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

Gindele R1, Oláh Z2, Ilonczai P2, Speker M1, Udvari Á1, Selmeczi A1, Pfliegler G3, Marján E4, Kovács B1, Boda Z2, Muszbek L1,5, Bereczky Z1.

Author information

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 as 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 8 intragenic SNP's, a 5'-length dimorphism and 5 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-FXa 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 very young age and conferred a high thrombotic risk. Half of the heterozygotes (n=41/76, 53.9%) also suffered from 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 where the clinical characterization of ATBp3 mutation was executed in a large population. This article is protected by copyright. All rights reserved.