Medicina de precisão do Hospital Israelita Albert Einstein

Personalized medicine: the 21st century cardiology

Know how NGS has helped to discover the genetic causes of hereditary cardiovascular diseases (CHD) and more.

Personalized medicine is based on patient phenotype and genotype information for routine clinical management. Currently, genetic tests are already popular in medical practice, due to the technological advancement of DNA sequencers, which allows the analysis of expanded panels of genes, and even the entire exome and genome, at an increasingly lower cost.

Cardiology has followed the same path, driven by studies of cardiovascular hereditary diseases (CHD). In this group, channelopathies and cardiomyopathies have a great social impact as they are the main cause of sudden cardiac death (SCD), including young people, competitive athletes. MSC may be the first manifestation of these diseases in the individual [Magi et al. 2017; Marian and Roberts, 2001]. Therefore, early diagnosis is essential to enable the assessment of the risk of SCD and preventive measures to be taken.

Use of genetic tests in clinical cardiology

In the last few decades, the discovery of the genetic causes of CHD has increased dramatically, with the advent of Next-Generation Sequencing (NGS). As a result, new mutations and new genes are discovered at all times, making it necessary to have a permanent dialogue between clinical and research laboratories with medical assistants, for the improvement of diagnostic tests, more accurate interpretations of the results and a better understanding of the causes of these pathologies. In addition to cardiomyopathies and channelopathies, genetic tests have also been used in the diagnosis of hereditary dyslipidemias and aortopathies. These CHD manifest themselves in a monogenic (Mendelian) way, and the molecular diagnosis can accurately determine the pathology presented, distinguishing it from possible phenocopies, in addition to allowing detection in asymptomatic individuals.

Next-Generation Sequencing

Next-Generation Sequencing (NGS) is widely used in clinical practice and the main platforms used are Illumina and Ion Torrent. Massive sequencing of thousands of bases in parallel by NGS allows the detection of single nucleotide variants (SNV), including insertions or deletions of bases, and major changes, such as copy number variations (CNV). Different strategies can be used in the investigation of CHD, such as the sequencing of the complete exome (~ 20 thousand genes), however the most common and with the best “cost-benefit” are the genetic panels directed to each pathology. Genetic panels contain a defined number of genes, which can vary from laboratory to laboratory, and generally do not reach 100, which allows more samples per run.

In this way, the analysis of the data is facilitated, in comparison with an exome, by reducing the number of variants without any known clinical effect in genes with no proven association with the disease. For example, in hypertrophic cardiomyopathy more than 60% of the variants noted in ClinVar are variants of uncertain significance, which are considered neither pathogenic nor a benign polymorphism [Inglês et al. 2019]. Therefore, the great challenge of this routine is to find the variant (s) responsible for the investigated clinical condition among thousands of detected variants, and to interpret its clinical effects.


Cardiomyopathies encompass a clinically and genetically heterogeneous group of diseases of the heart muscle defined by the presence of an abnormal myocardial structure resulting in systolic and/or diastolic dysfunction, in the absence of other abnormal, cardiac or systemic conditions. Hypertrophic cardiomyopathy (HCM) is the most common inherited genetic cardiomyopathy with an estimated prevalence in the general population of up to 1: 200 [Bick et al. 2012]. HCM, which is characterized by hypertrophy of the left ventricular wall, is mainly caused by mutations in the genes of the cardiac sarcomere proteins; has an autosomal dominant transmission pattern in which only one mutated copy of the gene is sufficient to cause the disease. Changes in non-sarcomeric genes may also be responsible for the development of HCM. Arrhythmogenic right ventricular cardiomyopathies, dilated with and without conduction defects, non-compacted left ventricle and restrictive are other cardiomyopathies of genetic origin.


Primary arrhythmia syndromes are caused by dysfunction of the cardiac muscle ion channels (canalopathies), without a structural defect of the heart. Hereditary arrhythmia syndromes are rare and often lead to sudden death, especially in young people [Schwartz et al. 2012]. Congenital Long QT Syndrome (LQTS) is the most common channelopathy, with an estimated prevalence between 1: 10,000 to 1: 2000. Its main characteristic is the increase in the QT interval on the electrocardiogram, which can lead to a potentially fatal arrhythmia. 13 types of LQTS are recognized associated with mutations in genes encoding several subunits of ion channels involved in the generation of the cardiac action potential [Schwartz et al. 2012]. Preventive measures can be taken in the face of a positive genetic test for channelopathy. Brugada syndromes, Short QT, catecholaminergic polymorphic ventricular tachycardia and progressive conduction heart disease are more rare types of canalopathy.


The main genetic dyslipidemia is familial hypercholesterolemia (FH). FH is caused by mutations in genes related to the metabolism of LDL-cholesterol (LDL-c) and characterized by an exacerbated increase in plasma levels of LDL-c since childhood, which is difficult to control by drugs. This condition can manifest itself in heterozygous and homozygous forms (more severe), which can result in early coronary artery disease. HF has a prevalence of up to 1 in 300 individuals, and the main gene affected (~ 90% of cases) is the LDL membrane receptor (LDLR) [Nordestgaard et al. 2013]

About the author: 

Glauber Monteiro Dias, bachelor of Biological Sciences, master’s and PhD in Biosciences and Biotechnology from the State University of Norte Fluminense. He is currently a biologist/researcher at the National Institute of Cardiology working on genetic analysis of cardiovascular diseases.


[1] Magi S, Lariccia V, Maiolino M, et al. Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies. J Biomed Sci. 2017;24(1):56.

[2] Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2001; 33: 655-670.

[3] Ingles J, Goldstein J, Thaxton C, et al. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med. 2019;12(2):e002460.

[4] Bick AG, Flannick J, Ito K, et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet 2012;91:513–9.

[5] Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868-77.

[6] Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-90a.

[7] Wooderchak-Donahue W, VanSant-Webb C, Tvrdik T, et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am. J. Med. Genet. A. 167A, 1747-1757, 2015.

[8] Milewicz DM, Regalado ES, Shendure J, et al. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med. 2014;24:53-60.

Glauber Dias, PhD

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