The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles
The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles
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DOI：
10.1111/jth.12130
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发表时间：
2013-03-01
影响因子：
10.4
通讯作者：
James, P.
中科院分区：
文献类型：
--
作者：
Bowman, M.;Tuttle, A.;James, P.
背景3型血管性血友病（VWD）是最严重的一种疾病，是典型的常染色体隐性遗传。目的本研究的目的是探讨加拿大3型血管性血友病患者的分子发病机制。患者和方法34个家庭组成的100个人进行了调查。包括表型数据，包括出血评分（BS），血管性血友病因子（VWF）实验室值和抗VWF抑制剂状态以及序列分析。结果共检测到31个突变（其中20个为新突变），其中移码突变8个，剪接位点突变5个，无义突变9个，基因转换突变1个，错义突变6个，部分基因缺失突变2个。发现的大多数突变在前肽中（42%）;具有这些突变的索引病例（IC）表现出比VWF其他突变（BS=13）更严重的出血（BS=22）。62个（91%）突变等位基因被确定。29例IC（85%）有VWF无效基因型鉴定; 17例纯合子，12例复合杂合子。在5例IC（15%）中，两个突变的VWF等位基因未被确定为解释3型VWD表型。在四个IC中，仅鉴定出一个突变VWF等位基因，并且在一个IC中未鉴定出突变VWF等位基因。结论我们研究了加拿大3型VWD患者的分子发病机制。在加拿大人群中，专性携带者并非表型沉默; 48%的人被诊断为1型VWD。在这项研究中，大约50%的家庭3型VWD的遗传模式是共显性的，而不是隐性的。
Background Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion. Objectives The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Patients and methods Thirty-four families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values and anti-VWF inhibitor status were included as well as sequence analysis. Results We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS=22) than those with mutations elsewhere in VWF (BS=13). Sixty-two out of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified. Conclusions We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In approximately 50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.