Clinical characteristics and genotypes of patients with Congenital fibrinogen disorders
10.3760/cma.j.cn511374-20240326-00196
- VernacularTitle:遗传性纤维蛋白原缺陷症患者的临床及遗传特征分析
- Author:
Haijian WANG
1
;
Shuang ZHENG
;
Xiaomin YU
;
Kaiwen WU
;
Misheng ZHAO
Author Information
1. 温州市人民医院 温州医科大学温州市第三临床学院医学检验中心，温州 325000
- Publication Type:Journal Article
- Keywords:
Fibrinogen;
Congenital fibrinogen disorders;
Genetic mutation;
FGA gene;
FGB gene;
FGG gene;
Clinical features
- From:
Chinese Journal of Medical Genetics
2025;42(3):264-273
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the clinical features and genetic mutation sites of 28 patients with Congenital fibrinogen disorders (CFDs).Methods:A total of 28 unrelated CFDs patients admitted to Wenzhou People′s Hospital from June 2018 to April 2023 were enrolled into this research. A total of 2.7 mL of peripheral blood was collected from each patient for coagulation function tests, which included thrombin time (TT), fibrinogen activity (Fg: C), fibrinogen antigen (Fg: Ag), and gene detection. The Sanger sequencing method was employed to verify variations in the fibrinogen (Fg) protein-coding gene across 28 patients. Bioinformatics analyses, including harmfulness analysis, conservation analysis across different species, and spatial simulation predictions of variant proteins, were conducted by PolyPhen-2, PROVEAN, SnapGene, and Pymol softwares on the variant sites of these patients. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study received approval from the Ethics Committee of Wenzhou People′s Hospital (Approval No. KY-2023-269), and informed consent was obtained from all participants before enrollment.Results:The clinical and genetic characteristics of 28 patients with CFDs in this study were as follows. ①Clinical data: Among the 28 patients, 2 cases were diagnosed with type I CFDs, while 26 cases were diagnosed with type II CFDs. And 50.0% (14/28) of the patients exhibited no clinical manifestations, while 28.6% (8/28) presented with bleeding manifestations, and 7.1% (2/28) exhibited thrombus manifestations, 3.6% (1/28) experienced both bleeding and thrombosis. Among female patients, 13.0% (3/23) exhibited a history of habitual abortion. All patients demonstrated TT and a significant decrease in Fg: C. ②Sanger sequencing revealed a total of 10 types of heterozygous variations in the FGA, FGB, and FGG genes across 28 patients, distributed among 9 loci. The variation at the γ c. 902G>A/c.901C>T accounted for the highest proportion (35.7%, 10/28), followed by the Bβ c. 569 A>G (28.6%, 8/28). ③Biological informatics analysis: the Aα c. 180+ 1G>T mutation was predicted to be highly deleterious. And the Aα c. 104G>A, Bβ c. 425T>G, Bβ c. 586C>T, and γ c. 902G>A/c.901C>T variations were also predicted to be harmful. Conservation analysis indicates that the 9 variant sites were highly conserved among homo sapiens, musculus, ovis aries, scrofa, and rattus. Spatial conformation analysis revealed that some variations lead to an increase or decrease in the number of hydrogen bonds. ④ACMG guideline rating analysis: Among the ten variations in the Fg protein-coding genes FGA, FGB, and FGG identified in 28 patients, 9 variations (Aα c. 104G>A, Aα c. 180+ 1G>T, Bβ c. 425T>G, Bβ c.569A>G, Bβ c. 586C>T, Bβ c. 643G>A, γ c. 901C>T, γ c. 902G>A, γ c. 1001A>C) were classified as pathogenic, while one variation (γ c. 908C>G) was classified as likely pathogenic. Conclusion:In this study, the majority of CFDs patients are diagnosed with type II CFDs, with 50% presenting clinical symptoms predominantly manifesting as bleeding, thrombosis, and recurrent miscarriage. The mutation hotspots are mainly located in exon 2 of FGA, exon 4 of FGB, and exon 8 of FGG.
