Related Experiment Video
Updated: Mar 14, 2026
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Sudden death and cardiac arrest without phenotype: the utility of genetic testing
Yanushi D Wijeyeratne1, Elijah R Behr1
1Cardiology Clinical Academic Group, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, United Kingdom; Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, United Kingdom.
Insights
Genetic testing aids in diagnosing unexplained sudden cardiac death (SADS) and idiopathic ventricular fibrillation (IVF). However, its diagnostic yield is modest, with challenges in interpreting variants of unknown significance, especially in IVF cases without clear phenotypes.
Area of Science:
- Cardiovascular Genetics
- Molecular Autopsy
- Sudden Arrhythmic Death Syndrome (SADS)
Background:
- Sudden arrhythmic death syndrome (SADS) accounts for ~4% of unexplained sudden cardiac deaths.
- Idiopathic ventricular fibrillation (IVF) affects 6-10% of cardiac arrest survivors without identifiable cardiac abnormalities.
- Genetic testing offers potential diagnostic avenues for SADS and IVF.
Purpose of the Study:
- To evaluate the diagnostic utility and limitations of genetic testing in SADS and IVF.
- To explore the role of post-mortem genetic testing (molecular autopsy).
- To identify future improvements for genetic variant interpretation.
Main Methods:
- Clinical evaluation for identifying phenotypes in index cases and families.
- Targeted genetic testing based on clinical phenotypes.
- Next-generation sequencing for broad gene screening.
- Post-mortem genetic analysis ('molecular autopsy').
Main Results:
- Genetic testing has a modest diagnostic yield, with a high probability of variants of unknown significance (VUS).
- The yield is significantly lower in IVF cases lacking suggestive phenotypes.
- Next-generation sequencing increases gene screening but also introduces genetic noise.
Conclusions:
- Genetic testing can diagnose underlying causes in SADS/IVF, particularly with clear phenotypes or pathogenic variants in post-mortem analysis.
- Genetic testing in IVF without a suggested phenotype is currently discouraged due to low yield.
- Future research should focus on improving variant-calling pipelines, shared databases, and patient-specific models to enhance diagnostic accuracy.
Abstract:
Approximately 4% of sudden cardiac deaths are unexplained [the sudden arrhythmic death syndrome (SADS)], and up to 6-10% of survivors of cardiac arrest do not have an identifiable cardiac abnormality after comprehensive clinical evaluation [idiopathic ventricular fibrillation (IVF)]. Genetic testing may be able to play a role in diagnostics and can be targeted to an underlying phenotype present in family members following clinical evaluation. Alternatively, post-mortem genetic testing (the "molecular autopsy") may diagnose the underlying cause if a clearly pathogenic rare variant is found. Limitations include a modest yield, and the high probability of finding a variant of unknown significance (VUS) leading to a low signal-to-noise ratio. Next generation sequencing enables cost-efficient high throughput screening of a larger number of genes but at the expense of increased genetic noise. The yield from genetic testing is even lower in IVF in the absence of any suggestion of another phenotype in the index case or his/her family, and should be actively discouraged at this time. Future improvements in diagnostic utility include optimization of the use of variant-calling pipelines and shared databases as well as patient-specific models of disease to more accurately assign pathogenicity of variants. Studying "trios" of parents and the index case may better assess the yield of sporadic and recessive disease.
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