Sick sinus syndrome (SSS) refers to an arrhythmic phenotype attributed to sinus node dysfunction manifesting as sinus bradycardia, sinus arrest and/or sinoatrial block. Recently Benson et al. (2003) reported that heterozygous mutations of SCN5A, the gene that encodes for the alpha subunit of the cardiac sodium channel, caused congenital SSS characterized as an autosomal recessive disorder of this channel. Here we report a novel mutation (R878C) of SCN5A associated with SSS in a Chinese family. In contrast to Benson et al. (2003), the transmission of the phenotype of this mutation is autosomal dominant with reduced penetrance in this family. Based on associations with disorders of cardiac rhythm and conduction, we screened SCN5A as a candidate gene in three generations of this Chinese family. Four individuals from this family exhibit a heterozygosic mutation C to T transition at nucleotide 2826 (Gen-Bank accession number: DQ086162), encoding cysteine in place of arginine 878 (designated as R878C). This novel mutation is located in the linker between S5 and S6 of Domain II (DII), a region which forms the pore of the Nav1.5 channel. Two mutation carriers are SSS patients, one carrier has a Brugada syndrome-like ECG and one carrier is clinical normal. Interestingly, three other mutations (F892I, C896S and S901L; Priori et al. 2002) were also identified in the pore region between S5 and S6 in the DII in this channel. All these mutations are associated with Brugada syndrome and are loss-of-function mutations. Therefore, it is likely that this region plays a crucial role for maintaining normal function of the cardiac sodium channel. Further biophysical characterization of this novel mutation is being conducted in the mammalian cell expression system.