Abstract Number: PB2240
Meeting: ISTH 2020 Congress
Background: Hereditary antithrombin deficiency is a rare autosomal dominant disorder predisposing to recurrent venous thromboembolism (VTE). To date, only two founder variants have been described, both in Caucasians.
Aims: To characterize a new recurrent SERPINC1 variant, p.Thr147Ala, identified in people from African ancestry.
Methods: The study included 10 patients from African origin living in Belgium. Eight of them experienced VTE, stroke or obstetric complications.
Antithrombin was functionally and biochemically characterized using patient plasma and a recombinant model. SERPINC1 (14480bp) was amplified by 2 long-range-PCRs (LR-PCR) (Figure 1) and sequenced with nanopore technology (MinION). SNVs were analyzed by Illumina Variant Studio and Integrative Genomics Viewer. Haplotype was verified by studying the reads carrying p.Thr147Ala by specific bioinformatic algorithms using grep command in Linux.
Results: All patients carried the same variant, p.Thr147Ala (rs2227606), being, absent in Caucasians and Asians but present in 1% of Afro-Americans, according to ExAC, 1000 Genomes, and gnomeAD.
Anti-FXa activity was reduced (61.8±9.3%) while anti-FIIa activity and antigen levels were normal (100.9±10.2% and 91.2±14.9%, respectively). On crossed-immunoelectrophoresis under high ionic strength conditions, an increase of antithrombin fractions with reduced heparin affinity was observed, not detected in physiological conditions. Purified recombinant p.Thr147Ala showed a reduced anti-FXa activity (61.6%±1.6%) but normal heparin affinity. Structural modelling revealed that the variant abolished three hydrogen bonds of Thr147, one of them involving Arg49, a residue directly interacting with heparin.
Nanopore sequencing revealed a common haplotype containing 13 intragenic markers (Figure 2), confirmed by grep analysis.
Conclusions: Nanopore sequencing efficiently and rapidly determines the haplotype of a genetic variant without requiring family studies or cloning strategies. Our study describes the first pathogenic founder variant from African origin, p.Thr147Ala, responsible for a mild antithrombin type II HBS deficiency. This study contributes to the knowledge about population-specific thrombotic risk factors.
PI18/00598 (ISCIII&FEDER); 19873/GERM/15 (Fundación Séneca)
Wetenschappelijk Fonds Willy Gepts
To cite this abstract in AMA style:de la Morena-Barrio B, Padilla J, Pareyn I, Bravo-Pérez C, Vanhoorelbeke K, Martínez-Martínez I, Vicente V, Corral J, Jochmans K, de la Morena-Barrio ME, Orlando C. Characterisation of Antithrombin p.Thr147Ala, the First Common Founder Variant from African Origin Responsible for Inherited Antithrombin Deficiency [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/characterisation-of-antithrombin-p-thr147ala-the-first-common-founder-variant-from-african-origin-responsible-for-inherited-antithrombin-deficiency/. Accessed October 2, 2023.
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