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

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.