Analysis of a Chinese pedigree affected with Hereditary coagulation factor Ⅻ deficiency due to compound heterozygous variants ofF12 gene
程晓丽 1杨婷 2杨柳 1辛毅娟 1朱琳 1何睦 1刘家云 1李岭
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作者信息
1. 1空军军医大学第一附属医院检验科，西安 710032
2. 2温州医科大学附属衢州医院（衢州市人民医院）检验科，衢州 324002
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摘要
目的 对1个遗传性凝血因子Ⅻ(FⅫ)缺陷症家系进行临床表型及基因变异分析。 方法 以2021年12月24日空军军医大学第一附属医院检验科发现的1个FⅫ缺陷症家系作为研究对象。用凝固法检测活化部分凝血活酶时间(APTT)与凝血因子Ⅻ的活性(FⅫ：C)，用ELISA法检测FⅫ抗原(FⅫ：Ag)。提取基因组DNA，用Sanger法测定F12基因的所有外显子及其侧翼序列。用ClustalX-2.1-win、PROVEAN及Swiss-Pdb Viewer软件分析变异位点氨基酸的保守性、变异的有害性以及对蛋白质结构的影响。 结果 先证者APTT延长至70.2 s，FⅫ：C和FⅫ：Ag分别降低至12%和13%。基因测序发现先证者F12基因第5和13外显子分别存在c.346G>A(p.Gly97Ser)和c.1583C>A(p.Ser509Tyr)杂合错义变异；其父亲和姐姐均携带c.346G>A(p.Gly97Ser)杂合变异，母亲和哥哥均携带c.1583C>A(p.Ser509Tyr)杂合变异。 结论 c.346G>A(p.Gly97Ser)和c.1583C>A(p.Ser509Tyr)复合杂合变异很可能是该家系遗传性FⅫ缺陷症的遗传学病因。 Objective To analyze the clinical phenotypes and genetic variants of a Chinese pedigree affected with Hereditary coagulation factor Ⅻ (FⅫ) deficiency. Methods A pedigree presented at the First Affiliated Hospital of Air Force Medical University on December 24, 2021 was selected as the study subject. Activated partial thromboplastin time (APTT) and coagulation factor Ⅻ activity (FⅫ: C) were determine by a clotting method, and FⅫ antigen was detected with an ELISA assay. Following the extraction of genomic DNA, all exons and flanking regions of the F12 gene were subjected to Sanger sequencing. Clustalx-2.1-win, PROVEAN and Swiss-PDB Viewer software was used to analyze the conservation of amino acids at the variant sites, impact of of the variants on the amino acid substitutions and the protein structure. Results The APTT of the proband has prolonged to 70.2 s. Her FⅫ: C and FⅫ: Ag have decreased to 12% and 13%, respectively. DNA sequencing revealed that the proband has harbored c. 346G>A (p.Gly97Ser) and c. 1583C>A (p.Ser509Tyr) heterozygous compound missense variants in exons 5 and 13 of theF12 gene, respectively. Her father and sister were heterozygous carriers for the c. 346G>A (p.Gly97Ser) variant, whilst her mother and brother were heterozygous for the c. 1583C>A (p.Ser509Tyr) variant. Conclusion The c. 346G>A (p.Gly97Ser) and c. 1583C>A (p.Ser509Tyr) compound heterozygous variants of theF12 gene probably underlay the pathogenesis of hereditary coagulation FⅫ deficiency in this pedigree.
Abstract
Objective To analyze the clinical phenotypes and genetic variants of a Chinese pedigree affected with Hereditary coagulation factor Ⅻ (FⅫ) deficiency. Methods A pedigree presented at the First Affiliated Hospital of Air Force Medical University on December 24, 2021 was selected as the study subject. Activated partial thromboplastin time (APTT) and coagulation factor Ⅻ activity (FⅫ: C) were determine by a clotting method, and FⅫ antigen was detected with an ELISA assay. Following the extraction of genomic DNA, all exons and flanking regions of the F12 gene were subjected to Sanger sequencing. Clustalx-2.1-win, PROVEAN and Swiss-PDB Viewer software was used to analyze the conservation of amino acids at the variant sites, impact of of the variants on the amino acid substitutions and the protein structure. Results The APTT of the proband has prolonged to 70.2 s. Her FⅫ: C and FⅫ: Ag have decreased to 12% and 13%, respectively. DNA sequencing revealed that the proband has harbored c. 346G>A (p.Gly97Ser) and c. 1583C>A (p.Ser509Tyr) heterozygous compound missense variants in exons 5 and 13 of theF12 gene, respectively. Her father and sister were heterozygous carriers for the c. 346G>A (p.Gly97Ser) variant, whilst her mother and brother were heterozygous for the c. 1583C>A (p.Ser509Tyr) variant. Conclusion The c. 346G>A (p.Gly97Ser) and c. 1583C>A (p.Ser509Tyr) compound heterozygous variants of theF12 gene probably underlay the pathogenesis of hereditary coagulation FⅫ deficiency in this pedigree.
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