Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene
10.3760/cma.j.cn511374-20210407-00308
- VernacularTitle:SERPINC1基因变异所致遗传性抗凝血酶缺陷症家系的临床表型和遗传学分析
- Author:
Yingying CHEN
1
;
Yating YAO
;
Ting LI
;
Kuangyi SHU
;
Xiao YANG
;
Shanshan LI
;
Xiaoou WANG
;
Jinyuan WANG
;
Ting ZHANG
;
Minghua JIANG
Author Information
1. 温州医科大学附属第二医院·育英儿童医院耳鼻咽喉科，温州 325027
- Keywords:
Blood coagulation disorders, inherited;
Hereditary antithrombin deficiency;
SERPINC1 gene;
Gene variant
- From:
Chinese Journal of Medical Genetics
2024;41(3):312-316
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency.Methods:A pedigree diagnosed at the the Second Affiliated Hospital of Wenzhou Medical University, Yuying Children’s Hospital in June, 2020 was selected as the study subject. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and thrombin time (TT) of the probands and their pedigree members were determined using a STA-R automatic coagulation analyzer. Antithrombin activity (AT: A) and antithrombin antigen (AT: Ag) in plasma were determined with chromogenic substrate and immunonephelometry assays. All exons and flanking sequences of the anticoagulant protein gene SERPINC1 were amplified by PCR and subjected to Sanger sequencing. Candidate variants were verified with bioinformatic tools (PolyPhen-2, SIFT, Mutation Taster and PYMOL) to explore their effect on the function and structural conformation of the protein. Results:The probands (Ⅱ 2, Ⅱ 10), their brother (Ⅱ 5) and sons (Ⅲ 1, Ⅲ 8) had shown normal PT, APTT, FIB, and TT, but significantly decreased AT: A and AT: Ag, with their levels being 34%, 57%, 56%, 48%, 53% and 13.51 mg/dL, 13.44 mg/dL, 18.39 mg/dL, 17.36 mg/dL, 17.71 mg/dL, respectively. The remaining pedigree members had normal values. Sanger sequencing revealed that the probands and all affected pedigree members had harbored a heterozygous c. 851T>C (p.Met284Thr) missense variant in exon 5 of the SERPINC1 gene. Bioinformatic analysis and simulation suggested that the variant has resulted in alteration of hydrogen bonds at the c. 851 position, which may affect the structure of the protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS1+ PM1+ PM5+ PP1+ PP4). Conclusion:The probands and other affected members were all diagnosed with type I hereditary AT deficiency, for which the c. 851 T>C (p.Met284Thr) variant of the SERPINC1 gene may be accountable.
