摘要目的:回顾性分析2个新的杂合错义变异所致遗传性低纤维蛋白原血症(IFD)家系的表型和基因变异，并探讨其分子发病机制。方法:选取2个分别于2021年3月30日和2021年5月27日就诊于温州医科大学附属第一医院的IFD先证者及其家系成员作为研究对象。收集临床资料，并检测先证者及其家系成员的凝血指标，用Sanger测序法分析先证者 FGA、FGB及 FGG基因的变异位点。利用生物信息学软件分析候选变异位点的保守性并预测变异蛋白的致病性，同时模拟变异前后蛋白质结构及分子间作用力的变化。 结果:先证者1为18岁男性，血浆纤维蛋白原活性(Fg：C)和血浆纤维蛋白原抗原(Fg：Ag)均明显偏低，分别为0.80 g/L和1.00 g/L。先证者2为43岁男性，其Fg：C和Fg：Ag分别为1.35 g/L和1.30 g/L，均偏低；先证者1的父亲、先证者2的父亲及儿子的Fg：C和Fg：Ag均偏低。测序结果发现先证者1及其父亲 FGG基因的第7外显子均存在c.688T>G(p.Phe230Val)杂合错义变异；先证者2及其父亲和儿子 FGA基因的第6外显子均存在c.2516A>C(p.Asn839Thr)杂合错义变异。同源性分析表明Phe230和Asn839残基在进化上高度保守。生物信息学软件预测提示p.Phe230Val和p.Asn839Thr变异均为致病性；蛋白模拟模型结果显示p.Asn839Thr变异使氨基酸之间的氢键发生改变，从而影响蛋白空间结构的稳定性。 结论:p.Phe230Val和p.Asn839Thr杂合错义变异可能是这2个家系发生IFD的原因。

abstractsObjective:To retrospectively analyze the clinical phenotypes and genetic variants in two Chinese pedigrees affected with Hereditary hypofibrinemia (IFD) and explore their molecular pathogenesis.Methods:Two probands and their pedigree members were admitted to the First Affiliated Hospital of Wenzhou Medical University on March 30, 2021 and May 27, 2021, respectively. Clinical phenotypes of the probands were collected, and blood clotting indexes of the probands and their pedigree members were determined. Variants of the FGA, FGB and FGG genes were analyzed by Sanger sequencing, and candidate variants were verified by sequence comparison. Bioinformatic software was used to analyze the conservation of the amino acids and pathogenicity of the proteins. Alteration in protein structure and intermolecular force before and after the variant was analyzed by simulating the protein model. Results:Proband 1, a 18-years-old male, had significantly low plasma fibrinogen activity (Fg: C) and plasma fibrinogen antigen (Fg: Ag), respectively at 0.80 g/L and 1.00 g/L. Proband 2, a 43-year-old male, had slightly low Fg: C and Fg: Ag at 1.35 g/L and 1.30 g/L, respectively. The Fg: C and Fg: Ag of proband 1′s father, proband 2′s father and son were also below the normal level. Genetic testing showed that proband 1 had harbored a heterozygous missense variant of c. 688T>G (p.Phe230Val) in exon 7 of the FGG gene, which was inherited from his father. Proband 2, his father and son all had harbored a heterozygous variant of c. 2516A>C (p.Asn839Thr) in exon 6 of the FGA gene. Homology analysis showed that the Phe230 and Asn839 residues were highly conserved among homologous species. Bioinformatic analysis predicted that both p. Phe230Val and p.Asn839Thr were pathogenic variants. Analysis of protein simulation model showed that the p. Asn839Thr variant has changed the hydrogen bond between the amino acids, thus affecting the stability of the protein structure. Conclusion:The heterozygous missense variants of p. Phe230Val and p. Asn839Thr probably underlay the IFD in the two pedigrees.