Genetic Analysis of Heart Channelopathies in Brazilian Patients and Their Relatives

Inherited arrhythmias are characterized by variable expressiveness and incomplete penetrance. Extensive genotype-phenotype studies are needed to elucidate the genetic basis of these diseases. There are several reasons for studying the molecular genetics of channelopathies, such as determining the molecular epidemiology of these diseases, offering evidence for a better understanding of the molecular basis of diseases, determining the genetic patterns of occurrence (inherited or again), and improving the diagnosis and genetic counseling. Besides, the genetic study of these diseases can lead to the discovery of new genetic variants associated with these diseases and to the creation of experimental models.

Genetic testing is recommended (Class I) for any patient with a strong clinical suspicion of genetically inherited channelopathies including long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. Specific genetic testing for the mutation identified in the index case is also recommended (Class I) for family members.

The molecular genetics of cardiac channelopathies has been extensively studied in populations in developed countries. In the past, the most frequently used methods were the sequencing of a single or a few suspect genes. More recently, wider panels or even the sequencing of the complete exome have been increasingly used. This procedure has allowed the discovery of an increasing number of genetic variants.

Although the genetic basis for many cases of these diseases is known, many families do not yet have a definite genetic cause. Besides, it is difficult to predict the pathogenicity and clinical evolution of individual mutations. Recent advances in the generation of induced pluripotent stem cells (iPS) may allow considerable progress in the translational research of arrhythmias.

Since the discovery of the first channelopathy in 1995 , the use of genetic tests for diagnostic and prognostic purposes has evolved considerably and is now being used in clinical practice and not just for research purposes. Despite all these advances, the use of DNA sequencing to determine the presence or absence of some diseases is a challenge, since all these clinical syndromes can be associated with different mutations, many of which have not yet been described. The genetic sequencing of patients with genetically inherited arrhythmias is essential not only to provide clinical information related to well-characterized mutations but also to contribute to the discovery of new genetic alterations. In Brugada syndrome, for example, although 12 genotypes have been described so far, genetic changes have been identified in only 30% of cases. The reason for these discrepancies is related to still incomplete knowledge of all the pathways involved in the function and regulation of cardiac ion channels.