Po-04-015 biventricular arrhythmogenic cardiomyopathy associated with a novel heterozygous plakophilin-2 early truncating variant

N/A N/A N/A A 31-year-old male patient suffered from palpitations, which occurred particularly during and shortly after physical activity. The patient was very athletic and took part in marathons. His family history was unremarkable. The electrocardiogram showed T wave inversions in V1-V3 (Figure 1A). During bicycle ergometry monomorphic premature ventricular complexes (PVC) and non-sustained ventricular tachycardia episodes (left-bundle branch block morphology, inferior axis) evolved (Figure 1B, black arrow). Of note, under maximal physical stress a second PVC with a right-bundle branch block morphology occurred (Figure 1B, red arrow) suggesting left ventricular (LV) involvement. Echocardiographic evaluation showed a dilated right ventricle (RV) with reduced systolic function, a subtricuspid aneurysm and multiple sacculations of the RV free wall (Figure 1C-D, white markers). Cardiac magnetic resonance imaging (MRI) confirmed the right ventricular findings (Figure 1E, red arrows). In addition, late gadolinium enhancement and fatty deposits were visible in the LV lateral wall (Figure 1F-G, yellow arrows and blue asterix). Genetic testing was performed using a panel covering 173 genes (Agilent, SureSelectQXTTarget Enrichment) and next generation sequencing (NGS) (Illumina MiSeq). It revealed a novel heterozygous nonsense variant in the plakophilin-2 (PKP2) gene (808C>T p. (Gln270Ter) in exon 3) that causes an early truncation, which was confirmed by Sanger sequencing. It was classified as pathogenic (class V). Cascade screening of the asymptomatic patient’s mother (64-y-old), father (70-y-old) and sister (33-y-old) showed that the patient's father and sister harbored the same PKP-2 variant. Both did not report a history of participating in competitive sports, and thorough cardiac evaluation of these two genotype positive family members showed normal findings. Previous studies have indicated that early truncation of the PKP2 C-terminus likely causes arrhythmogenic right ventricular cardiomyopathy (ARVC) irrespective of transcript position. Although desmosomal and non-desmosomal variants create certain genetic potential for the development of ARVC, exercise has an important role in determining the development, severity, and pattern of phenotypic expression. The fact that the only index patient, as a marathon runner, developed ARVC, suggests that the novel PKP2 variant poses a genetic risk, but is not sufficient for inducing an ARVC phenotype by itself.