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Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection
Marina Gago-Díaz1,2, Eva Ramos-Luis1,2, Silvia Zoppis1,2,3
1Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
Insights
This study validates massive parallel sequencing for diagnosing sudden cardiac death from aortic dissection in forensic autopsies. This genetic testing approach aids in identifying at-risk family members.
Area of Science:
- Genetics
- Forensic Pathology
- Cardiovascular Medicine
Background:
- Acute thoracic aortic dissections and ruptures are life-threatening complications of aneurysms and a major cause of sudden cardiac death.
- Molecular diagnosis is valuable clinically but underexplored in forensic settings.
- This study aimed to validate a novel massive parallel sequencing assay for diagnosing acute thoracic aortic dissection in autopsy cases.
Purpose of the Study:
- To explore and validate a new massive parallel sequencing (MPS) candidate gene assay.
- To apply this assay as a diagnostic tool in acute thoracic aortic dissection autopsy cases.
- To assess the utility of MPS in the forensic field for sudden cardiac death investigations.
Main Methods:
- Massive parallel sequencing of 22 thoracic aortic disease candidate genes was performed on 17 autopsy cases.
- AmpliSeq and Ion Proton technologies were utilized.
- Genetic variants were filtered and classified using ACMG 2015 guidelines, with confirmation by traditional sequencing.
Main Results:
- Ten potentially pathogenic genetic variants were identified in 7 of the 17 samples.
- Two variants were classified as pathogenic, and two as likely pathogenic.
- The molecular autopsy yield was approximately 23%.
Conclusions:
- The MPS candidate gene approach is effective for molecular autopsy in sudden cardiac death cases due to aortic dissection.
- This method should be integrated into forensic practice.
- It offers benefits for early diagnosis and risk stratification in affected families.
Background:
Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.
Materials And Methods:
Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing.
Results:
From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.
Conclusions:
This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.
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