Identification of new molecular mechanisms of antithrombin deficiency: six new SERPINC1 variants in a Polish cohort.

INTRODUCTION

Inherited antithrombin (AT) deficiency, mainly caused by variants in the SERPINC1 gene, is a high-risk inherited thrombophilia.

OBJECTIVES

We sought to characterize the molecular mechanisms underlying AT deficiency in a series of Polish patients including long-term follow-up data.

PATIENTS AND

METHODS

Twenty-nine unrelated probands (13 women [44.8%], mean [SD] age, 44.2 [13.0] years) with type I AT deficiency (n = 21, 72.4%) and type II AT deficiency (n = 8, 27.6%) who mostly had prior venous thromboembolism (n = 21, 72.4%) were screened for mutations using next-generation sequencing (NGS), long-read whole-genome sequencing or multiplex ligation-dependent probe amplification (MLPA). Hypoglycosylation was evaluated by Western blot and HPLC.

RESULTS

NGS sequencing and MLPA of SERPINC1 detected variants in 22 probands (75.9%): 13 missense (44.8%, including a new AT Kraków III: c.457T>C); 6 small deletions/insertions (20.7%, including 2 new: AT Ostrowiec: c.962dup and AT Poznań: c.[400_401insG;402_403del;406_408 + 1del]), 2 nonsense (6.9%, one new: AT Tychy: c.81G>A) and one new deletion covering exons 1 and 2 (AT Częstochowa). The nanopore sequencing revealed a new insertion of 2940 bp (a SINE-VNTR-Alu element) in intron 3 of SERPINC1 (AT Tkaczew). Congenital disorders of glycosylation were detected in two patients (7%) without any other variants. During a median follow-up of 27 (12-39) months, 21 (72.4%) patients with prior VTE receiving oral anticoagulants and no thrombotic events were recorded.

CONCLUSION

Our findings indicate the need for advanced genomic analyses to detect complex structural variants in subjects with AT deficiency including retrotransposon insertions and intronic variants.