Background— Familial preexcitation syndrome is linked to mutations in PRKAG2 . Previous studies on the R302Q mutation have provided evidence for a remarkably high proportion of otherwise rare accessory pathways with atrioventricular (AV) node-like conduction properties (Mahaim fibers). Yet, histopathologic proof is still lacking. We aimed to provide such proof. Methods and Results— We retrospectively studied the medical records of 17 members of a 5-generation family. Five subjects died prematurely. The R302Q mutation was found in 8 living subjects and 2 deceased subjects (obligate carriers). Cardiac hypertrophy was found in 7 mutation carriers. ECGs compatible with preexcitation were found in 13 subjects and AV block at varying degrees in 5 subjects. All mutation carriers had electrocardiographic evidence of preexcitation, AV block, or both. Three individuals had high-grade AV block with preexcited conducted beats. Electrophysiological studies in 3 individuals revealed bypasses with AV node–like properties. Histopathologic studies of 1 suddenly deceased mutation carrier revealed concentric hypertrophy of the left ventricle with extensive myocardial disarray associated with slight interstitial fibrosis but no lysosomal-bound glycogen. Moreover, there were 3 small nodoventricular tracts (Mahaim fibers) passing through the central fibrous body and connecting the AV node with the working myocardium of the interventricular septum. Conclusions— Preexcitation associated with the R302Q mutation in PRKAG2 is associated with Mahaim fibers. These findings support the novel insight that PRKAG2 may be involved in the development of the cardiac conduction system.

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