Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study
Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study
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DOI：
10.1111/j.1538-7836.2007.02666.x
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发表时间：
2007-09-01
影响因子：
10.4
通讯作者：
Lillicrap, D.
中科院分区：
文献类型：
--
作者：
James, P. D.;Notley, C.;Lillicrap, D.
背景/方法：为了更好地描述2 M型血管性血友病（VWD）的基因型-表型相关性，我们对血管性血友病因子（VWF）基因成熟亚基的编码区进行了测序（外显子18-52，包括外显子/内含子边界）在最初作为I型VWD提交给加拿大I型VWD研究的16例索引病例中，但根据表型重新分类为2 M型VWD（过度粘膜皮肤出血和血管性血友病因子：抗原（VWF：Ag）和/或血管性血友病因子：瑞斯托康辅因子（VWF：RCo）在0.05和0.50 IU/mL（-1）之间，至少两次，RCo/Ag比值< 0.6，且无高分子量多聚体损失）。对可用的家族成员（16个受影响的，23个未受影响的和6个未知的）进行测序以确定突变。结果如下：我们在这16个家族中发现了8种不同的错义突变（R854 Q、T1054 M、R1315 C、R1374 C、R1374 H、L1382 P、S2179 F和T2647 M）。在RCo/Ag比值< 0.50的病例中，我们更有可能发现VWF突变（P < 0.05，卡方检验）。重要的是，RCo/Ag比率< 0.40的每个指标病例（4/4个指标病例）具有在A1结构域内鉴定的突变，与RCo/Ag比率> 0.40的1/12个病例相反。VWF：RCo标准化的困难可能是RCo/Ag比值在0.40和0.60之间的病例异质性的原因。结论：RCo/Ag比值< 0.40的病例的基因型-表型相关性是明确的。根据我们的研究结果，2 M型VWD的表型定义可能需要更严格，并应成为国际标准化倡议的主题。
Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18-52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type I VWD Study as type I VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL(-1) on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. Results: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chi-squared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A I domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. Conclusions: The genotype-phenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.