[F11基因复合杂合变异导致的遗传性凝血因子XI缺乏症家系分析]
[Analysis of a pedigree affected with hereditary coagulation factor XI deficiency due to compound heterozygous variants of F11 gene].
作者信息
Yang Ting, Zhu Jin, Yang Qing, Liu Jun, Yang Liping, Wang Mingshan
机构信息
Department of Laboratory Medicine, the People's Hospital of Quzhou, Quzhou, Zhejiang 324000, China.
出版信息
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Mar 10;38(3):242-246. doi: 10.3760/cma.j.cn511374-20200123-00047.
OBJECTIVE
To analyze the clinical phenotype and genetic basis for a Chinese pedigree affected with coagulation factor XI (FXI) deficiency.
METHODS
Activated partial thromboplastin time (APTT) and other blood coagulation factors, and activities of FXI:C and other relevant coagulation factors for a large Chinese pedigree including 6 patients from 3 generations were determined on a Stago automatic coagulometer. The FXI:Ag was determined with an ELISA method. All exons and flanking regions of the F11 gene were subjected to Sanger sequencing. ClustalX-2.1-win software was used to analyze the conservation of amino acids. Pathogenicity of the variants was predicted with online bioinformatics software including Mutation Taster and Swiss-Pdb Viewer.
RESULTS
The APTT of the proband was prolonged to 94.2 s. The FXI:C and FXI:Ag were decreased to 1% and 1.3%, respectively. The APTT of her father, mother, son and daughter was 42.1 s, 43.0 s, 42.5 s and 41.0 s, respectively. The FXI:C and FXI:Ag of them were almost halved compared with the normal values. The APTT, FXI:C and FXI:Ag of her husband were all normal. Genetic testing revealed that the proband has carried a heterozygous missense c.1103G>A (p.Gly350Glu) variant in exon 10 and a heterozygous missense c.1556G>A (p.Trp501stop) variant in exon 13 of the F11 gene. The father and daughter were heterozygous for the c.1103G>A variant, whilst the mother and son were heterozygous for the c.1556G>A variant. Both Gly350 and Trp501 are highly conserved among homologous species, and both variants were predicted to be "disease causing" by Mutation Taster. Protein modeling indicated there are two hydrogen bonds between Gly350 and Phe312 in the wild-type, while the p.Gly350Glu variant may add a hydrogen bond to Glu and Tyr351 and create steric resistance between the two, both may affect the structure and stability of protein.
CONCLUSION
The c.1103G>A and c.1556G>A compound heterozygous variants probably underlay the pathogenesis of congenital FXI deficiency in this pedigree.
目的
分析一个患凝血因子XI（FXI）缺乏症的中国家系的临床表型和遗传基础。
方法
使用Stago自动凝血仪测定一个包含来自三代的6名患者的大型中国家系的活化部分凝血活酶时间（APTT）及其他凝血因子，以及FXI:C和其他相关凝血因子的活性。采用ELISA法测定FXI:Ag。对F11基因的所有外显子及其侧翼区域进行Sanger测序。使用ClustalX-2.1-win软件分析氨基酸的保守性。利用Mutation Taster和Swiss-Pdb Viewer等在线生物信息学软件预测变异的致病性。
结果
先证者的APTT延长至94.2秒。FXI:C和FXI:Ag分别降至1%和1.3%。其父亲、母亲、儿子和女儿的APTT分别为42.1秒、43.0秒、42.5秒和41.0秒。他们的FXI:C和FXI:Ag与正常值相比几乎减半。其丈夫的APTT、FXI:C和FXI:Ag均正常。基因检测显示，先证者在F11基因第10外显子携带一个杂合错义c.1103G>A（p.Gly350Glu）变异，在第13外显子携带一个杂合错义c.1556G>A（p.Trp501stop）变异。父亲和女儿为c.1103G>A变异的杂合子，而母亲和儿子为c.1556G>A变异的杂合子。Gly350和Trp501在同源物种中均高度保守，且两个变异经Mutation Taster预测均为“致病”。蛋白质建模表明，野生型中Gly350和Phe312之间有两个氢键，而p.Gly350Glu变异可能在Glu和Tyr351之间增加一个氢键并在两者之间产生空间阻力，两者均可能影响蛋白质结构和稳定性。
结论
c.1103G>A和c.1556G>A复合杂合变异可能是该家系先天性FXI缺乏症发病机制的基础。
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