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Cardiogenomics: a modern lecture of an old cardiology

In the last decades, major milestones have been achieved in the field of cardiology. A patient’s cardiological condition can now be deeply characterised using a combination of a thorough clinical assessment, modern multimodality imaging, advanced electrophysiology, and extended pathological analysis.

Altogether, those 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.

At the border of many fields in cardiology, cardiogenetics appears as a new sub-speciality in cardiology which requires expertise for careful variant interpretation and its subsequent use for relative risk assessment in light of the patient’s condition.

When to think about cardiogenomics? When to refer a patient to a “cardiogeneticist”? How to implement cardiogenomics in your daily practice? This is a challenge for every cardiologist. In that view, we elaborated a set of 10 attention points for daily cardiological practice.

  1. 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. Standardized 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.
  2. 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. 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. Select or refer preferentially the index case to the geneticist ie 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. Respect confidentiality and ethical rules. Respect the individual’s right “not to know”. Provide genetic counselling in expert centers, with access to psychologists, paediatricians, 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. 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. 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. 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. 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.
  10. Keep educating yourself and your team about cardiogenetics including variants classification, methodology and database registries combining clinical and genomic informations.