Genetic analysis of a family with inheritary coagulation factor Ⅹ deficiency due to compound heterozygous variants p.Phe71Ser and p.Val424Phe.
10.3760/cma.j.cn511374-20250706-00408
- Author:
Shuangnyu LIN
1
,
2
;
Bile CHEN
;
Zuoting XIE
;
Lihong YANG
;
Mingshan WANG
;
Yanhui JIN
Author Information
1. Center of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China. jyh603@
2. com.
- Publication Type:Journal Article
- MeSH:
Humans;
Female;
Male;
Pedigree;
Adult;
Heterozygote;
Mutation;
Middle Aged;
Factor X/genetics*;
Exons;
Factor X Deficiency/genetics*
- From:
Chinese Journal of Medical Genetics
2025;42(10):1272-1277
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To analyze the phenotype and genotype of a family with hereditary coagulation factor Ⅹ (FⅩ) deficiency and preliminarily explore its molecular pathogenesis.
METHODS:A hereditary FⅩ deficiency pedigree presented at the First Affiliated Hospital of Wenzhou Medical University on August 13, 2024 was selected as the study subject. Coagulation parameters of the proband and her family members (7 individuals from 3 generations) were measured using a one-stage clotting assay. All of the 8 exons and flanking sequences of the F10 gene were amplified by PCR and directly sequenced. Bioinformatics software was used to analyze the functional impact and pathogenicity of the variant proteins, as well as the spatial conformational changes and evolutionary conservation of the mutation sites. This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (Ethics No.: KY2022-R193).
RESULTS:The proband exhibited significantly abnormal prothrombin time (PT, 33.3 s), activated partial thromboplastin time (APTT, 47.7 s), and FⅩ activity (FⅩ:C, 3%), while other coagulation parameters remained normal. The plasma thromboplastin generation test (PTGT) demonstrated that the proband and her children had lower thromboplastin generation levels compared with the healthy control group, and the proband's thromboplastin generation capacity was more severely impaired. Genetic analysis revealed that the proband, her daughter, and grandson have all harbored a heterozygous missense variant c.212T>C (p.Phe71Ser) in exon 2 of the F10 gene, which was located in the β-sheet core region of the Gla domain. The variant has altered surrounding hydrogen bonds and disrupted calcium-binding sites. Additionally, the proband, her son, and granddaughter have all carried a heterozygous missense variant c.1270G>T (p.Val424Phe) in exon 8, which increased the side-chain volume, leading to steric hindrance in the catalytic domain and impaired coagulation function. Bioinformatics analysis confirmed that both p.Phe71Ser and p.Val424Phe were pathogenic variants, with Phe71 and Val424 being highly conserved residues.
CONCLUSION:The reduced FⅩ levels in this hereditary FⅩ-deficient family may be attributed to the heterozygous missense variants c.212T>C (p.Phe71Ser) in the exon 2 and c.1270G>T (p.Val424Phe) in the exon 8 of the F10 gene.
