Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations
Оbjective. To study the spectrum of clinical manifestations for patients with cardiac sodium channelopathy and to perform the comparative analysis of the results of phenotyping and genotyping in order to determine the relationship between the functional effect of SCN5A gene mutation and the development of Brugada syndrome, and also to establish the differences in functional effects that may cause development of оverlap syndrome (if exist). Material and methods. The phenotypic profile of 14 unrelated probands (10 males, mean age 35.6±19.2 years) with genetically confirmed Brugada syndrome was studied. Тhree families met the study criteria and presented phenotype variability among 11 carriers. Results. Six (43%) probands demonstrated isolated Brugada syndrome. Eight (57%) probands, in addition to the phenotype of the Brugada syndrome, exhibited distinct clinical manifestations: sinus-atrial node dysfunction - 6 (43%), cardiac conduction defect - 6 (43%), atrial arrhythmias - 4 (29%), 3 (21%) of them - atrial fibrillation, as well as a single 520 ms increase in the Q-Tc interval. Phenotypic screening of all 25 genotype- positive patients revealed the sinus-atrial node dysfunction in 9 (36%) cases, atrial arrhythmias in 9 (36%) cases and anomalies of atrioventricular and intraventricular conduction in 17 (68%) cases, including a complete (6) or incomplete (10) right bundle branch block, left bundle branch block (1), right bundle branch block plus hemiblock (2), and atrioventricular block (10). Finally, for 3 (12%) unrelated family members, the main clinical phenotype was conduction defect and sinus node disease in the absence of life-threatening ventricular arrhythmias, which led to pacemaker implantation, while for 18 (72%) carriers cardioverter-defibrillators were implanted. Conclusions. А significant phenotypic overlap was found between Brugada syndrome, conduction defects and sinus node weakness syndrome in patients carrying loss-of-function mutation of the cardiac SCN5A sodium channel gene. It is possible that phenotypic diversity could interact with many factors such as age, sex, and other modifying genes and proteins. In-depth examination and further genetic screening of patients and family members are important for risk stratification of life-threatening ventricular arrhythmias and differentiating of conduction defects, for both are capable of leading to sudden cardiac death.