1个FGG基因新变异致遗传性异常纤维蛋白原血症家系的临床特征和遗传学分析

Clinical characteristics and genotype analysis of a family with congenital dysfibrinogenemia due to a novel variant of FGG gene

目的:对1例遗传性异常纤维蛋白原血症(CD)家系进行临床特征和遗传学分析。方法:分析患者的临床特点、凝血指标及纤维蛋白原(Fg)三个编码基因FGA、FGB和FGG测序的结果。应用PolyPhen-2、PROVEAN和Mutation Taster三款生物信息学预测软件分析变异的致病性;利用Clustal X软件对变异氨基酸进行保守性分析;突变蛋白的模型分析采用PyMol软件;单点变异对蛋白质稳定性的影响用I-Mutant Suite软件进行分析。运用血栓弹力图对该家系成员进行Fg功能的评价。结果:先证者纤维蛋白原抗原(Fg:Ag)正常(3.20 g/L),纤维蛋白原活性(Fg:C)显著降低(0.91 g/L),凝血酶时间(TT()22.0 s)延长;基因检测结果表明先证者为FGG第9号外显子G1133A存在碱基置换(p.Gly378Asp),其母亲和弟弟血样中检测到相同的变异位点。三款生信预测软件均提示c.1133G>A变异为有害和致病变异;Clustal X Software保守性分析结果表明,Gly378在同源物种之间高度保守。血栓弹力图的指标K值延长,Angle值减小,提示家系三位携带c.1133G>A变异的成员Fg功能均下降。根据美国医学遗传学与基因组学学会(ACMG)遗传变异标准与指南,支持证据组合(PM2+PP1+PP2+PP3+PP4),判定c.1133G>A(p.Gly378Asp)变异为可能致病性变异。结论:Fgγ链Gly378Asp变异是引起该家系CD的原因。

Objective:To analyze the clinical features and genotype of a family with congenital dysfibrinogenemia.Methods:Coagulation tests of the proband and his pedigree members were detected.The three fibrinogen genes(FGA,FGB and FGG)were amplified,then sequenced to find the varint.Three bioinformatics software(PolyPhen-2,PROVEAN and Mutation Taster)and PyMol were used to forecast the possible impact of the variant on the function of the protein.Conservation of the amino acids were analyzed by Clustal X.The effect of single point variants on protein stability was analyzed by I-Mutant Suite.The coagulation function of proband and his predigree members with thrombelastography(TEG)was evaluated.Results:The antigen of fibrinogen(Fg:Ag)of the proband in plasma was normal(3.20 g/L),but the activity(Fg:C)was significantly decreased(0.91 g/L).Genetic analysis revealed a heterozygous c.1133G>A mutation in the exon 9 of FGG,which resulted in p.Gly378Asp substitution.Family studies revealed that the mother and brother bear the same variant.All bioinformatics software that were used showed the variant could affect the function of Fg.Clustal X software showed that Gly378 was highly conserved among homologous species.The results of TEG indicated that the fibrinogen function of three members carrying the c.1133G>A mutation decreased.Conclusion:The proband with dysfibrinogenemia was caused by the mutation of γ chain Gly378Asp.