Semin Thromb Hemost 2019; 45(07): 708-719
DOI: 10.1055/s-0039-1679922
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Update on Molecular Testing in von Willebrand Disease

Javier Batlle
1   Servicio Hematología, Complexo Hospitalario Universitario ACoruña, INIBIC, A Coruña, Spain
,
Almudena Pérez-Rodríguez
1   Servicio Hematología, Complexo Hospitalario Universitario ACoruña, INIBIC, A Coruña, Spain
,
Irene Corrales
2   Banc de Sang iTeixits, Barcelona, Spain
3   Medicinatransfusional, Valld'Hebron Research Institute, UniversitatAutònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Nina Borràs
2   Banc de Sang iTeixits, Barcelona, Spain
3   Medicinatransfusional, Valld'Hebron Research Institute, UniversitatAutònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Joana Costa Pinto
1   Servicio Hematología, Complexo Hospitalario Universitario ACoruña, INIBIC, A Coruña, Spain
,
María Fernanda López-Fernández
1   Servicio Hematología, Complexo Hospitalario Universitario ACoruña, INIBIC, A Coruña, Spain
,
Francisco Vidal
2   Banc de Sang iTeixits, Barcelona, Spain
3   Medicinatransfusional, Valld'Hebron Research Institute, UniversitatAutònoma de Barcelona (VHIR-UAB), Barcelona, Spain
4   CIBER de Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain
,
on behalf of PCM-EVW-ES Investigators Team › Author Affiliations
Further Information

Publication History

Publication Date:
30 April 2019 (online)

Abstract

Diagnosis of von Willebrand disease (VWD) depends on personal and family history of bleeding and confirmatory laboratory testing. Currently available phenotypic tests for VWD contain potential sources for error that may distort results. Despite an exponential growth of information about the von Willebrand factor gene (VWF), the role of molecular diagnosis in VWD is still controversial. Due to the complexity and high cost of conventional molecular analyses, some investigators have recommended limiting this approach to distinguish suspected type 2N VWD from hemophilia A, type 2B from platelet-type VWD, and the exploration of type 3 VWD. New genetic methodologies and approaches are becoming available, but there is still some reluctance for their implementation in VWD diagnosis. This article discusses the pros and cons of molecular testing in VWD considering the experience obtained through the multicenter project “Molecular and Clinical Profile of VWD in Spain (PCM-EVW-ES).”

Authors' Contribution

J.B., A.P.R., I.C., N.B., M.F.L.F., and F.V.: Conceptualization, data curation, formal analysis, investigation, validation, writing original draft, supervision.


J.B. and F.V.: Project administration and funding acquisition.


FBL: Software management.


The remaining authors: Supervision contributing equally to this work.


Rose Kenn, medical editing: Writing, review, and editing.


* A list of PCM-EVW-ES Investigators is presented in the Appendix.


