Dual Variations in SCN5A and CACNB2b Underlie Cardiac Conduction Disease without Brugada Syndrome

Introduction: Inherited loss of function mutations in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), have been linked to overlapping syndromes including cardiac conduction disease (CCD) and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood.Methods: Direct sequencing analysis was performed in a family with CCD. Wild type (WT) and variant channels were co-expressed with CD8 cDNA in TSA201 cells for electrophysiological study. Green fluorescent protein (GFP)-fused WT or mutant SCN5A genes were used for confocal microscopy to assess channel trafficking.Results: A novel SCN5A missense mutation, P1008S, was identified in all family members displaying 1st degree AV block, but not in unaffected family members nor in 430 reference alleles. Peak P1008S current was 11.77% of WT (p