title: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: R
authors.initials: R
authors.lastname: Gindele
authors.affiliation: Thrombosis and Haemostasis Center, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Oláh
authors.affiliation: Thrombosis and Haemostasis Center, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
authors.forename: P
authors.initials: P
authors.lastname: Ilonczai
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Speker
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Á
authors.initials: Á
authors.lastname: Udvari
authors.affiliation: Thrombosis and Haemostasis Center, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Selmeczi
authors.affiliation: Division of Rare Diseases, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Pfliegler
authors.affiliation: Department of Pediatrics, A. Jósa Teaching Hospital, Nyíregyháza, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Marján
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Kovács
authors.affiliation: Thrombosis and Haemostasis Center, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Boda
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Haemostasis, Thrombosis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Muszbek
authors.affiliation: Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Bereczky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000991:Antithrombins / Q000737:chemistry*; D001158:Arteries / Q000503:physiopathology; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015951:Factor Xa / Q000235:genetics; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D006493:Heparin / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006814:Hungary; D007930:Leucine / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010649:Phenylalanine / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D012680:Sensitivity and Specificity; D013927:Thrombosis / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000991:Antithrombins; D010649:Phenylalanine; D006493:Heparin; D015951:Factor Xa; D007930:Leucine
keywords: antithrombin III; antithrombin III deficiency; founder effect; thrombophilia; venous thromboembolism