Liang Qian, Qin Huanhuan, Ding Qiulan, Xie Xiaoling, Wu Runhui, Wang Hongli, Hu Yiqun, Wang Xuefeng
Xuefeng Wang, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No.197 Ruijin Second Road, Shanghai, 200025, China, Tel.: +86 21 54667770, Fax: +86 21 64333548, E-mail:
Thromb Haemost. 2017 Jul 26;117(8):1534-1548. doi: 10.1160/TH16-10-0794. Epub 2017 May 24.
Von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency, heterogeneous laboratory phenotype and race specific distribution of mutations. The present study aimed to determine the correlation of genotype and phenotype in 200 Chinese individuals from 90 unrelated families with VWD. Next generation sequencing (NGS) of the whole coding VWF, copy number analysis of VWF by CNVplex technique as well as a comprehensive phenotypic assessment were carried out in all index patients (IPs). We identified putative mutations in all IPs except five mild type 1 (85/90, 94.4 %). In total, 98 different mutations were detected, 62 (63.3 %) of which were reported for the first time (23 missense mutations, 1 regulatory mutation, 12 splice site mutations and 26 null mutations). Mutations p.Ser1506Leu and p.Arg1374His/Cys/Ser were the most frequent mutations in 2A (33 % of cases) and 2M VWD (67 % of cases), respectively. In addition, mutation p.Arg816Trp was detected repeatedly in type 2N patients, while mutation p.Arg854Gln, extremely common in Caucasians, was not found in our cohort. Thirty-three patients had two or more putative mutations. Unlike most cases of type 1 and type 2 VWD, which were transmitted dominantly, we presented seven severe type 1, two type 2A and one type 2M with autosomal recessive inheritance. Here the phenotypic data of patients with novel mutations will certainly contribute to the better understanding of the molecular genetics of VWF-related phenotypes.
血管性血友病（VWD）是最常见的遗传性出血性疾病，其特征为出血倾向各异、实验室表型异质性以及突变的种族特异性分布。本研究旨在确定来自90个无关家族的200名中国VWD患者的基因型与表型之间的相关性。对所有索引患者（IP）进行了整个VWF编码区的二代测序（NGS）、采用CNVplex技术对VWF进行拷贝数分析以及全面的表型评估。除了5例轻度1型患者外，我们在所有IP中均鉴定出了推定突变（85/90，94.4%）。总共检测到98种不同的突变，其中62种（63.3%）为首次报道（23种错义突变、1种调控突变、12种剪接位点突变和26种无义突变）。p.Ser1506Leu和p.Arg1374His/Cys/Ser突变分别是2A型（占病例的33%）和2M型VWD（占病例的67%）中最常见的突变。此外，在2N型患者中反复检测到p.Arg816Trp突变，而在我们的队列中未发现白种人中极为常见的p.Arg854Gln突变。33例患者有两个或更多推定突变。与大多数1型和2型VWD以显性方式遗传不同，我们报告了7例严重1型、2例2A型和1例2M型呈常染色体隐性遗传。此处具有新突变患者的表型数据肯定有助于更好地理解VWF相关表型的分子遗传学。
