Background: Brugada syndrome (BrS) is genetically heterogeneous. In Japanese BrS patients, except for SCN5A and KCNE5, mutations in the responsible genes have not yet been identified, and therefore the genetic heterogeneity remains poorly elucidated.
Methods and results: Forty consecutive patients with Brugada-pattern electrocardiogram (ECG) underwent comprehensive genetic analysis of BrS-causing genes including SCN5A, SCN1B, SCN3B, CACNA1C, CACNB2, KCNE3 and KCNE5. Besides identifying 8 SCN5A mutations in the present cohort, a KCNE3 T4A mutation was found in a 55-year-old male patient who had experienced several episodes of syncope. A head-up tilt test during passive tilt provoked both hypotension and bradycardia, followed by syncope. He was therefore diagnosed with neurally mediated syncope (NMS). To characterize the functional consequence of the mutant, electrophysiological experiments using whole-cell patch-clamp methods and computer simulations using human right ventricular wall model were carried out. It was found that KCNE3 T4A increased I(to) recapitulated by heterologously coexpressing Kv4.3+KChIP2b+KCNE3-wild type or KCNE3-T4A in CHO cells.
Conclusions: A KCNE3 T4A mutation was identified in a Japanese patient presenting Brugada-pattern ECG and NMS. Its functional consequence was the gain of function of I(to), which could underlie the pathogenesis of Brugada-pattern ECG. The data provide novel insights into the genetic basis of Japanese BrS.