This syndrome is genetically determined. Approximately 60% of patients with (aborted) sudden death with the typical electrocardiogram have a family history of sudden death, or have family members with the same electrocardiographic abnormalities. There are also sporadic cases who are probably the patients with a de novo mutation in the family. The pattern of transmission is autosomic dominant. There is a predominance of affected males. In Thailand the disease almost exclusively affects males. The explanation to this predominance is not clear but it is possibly related to some modifier genes. Several mutations linked to this syndrome affecting the gene SCN5A which encodes for the cardiac sodium channel have been described. Some of the families studied do not present these mutations in this gene, indicating that other genetic defects will be found and that this is a genetically heterogeneous disease.

The mutations affecting patients in Japan and South Asia are still unknown. The in vitro studies show that the mutant channel has altered function, with a loss of sodium current that is temperature dependent. The loss of current leaves Ito unopposed, creating heterogeneity of refractory periods and a perfect substrate for arrhythmias based on phase 2 re-entry.