BACKGROUND: Loss-of-function mutations in SCN5A have been associated with the 
Brugada syndrome. We report the first Brugada syndrome family with compound 
heterozygous mutations in SCN5A. The proband inherited 1 mutation from each 
parent and transmitted 1 to each daughter.
METHODS AND RESULTS: The effects of the mutations on the function of the sodium 
channel were evaluated with heterologous expression in TSA201 cells, patch-clamp 
study, and confocal microscopy. Genetic analysis revealed that the proband 
carried 2 heterozygous missense mutations (P336L and I1660V) on separate 
alleles. He displayed a coved-type ST-segment elevation and a prolonged PR 
interval (280 ms). One daughter inherited P336L and exhibited a prolonged PR 
(210 ms). The other daughter inherited mutation I1660V and displayed a normal PR 
interval. Both daughters had a slightly elevated, upsloping ST-segment 
elevation. The parents had normal ECGs. Patch-clamp analysis showed that the 
P336L mutation reduced I(Na) by 85% relative to wild type. The I1660V mutation 
produced little measurable current, which was rescued by room temperature 
incubation for 48 hours. Sodium channel blockers also rescued the I1660V 
current, with mexiletine proving to be the most effective. Confocal 
immunofluorescence showed that I1660V channels conjugated to green fluorescent 
protein remained trapped in intracellular organelles.
CONCLUSIONS: Mutation P336L produced a reduction in cardiac I(Na), whereas 
I1660V abolished it. Only the proband carrying both mutations displayed the 
Brugada syndrome phenotype, whereas neither mutation alone produced the clinical 
phenotype. I1660V channels could be rescued pharmacologically and by incubation 
at room temperature. The present data highlight the role of compound 
heterozygosity in modulating the phenotypic expression and penetrance of Brugada 
syndrome.