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Genetics and genomics of dilated cardiomyopathy and systolic heart failure
Upasana Tayal1,2, Sanjay Prasad1,2, Stuart A Cook3,4
1National Heart Lung Institute, Imperial College London, Cale Street, London, SW3 6LY, UK.
Insights
Genetic research has identified key variants in dilated cardiomyopathy (DCM) and systolic heart failure. Understanding these genetic factors is crucial for improving patient risk stratification and developing new treatments.
Area of Science:
- Cardiovascular Genetics
- Genomics
- Molecular Cardiology
Background:
- Heart failure affects 40 million globally, with dilated cardiomyopathy (DCM) being a primary cause of systolic heart failure and a leading reason for heart transplantation.
- Advances in next-generation sequencing and genome-wide association studies (GWAS) have significantly improved the understanding of the genetic underpinnings of DCM and systolic heart failure.
- Identifying genetic variants is complex due to the diverse etiologies of systolic heart failure, though DCM presents a more defined target for rare variant discovery.
Purpose of the Study:
- To review the progress and challenges in detecting rare and common genetic variants associated with DCM and systolic heart failure.
- To discuss the difficulties in accurately interpreting genetic variants and understanding their functional impact.
- To explore how enhanced genetic knowledge can influence clinical management strategies for heart failure patients.
Main Methods:
- Application of next-generation sequencing for large-scale genetic analysis.
- Utilizing genome-wide association studies (GWAS) to identify common variants.
- Review of existing literature on genetic variant detection and interpretation in heart failure.
Main Results:
- Discovery of numerous novel rare variants in DCM and common variants in both systolic heart failure and DCM.
- Truncating variants in the titin gene identified as the most significant genetic cause of DCM.
- Progress in identifying genetic contributors, alongside persistent challenges in variant interpretation and functional analysis.
Conclusions:
- Genetic insights are advancing, particularly for DCM, with titin variants being a major factor.
- Accurate variant interpretation and understanding their effects remain critical challenges.
- Translating genetic discoveries into improved risk stratification and novel therapeutics is an unmet need for heart failure management.
Abstract:
Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.
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