Background: Mutations in cardiac ion channel genes have been identified to cause sudden unexplained deaths (SUD), and polymorphisms have also been suggested to be risk factors. Therefore, postmortem genetic testing has become an important tool in elucidating the cause of death.
Methods and results: In a sudden death case, a LQT-3-associated mutation (Il768V) in the cardiac sodium channel gene SCN5A was detected beside the common polymorphism H558R which is known to mitigate the effect of mutations in the gene. Both sequence variations were heterozygous. Large number of intervening base pairs make it impossible to identify whether they were located in cis or trans. Functional consequences of both variants were characterized after expressing different cRNAs in Xenopus oocytes by voltage clamp measurements. Western blot analysis indicates that the cis configuration of both variants may lead to a null allele. Since the woman had received an injection of Ultracain®, the potential effect of this drug was tested. In a trans configuration of both variants, the mutant channel exhibited an increase susceptibility of at least 10% for blocking with the drug articaine. Another novel finding is that the midpoint of activation in the case of the mutant channel is leftward shifted of at least -10 mV.
Conclusion: The results of the study suggest that postmortem molecular screening is an important tool to elucidate the cause of SUD and that the administration of a drug and a functional interaction between polymorphisms and ion channel mutations may trigger the risk for sudden death.