Genotype phenotype correlation in a pediatric population with antithrombin deficiency
Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the AT gene (SERPINC1). Considering that the genotype phenotype relationship in AT deficiency patients remains unclear, especially in pediatric patients, the aim of our study was to evaluate genotype phenotype correlation in a Serbian pediatric population. A retrospective cohort study included 19 children younger than 18 years, from 15 Serbian families, with newly diagnosed AT deficiency. In 21% of the recruited families, mutations affecting exon 4, 5, and 6 of the SERPINC1 gene that causes type I AT deficiency were detected. In the remaining families, the mutation in exon 2 causing type II HBS (AT Budapest 3) was found. Thrombosis events were observed in 1 (33%) of those with type I, 11 (85%) of those with AT Budapest 3 in the homozygous respectively, and 1(33%) in the heterozygous form. Recurrent thrombosis was observed only in AT Budapest 3 in the homozygous form, in 27% during initial treatment of the first thrombotic event. Abdominal venous thrombosis and arterial ischemic stroke, observed in almost half of the children from the group with AT Budapest 3 in the homozygous form, were unprovoked in all cases.
What is Known:
• Inherited AT deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1gene.
• The genotype phenotype correlation in AT deficiency patients remains unclear, especially in pediatric patients.
What is New:
• The genetic results for our paediatric population predominantly showed the presence of a single specific mutation in exon 2, that causes type II HBS deficiency (AT Budapest 3).
• In this group thrombosis mostly occurred as unprovoked, in almost half of them as abdominal thrombosis or stroke with high incidence of recurrent thrombosis, in 27% during initial treatment.
KeywordsAntithrombin deficiency SERPINC1 mutations Pediatric population
Deep venous thrombosis
Human genome mutation database
Low molecular weight heparin
Multiplex ligation-dependent probe amplification
Serine protease inhibitors
Tissue factor pathway inhibitor
Vitamin K antagonist
Mirjana Kovac: designed the study, provided funding of the study, analyzed the data, drafted this manuscript, and agreed on the final version of this manuscript.
Gorana Mitic: participated on the design of this study, analyzed the data, revised the manuscript critically, and agreed on the final version of this manuscript.
Branko Tomic: run statistical analysis of the study data together with Iva Djilas and agreed on the final version of this manuscript.
Milos Kuzmanovic, Olivera Serbic and Danijela Lekovic participated on the design of this study, revised the manuscript critically, and agreed on the final version of this manuscript.
Zsuzsanna Bereczky: provided funding of the study, revised the manuscript critically and agreed on the final version of this manuscript.
This study was supported by grant 173008 from the Ministry of Education, Science and Technological Development, Serbia and from the Hungarian National Research Fund (OTKA K116228) and by the Ministry of National Economy, Hungary (GINOP-2.3.2-15-2016-00039).
Compliance with ethical statements
Conflict of interest
The authors declare that they have no conflict of interest.
Institutional approval for the study was granted by the Local Research Ethics Committee (EK-number 2471/1) in accordance with internationally accepted ethical standards.
Informed consent was obtained from all individual participants included in the study.
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