SERPINC1 mutations and thrombotic events in inherited antithrombin deficiency: a study on the han population of East China

Inherited antithrombin deficiency (ATD), a rare autosomal dominant disorder due to SERPINC1 gene mutations, is the most severe inherited thrombophilia. Limited literature exists that focuses on ATD and its mutations in the Chinese population. This study aimed to characterize SERPINC1 gene mutations in a Chinese cohort and to explore their relationship with thrombophilia. Coagulation screening results and clinical data were meticulously collected from 23 unrelated probands with ATD and their family members. Genomic DNA was extracted and subjected to PCR amplification and direct sequencing. Putative mutations were analyzed using in silico bioinformatic tools. Mutant antithrombin (AT) proteins were expressed in HEK293 cells, and ELISA was used to detect wild-type and mutant AT. RT-qPCR was used to measure AT mRNA expression in transfected cells. Among the 23 probands, 15 (65.2%) exhibited concurrent reductions in both AT: A and AT: Ag (type I defects), while the remaining 8 (34.8%) had normal AT: Ag levels (type II defects). Genetic analysis revealed a spectrum of 21 distinct mutations across 87.0% (20/23) of the probands. Most were point mutations predicted to be deleterious and were primarily located in exons 5 and 3. Among the 20 mutation carriers, 15 (75%) were heterozygous and most of them experienced thrombosis with identifiable triggers. The other 5 (25%) were compound heterozygous and primarily presented with spontaneous thrombosis. Notably, the missense mutations c.1346T > A and c.442T > C were recurrent. These mutations exhibited high heterogeneity, with no ethnic-specific mutations observed. In vitro expression confirmed that synthesis and/or secretion defects in the mutant proteins are the primary mechanism underlying the antithrombin deficiency. SERPINC1 gene analysis benefits asymptomatic family members, especially child-bearing women, by informing venous thromboembolism prevention strategies and guiding anticoagulant choice in cases involving heparin-binding site mutations. This underscores the essential role of genetic diagnosis in ATD management.