Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Ferdows Atiq; Johan Boender; Waander L. Van Heerde; Juan M. Tellez Garcia; Selene C. Schoormans; Sandy Krouwel; Marjon H. Cnossen; Britta A.P. Laros-Van Gorkom; Joke De Meris; Karin Fijnvandraat; Johanna G. Van Der Bom; Karina Meijer; Karin P.M. Van Galen; Jeroen Eikenboom; Frank W.G. Leebeek

doi:10.1097/HS9.0000000000000718

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Ferdows Atiq, Johan Boender, Waander L. Van Heerde, Juan M. Tellez Garcia, Selene C. Schoormans, Sandy Krouwel, Marjon H. Cnossen, Britta A.P. Laros-Van Gorkom, Joke De Meris, Karin Fijnvandraat, Johanna G. Van Der Bom, Karina Meijer, Karin P.M. Van Galen, Jeroen Eikenboom, Frank W.G. Leebeek^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

13 Citations (Scopus)

38 Downloads (Pure)

Abstract

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

Original language	English
Article number	E718
Journal	HemaSphere
Volume	6
Issue number	6
DOIs	https://doi.org/10.1097/HS9.0000000000000718
Publication status	Published - Jun 2022

Bibliographical note

Funding Information:
FA received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. JB started working at Sobi after finishing this research project. WLvH reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also cofounder and CSO of Enzyre. MHC has received investigator-initiated research grants over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter/Baxalta/Shire, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as institution. The institution of KF has received unrestricted research grants from CSL Behring, Sobi, and NovoNordisk, and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from uniQure, of which all fees go to the institution. BAPL-vG has received unrestricted educational grants from Baxter and CSL Behring. JE received research support from CSL Behring, and he has been a teacher on educational activities of Roche. KPMvG received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda. JGvdB has been a teacher on educational activities of Bayer and received consultancy fees from Novo Nordisk, paid to the Leiden University Medical Center. FWGL received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure for a study not related to this article, and is consultant for uniQure, Sobi, Biomarin, and Shire/Takeda, of which the fees go to the institution, and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. All the other authors have no conflicts of interest to disclose.

Funding Information:
The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda) and CSL Behring (unrestricted grant).

Publisher Copyright:
© 2022 Wolters Kluwer Health. All rights reserved.

Access to Document

10.1097/HS9.0000000000000718Licence: CC BY-NC-ND

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in PhenotypeFinal published version, 1.04 MBLicence: CC BY-NC-ND

Cite this

Atiq, F., Boender, J., Van Heerde, W. L., Tellez Garcia, J. M., Schoormans, S. C., Krouwel, S., Cnossen, M. H., Laros-Van Gorkom, B. A. P., De Meris, J., Fijnvandraat, K., Van Der Bom, J. G., Meijer, K., Van Galen, K. P. M., Eikenboom, J., & Leebeek, F. W. G. (2022). Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype. HemaSphere, 6(6), Article E718. https://doi.org/10.1097/HS9.0000000000000718

@article{cbf9d52e9b5f420cb7af998398799551,

title = "Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype",

abstract = "Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.",

author = "Ferdows Atiq and Johan Boender and {Van Heerde}, {Waander L.} and {Tellez Garcia}, {Juan M.} and Schoormans, {Selene C.} and Sandy Krouwel and Cnossen, {Marjon H.} and {Laros-Van Gorkom}, {Britta A.P.} and {De Meris}, Joke and Karin Fijnvandraat and {Van Der Bom}, {Johanna G.} and Karina Meijer and {Van Galen}, {Karin P.M.} and Jeroen Eikenboom and Leebeek, {Frank W.G.}",

note = "Funding Information: FA received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. JB started working at Sobi after finishing this research project. WLvH reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also cofounder and CSO of Enzyre. MHC has received investigator-initiated research grants over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter/Baxalta/Shire, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as institution. The institution of KF has received unrestricted research grants from CSL Behring, Sobi, and NovoNordisk, and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from uniQure, of which all fees go to the institution. BAPL-vG has received unrestricted educational grants from Baxter and CSL Behring. JE received research support from CSL Behring, and he has been a teacher on educational activities of Roche. KPMvG received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda. JGvdB has been a teacher on educational activities of Bayer and received consultancy fees from Novo Nordisk, paid to the Leiden University Medical Center. FWGL received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure for a study not related to this article, and is consultant for uniQure, Sobi, Biomarin, and Shire/Takeda, of which the fees go to the institution, and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. All the other authors have no conflicts of interest to disclose. Funding Information: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda) and CSL Behring (unrestricted grant). Publisher Copyright: {\textcopyright} 2022 Wolters Kluwer Health. All rights reserved.",

year = "2022",

month = jun,

doi = "10.1097/HS9.0000000000000718",

language = "English",

volume = "6",

journal = "HemaSphere",

issn = "2572-9241",

publisher = "John Wiley & Sons Inc.",

number = "6",

}

Atiq, F , Boender, J, Van Heerde, WL, Tellez Garcia, JM, Schoormans, SC, Krouwel, S, Cnossen, MH, Laros-Van Gorkom, BAP, De Meris, J, Fijnvandraat, K, Van Der Bom, JG, Meijer, K, Van Galen, KPM, Eikenboom, J & Leebeek, FWG 2022, 'Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype', HemaSphere, vol. 6, no. 6, E718. https://doi.org/10.1097/HS9.0000000000000718

TY - JOUR

T1 - Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

AU - Atiq, Ferdows

AU - Boender, Johan

AU - Van Heerde, Waander L.

AU - Tellez Garcia, Juan M.

AU - Schoormans, Selene C.

AU - Krouwel, Sandy

AU - Cnossen, Marjon H.

AU - Laros-Van Gorkom, Britta A.P.

AU - De Meris, Joke

AU - Fijnvandraat, Karin

AU - Van Der Bom, Johanna G.

AU - Meijer, Karina

AU - Van Galen, Karin P.M.

AU - Eikenboom, Jeroen

AU - Leebeek, Frank W.G.

N1 - Funding Information: FA received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. JB started working at Sobi after finishing this research project. WLvH reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also cofounder and CSO of Enzyre. MHC has received investigator-initiated research grants over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter/Baxalta/Shire, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as institution. The institution of KF has received unrestricted research grants from CSL Behring, Sobi, and NovoNordisk, and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from uniQure, of which all fees go to the institution. BAPL-vG has received unrestricted educational grants from Baxter and CSL Behring. JE received research support from CSL Behring, and he has been a teacher on educational activities of Roche. KPMvG received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda. JGvdB has been a teacher on educational activities of Bayer and received consultancy fees from Novo Nordisk, paid to the Leiden University Medical Center. FWGL received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure for a study not related to this article, and is consultant for uniQure, Sobi, Biomarin, and Shire/Takeda, of which the fees go to the institution, and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. All the other authors have no conflicts of interest to disclose. Funding Information: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda) and CSL Behring (unrestricted grant). Publisher Copyright: © 2022 Wolters Kluwer Health. All rights reserved.

PY - 2022/6

Y1 - 2022/6

N2 - Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

AB - Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

UR - http://www.scopus.com/inward/record.url?scp=85130996416&partnerID=8YFLogxK

U2 - 10.1097/HS9.0000000000000718

DO - 10.1097/HS9.0000000000000718

M3 - Article

C2 - 35747851

AN - SCOPUS:85130996416

SN - 2572-9241

VL - 6

JO - HemaSphere

JF - HemaSphere

IS - 6

M1 - E718

ER -

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this