An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type I von Willebrand disease
An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type I von Willebrand disease
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DOI：
10.1160/th06-07-0383
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发表时间：
2006-11-01
影响因子：
6.7
通讯作者：
Collins, Peter
中科院分区：
文献类型：
--
作者：
Cumming, Anthony;Grundy, Pamela;Collins, Peter
被英国中心诊断为I型VWD的40个家庭被招募进来。回顾后，6个家庭被重新诊断为2型VWD，1个家庭患有血小板储存池障碍，1个家庭被确定为未受影响。对VWF基因启动子区域及所有外显子和内含子边界的直接DNA测序在32个确诊的I型VWD家系中的9个(28%)指示病例中发现了6个可能导致VWD的突变。这些突变包括R1205H(3614G>；A)、P1648fsX45(4944delT)、D141G(422A>；G)和三个剪接点突变：3108+5G>；A、7437+1G>；A和3379+1G>；A。在32例I型VWD指征病例中，15例(47%)未发现明显的VWF基因突变或多态。利用一组VWF基因多态进行单倍型研究，以了解携带VWF基因的VWD表型家系的分离情况。在32个家系中，有13个VWD可能与VWF基因分离。在8个家系(25%)中，VWD明显没有与VWF基因分离。我们认为，VWF基因突变筛查在I型VWD的遗传学诊断和家系研究中的普遍应用有限。如果进行遗传学研究，必须考虑I型VWD的不完全外显性和可变表现性。除非能够清楚地证明VWD表型与VWF基因的关联，否则任何遗传家系研究的结果都应谨慎解释。
Forty families diagnosed by UK centres to have type I VWD were recruited. Following review, six families were re-diagnosed to have type 2 VWD, one to have a platelet storage pool disorder, and one family was determined to be unaffected. Direct DNA sequencing of the promoter region and all exons and intronic boundaries of the VWF gene identified six mutations likely to be causative of VWD in index cases of nine of the 32 (28%) confirmed type I VWD families. These included R1205H (3614G > A) VWD Vicenza, P1648fsX45 (4944delT), D141G (422A > G) and three splice site mutations: 3108+5G > A, 7437+1G > A and 3379+1G > A. The Y1584C (4751A > G) polymorphism was present in eight additional families. No significant VWFgene mutation or polymorphism was identified in 15 of the 32 type I VWD index cases (47%). Haplotype studies were performed using a panel of VWF polymorphisms to investigate the segregation in families of VWD phenotype with the VWF gene. In 13 of the 32 families it was likely that VWD segregated with the VWF gene. In eight families (25%) VWD clearly did not segregate with the VWF gene. We suggest that mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in type I VWD. If genetic studies are performed, the incomplete penetrance and variable expressivity of type I VWD must be taken into account. Unless linkage of VWD phenotype with the VWF gene can be clearly demonstrated, the results of any genetic family studies should be interpreted with caution.