 
  • References

  • 1 Sadler JE, Budde U, Eikenboom JC. , et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
  • 2 Goodeve A, James P. von Willebrand Disease. June 4, 2009 (updated October 5, 2017). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2018. Available at: http://www.ncbi.nlm.nih.gov/books/NBK7014/ . Accessed September 15 2018
  • 3 Batlle J, Pérez Rodríguez A, López Fernández MF. Classification of von Willebrand disease. In: Federici A, Lee C, Berntorp E. , et al. eds. Von Willebrand Disease: Basic and Clinical Aspects. London: Wiley-Blackwell; 2011: 74-85
  • 4 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
  • 5 Montgomery RR, Christopherson PA, Bellissimo D. , et al. The complete type I VWD cohort of the Zimmerman program for the molecular and clinical biology of VWD – phenotypic assignment, mutation frequency, and bleeding assessment. Blood 2013; 122: 332
  • 6 Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014; 25 (03) 206-216
  • 7 Swystun LL, Lillicrap D. How much do we really know about von Willebrand disease?. Curr Opin Hematol 2016; 23 (05) 471-478
  • 8 Batlle J, Pérez-Rodríguez A, Franqueira MD, López-Fernández MF. Type 2M von Willebrand disease: a variant of type 2A?. J Thromb Haemost 2008; 6 (02) 388-390
  • 9 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
  • 10 Sadler JE. Von Willebrand disease type 1: a diagnosis in search of a disease. Blood 2003; 101 (06) 2089-2093
  • 11 Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood 2013; 122 (23) 3735-3740
  • 12 Dan Hampshire. von Willebrand factor Variant Database (VWFdb) homepage. Available at: http://www.vwf.group.shef.ac.uk/ . Accessed September 15, 2018
  • 13 EHAD-VWD-LOVD. Available at: https://databases.lovd.nl/shared/genes/VWF . Accessed September 15, 2018
  • 14 Eikenboom JC, Castaman G, Vos HL, Bertina RM, Rodeghiero F. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79 (04) 709-717
  • 15 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
  • 16 Othman M, Chirinian Y, Brown C. , et al. Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease. Blood 2010; 116 (18) 3645-3652
  • 17 Flood VH. Perils, problems, and progress in laboratory diagnosis of von Willebrand disease. Semin Thromb Hemost 2014; 40 (01) 41-48
  • 18 Castaman G, Goodeve A, Eikenboom J. ; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica 2013; 98 (05) 667-674
  • 19 Laffan MA, Lester W, O'Donnell JS. , et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
  • 20 Nichols WL, Hultin MB, James AH. , et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
  • 21 Vangenechten I, Mayger K, Smejkal P. , et al. A comparative analysis of different automated von Willebrand factor glycoprotein Ib-binding activity assays in well typed von Willebrand disease patients. J Thromb Haemost 2018; 16 (07) 1268-1277
  • 22 Flood VH, Schlauderaff AC, Haberichter SL. , et al; Zimmerman Program Investigators. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 2015; 125 (14) 2297-2304
  • 23 Batlle J, Perez-Rodriguez A, Pinto JC, Fraga EL, Rodriguez-Trillo Tch A, Fernanda Lopez-Fernandez M. Diagnosis and management of von Willebrand disease in Spain. Semin Thromb Hemost 2011; 37 (05) 503-510
  • 24 Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A 1985; 82 (19) 6394-6398
  • 25 Ginsburg D, Handin RI, Bonthron DT. , et al. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228 (4706): 1401-1406
  • 26 Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J 1986; 5 (08) 1839-1847
  • 27 Lynch DC, Zimmerman TS, Collins CJ. , et al. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. Cell 1985; 41 (01) 49-56
  • 28 Vidal F, Julià A, Altisent C, Puig L, Gallardo D. Von Willebrand gene tracking by single-tube automated fluorescent analysis of four short tandem repeat polymorphisms. Thromb Haemost 2005; 93 (05) 976-981
  • 29 James P, Lillicrap D. The role of molecular genetics in diagnosing von Willebrand disease. Semin Thromb Hemost 2008; 34 (06) 502-508
  • 30 Hashemi Soteh M, Peake IR, Marsden L. , et al; MCMDM-1VWD Study Group. Mutational analysis of the von Willebrand factor gene in type 1 von Willebrand disease using conformation sensitive gel electrophoresis: a comparison of fluorescent and manual techniques. Haematologica 2007; 92 (04) 550-553
  • 31 Kakela JK, Friedman KD, Haberichter SL. , et al. Genetic mutations in von Willebrand disease identified by DHPLC and DNA sequence analysis. Mol Genet Metab 2006; 87 (03) 262-271
  • 32 Ribba AS, Lavergne JM, Bahnak BR, Derlon A, Piétu G, Meyer D. Duplication of a methionine within the glycoprotein Ib binding domain of von Willebrand factor detected by denaturing gradient gel electrophoresis in a patient with type IIB von Willebrand disease. Blood 1991; 78 (07) 1738-1743
  • 33 Keeney S, Cumming A, Hay C. Mutations in von Willebrand factor multimerization domains are not a common cause of classical type 1 von Willebrand disease. Thromb Haemost 1999; 82 (05) 1446-1450
  • 34 Baronciani L, Goodeve A, Peyvandi F. Molecular diagnosis of von Willebrand disease. Haemophilia 2017; 23 (02) 188-197
  • 35 Mancuso DJ, Tuley EA, Westfield LA. , et al. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30 (01) 253-269
  • 36 James PD, Lillicrap D. The molecular characterization of von Willebrand disease: good in parts. Br J Haematol 2013; 161 (02) 166-176
  • 37 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
  • 38 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
  • 39 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24 (03) 123-134
  • 40 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
  • 41 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
  • 42 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
