SERPINC1 gene mutations in antithrombin deficiency

Abstract

Existing evidence suggests that in most cases antithrombin deficiency can be explained by mutations in its gene, SERPINC1. We investigated the molecular background of antithrombin deficiency in a single centre family cohort study. We included a total of 21 families comprising 15 original probands and sixty-six relatives, 6 of who were surrogate probands for the genetic analysis. Antithrombin activity and antigen levels were measured. The heparin-antithrombin binding ratio assay was used to distinguish between the different subtypes of type II antithrombin deficiency. SERPINC1 mutations were detected by direct sequencing of all 7 exons and regulatory regions, and multiplex ligation-dependent probe amplification. Eighty-six per cent of the families had a detrimental SERPINC1 gene mutation that segregated in the family. We detected 13 different SERPINC1 gene mutations of which 5 were novel. Among all these mutations, 44% was associated with type I deficiency, whereas the remainder was associated with type II heparin binding site (11%), type II pleiotropic effect (33%), type II reactive site (6%) or had the antithrombin Cambridge II mutation (6%). The current study reports several novel SERPINC1 mutations, thereby adding to our knowledge of the molecular background of antithrombin deficiency. Finally, our results point out the importance of future research outside the conventional SERPINC1 gene approach.

How I treat patients with hereditary antithrombin deficiency

“…We have summarized a practical approach for the diagnostic workup of hereditary AT deficiency in Figure 1. In our experience and according to data from the literature, AT levels of patients with AT deficiency are usually clearly below the normal range (ie, ,80%; most have levels ,70%) 17,41 ; however, patients with type 1 defects can also have levels up to 72% or even 78%. 17,42 AT activity ,70% is highly suggestive of AT deficiency, and a single measurement is sufficient to guide further treatment of VTE patients in the acute phase, particularly if the family history is positive.…”

Association of SERPINC1 Gene Polymorphism (rs2227589) With Pulmonary Embolism Risk in a Chinese Population

“…Previous studies in an Asian population reported that the incidence of antithrombin deficiency in VTE was around 5.9%–9.61% (Liu et al, 1994; Zheng et al, 2009). Most VTE subjects with antithrombin deficiency have been found to carry genetic variants of SERPINC1 (Zeng et al, 2015; Mulder et al, 2017). However, the functional mechanism of variant rs2227589 underlying the levels of antithrombin in plasma remains largely unknown (Anton et al, 2009).…”

Genetic testing of hereditary antithrombin deficiency in a large US pedigree using saliva samples

“…Existing evidence suggests that in most cases antithrombin deficiency can be explained by mutations in its gene SERPINC1 3 . To date, about 300 SERPINC1 gene mutations have been reported to be associated with antithrombin deficiency 4 .…”

“…In 2019, our Thrombosis & Haemostasis Center was contacted by a family member with the question whether we could help elucidate the antithrombin deficiency that runs in the family. As we have a special interest in antithrombin deficiency, 3 we agreed to do so. Because our medical center is located in the Netherlands and participants live in United States of America, we choose to collect saliva instead of blood samples.…”