Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

Christopherson, Pamela A.; Haberichter, Sandra L.; Flood, Veronica H.; Perry, C.L.; Sadler, Brooke; Bellissimo, Daniel B.; Paola, Jorge Di; Montgomery, Robert R.; Abshire, Thomas C.; Weiler, Hartmut; Lillicrap, David; James, Paula D.; O’Donnell, James S.; Ng, Christopher J.; Bennett, Carolyn M.; Sidonio, Robert F.; Journeycake, Janna M.; Zia, Ayesha; Lusher, Jeanne M.; Rajpurkar, Madhvi; Shapiro, Amy D.; Lentz, Steven R.; Gill, Joan Cox; Leissinger, Cindy; Ragni, Margaret V.; Tarantino, Michael D.; Roberts, Jonathan C.; Hord, Jeffrey D.; Strouse, John J.; Ma, Alice; Valentino, Leonard A.; Boggio, Lisa; Sharathkumar, Anjali; Gruppo, Ralph A.; Kerlin, Bryce A.; Kulkarni, Roshini; Green, D; Hoots, Keith; Brown, Deborah L; Mahoney, Donald H.; Mathias, Liesl; Bedros, Antranik A.; Diamond, Carol; Neff, Anne T.; DiMichele, Donna; Giardina, Patricia J.; Cohen, Alan; Paidas, Michael J.; Werner, Eric; Matsunaga, Atsuko; Shafer, Frank; Konkle, Barbara A.; Cuker, Adam; Kouides, Peter A.; Stein, Dagmar

doi:10.1111/jth.15713

Cited by 12 publications

(4 citation statements)

References 43 publications

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“…We depicted a full picture of the VWF domain distribution in different VWD types using all the so-far SNVs or short insertions/ deletions reported pathogenic VWF variants (n = 927). Our data showed that missense variants are responsible for the majority of reported and gnomAD variants, in agreement with established knowledge that the majority of type 1, almost all type 2 and some type 3 VWD are due to missense mutations [12][13][14][15] .…”

Section: Discussionsupporting

confidence: 92%

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Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Seidizadeh,

Cairo,

Baronciani

et al. 2023

npj Genom. Med.

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Von Willebrand disease (VWD) is a common bleeding disorder caused by mutations in the von Willebrand factor gene (VWF). The true global prevalence of VWD has not been accurately established. We estimated the worldwide and within-population prevalence of inherited VWD by analyzing exome and genome data of 141,456 individuals gathered by the genome Aggregation Database (gnomAD). We also extended our data deepening by mining the main databases containing VWF variants i.e., the Leiden Open Variation Database (LOVD) and the Human Gene Mutation Database (HGMD) with the goal to explore the global mutational spectrum of VWD. A total of 4,313 VWF variants were identified in the gnomAD population, of which 505 were predicted to be pathogenic or already reported to be associated with VWD. Among the 282,912 alleles analyzed, 31,785 were affected by the aforementioned variants. The global prevalence of dominant VWD in 1000 individuals was established to be 74 for type 1, 3 for 2A, 3 for 2B and 6 for 2M. The global prevalences for recessive VWD forms (type 2N and type 3) were 0.31 and 0.7 in 1000 individuals, respectively. This comprehensive analysis provided a global mutational landscape of VWF by means of 927 already reported variants in the HGMD and LOVD datasets and 287 novel pathogenic variants identified in the gnomAD. Our results reveal that there is a considerably higher than expected prevalence of putative disease alleles and variants associated with VWD and suggest that a large number of VWD patients are undiagnosed.

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Section: Discussionsupporting

confidence: 92%

“…Qualitative defects result in four different VWD types 2 (2A, 2B, 2M, and 2N) 11 . The genetic variants responsible for type 1 (mostly dominant) and 3 VWD (recessive) are spread across the 52 exons of VWF 12 – 14 , whereas type 2 VWD variants are confined to VWF functional domains 12 , 15 .…”

Section: Introductionmentioning

confidence: 99%

Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Seidizadeh,

Cairo,

Baronciani

et al. 2023

npj Genom. Med.

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show abstract

“…Type 3 VWD is typically caused by recessive biallelic (homozygous or compound heterozygous) null VWF gene mutations across functional VWF domains, but with a higher incidence in the VWF pro-peptide region. 32 Type 2 von Willebrand Disease VWF functional defects cause type 2 VWD, but these may also be associated with quantitative deficiencies. Based on the VWF functional defect and multimer patterns, type 2 VWD can be classified into 2A, 2B, 2M, or 2N.…”

Section: Type 1 Von Willebrand Diseasementioning

confidence: 99%

Von Willebrand Factor Multimer Analysis and Classification: A Comprehensive Review and Updates

Saadalla

Seheult

Pruthi

et al. 2022

Semin Thromb Hemost

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Von Willebrand factor (VWF) is a multimeric glycoprotein with essential roles in primary hemostasis. Patients with von Willebrand disease (VWD), due to quantitative and/or qualitative defects of VWF usually experience mucocutaneous bleeding. Based on the laboratory results of VWF antigen, various VWF activities, factor VIII activity, and VWF multimer patterns, VWD can be categorized as type 1, 2, and 3 VWD. VWF multimer analysis by either manual or semi-automated electrophoresis and immunoblotting is a critical part of the laboratory testing to differentiate type 1, type 2 VWD, and subtypes of type 1 or 2 VWD. The multimer distribution patterns can also help to understand the underlying molecular mechanism of VWF synthesis, multimerization, and clearance defects in VWD. This review will cover VWF synthesis, multimerization, secretion, VWF multimer analysis, and VWF multimer interpretation of various types and subtypes of VWD.

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“…Qualitative defects result in four different type 2 VWD (2A, 2B, 2M and 2N) [11]. The genetic variants responsible for type 1 (mostly dominant) and 3 VWD (recessive) are spread across the 52 exons of VWF [12][13][14], whereas type 2 VWD variants are con ned to VWF functional domains [12,15].…”

Section: Introductionmentioning

confidence: 99%

Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Peyvandi

Seidizadeh

Cairo³

et al. 2023

Preprint

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Von Willebrand disease (VWD) is a common bleeding disorder caused by mutations in the von Willebrand factor gene (VWF). The true global prevalence of VWD has not been accurately established. We estimated the worldwide and within-population prevalence of inherited VWD by analyzing exome and genome data of 141,456 individuals gathered by the genome Aggregation Database (gnomAD). We also extended our data deepening by mining the main databases containing VWF variants i.e., the Leiden Open Variation Database (LOVD) and the Human Gene Mutation Database (HGMD) with the goal to explore the global mutational spectrum of VWD. A total of 4,313 VWF variants were identified in the gnomAD population, of which 505 were predicted to be pathogenic or already reported to be associated with VWD. Among the 282,912 alleles analyzed, 31,785 were affected by the aforementioned variants. The global prevalence of dominant VWD in 1000 individuals was established to be 74 for type 1, 3 for 2A, 3 for 2B and 6 for 2M. The global prevalences for recessive VWD forms (type 2N and type 3) were 0.03 and 3 in 1000 individuals, respectively. This comprehensive analysis provided a global mutational landscape of VWF by means of 927 already reported variants in the HGMD and LOVD datasets and 287 novel pathogenic variants identified in the gnomAD. Our results reveal that there is a considerably higher than expected prevalence of putative disease alleles and variants associated with VWD and suggest that a large number of VWD patients are undiagnosed.

show abstract

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

Cited by 12 publications

References 43 publications

Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Von Willebrand Factor Multimer Analysis and Classification: A Comprehensive Review and Updates

Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

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