Clinical Phenotype and Genetic Analysis of a Family with Hereditary Antithrombin Deficiency Caused by SERPINC1 Gene Mutation

Abstract

Background

Inherited deficiency of the antithrombin (hereditary antithrombin deficiency, AT deficiency, OMIM #613118) is a relatively rare (1:2,000–3,000) autosomal-dominant disorder with high risk of venous thromboembolism. The molecular basis of this condition has not yet fully understood, highlighting the need for further research to elucidate the underlying pathological mechanisms.

Objective

This study aimed to investigate coagulation parameters and genetic phenotypes in a proband with hereditary antithrombin deficiency and her family members. Additionally, the investigation sought to provide preliminary insights for the molecular pathogenesis of this condition.

Methods

Blood coagulation parameters, including plasma antithrombin activity (AT:A), antithrombin antigen (AT:Ag), protein C activity (PC:A), and protein S activity (PS:A) were measured in the peripheral blood of each family member by a Stago instrument. Peripheral blood was also extracted and sequenced to identify possible genetic mutation sites. The functional impact of variants on protein was subsequently analyzed by bioinformatics software.

Results

The proband, her mother, and brother all exhibited decreased activity and antigen of AT but normal PC and PS activity. The proband's father had normal activity and antigen levels of AT, PC, and PS. Sequencing revealed the proband's mother inherited the SERPINC1:c.661T > C,p.(Trp221Arg) heterozygous variant and her father harbored PROC:c.572_574del,p.(Lys193del) heterozygous variant while the proband as well as her brother carried both. Conservation analysis revealed that Trp221 is highly conserved across homologous species. Bioinformatics tools consistently classify the p.Trp221Arg mutation as “pathogenic” or “deleterious.” Protein modeling indicated that the p.Trp221Arg variant does not alter the protein structure but may modify glycosylation sites to affect its function.

Conclusion

The proband and family members exhibited varying degrees of decreased levels of AT and thrombosis, which were closely associated with inheritance of SERPINC1:c.661T > C,p.(Trp221Arg).

Keywords

antithrombin - inherited AT deficiency - SERPINC1 gene - PROC gene - mutation

Authors' Contribution

Conception and design: X.Z. and C.S.; Administrative support: S.Z.; Provision of study materials or patients: Y.Z., L.D.; Collection and assembly of data: S.L. and Y.C.; Data analysis and interpretation: L.B. and M.Y.; Manuscript writing: All authors; Final approval of manuscript: All authors.

^* These authors contributed equally to this article.

Publication History

Received: 14 October 2024

Accepted: 14 March 2025

Accepted Manuscript online:
17 March 2025

Article published online:
09 April 2025

• References

• 1 Rezaie AR, Giri H. Anticoagulant and signaling functions of antithrombin. J Thromb Haemost 2020; 18 (12) 3142-3153
• 2 Peacock RB, McGrann T, Tonelli M, Komives EA. Serine protease dynamics revealed by NMR analysis of the thrombin-thrombomodulin complex. Sci Rep 2021; 11 (01) 9354
• 3 de la Morena-Barrio ME, Suchon P, Jacobsen EM. et al. Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays. Blood 2022; 140 (02) 140-151
• 4 Bucciarelli P, Passamonti SM, Biguzzi E. et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. J Thromb Haemost 2012; 10 (09) 1783-1791
• 5 Wang HL, Ruan DD, Wu M. et al. Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency. Thromb J 2023; 21 (01) 3
• 6 Corral J, de la Morena-Barrio ME, Vicente V. The genetics of antithrombin. Thromb Res 2018; 169: 23-29
• 7 Corral J, Hernandez-Espinosa D, Soria JM. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109 (10) 4258-4263
• 8 Ishiguro K, Kojima T, Kadomatsu K. et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000; 106 (07) 873-878
• 9 Bauer KA, Nguyen-Cao TM, Spears JB. Issues in the diagnosis and management of hereditary antithrombin deficiency. Ann Pharmacother 2016; 50 (09) 758-767
• 10 Rodgers GM, Mahajerin A. Antithrombin therapy: current state and future outlook. Clin Appl Thromb Hemost 2023 ;29:10760296231205279
• 11 Pejaver V, Byrne AB, Feng BJ. et al; ClinGen Sequence Variant Interpretation Working Group. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet 2022; 109 (12) 2163-2177
• 12 Polyak ME, Zaklyazminskaya EV. New genetic variant in the SERPINC1 gene: hereditary antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling. BMC Med Genet 2020; 21 (01) 73
• 13 ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0. Accessed at: https://cspec.genome.network/cspec/ui/svi/doc/GN084
• 14 Ong J, Bennett A. A review of laboratory considerations in thrombophilia testing. Pathology 2022; 54 (07) 835-841
• 15 Asmis L, Hellstern P. Thrombophilia testing—a systematic review. . Clin Lab 2023;69(04):
• 16 Thrombosis and Hemostasis Group, Chinese Society of Hematology, Chinese Medical Association. [Chinese guidelines for diagnosis, prevention and treatment of thrombophilia (2021)]. Zhonghua Xue Ye Xue Za Zhi 2021; 42 (11) 881-888
• 17 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 18 Rogenhofer N, Bohlmann MK, Beuter-Winkler P. et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol 2014; 93 (03) 385-392
• 19 Fitches AC, Lewandowski K, Olds RJ. Creation of an additional glycosylation site as a mechanism for type I antithrombin deficiency. Thromb Haemost 2001; 86 (04) 1023-1027
• 20 Zeng W, Hu B, Tang L. et al. Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent antithrombin deficiency. Oncotarget 2017; 8 (48) 84417-84425
• 21 Deshpande R, Kulkarni B, Ghosh K, Shetty S. A common missense variant in exon 5 of antithrombin gene (SERPINC1) in Indian patients with thrombosis. Thromb Res 2016; 143: 1-2
• 22 Tang L, Wang HF, Lu X. et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet 2013; 92 (02) 177-187
• 23 Lu X, Tang L, Xu K. et al. Novel association of a PROC variant with ischemic stroke in a Chinese Han population. Hum Genet 2013; 132 (01) 69-77
• 24 Iijima K, Nakamura A, Kurokawa H, Monobe S, Nakagawa M. A homozygous protein C deficiency (Lys 192 del) who developed venous thrombosis for the first time at adulthood. Thromb Res 2010; 125 (01) 100-101