Cardiology
Placing genetics at the core of medical decisions
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, accounting for approximately 32% of all deaths (WHO, 2021). While the majority of cases are multifactorial, a significant proportion is attributable to hereditary cardiovascular diseases (hCVDs), which follow Mendelian inheritance patterns and have direct implications for risk assessment, prognosis, and therapy. These disorders include aortopathies, cardiomyopathies, inherited arrhythmia syndromes due to ion channel disease, congenital heart defects, and premature coronary artery disease secondary to familial hypercholesterolaemia (FH).
Hereditary cardiovascular diseases are caused by pathogenic variants in genes encoding structural, metabolic, or regulatory proteins of the cardiovascular system. Their estimated prevalence is around 3% in the general population. Most are transmitted in an autosomal dominant manner, conferring a 50% risk of transmission to offspring. However, penetrance and expressivity can vary widely, underscoring the complexity of genotype-phenotype correlations.
Hereditary cardiovascular disorders include:
- Cardiomyopathies (e.g., , , , and forms) are most often caused by pathogenic variants in genes encoding sarcomeric, cytoskeletal, or desmosomal proteins. They predispose individuals to heart failure, arrhythmias, and sudden cardiac death.
- Inherited arrhythmia syndromes (e.g., , , and ) result from ion channel dysfunction and are major causes of sudden cardiac death in structurally normal hearts.
- Aortopathies (e.g., , , and familial thoracic aortic aneurysm and dissection) are associated with pathogenic variants in genes regulating connective tissue architecture or vascular signalling pathways. Early molecular diagnosis informs surveillance intervals and surgical thresholds.
- Congenital heart defects (CHDs): While often sporadic, a proportion of CHD cases follows Mendelian inheritance or occurs within syndromic contexts (e.g., 22q11.2 deletion syndrome). Genetic characterisation is increasingly important in defining recurrence risk and tailoring long-term surveillance.
- (FH): FH is a prototypical inherited metabolic cardiovascular disorder characterised by markedly elevated LDL cholesterol from birth and a dramatically increased risk of premature coronary artery disease.
Cardiology genetic testing
Genetic testing has emerged as an essential adjunct to traditional clinical assessment. Beyond confirming a suspected diagnosis, it facilitates differential diagnosis in cases with overlapping phenotypes, such as hypertrophic cardiomyopathy versus athlete’s heart, or electrocardiographic abnormalities that may be associated with multiple ion channel diseases.
From a prognostic standpoint, specific genotypes are associated with disease severity, arrhythmic risk, and response to therapy. For example, certain genotypes, such as LMNA-associated dilated cardiomyopathy, confer particularly high arrhythmic risk and warrant early consideration of implantable cardioverter-defibrillator (ICD) therapy [ESC DCM Guidelines, 2022].
Therapeutically, genetic insights increasingly inform precision medicine approaches. FH serves as a paradigm, whereby identification of pathogenic variants leads to targeted lipid-lowering interventions and cascade screening of relatives. In arrhythmia syndromes, genotype-directed therapy can refine drug selection (e.g., beta-blocker responsiveness in long QT syndrome subtypes) and guide lifestyle modification.
Genetic testing is now recognised as a cornerstone in the evaluation of hCVDs. Its utility extends beyond confirming a clinical diagnosis:
- Confirmation of diagnosis: In patients with a clinical phenotype suggestive of an inherited cardiovascular disease, genetic testing provides diagnostic certainty. This is particularly relevant when phenotypic overlap with acquired or non-genetic disorders complicates the clinical picture.
- Differential diagnosis: Genetic testing distinguishes phenocopies (e.g., hypertrophic cardiomyopathy versus athlete’s heart; arrhythmogenic right ventricular cardiomyopathy versus myocarditis).
- Prognostication: Specific pathogenic variants may predict disease severity, arrhythmic risk, and therapeutic response.
- Therapy guidance: Genetic findings can enable genotype-directed pharmacological and interventional approaches (e.g., beta-blocker selection in long QT syndrome and timing of aortic surgery in Loeys-Dietz syndrome).
- Cascade screening: Testing identifies at-risk relatives before symptom onset, permitting structured surveillance and preventive measures.
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