Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort

Abstract

Summary Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.

Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing

“…Unexpectedly, upon NGS screening in the patient carrying FGB p.Arg196Cys mutation (patient 7/1 in Supplementary Table S3 ) a novel variant within VWF was also found. Mutations, described at the same position, so far, were associated with type 3 disease and it was suggested associate with type 1 in heterozygous form [ 53 , 54 ]. VWF p.Arg34 is completely conserved across species, and the p.Arg34Gln is predicted to have a detrimental effect on vWF.…”

Mutation Awareness of von Willebrand's Disease in Medical and Genetic Differences Screening: A Systematic Review

“…Analysis of vWD was made second-hand truthful by CSS techniques in most research (Boylan et al, 2015;Jiang et al, 2012;Liang et al, 2017;Veyradier et al, 2016;Wang et al, 2013). Only one research was used the NGS (Batlle et al, 2016), even as those studies used MLPT ( Hampshire et al, 2013;Kasatkar et al, 2014) but others used CSS in addition to NGS (Fidalgo et al, 2016) or MLPT (Yadegari et al, 2012) to screen VWD mutations. Within the analysis of vWD in research with one exclusion, some consistencies are outstanding having utilization vWF activity and suggested analysis while the patient's genetic evidence is supported on the evaluation of the vWF gene.…”

In silico analysis highlights the copy number variation mechanism responsible for the historically reported VWF exon 42 deletion

“…large deletions or duplications) within the human genome result from structural aberrations of chromosomal DNA, whereby previously independent regions of DNA sequence are joined together, resulting in loss or gain of DNA when compared to the reference genome [1]. Exonic deletions of the von Willebrand factor gene ( VWF ) contribute to all three types of von Willebrand disease (VWD), for example deletion of exons 4–5 in type 1 [2], exons 26–34 in type 2A [3] and exons 17–18 in type 3 [4]. Where investigated, VWF deletion breakpoints show a clear transition from 5′ to 3′ flanking DNA sequence and the mechanism resulting in the structural aberration is either Alu -mediated homologous recombination [2] or non-homologous (microhomology-mediated) end joining [4].…”