Genetic analysis of a Chinese pedigree affected with Congenital dysfibrinogenemia due to variant ofFGG gene
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目的 探讨1个无症状遗传性异常纤维蛋白原血症(CD)家系的凝血异常和分子遗传学特征。 方法 选取2021年8月3日因"患卵巢畸胎瘤准备行腹腔镜手术，术前凝血功能异常"就诊于哈尔滨市第一医院血液肿瘤研究所的女性先证者及其家系成员(共3代8人)作为研究对象，收集先证者及其家系成员的临床资料。用Clauss法和衍算法(DFg-PT)检测先证者及其父母、儿子的血浆纤维蛋白原的活性(Fg：C)，用免疫比浊法测定抗原(Fg：Ag)水平。用PCR扩增仪进行纤维蛋白原(Fg)相关基因检测变异位点。 结果 先证者为32岁女性。先证者及其父亲Fg：C分别为0.71 g/L和0.87 g/L，明显低于正常范围，先证者母亲及儿子Fg：C均在正常范围。先证者及其父亲Fg：C/Fg：Ag比值为<0.7，明显下降，而母亲及儿子>0.7。先证者及其父亲的凝血酶时间延长，而母亲及儿子正常。先证者及其父母和儿子的凝血酶原时间、活化部分凝血活酶时间未见明显异常。基因检测结果提示先证者及其父亲FGA基因存在已报道为良性的c.991A>G(p.Thr331Ala)错义变异以及FGG基因的c.1211C>T(p.Ser404Phe)错义变异。根据美国医学遗传学与基因组学学会变异评级相关指南，c.1211C>T错义变异评级为可能致病的变异(PM2_Supporting+PM5+PP3+PP4)。蛋白模拟预测模型提示c.1211C>T导致Fg γ链第404位氨基酸残基从丝氨酸变异为苯丙氨酸，可能造成局部的氨基酸之间的作用力发生变化，从而影响纤维蛋白原γ链之间聚合或者与另一纤维蛋白原α链的结合。 结论 FGG基因的c.1211C>T(p.Ser404Phe)错义变异可能是先证者的致病原因。上述发现为该家系的诊断及遗传咨询提供了帮助。 Objective To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD). Methods Peripheral venous blood samples of the proband and her family members (including 4 individuals from three generations) were subjected to routine blood test and assays of liver and kidney functions and viral hepatitis to exclude related diseases. Clauss method and DFg-PT method were used to determine the fibrinogen activity (Fg: C), and an immunoturbidimetric assay was used to determine the level of fibrinogen antigen (Fg: Ag). All of the exons (22 in total) and their flanking sequences of the FGA, FGB and FGG genes were amplified by PCR and directly sequenced. Variants in the coding regions of the three genes and transcriptional splicing sites were screened by using Mutation Surveyor™ software. Results The Clauss method showed that Fg: C was significantly reduced in the proband and her father, whilst her mother and son were normal. With the DFg-PT method, the proband, her parents and son were all within the normal range. The Fg: C/Fg: Ag ratio of the proband and her father was lower than 0.7, whilst her mother and son were above 0.7. No significant change in the prothrombin time, activated partial thromboplastin clotting time and thrombin time was noted. Two genetic variants were detected, which included a homozygous missense variant in the FGA gene [c.991A>G (p.Thr331Ala)], which was predicted to be benign, and a heterozygous missense variant of the γ chain of theFGG gene [c.1211C>G (p.Ser404Phe)], which is located in a conserved region and unreported in the CLINVAR/HGMD/EXAC/1000G databases and literature. Conclusion This pedigree has conformed to the autosomal dominant inheritance of CD. The c. 1211C>T (p.Ser404Phe) missense variant of the γ chain of theFGG gene probably underlay the pathogenesis of CD in this pedigree. The variant was unreported previously and named as "Fibrinogen Harbin II Ser404Phe" .
Objective To explore the coagulation deficit and genetic basis for a Chinese pedigree affected with Congenital dysfibrinogenemia (CD). Methods Peripheral venous blood samples of the proband and her family members (including 4 individuals from three generations) were subjected to routine blood test and assays of liver and kidney functions and viral hepatitis to exclude related diseases. Clauss method and DFg-PT method were used to determine the fibrinogen activity (Fg: C), and an immunoturbidimetric assay was used to determine the level of fibrinogen antigen (Fg: Ag). All of the exons (22 in total) and their flanking sequences of the FGA, FGB and FGG genes were amplified by PCR and directly sequenced. Variants in the coding regions of the three genes and transcriptional splicing sites were screened by using Mutation Surveyor™ software. Results The Clauss method showed that Fg: C was significantly reduced in the proband and her father, whilst her mother and son were normal. With the DFg-PT method, the proband, her parents and son were all within the normal range. The Fg: C/Fg: Ag ratio of the proband and her father was lower than 0.7, whilst her mother and son were above 0.7. No significant change in the prothrombin time, activated partial thromboplastin clotting time and thrombin time was noted. Two genetic variants were detected, which included a homozygous missense variant in the FGA gene [c.991A>G (p.Thr331Ala)], which was predicted to be benign, and a heterozygous missense variant of the γ chain of theFGG gene [c.1211C>G (p.Ser404Phe)], which is located in a conserved region and unreported in the CLINVAR/HGMD/EXAC/1000G databases and literature. Conclusion This pedigree has conformed to the autosomal dominant inheritance of CD. The c. 1211C>T (p.Ser404Phe) missense variant of the γ chain of theFGG gene probably underlay the pathogenesis of CD in this pedigree. The variant was unreported previously and named as "Fibrinogen Harbin II Ser404Phe" .
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