Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex® technique

Qian Liang; Huanhuan Qin; Qiulan Ding; Xiaoling Xie; Runhui Wu; Hongli Wang; Yiqun Hu; Xuefeng Wang

doi:10.1160/TH16-10-0794

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(08): 1534-1548
DOI: 10.1160/TH16-10-0794

Coagulation and Fibrinolysis

Schattauer GmbH

Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex^® technique

Qian Liang

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Huanhuan Qin

²Department of clinical laboratory, Huashan Hospital (North), Fudan University, Shanghai, China

,

Qiulan Ding

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Xiaoling Xie

³State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Runhui Wu

⁴Hemophilia Work Group, Beijing Children’s Hospital affiliated to Capital Medical University, Beijing, China

,

Hongli Wang

³State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Yiqun Hu

⁵Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Xuefeng Wang

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

› Author Affiliations

Abstract

Summary

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency, heterogeneous laboratory phenotype and race specific distribution of mutations. The present study aimed to determine the correlation of genotype and phenotype in 200 Chinese individuals from 90 unrelated families with VWD. Next generation sequencing (NGS) of the whole coding VWF, copy number analysis of VWF by CNVplex^® technique as well as a comprehensive phenotypic assessment were carried out in all index patients (IPs). We identified putative mutations in all IPs except five mild type 1 (85/90, 94.4%). In total, 98 different mutations were detected, 62 (63.3% of which were reported for the first time (23 missense mutations, 1 regulatory mutation, 12 splice site mutations and 26 null mutations). Mutations p.Ser1506Leu and p.Arg1374His/Cys/ Ser were the most frequent mutations in 2A (33% of cases) and 2M VWD (67% of cases), respectively. In addition, mutation p.Arg816Trp was detected repeatedly in type 2N patients, while mutation p.Arg854Gln, extremely common in Caucasians, was not found in our cohort. Thirty-three patients had two or more putative mutations. Unlike most cases of type 1 and type 2 VWD, which were transmitted dominantly, we presented seven severe type 1, two type 2A and one type 2M with autosomal recessive inheritance. Here the phenotypic data of patients with novel mutations will certainly contribute to the better understanding of the molecular genetics of VWF-related phenotypes.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

