一例P．Gly400Val和P．Arg532Ter导致的遗传性FXI缺陷症患者的临床表型CSCD

目的分析1例遗传性凝血因子XI（FXI）缺陷症患者的临床表型和基因突变特征。方法用凝固法检测先证者及家系成员活化部分凝血活酶时间（activated partial thromboplastin time, APTT）、凝血酶原时间（prothrombintime，PT）、凝血因子Ⅺ活性（FⅪactivity，FXI：C），ELISA方法检测凝血因子Ⅺ抗原（FXI antigen，FXI：Ag）。对F11基因第1～15外显子及其侧翼序列进行PCR扩增、纯化和测序，寻找突变位点并用Pymol软件对突变进行分析。结果先证者APTT为70．3S，明显延长，FXI：C和FⅪ：Ag同时下降为6％和1．9％。先证者儿子FⅪ：C和FⅪ：Ag均下降为31％和39％。测序结果显示先证者携带F11基因第11外显子C．1296G〉T（P．Gly400Val）错义突变和第14外显子C．1691A〉T（P．Arg532Ter）无义突变；先证者儿子为C．1296G〉T（P．Gly400Val）杂合突变携带者。Pymol软件分析显示P．Gly400Val突变导致FⅪ蛋白氢键数量变化，使蛋白质二级结构改变。根据人类基因突变数据库（HGMD professional 2016．4），F11 NM_13142C．1691A〉T（p．Arg532Ter）为未报道过的新突变，根据美国医学遗传学与基因组学学会（ACMG）2015年指南判断为功能缺失型突变。结论F11NM_13142 C．1296G〉T（p．Gly400Val）和F11 NM_13142C．1691A〉T（P．Arg532Ter）复合杂合突变是导致先证者遗传性FXI缺陷症的致病原因，引起FXI抗原和活性同时下降。

Identification of compound heterozygous mutations p. Gly400Val and p. Arg532Ter of the F11 gene in a Chinese patient with hereditary factor XI deficiencyCSCD

Objective: To investigate the phenotype and genotype defect characteristics of a Chinese patient with hereditary factor XI deficiency. Methods: The activated partial thromboplastin time (APTT), prothrombin time (PT), FXI activity (FXI ' C) of the proband and his relatives were measured by a clotting method using automatic coagulation analyzer. FXI antigen (FXI: Ag) was assayed by enzyme-linked immunosorbent assay (ELISA). Fifteen exons of the F11 gene were amplified by PCR and sequenced. Pymol software was used to analyze the novel mutations. Results: The APTT of the proband was significantly prolonged (70. 3 s, reference 34. 5 s) with decreased FXI activity (6%, reference 50^-150%) and FXJ antigen (1. 9%, reference 50%-150%). The FXI activity and FXI antigen of his son was 31% and 39%, respectively. Two heterozygous Fll mutations were identified in the proband, which included a G>T substitution at nucleotide 1296 in exon 11 resulting in substitution of glycine by valine at codon 400 (p. Gly400Val) and a A>T substitution at nucleotide 1691 in exon 14 resulting in substitution of arginine (AGA) by a termination codon (TGA) at codon 532 (p. Arg532Ter). Analysis using Pymol indicated that the number of hydrogen bonds has changed, which led to a transformation of the structure of the FXI protein. The son of the proband was found to be heterozygous for the c. 1296G>T (p. Gly400Val) mutation. NM-13142 c. 1691A>T (p. Arg532Ter) is a novel mutation based on HGMD professional 2016.4. Based on 2015 Guidelines of ACMG, it is PVS1 (very strong pathogenicity). Conclusion: The compound heterozygous mutations of F11 NM-13142 c. 1296G>T (p. Gly400Val) and Fll NM-13142 c. 1691A>T(p. Arg532Ter) probably underlies the FXI deficiency in the proband. © 2018 MeDitorial Ltd. All rights reserved.