SERPINC1 variants causing hereditary antithrombin deficiency in a Danish population

Introduction: Antithrombin deficiency is associated with increased risk of venous thromboembolism (VTE). We aimed to identify variants causing antithrombin deficiency in a Danish population. Materials and methods: We performed Sanger sequencing and, in relevant cases, multiplex ligation-dependent probe amplification analyses, in 46 individuals (23 index cases) with and 9 relatives without antithrombin deficiency. Furthermore, in order to explore whether a combination of antithrombin type II heparin binding site (HBS) deficiency and factor V Leiden single nucleotide variant (SNV) conferred a higher risk of VTE than either risk factor alone, we performed genotyping for factor V Leiden in most of the carriers of type II HBS deficiency (n=25). Results: We detected causal variants in all 46 carriers: three large and two small deletions, all causing type I antithrombin deficiency, and seven SNVs: one causing type I, one causing type II reactive site (RS), four causing type II HBS and one causing pleiotropic effect (PE) type II antithrombin deficiency. None of the relatives without antithrombin deficiency had the family variant. All detected SNVs have been reported previously. Majority (n=27) of carriers had type II HBS deficiency, most often caused by the p.(Pro73Leu) SNV (n=19). Heterozygosity for factor V Leiden was observed in three (3/25=12%) carriers of type II HBS deficiency. Only four (4/25=16%) carriers of type II HBS antithrombin deficiency experienced VTE, and two of these were heterozygous for factor V Leiden. Conclusions: In a systematic search to identify variants causing hereditary antithrombin deficiency in a Danish population, we achieved a variant detection rate of 100%.