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The development of Brugada syndrome phenotype is multifactorial, combining genetic and environmental factors.

Dear Editor, we read with great interest the article titled “Putative role of Brugada syndrome genes in familial atrial fibrillation” by Maltese et al1. The authors present an excellent study regarding the genetic basis of familial atrial fibrillation (FAF) and the association of Brugada genes with FAF1. However, the study has several methodological flaws1. The study involves only Russian families, but in conclusion the article suggests an association of FAF and Brugada genes in the general population1. It may not be possible to generalize the results to other populations. The authors found several pathogenic genes in certain individuals1. None of the subjects, though, showed electrocardiographic patterns of Brugada syndrome (BrS), and the authors did not proceed to pharmacological challenge to unmask BrS according to current guidelines1,2. As a result, the conclusion that the study can identify subjects at risk of sudden death is not correct, because the screening for BrS was not complete. The critical question is whether the novel variants cause BrS in these families1,3. The American College of Medical Genetics has recently published recommendations focused on classification of genetic variants to clarify their pathogenic roles3. Despite these guidelines, most of the BrS variants remain of unknown or ambiguous significance, and translation into clinical practice should be done with caution3,4. The proportion of pathogenic variants associated with BrS should be further analyzed to clarify the real percentage of BrS cases associated with each gene3,4. Family segregation and a comprehensive genotype-phenotype correlation help to interpret genetic variation3. However, incomplete penetrance and variable expressivity exacerbated by the unknown pathophysiological mechanism induced by each genetic variant clouds their definitive roles3. To provide insight into the functional effects of the genetic variants, a novel human cellular model using cardiomyocytes has been developed from human induced pluripotent stem cells. These patient-specific cardiomyocytes can incorporate phenotype features of single cells from a patient in vitro, and allow study of the electrophysiological properties of myocytes that lead to characteristic electrocardiographic alterations in BrS3,5.