Introduction: : Brugada Syndrome (BrS) is characterized by ST segment elevation in right precordial leads and increased susceptibility to sudden cardiac death (SCD). Inferolateral location of the Brugada ECG pattern is seen rarely and potentially associated with higher risk of SCD.
Methods: We studied a 24-year-old male without family history of syncope or SCD, who presented his first syncopal episode at age 21 while dancing. Three years later, he had SCD while sleeping. Mutational analysis of SCN5A was performed using PCR, DHPLC and direct sequencing. The BrS-associated mutation was engineered by site directed mutagenesis and transfected into HEK-293 cells for functional chraracterization using the patch clamp technique.
Results: A sporadic de novo missense mutation, R893H-SCN5A (c. 2678 G>A) that localized to the DII pore of NaV1.5, was identified and was absent in 2000 reference alleles. Cells expressing the R893H-SCN5A exhibit significant decrease in sodium current density of 1±1pA/pF compared to 327±121 pA/pF in SCN5A+WT (n=6-14).
Conclusions: The R893H-SCN5A mutation had a profound decrease in sodium current, which provides the molecular/cellular basis for the phenotype described for SCN5A mutations causing BrS and generates an atypical ST segment elevation in inferior-lateral leads and premature sudden cardiac death.