The rise of cardiogenomics
In the last decades, major milestones have been achieved in the field of cardiology. A patient’s cardiological condition can now be characterised using a combination of a thorough clinical assessment, modern multimodality imaging, advanced electrophysiology, and extended pathological analysis. Altogether, these achievements have broadened the spectrum of cardiovascular diseases’ description, enabling cardiologists to provide a clinical diagnosis in most cases. Nevertheless, the eye of the clinician is limited to what can be seen and highly depends on the type of exam chosen to characterise the patient’s condition. Remember the Belgian painter René Magritte saying: “This is not an apple”! This is exactly where the opportunity stands: each of us could either consider the clinical diagnosis of a disease as the final step, or try to go beyond this “appearance” and search for a further explanation to the clinical presentation.
Moreover, in the field of cardiology, many diseases can present with the same initial clinical manifestation (such as unexplained left ventricular hypertrophy, dilated cardiomyopathy, aortic aneurysm, sudden cardiac death….) leaving room for improvement in disease characterisation. Ranging from rare to common diseases, this vision drives cardiologists towards cardiovascular genetics: deciphering the molecular heterogeneity behind an observed phenotype by looking for genomic disease determinants through the analysis of genes and their regulatory elements, and leveraging the influence of acquired conditions on disease expressivity. In this modern view of cardiology, cardiogenomics challenges disease classification and brings cardiologists into the world of personalised medicine. By identifying and integrating inherited determinants in rare but also in common diseases, cardiogenomics takes on a growing role in patient management, opening new doors in disease comprehension and targeted therapies.
Cardiogenomics in modern cardiology
When should we consider cardiogenomics? When should we refer a patient to a “cardiogeneticist”? How does one implement cardiogenomics in daily practice? This is a challenge for every cardiologist.
To help in daily cardiological practice, we elaborated a set of 10 points. Comments will be added regularly.
1. Genetic contribution
Be aware of a possible genetic contribution (with variable effect size) to the observed phenotype and keep looking for ‘red flags’, especially in patients with early onset of disease. Standardised and deep clinical evaluation including imaging and biomarkers are the initial steps towards any genetic diagnosis. Challenge and periodically re-challenge the clinical diagnosis considering the possibility of phenocopies.
When assessing the probability of a genetic involvement in a certain case, there is no substitute for a complete clinical and family history. However, when taking a family history, it is important to ask questions focused on different relevant signs/ or symptoms in a comprehensible manner, considering the full spectrum of the relevant clinical elements for a given heritable condition. Deep phenotyping of the patient remains a key step, keeping in mind the possible large set of clinical presentations that are associated with a given inherited condition. Also, clinical evaluation should be repeated: even if the current interview and clinical examination might not reveal any red flags, one should practice the "constant genetic suspicion", as some potential red flags might develop in time. Hence, particularly in diseases with an early onset, a systematic, repetitive and dynamic approach is encouraged, in order to reveal valuable signs and symptoms which might occur only later in the course of the disease. Therefore, a genetic contribution should not be excluded or underestimated in cases which lack certain red flags at the initial visit. Genetic suspicion is a continuum which can be proven only if there is an active approach based on clinician's awareness.
2. Genetic testing
Do not overestimate the diagnostic power of genetic testing, but keep in mind that knowledge of specific gene variants may change patient management and prognosis. A negative genetic test does not exclude or rule out an inherited cardiovascular disease (consider a partial coverage of the analysis, or the possibility of an oligogenic or complex hereditary condition or a genetic cause that is not yet known). Genetic testing in routine clinical practice becomes available for a growing number but is still for selected disorders. The most common indications for routine cardiac genetic evaluation include but are not restricted to: cardiomyopathies, sudden cardiac arrest in a young person, inherited arrhythmias, neuromuscular disorders, aortopathies, valvular heart diseases and lipid disorders.
