背景:血管性血友病(VWD),最常见的遗传性出血性疾病,血管性血友病因子(VWF)缺乏的结果。
目的:这项大型队列研究旨在全面探索VWF定量缺陷的突变光谱和实验室特征,阐明遗传基础和基因型-表型关联。
方法:我们的队列由221名具有定量VWD的高加索人指数患者组成,以及47名血浆VWF水平落在正常下限范围内的个体(50-70%)。我们进行了全面的VWF检测和遗传分析,包括VWF基因测序,拷贝数变异调查,和生物信息学评估。
结果:遵循ISTH-SSCVWF指南,77指数患者的特征为1型VWD(VWF:Ag<30%),111为1型VWD(VWF:Ag30-50%),和33型3VWD。突变检出率为88%,65%,92%,分别。值得注意的是,在VWF:Ag为30-50%的1型患者中,血型O的过度表达是明显的,特别是在突变阴性患者中,提示血型O的潜在因果作用。总共223个VWF变体,包括147个不同的变化,在定量VWD患者中鉴定,其中57个是新的变异(39%)。此外,约70%的VWF水平在较低正常边界内的个体(50-70%)显示VWF变异。
结论:我们的数据促进了我们对定量VWD的分子机制的理解,为未来的研究和临床管理提供有价值的见解。在亚组之间观察到不同的突变模式,特别是1型VWD(VWF:Ag<30%)和1型(VWF:Ag30-50%)之间的对比,事先调查有限的区域。
BACKGROUND: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF).
OBJECTIVE: This large cohort
study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations.
METHODS: Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70 IU/dL). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments.
RESULTS: Following International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee VWF guidelines, 77 index patients were characterized as having type 1 VWD (VWF antigen [VWF:Ag] < 30 IU/dL), 111 as having type 1 VWD (VWF:Ag, 30-50 IU/dL), and 33 as having type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30 to 50 IU/dL, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70 IU/dL) displayed VWF variants.
CONCLUSIONS: Our data advance our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag < 30 IU/dL) and type 1 VWD (VWF:Ag, 30-50 IU/dL), an area with limited prior investigation.