背景:因子XI(FXI)缺乏症是一种常染色体出血性疾病,其特征是血浆FXI水平降低。在德系犹太人和其他选定的欧洲人群中,已经发现了F11基因的多种祖先变体。然而,在中国和/或东亚人群中很少有主要变异的报道.这项研究的目的是表征FXI缺乏症的基因型和表型,并确定主要变体。
结果:在41名FXI缺陷患者中,39显示出严重的FXI缺陷,远远超过那些有部分缺陷的。APTT水平与FXI活性水平呈负相关(系数=-0.584,P<.001)。只有9名患者出现轻度出血,包括一名部分缺陷患者和八名严重缺陷患者。大多数患者接受术前筛查(n=22)和检查(n=14)。基因分析显示90%的患者有遗传缺陷,杂合2、16和19例,纯合子,和复合杂合患者,分别。在F11基因中检测到17个变异(6个新的),包括11种错觉变体,四个废话变体,和两个小的删除散布在整个F11。在11种错觉变体中,六个尚未进行体外表达研究。蛋白质建模分析表明,所有这些变体通过改变侧链取向和氢键破坏了局部结构稳定性。九个变种,由三个错义和六个无效变体组成,被检测到的频率为两个或更多。在p.Q281*中观察到最高的等位基因频率(21.25%),p.W246*(17.50%),p.Y369*(12.50%),和p.L442CFS*8(12.50%)。前两者是东亚特有的变体,而其余两个是中国东南部特有的变体。
结论:我们以人群为基础的队列研究表明,FXI缺乏患者的FXI活性水平与出血严重程度无相关性。此外,FXI缺乏症的患病率可能被低估了.无意义的p.Q281*是中国东南部最常见的变种,暗示可能的创始人效应。
BACKGROUND: Factor XI (FXI) deficiency is an autosomal hemorrhagic disorder characterized by reduced plasma FXI levels. Multiple ancestral variants in the F11 gene have been identified in Ashkenazi Jews and other selected European populations. However, there are few reports of predominant variants in Chinese and/or East Asian populations. The aim of this study is to characterize the genotypes and phenotypes of FXI deficiency and identify the predominant variants.
RESULTS: Of the 41 FXI-deficient patients, 39 exhibited severe FXI defects, considerably more than those with partial defects. The APTT levels showed a negative correlation with FXI activity levels (coefficient=-0.584, P < .001). Only nine patients experienced mild bleeding, including one partially defective patient and eight severely defective patients. The majority of patients were referred for preoperative screenings (n = 22) and checkups (n = 14). Genetic analysis revealed that 90% of the patients had genetic defects, with 2, 16, and 19 cases of heterozygous, homozygous, and compound heterozygous patients, respectively. Seventeen variants were detected in the F11 gene (6 novel), including eleven missense variants, four nonsense variants, and two small deletions scattered throughout the F11. Of the 11 missense variants, six have not yet been studied for in vitro expression. Protein modeling analyses indicated that all of these variants disrupted local structural stability by altering side-chain orientation and hydrogen bonds. Nine variants, consisting of three missense and six null variants, were detected with a frequency of two or more. The highest allele frequency was observed in p.Q281* (21.25%), p.W246* (17.50%), p.Y369* (12.50%), and p.L442Cfs*8 (12.50%). The former two were variants specific to East Asia, while the remaining two were southeast China-specific variants.
CONCLUSIONS: Our population-based cohort demonstrated that no correlation between the level of FXI activity and the bleeding severity in FXI deficiency. Additionally, the prevalence of FXI deficiency may have been underestimated. The nonsense p.Q281* was the most common variant in southeast China, suggesting a possible founder effect.