, SCARA5, STAB2, and TC2N as candidate QTL. Secondly, I evaluated VWF single nucleotide polymorphisms (SNPs) as sources of genetic variation of VWF levels in the Amish pedigree. I replicated association with two SNPs in three replication cohorts (n=3,316). I also found ...
Blood Advances
Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D′D3 and D4 domains
2020 •
FRANCESCO BERNARDI
We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G>A and (2) c.6532G>T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D′D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient’s daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C>T mutation in exon 25 of the VWF gene causing the p.P1127...
Journal of Thrombosis and Haemostasis
Mutations C1157F and C1234W of von Willebrand factor cause intracellular retention with defective multimerization and secretion
2006 •
Alain Stepanian
Blood
A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3
2009 •
Andrew Will
British Journal of Haematology
hom*ozygous C2362F von Willebrand factor induces intracellular retention of mutant von Willebrand factor resulting in autosomal recessive severe von Willebrand disease
2006 •
Jeroen Eikenboom
Blood Reviews
The genetic basis of von Willebrand disease
2010 •
Anne C Goodeve
Journal of Thrombosis and Haemostasis
Clinical and laboratory phenotype variability in type 2M von Willebrand disease
2017 •
Lisa Boggio
Thrombosis and Haemostasis
Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS
2016 •
Paula Kjöllerström
SummaryThe diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency and heterogeneous laboratory phenotype. The sequencing of the entire VWF coding region has not yet become a routine practice in diagnostic laboratories owing to its high costs. Nevertheless, nextgeneration sequencing (NGS) has emerged as an alternative to overcome this limitation. We aimed to determine the correlation of genotype and phenotype in 92 Portuguese individuals from 60 unrelated families with VWD; therefore, we directly sequenced VWF. We compared the classical Sanger sequencing approach and NGS to assess the value-added effect on the analysis of the mutation distribution in different types of VWD. Sixty-two different VWF mutations were identified, 27 of which had not been previously described. NGS detected 26 additional mutations, contributing to a broad overview of the mutant alleles present in each VWD type. Twenty-nine prob...
