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

Abstract

von Willebrand factor (VWF) level and function are influenced by genetic variation in VWF and several other genes in von Willebrand disease type 1 (VWD1) patients. This study comprehensively screened for VWF variants and investigated the presence of ABO genotypes and common and rare VWF variants in Swedish VWD1 patients. The VWF gene was resequenced using Ion Torrent and Sanger sequencing in 126 index cases historically diagnosed with VWD. Exon 7 of the ABO gene was resequenced using Sanger sequencing. Multiplex ligation-dependent probe amplification analysis was used to investigate for copy number variants. Genotyping of 98 single nucleotide variants allowed allele frequency comparisons with public databases. Seven VWD2 mutations and 36 candidate VWD1 mutations (5 deletions, 4 nonsense, 21 missense, 1 splice, and 5 synonymous mutations) were identified. Nine mutations were found in more than one family and nine VWD1 index cases carried more than one candidate mutation. The T-allele of rs1063857 (c.2385T > C, p.Y795 = ) and blood group O were both frequent findings and contributed to disease in the Swedish VWD1 population. VWD2 mutations were found in 20 and candidate VWD1 mutations in 51 index cases out of 106 (48%). VWF mutations, a VWF haplotype, and blood group O all contributed to explain disease in Swedish VWD1 patients.

Keywords

DNA - molecular - diagnosis - Sweden - von Willebrand disease - von Willebrand factor

• References

• 1 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24 (03) 123-134
• 2 De Jong A, Eikenboom J. Developments in the diagnostic procedures for von Willebrand disease. J Thromb Haemost 2016; 14 (03) 449-460
• 3 Goodeve A, Eikenboom J, Castaman G. , et al. 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). Blood 2007; 109 (01) 112-121
• 4 James PD, Notley C, Hegadorn C. , et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
• 5 Eikenboom J, Hilbert L, Ribba AS. , et al. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost 2009; 7 (08) 1304-1312
• 6 Haberichter SL, Castaman G, Budde U. , et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111 (10) 4979-4985
• 7 Bellissimo DB, Christopherson PA, Flood VH. , et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood 2012; 119 (09) 2135-2140
• 8 Johnsen JM, Auer PL, Morrison AC. , et al; NHLBI Exome Sequencing Project. Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood 2013; 122 (04) 590-597
• 9 Wang QY, Song J, Gibbs RA, Boerwinkle E, Dong JF, Yu FL. Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes. J Thromb Haemost 2013; 11 (02) 261-269
• 10 Smith NL, Chen MH, Dehghan A. , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
• 11 Campos M, Sun W, Yu F. , et al. Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort. Blood 2011; 117 (19) 5224-5230
• 12 Huffman JE, de Vries PS, Morrison AC. , et al. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood 2015; 126 (11) e19-e29
• 13 Lanke E, Johansson AM, Halldén C, Lethagen S. Genetic analysis of 31 Swedish type 1 von Willebrand disease families reveals incomplete linkage to the von Willebrand factor gene and a high frequency of a certain disease haplotype. J Thromb Haemost 2005; 3 (12) 2656-2663
• 14 Sadler JE, Rodeghiero F. ; ISTH SSC Subcommittee on von Willebrand Factor. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005; 3 (04) 775-777
• 15 R Development Core Team. R: a language and environment for statistical computing. Vienna, Austria: The R Foundation for Statistical Computing; 2011. . Available at: http://www.R-project.org/ . Accessed August 18, 2017
• 16 Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21 (02) 263-265
• 17 Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73 (05) 1162-1169
• 18 Mufti AH, Alyami NH, Peake IR. , et al. Silent von Willebrand factor variant c.4146G>T (p.Leu1382=) causes type 1 von Willebrand disease via disruption of an exonic splice enhancer motif [abstract]. Res Pract Thromb Haemost 2017; 1 (Suppl. 01) 147-148
• 19 Pruss CM, Golder M, Bryant A. , et al. Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models. Blood 2011; 117 (16) 4358-4366
• 20 Cumming A, Grundy P, Keeney S. , et al; UK Haemophilia Centre Doctors' Organisation. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost 2006; 96 (05) 630-641
• 21 Nitu-Whalley IC, Riddell A, Lee CA. , et al. Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling. Thromb Haemost 2000; 84 (06) 998-1004
• 22 Penas N, Pérez-Rodríguez A, Torea JH. , et al. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am J Hematol 2005; 80 (03) 188-196
• 23 Batlle J, Pérez-Rodríguez A, Corrales I. , et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): proposal for a new diagnostic paradigm. Thromb Haemost 2016; 115 (01) 40-50
• 24 Hilbert L, Gaucher C, Mazurier C. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (vWF) responsible for type 2 von Willebrand disease with decreased platelet-dependent function of vWF. Blood 1995; 86 (03) 1010-1018
• 25 Berber E, Pehlevan F, Akin M, Capan OY, Kavakli K, Çaglayan SH. A common VWF exon 28 haplotype in the Turkish population. Clin Appl Thromb Hemost 2013; 19 (05) 550-556
• 26 Zhang ZP, Lindstedt M, Falk G, Blombäck M, Egberg N, Anvret M. Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. Am J Hum Genet 1992; 51 (04) 850-858
• 27 Zhang ZP, Blombäck M, Egberg N, Falk G, Anvret M. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics 1994; 21 (01) 188-193
• 28 Jokela V, Lassila R, Szanto T. , et al. Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations. Haemophilia 2013; 19 (06) e344-e348
• 29 Ahmad F, Jan R, Kannan M. , et al. Characterisation of mutations and molecular studies of type 2 von Willebrand disease. Thromb Haemost 2013; 109 (01) 39-46
• 30 Lethagen S, Isaksson C, Schaedel C, Holmberg L. Von Willebrand's disease caused by compound heterozygosity for a substitution mutation (T1156M) in the D3 domain of the von Willebrand factor and a stop mutation (Q2470X). Thromb Haemost 2002; 88 (03) 421-426
• 31 Casaña P, Martínez F, Haya S, Espinós C, Aznar JA. Association of the 3467C>T mutation (T1156M) in the von Willebrand's factor gene with dominant type 1 von Willebrand's disease. Ann Hematol 2001; 80 (07) 381-383
• 32 Johansson AM, Halldén C, Säll T, Lethagen S. Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease. Ann Hum Genet 2011; 75 (04) 447-455
• 33 Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost 2009; 101 (03) 570-576
• 34 James PD, Notley C, Hegadorn C. , et al; Association of Hemophilia Clinic Directors of Canada. Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study. J Thromb Haemost 2007; 5 (09) 1914-1922
• 35 Flood VH, Christopherson PA, Gill JC. , et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016; 127 (20) 2481-2488
• 36 Johansson AM, Lanke E, Säll T, Lethagen S, Halldén C. A large deletion identified in a Swedish family with type 1 VWD. Thromb Haemost 2011; 105 (04) 733-734