Background: Familial dilated cardiomyopathy is a highly heterogeneous genetic disease. Thus, identification of disease-causing mutations is a challenging and time-consuming task. Genotype-phenotype associations may alleviate identification of the underlying mutation.
Objective: The purpose of this study was to investigate cardiac phenotypes within a family harboring a familial dilated cardiomyopathy-related mutation in the gene encoding phospholamban.
Methods: Complete genetic and clinical analyses were performed in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. Family relatives were studied by ECG, Holter ECG, echocardiography, ECG body surface potential mapping, and cardiac magnetic resonance imaging.
Results: A candidate gene approach resulted in identification of a heterozygous deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del) segregating with dilated cardiomyopathy in the family pedigree. Mutation carriers suffered from familial dilated cardiomyopathy associated with cardiac death between the ages of 26 and 50 years. Interestingly, all adult mutation carriers revealed strikingly attenuated R amplitudes on standard ECG, regardless of the absence or presence of echocardiographic abnormalities. Gadolinium-enhanced cardiac magnetic resonance imaging showed late enhancement in PLN-R14Del carriers with preserved ejection fraction. Late enhancement was regionally related to areas of most pronounced R-amplitude attenuation as assessed by body surface potential mapping.
Conclusion: Attenuated R amplitudes were identified as an early ECG phenotype in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. All adults harboring PLN-R14Del had attenuated R waves irrespective of echocardiographic abnormalities. The study findings suggest a mutation-related remodeling process preceding ventricular dysfunction.