  • 43 Bowman M, Tuttle A, Notley C. , et al; Association of Hemophilia Clinic Directors of Canada. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost 2013; 11 (03) 512-520
  • 44 Kasatkar P, Shetty S, Ghosh K. Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients. PLoS One 2014; 9 (03) e92575
  • 45 Corrales I, Catarino S, Ayats J. , et al. High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods. Haematologica 2012; 97 (07) 1003-1007
  • 46 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
  • 47 Borràs N, Batlle J, Pérez-Rodríguez A. , et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica 2017; 102 (12) 2005-2014
  • 48 Batlle J. The PCM-EVW-ES Experience. von Willebrand Factor. 63rd Annual SSC meeting, Montpellier, France Meeting. Available at: Minuteshttps://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_minutes/2016_SSC_minutes.pdf. Accessed October 15, 2018
  • 49 Pérez-Rodríguez A, Batlle J, Corrales I. , et al. Role of multimeric analysis of von Willebrand factor (VWF) in von Willebrand disease (VWD) diagnosis: Lessons from the PCM-EVW-ES Spanish project. PLoS One 2018; 13 (06) e0197876
  • 50 Batlle J, Pérez-Rodríguez A, Corrales I. , et al. Diagnosis and management of von Willebrand disease in Spain. Ann Blood 2018; 3: 5
  • 51 Fidalgo T, Salvado R, Corrales I. , et al. Genotype-phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS. Thromb Haemost 2016; 116 (01) 17-31
  • 52 Liang Q, Qin H, Ding Q. , et al. Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex® technique. Thromb Haemost 2017; 117 (08) 1534-1548
  • 53 Borràs N, Corrales I, Ramírez L. , et al. Diseño, optimización y validación de un panel de secuenciación de 23 genes como herramienta de diagnóstico e investigación de las coagulopatías congénitas. Abstract presented at: XXXI Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia; Valencia, Spain; October 2015
  • 54 Bastida JM, Del Rey M, Lozano ML. , et al. Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders. Haemophilia 2016; 22 (04) 590-597
  • 55 Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014; 133 (01) 1-9
  • 56 Tchernitchko D, Goossens M, Wajcman H. In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. Clin Chem 2004; 50 (11) 1974-1978
  • 57 Houdayer C, Dehainault C, Mattler C. , et al. Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 2008; 29 (07) 975-982
  • 58 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013;Chapter 7:Unit7.20
  • 59 Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4 (07) 1073-1081
  • 60 Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouzé P, Brunak S. Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res 1996; 24 (17) 3439-3452
  • 61 Brunak S, Engelbrecht J, Knudsen S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 1991; 220 (01) 49-65
  • 62 Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37 (09) e67
  • 63 Lee M, Roos P, Sharma N. , et al. Systematic computational identification of variants that activate exonic and intronic cryptic splice sites. Am J Hum Genet 2017; 100 (05) 751-765
  • 64 Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 2002; 3 (04) 285-298
  • 65 Yadegari H, Biswas A, Akhter MS. , et al. Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5′ splice site. Blood 2016; 128 (17) 2144-2152
  • 66 Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes. J Thromb Haemost 2011; 9 (04) 679-688
  • 67 Daidone V, Gallinaro L, Grazia Cattini M. , et al. An apparently silent nucleotide substitution (c.7056C>T) in the von Willebrand factor gene is responsible for type 1 von Willebrand disease. Haematologica 2011; 96 (06) 881-887
  • 68 Veyradier A, Boisseau P, Fressinaud E. , et al; French Reference Center for von Willebrand disease. A laboratory phenotype/genotype correlation of 1167 French patients from 670 families with von Willebrand disease: a new epidemiologic picture. Medicine (Baltimore) 2016; 95 (11) e3038
  • 69 Berntorp E, Ågren A, Aledort L. , et al. Fifth Åland Island conference on von Willebrand disease. Haemophilia 2018; 24 (Suppl. 04) 5-19
  • 70 Goodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 678-682
  • 71 Hamilton A, Ozelo M, Leggo J. , et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 2011; 105 (03) 501-508
  • 72 López-Fernández MF, López-Berges C, Martín-Bernal JA. , et al. Type IIB von Willebrand's disease associated with a complex thrombocytopenic thrombocytopathy. Am J Hematol 1988; 27 (04) 291-298
  • 73 James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood 2013; 122 (05) 636-640
  • 74 Flood VH, Gill JC, Morateck PA. , et al. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 2010; 116 (02) 280-286
  • 75 Desai AN, Jere A. Next-generation sequencing: ready for the clinics?. Clin Genet 2012; 81 (06) 503-510
  • 76 Pati HP, Sharma P. Molecular genetic diagnosis of the inherited bleeding disorders: are we close to the perfect test?. Indian J Hematol Blood Transfus 2016; 32 (04) 375-376
  • 77 Göpel W, Gortner L, Kohlmann T, Schultz C, Möller J. Low prevalence of large intraventricular haemorrhage in very low birthweight infants carrying the factor V Leiden or prothrombin G20210A mutation. Acta Paediatr 2001; 90 (09) 1021-1024
  • 78 Srámek A, Kriek M, Rosendaal FR. Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet 2003; 362 (9381): 351-354
  • 79 Castoldi E, Govers-Riemslag JW, Pinotti M. , et al. Coinheritance of factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation. Blood 2003; 102 (12) 4014-4020
  • 80 van Loon J, Dehghan A, Weihong T. , et al. Genome-wide association studies identify genetic loci for low von Willebrand factor levels. Eur J Hum Genet 2016; 24 (07) 1035-1040
  • 81 Schadt EE, Turner S, Kasarskis A. A window into third-generation sequencing. Hum Mol Genet 2010; 19 (R2): R227-R240