Discordant diagnoses obtained by different approaches in antithrombin mutation analysis

Area of Science:

• Genetics
• Molecular Biology
• Thrombosis Research

Background:

• Hereditary antithrombin (AT) deficiency diagnosis is crucial for assessing thromboembolism risk.
• Accurate identification of SERPINC1 gene mutations is essential due to varying clinical implications.
• Traditional DNA diagnostic methods may have limitations.

Purpose of the Study:

• To compare mutation detection rates in the SERPINC1 gene using two different DNA investigation approaches.
• To evaluate the impact of diagnostic discrepancies on clinical risk assessment in AT deficiency.

Main Methods:

• Investigated 16 patients with biochemical indications of AT deficiency and negative DHPLC screening.
• Employed direct sequencing of all SERPINC1 exons and exon-intron boundaries as an alternative method.
• Compared results from DHPLC screening with direct sequencing.

Main Results:

• Direct sequencing revealed discordant results in 10 out of 16 patients (62.5%) with prior negative DHPLC screening.
• Identified the Basel mutation (c.218C>T) in eight patients and the Cambridge II mutation (c.1246G>T) in two patients.
• Altered clinical risk assessment for future thromboses in seven of these ten patients.

Conclusions:

• Highlights potential discrepancies in DNA diagnostics, particularly with evolving techniques.
• Recommends re-analysis of results from earlier sequencing strategies to avoid overlooking clinically significant findings.
• Emphasizes the importance of accurate genetic diagnostics for hereditary antithrombin deficiency management.