Mutations in the cardiac
ryanodine type 2 receptor (
RyR2) gene are associated with
catecholaminergic polymorphic ventricular tachycardia. We hypothesized that these mutations could be detected at autopsy in cases of exercise-triggered
sudden death. Fourteen
sudden death patients, eight males and six females, were studied at autopsy based on apparent
sudden cardiac death, without significant anatomical abnormalities. The coding regions of
arrhythmia genes were amplified by polymerase chain reaction and directly sequenced. Three novel
RyR2 mutations, R414C, F2331S, and R2401L, were identified in three unrelated patients (two males and one female; mean age at death, 12 +/- 2 years), all performing strenuous activity at the time of death or collapse. These mutations were located in highly conserved regions where
arrhythmia-linked
RyR2 mutations clustered. Although G269S in the KVLQT1 gene was detected in a female with known family history of
syncope and
sudden cardiac death, no other mutations were found in any of the 14 cases, and no other mutations was found in 200 controls. The absence of structural
cardiac disease in physical activity-induced
sudden death and the finding of three novel
RyR2 mutations suggest that mutation screening in such cases should include
RyR2.