Pedigree analysis of novel missense mutations causing hereditary coagulation factor Ⅴ deficiency
10.3760/cma.j.cn121090-20240424-00161-1
- VernacularTitle:一个遗传性凝血因子Ⅴ缺陷症家系的分子致病机制研究
- Author:
Langyi QIN
1
;
Yi CHEN
;
Lingling HOU
;
Yanhui JIN
;
Yifan LU
;
Ke ZHANG
;
Mingshan WANG
Author Information
1. 温州医科大学附属第一医院医学检验中心，浙江省检验诊断及转化研究重点实验室，温州 325015
- Publication Type:Journal Article
- Keywords:
Coagulation factor Ⅴ deficiency;
Genetic disease;
Homozygous mutation;
Consanguineous marriage
- From:
Chinese Journal of Hematology
2024;45(12):1119-1124
- CountryChina
- Language:Chinese
-
Abstract:
Objective:This study aimed to primarily discuss the pathogenesis of hereditary coagulation factor Ⅴ (FⅤ) deficiency in a family with a consanguineous cousin marriage.Methods:The coagulation indices of the pedigree (three generations with seven individuals) and the thrombin levels of the proband and his father were assessed. All exons of the F5 gene were analyzed with Sanger sequencing, and a new mutation was confirmed with reverse sequencing. The corresponding sites of the family members were then determined. A set of online software was utilized to predict the conservation and pathogenicity of the mutation site. The pathogenicity of this mutation site was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines.Results:The prothrombin time (PT) and activated partial thromboplastin time (APTT) of the proband were 52.2 s and 108.3 s, respectively. FⅤ activity (FⅤ∶ C) and FⅤ antigen (FⅤ∶Ag) were greatly decreased by 2% and 4%, respectively. The problem was diagnosed as type Ⅰ F Ⅴ deficiency. PT and APTT of the proband’s father, mother, and grandfather were slightly higher than the upper limit of the reference range, and FⅤ∶C and FⅤ∶Ag were approximately 50% of normal. The thromboplastin generation assay revealed that the amount of thromboplastin produced by the proband and his father was lower than that of the healthy controls and that the proband’s ability to produce thromboplastin was more severely impaired. Sequencing analysis revealed that the proband demonstrated a homozygous missense mutation of c.5128T > C (p.Trp1682Arg) in exon 15 of the F5 gene. The grandfather, father, and mother of the proband were all heterozygous for c.5128 T > C. Conservative analysis revealed that p.Trp1682 was a highly conserved site in the homozygous species, and five online software programs, including Mutation Taster, SIFT, REVEL, PolyPhen-2, and CADD, indicated that the mutation was pathogenic. The ACMG guidelines recommend that the new mutation c.5128 T > C is a possible pathogenic mutation (PM2 + PM3 + PP1 + PP3 + PP4). The comparison of the protein models before and after the mutation revealed that the benzene ring and the hydrogen bond were reduced after the mutation, which changed the local structure of the F Ⅴ protein.Conclusion:The missense mutation c.5128T > C (p. Trp1682Arg) in exon 15 of the F5 gene was initially considered the genetic cause of the FⅤ deficiency family. This mutation is the first report globally, which further enriches the gene-phenotype spectrum of FⅤ deficiency.
