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

Michiels, Jan; Gadisseur, Alain; Planken, Marc van der; Schroyens, Wilfried; Berneman, Zwi N.

doi:10.1159/000214851

Cited by 6 publications

(4 citation statements)

References 25 publications

(43 reference statements)

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“…As shown in ▶ Figure 1, besides the additional mutations identified by NGS, the characteristic mutation distribution across VWF was preserved in each VWD type: in type 3 VWD, the mutations were scattered throughout VWF; in severe type 1 VWD, the profile was similar, but the absence of mutations in the regions coding for the A1, A2, D' and D3 domains was evident; in type 2N VWD, a mutation cluster in the region coding for the D1, D' and D3 domains was detected; in types 2A, 2B and 2M VWD, the mutation spreading was notable, but a mutation cluster in the regions coding for the A1 domain emerged. These findings are in line with previous reports (5,(31)(32)(33)(34).…”

Section: Discussionsupporting

confidence: 93%

Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS

Fidalgo¹,

Salvado²,

Corrales³

et al. 2016

Thromb Haemost

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The diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency and heterogeneous laboratory phenotype. The sequencing of the entire VWF coding region has not yet become a routine practice in diagnostic laboratories owing to its high costs. Nevertheless, next-generation sequencing (NGS) has emerged as an alternative to overcome this limitation. We aimed to determine the correlation of genotype and phenotype in 92 Portuguese individuals from 60 unrelated families with VWD; therefore, we directly sequenced VWF. We compared the classical Sanger sequencing approach and NGS to assess the value-added effect on the analysis of the mutation distribution in different types of VWD. Sixty-two different VWF mutations were identified, 27 of which had not been previously described. NGS detected 26 additional mutations, contributing to a broad overview of the mutant alleles present in each VWD type. Twenty-nine probands (48.3 %) had two or more mutations; in addition, mutations with pleiotropic effects were detected, and NGS allowed an appropriate classification for seven of them. Furthermore, the differential diagnosis between VWD 2B and platelet type VWD (n = 1), Bernard-Soulier syndrome and VWD 2B (n = 1), and mild haemophilia A and VWD 2N (n = 2) was possible. NGS provided an efficient laboratory workflow for analysing VWF. These findings in our cohort of Portuguese patients support the proposal that improving VWD diagnosis strategies will enhance clinical and laboratory approaches, allowing to establish the most appropriate treatment for each patient.

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Section: Discussionsupporting

confidence: 93%

Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS

Fidalgo¹,

Salvado²,

Corrales³

et al. 2016

Thromb Haemost

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“…Recently, it has been demonstrated that part of severe type 1 and type 2A VWD are also inherited in an autosomal recessive manner (1). Pathogenic variants responsible for dominant type 2A are predominantly located in A2, A1 and D3 domains, while mutations located in the propeptide or C-terminal cystine knot domain could cause recessive type 2A (46)(47)(48). Here we presented What is known about this topic?…”

Section: Vwfpp (%)mentioning

confidence: 89%

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

Liang¹,

Qin²,

Ding³

et al. 2017

Thromb Haemost

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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.

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“…The p.C295S substitution found in our patient, which also replaces a cystein in the D1 domain, is the first IIC mutation in exon 8. Previous mutations were described in exons 11, 12, 14 and 15 [38,39]. The IIC variant is a recessive phenotype, and the case of patient 25 is an example of the diagnostic difficulties (or overlap between phenotypes) faced by physicians taking care of patients with severe von Willebrand disease.…”

Section: Discussionmentioning

confidence: 99%

Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population

Mohl

Boda

Jáger

et al. 2011

Journal of Thrombosis and Haemostasis

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Summary. Background: Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWF gene and show high variability among different populations. Methods: Twenty‐five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWF gene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Results: Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1‐3) of the 5′‐region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730–10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. Conclusion: We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.

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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

Cited by 6 publications

References 25 publications

Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS

Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS

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

Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population

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