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

Autor:	Nazish Saqlain, Shehla Tariq, Shahtaj Masood, Arijit Biswas, Fazle Raziq, Hamideh Yadegari, Tahir Shamsi, Anna Pavlova, Arshi Naz, Ulrich Budde, Shariq Ahmed, Samina Amanat, Johannes Oldenburg
Rok vydání:	2019
Předmět:	Male Models Molecular medicine.medical_specialty Adolescent Genotype Hemorrhage von Willebrand Disease Type 3 030204 cardiovascular system & hematology medicine.disease_cause Gastroenterology Cohort Studies Young Adult 03 medical and health sciences 0302 clinical medicine Protein Domains Von Willebrand factor hemic and lymphatic diseases Internal medicine von Willebrand Factor medicine Von Willebrand disease Humans Missense mutation Computer Simulation Child Gene Genetics (clinical) Mutation biology Molecular pathology business.industry Hematology General Medicine medicine.disease Null allele Phenotype Cohort biology.protein Female business 030215 immunology
Zdroj:	Haemophilia. 25:1035-1044
ISSN:	1365-2516 1351-8216
DOI:	10.1111/hae.13841
Popis:	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.
Databáze:	OpenAIRE
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