Founder effect is responsible for the p.Leu131Phe heparin-binding-site antithrombin mutation common in Hungary: phenotype analysis in a large cohort

Abstract

Background: Antithrombin (AT) is a key regulator of the coagulation. In type II deficiency, the heparin-binding-site defect (type II HBS) is considered to be relatively low thrombosis risk.

Objectives: Our aims were to search for SERPINC1 mutation(s) and to describe the clinical and laboratory phenotype of a large number of AT Budapest3 (ATBp3, p.Leu131Phe) carriers and confirm the presence of a founder effect.

Patients/methods: AT-deficient patients were recruited and carriers of ATBp3, n = 102 (63 families) were selected. To investigate the founder effect, eight intragenic single nucleotide polymorphisms, a 5'-length dimorphism, and five microsatellite markers were detected. Clinical and laboratory data of the patients were collected and analyzed.

Results: In AT deficiency, 16 different causative mutations were found, and the great majority of patients were of type II HBS subtype. Most of them (n = 102/118, 86.5%) carried the ATBp3 mutation. The ATBp3 mutant allele was associated with one single haplotype, while different haplotypes were detected in the case of normal allele. The anti-factor Xa-based AT activity assay that we used could detect all ATBp3 patients with high sensitivity in our cohort. ATBp3 homozygosity (n = 26) was associated with thrombosis at a young age and conferred a high thrombotic risk. Half of the heterozygotes (n = 41/76, 53.9%) also had venous and/or arterial thrombosis, and pregnancy complications were also recorded.

Conclusion: In Hungary, the founder mutation, ATBp3, is the most common AT deficiency. Our study is the first in which the clinical characterization of ATBp3 mutation was executed in a large population.

Keywords: antithrombin III; antithrombin III deficiency; founder effect; thrombophilia; venous thromboembolism.