Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Elayaperumal, S.; Fouzia, N A; Biswas, Arijit; Nair, Sukesh C.; Viswabandya, Auro; George, Biju; Abraham, Aby; Oldenburg, Johannes; Edison, Eunice Sindhuvi; Srivastava, Alok

doi:10.1111/hae.13542

Cited by 9 publications

(24 citation statements)

References 47 publications

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“…This study is the first report of detailed mutation spectrum in type 3 VWD in the Pakistani population with a high rate of consanguineous marriage. This highlights the high predisposition of VWF for sequence variations and mutational heterogeneity in type 3 VWD.The candidate mutations were scattered throughout the entire VWF, not confined to the specific region or domain of VWF, as observed in the other cohorts 12,26,28,29. In this study, we were able to detect both VWF mutations in ~96% of the patients (46 out of 48 IPs) which were mainly homozygous.…”

supporting

confidence: 65%

“…However, the incidence of the gene conversion variations in our cohort (23%) was greater when is compared with those reported for different Indian cohorts, for example 18.5%, 10.2% and 4.5% reported by Gupta 26,27,33 In conclusion, our study represents one of the few studies reporting the spectrum of mutations in type 3 VWD cohort with a high rate of consanguinity, providing further insights into the VWD pathogenesis in a consanguineous population. However, the incidence of the gene conversion variations in our cohort (23%) was greater when is compared with those reported for different Indian cohorts, for example 18.5%, 10.2% and 4.5% reported by Gupta 26,27,33 In conclusion, our study represents one of the few studies reporting the spectrum of mutations in type 3 VWD cohort with a high rate of consanguinity, providing further insights into the VWD pathogenesis in a consanguineous population.…”

supporting

confidence: 40%

“…This study is the first report of detailed mutation spectrum in type 3 Nonetheless, the incidence rate of missense variants in our cohort (~34%) was slightly higher compared to the other type 3 VWD cohorts, which is commonly 18%-24%. 12,16,26,27 This might be due to the high rate of consanguinity in our cohort, and a subsequently greater likelihood of homozygosity for missense mutations. The missense mutations were located in D1, D2, A1, A2, A3, D4, C1 and CK domains ( Figure 1B).…”

Section: Discussion and Con Clus I Onmentioning

confidence: 93%

“…12,16,26,27 This might be due to the high rate of consanguinity in our cohort, and a subsequently greater likelihood of homozygosity for missense mutations. 12,16,26,27 This might be due to the high rate of consanguinity in our cohort, and a subsequently greater likelihood of homozygosity for missense mutations.…”

Section: In Silico Structural Analysismentioning

confidence: 93%

“…Remarkably, previous cohort studies of type 3 VWD have persistently reported that a bulk of the putative mutations were reported for the first time 12,14,[26][27][28]. The cohort comprises 48 unrelated type 3 VWD patients, all coming from consanguinity marriage.…”

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confidence: 99%

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Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Ahmed

Yadegari²,

Naz

et al. 2019

Haemophilia

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Introduction Type 3 von Willebrand disease (VWD), a severe autosomal recessive hereditary bleeding disorder, is described by the virtual absence of von Willebrand factor (VWF). In consanguineous populations, for example Pakistan, the disease is reported with a higher incidence rate than the worldwide prevalence. Aims This study aims to characterize molecular pathology and clinical profile of type 3 VWD cohort of Pakistani origin. Methods In total, 48 patients were enrolled in the current study. Initially, the index patients (IPs) were evaluated by a standardized questionnaire for recording bleeding manifestations and by performing conventional coagulation tests. The diagnosis of VWD type 3 was confirmed by VWF antigens less than 5 IU/dL. Direct sequencing of VWF gene (VWF) was carried out to identify causative gene variations. We evaluated the potential consequence of novel splice site and missense variations by predictive computational programs and in silico structural analysis. Results VWF mutations were detected in 46 out of 48 IPs (95.8%), predominantly as homozygous variants. In total, twenty‐nine different gene defects were characterized in this cohort from which 10 (34.5%) are novel. The majority of the mutations were null alleles (66%; including gene conversions, nonsense, splice site variations, small deletions and insertions), and 34% of them were missense substitutions. Conclusion Herein, we reported for the first time, the pattern of gene defects in Pakistani type 3 VWD cohort. We identified a wide heterogeneous mutation spectrum along with variability in the type of bleeding episodes.

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supporting

confidence: 65%

supporting

confidence: 40%

Section: Discussion and Con Clus I Onmentioning

confidence: 93%

Section: In Silico Structural Analysismentioning

confidence: 93%

mentioning

confidence: 99%

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Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Ahmed

Yadegari²,

Naz

et al. 2019

Haemophilia

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Unravelling the spectrum of von Willebrand factor variants in quantitative von Willebrand disease: results from a German cohort study

Krahforst,

Yadegari,

Pavlova

et al. 2024

Journal of Thrombosis and Haemostasis

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Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

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Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Abstract: This study is one of the largest series to define the molecular basis of type-3 VWD.

Cited by 9 publications

References 47 publications

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Unravelling the spectrum of von Willebrand factor variants in quantitative von Willebrand disease: results from a German cohort study

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

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