3. Familial history
Look for a positive familial history, although its absence does not rule out an inherited cardiac condition. Establish a standardized and comprehensive family history (three generations family tree). Do not limit your family history only to cardiovascular pathology and keep asking about the general health of all the family members. Consider that several clinical manifestations (sometimes in multiple systems) can be in line with a single genetic disorder.
4. Index case
Select or refer preferentially the index case to the geneticist i.e. the patient with the most pronounced and the most characterized phenotype to maximize the likelihood of identifying a pathogenic variant. When more than one family member is affected, test the patient whose onset of disease was at a younger age, whose disease is best characterized, or who lacks confounding environmental factors that could result in a similar clinical presentation. When the index case is identified at autopsy, a postmortem blood or tissue sample should be obtained for DNA analysis.
5. Confidentiality and ethical rules
Respect confidentiality and ethical rules. Respect the individual’s right “not to know”. Provide genetic counselling in expert centers, with access to psychologists, pediatricians, clinical experts, and dedicated clinical nurses before performing any genetic test and before communicating test results. In a clinical setting, the result of the test should have an implication for the management of the patient or its relatives, including the need and timing of imaging follow-up, the optimal choice of medical therapy, lifestyle recommendations regarding exercise, the risk of pregnancy and the need for surgical intervention such as placement of an ICD, aortic root surgery or heart transplantation. Expectations and limits of the test should always be addressed. Clearly communicate to the patient and the family the differences between routine clinical genetic testing in the context of soundly established clinical diagnosis and exploratory genetic testing in a research setting.
6. Variant classification
Use ACMG guidelines to classify variants, and (re-)challenge variants pathogenicity in light of the actual knowledge in a dynamic fashion. Gene variants are classified into benign, likely benign, variants of unknown significance, likely pathogenic and pathogenic. Identification of a variant with a high frequency in a human control database is strong evidence for a benign or likely benign classification. In contrast, a variant which is likely to cause abnormal function in a gene known to cause a specific disease is strong evidence for a pathogenic or likely pathogenic variant, which are much less common than benign variants. Pathogenicity of variants needs to be permanently re-assessed based on actual knowledge.
7. Actionable variants
Genetic testing for clinically actionable variants should be offered to relatives through a cascade approach considering and anticipating the benefit/risk ratio of getting this genetic result, including testing in asymptomatic patients, in children and in the setting of prenatal or pre-implantation genetic diagnosis, in case of potentially severe or life-threatening disease according to national law and regulations. Provide relatives with repeated clinical assessment and with genetic counselling in case of a positive genetic test for the proband, even in clinically asymptomatic relatives. In the presence of a doubtful genetic result, use the clinically characterized family to strengthen the result and improve the power of your genetic test.
8. Cardiac phenotyping and targeted sequencing
If no affected patient is available for testing, cardiac phenotyping including ECG, imaging, exercise stress testing and more, followed by targeted sequencing of first-degree relatives, may be reasonable when there is a family history or specific indications (such as specific triggers preceding a sudden cardiac death) pointing towards a potential heritable cardiogenetic condition. This is well established but not restricted to familial arrhythmia syndromes with or without structural heart disease.
9. Genetic study
Blood and/or tissue samples should be collected and stored from the deceased of sudden death with suspected or confirmed inherited condition to enable genetic study ("molecular autopsy"). It would be desirable for each autonomous community to provide the means for the creation of reference centers for the macroscopic and microscopic study of the hearts and aortas of young patients with a suspected inherited cardiovascular disease who have died suddenly. These units should work in coordination.
Keep educating yourself and your team about cardiogenetics including variants classification, methodology and database registries combining clinical and genomic information.
- ESC Council on Cardiovascular Genomics - Recommended links for cardiovascular genomics
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Genomics Education Programme - Taking and drawing a family history
- ESC HCM Risk-HCD Calculator
- The Marfan Foundation - Aortic Root Z-Scores for Children
- ARVC Risk Calculator
- LMNA-risk VTA calculator
- Brugada Syndrome Risk Stratification
This article was originally published on 30 June 2021.