Seidizadeh Omid, Cairo Andrea, Baronciani Luciano, Valenti Luca, Peyvandi Flora
Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
NPJ Genom Med. 2023 Oct 16;8(1):31. doi: 10.1038/s41525-023-00375-8.
Von Willebrand disease (VWD) is a common bleeding disorder caused by mutations in the von Willebrand factor gene (VWF). The true global prevalence of VWD has not been accurately established. We estimated the worldwide and within-population prevalence of inherited VWD by analyzing exome and genome data of 141,456 individuals gathered by the genome Aggregation Database (gnomAD). We also extended our data deepening by mining the main databases containing VWF variants i.e., the Leiden Open Variation Database (LOVD) and the Human Gene Mutation Database (HGMD) with the goal to explore the global mutational spectrum of VWD. A total of 4,313 VWF variants were identified in the gnomAD population, of which 505 were predicted to be pathogenic or already reported to be associated with VWD. Among the 282,912 alleles analyzed, 31,785 were affected by the aforementioned variants. The global prevalence of dominant VWD in 1000 individuals was established to be 74 for type 1, 3 for 2A, 3 for 2B and 6 for 2M. The global prevalences for recessive VWD forms (type 2N and type 3) were 0.31 and 0.7 in 1000 individuals, respectively. This comprehensive analysis provided a global mutational landscape of VWF by means of 927 already reported variants in the HGMD and LOVD datasets and 287 novel pathogenic variants identified in the gnomAD. Our results reveal that there is a considerably higher than expected prevalence of putative disease alleles and variants associated with VWD and suggest that a large number of VWD patients are undiagnosed.
血管性血友病（VWD）是一种常见的出血性疾病，由血管性血友病因子基因（VWF）突变引起。VWD在全球的真实患病率尚未准确确定。我们通过分析基因组聚合数据库（gnomAD）收集的141456名个体的外显子组和基因组数据，估计了遗传性VWD在全球和特定人群中的患病率。我们还通过挖掘包含VWF变异的主要数据库，即莱顿开放变异数据库（LOVD）和人类基因突变数据库（HGMD），深化了我们的数据，目的是探索VWD的全球突变谱。在gnomAD人群中总共鉴定出4313个VWF变异，其中505个被预测为致病性变异或已报告与VWD相关。在分析的282912个等位基因中，有31785个受上述变异影响。1000人中1型显性VWD的全球患病率确定为74，2A型为3，2B型为3，2M型为6。隐性VWD形式（2N型和3型）在1000人中的全球患病率分别为0.31和0.7。这项综合分析通过HGMD和LOVD数据集中已报告的927个变异以及gnomAD中鉴定出的287个新的致病变异，提供了VWF的全球突变图谱。我们的结果表明，与VWD相关的假定疾病等位基因和变异的患病率大大高于预期，并表明大量VWD患者未被诊断出来。