von Willebrand disease - von Willebrand factor - NGS - genotype - phenotype

Full Text

References

References
1 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24: 123-134.
2 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 04: 2103-2114.
3 Corrales I, Catarino S, Ayats J. et al. High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods. Haematologica 2012; 97: 1003-1007.
4 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: 17-31.
5 Yadegari H, Driesen J, Pavlova A. et al. Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. Thromb Haemost 2012; 108: 662-671.
6 Batlle J, Perez-Rodriguez A, Corrales I. et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EV W-ES): Proposal for a new diagnostic paradigm. Thromb Haemost 2016; 115: 40-50.
7 Zhang X, Xu Y, Liu D. et al. A modified multiplex ligation-dependent probe amplification method for the detection of 22q11.2 copy number variations in patients with congenital heart disease. BMC Genomics 2015; 16: 364.
8 Sadler JE, Rodeghiero F. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005; 03: 775-777.
9 ISTH-BAT. Available from: https://bh.rockefeller.edu/ISTH-BATR/
10 Nesbitt IM, Hampton KK, Preston FE. et al. A common splice site mutation is shared by two families with different type 2N von Willebrand disease mutations. Thromb Haemost 1999; 82: 1061-1064.
11 Budde U, Schneppenheim R, Eikenboom J. et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost 2008; 06: 762-771.
12 Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: e164.
13 PolyPhen-2 prediction of functional effects of human nsSNPs. Available from: http://genetics.bwh.harvard.edu/pph2
14 Sorting Intolerant from Tolerant (SIFT). Available from: http://sift.jcvi.org
15 Mutation taster. Available from: www.mutationtaster.org
16 Protein Variation Effect Analyzer (PROVEAN). Available from: http://provean.jcvi.org/index.php
17 The interactive biosoftware Alamut v2.7. Available from: http://www.interactive-biosoftware.com/
18 Human Gene Mutation Database (HGMD). Available from: www.hgmd.cf.ac.uk/ac/index.php
19 ISTH-SSC VWF Online Database. Available from: http://vwf.group.shef.ac.uk/
20 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: 453-465.
21 Jenkins PV, O’Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46: 1836-1844.
22 Nichols WC, Lyons SE, Harrison JS. et al. Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment length polymorphism analysis. Proc Natl Acad Sci USA 1991; 88: 3857-3861.
23 Sanders YV, van der Bom JG, Isaacs A. et al. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. J Thromb Haemost 2015; 13: 956-966.
24 Smith NL, Chen MH, Dehghan A. et al. 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: 1382-1392.
25 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: 280-286.
26 Johnsen JM, Auer PL, Morrison AC. et al. 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: 590-597.
27 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: 2135-2140.
28 Castaman G, Rodeghiero F, Mannucci PM. The elusive pathogenesis of von Willebrand disease Vicenza. Blood 2002; 99: 4243-4244 author reply 4244.
29 Hampshire DJ, Abuzenadah AM, Cartwright A. et al. Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort. Thromb Haemost 2013; 110: 264-274.
30 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
31 Mathew P, Greist A, Maahs JA. et al. Type 2B vWD: the varied clinical manifestations in two kindreds. Haemophilia 2003; 09: 137-144.
32 Casonato A, Sartori MT, de Marco L. et al. 1-Desamino-8-D-arginine vasopressin (DDAVP) infusion in type IIB von Willebrand's disease: shortening of bleeding time and induction of a variable pseudothrombocytopenia. Thromb Hae-most 1990; 64: 117-120.
33 Casonato A, Steffan A, Pontara E. et al. Post-DDAVP thrombocytopenia in type 2B von Willebrand disease is not associated with platelet consumption: failure to demonstrate glycocalicin increase or platelet activation. Thromb Haemost 1999; 81: 224-228.
34 McKeown LP, Connaghan G, Wilson O. et al. 1-Desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease. Am J Hematol 1996; 51: 158-163.
35 Veyradier A, Boisseau P, Fressinaud E. et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine 2016; 95: e3038.
36 Casana P, Martinez F, Espinos C. et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol 1998; 59: 57-63.
37 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: 112-121.
38 Penas N, Perez-Rodriguez 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: 188-196.
39 Corrales I, Ramirez L, Altisent C. et al. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost 2009; 101: 570-576.
40 Favaloro EJ, Bonar RA, Mohammed S. et al. Type 2M von Willebrand disease – more often misidentified than correctly identified. Haemophilia 2016; 22: e145-155.
41 Favaloro EJ. . Utility of the von Willebrand factor collagen binding assay in the diagnosis of von Willebrand disease. Am J Hematol 2017; 92: 114-118.
42 Allen S, Abuzenadah AM, Hinks J. et al. A novel von Willebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion. Blood 2000; 96: 560-568.
43 Baronciani L, Federici AB, Cozzi G. et al. Expression studies of missense mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients with type 3 von Willebrand disease. Haemophilia 2008; 14: 549-555.
44 Haberichter SL, Allmann AM, Jozwiak MA. et al. Genetic alteration of the D2 domain abolishes von Willebrand factor multimerization and trafficking into storage. J Thromb Haemost 2009; 07: 641-650.
45 Yin J, Ma Z, Su J. et al. Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion. J Hematol Oncol 2015; 08: 73.
46 Hommais A, Stepanian A, Fressinaud E. et al. Impaired dimerization of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease. Thromb Haemost 2006; 95: 776-781.
47 Lanke E, Kristoffersson AC, Philips M. et al. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease. Thromb Haemost 2008; 100: 211-216.
48 Michiels JJ, Gadisseur A, van der Planken M. et al. Laboratory and molecular characteristics of recessive von Willebrand disease type 2C (2A subtype IIC) of variable severity due to homozygous or double heterozygous mutations in the D1 and D2 domains. Acta Haematol 2009; 121: 111-118.

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