A frameshift variant in PKP2 can be associated with a complex phenotype in sudden cardiac death: a case report

Whole-genome sequencing can be very useful in evaluation of cardiac arrest victims and family members when the underlying cause is uncertain. Arrhythmogenic cardiomyopathy can be associated with a complex phenotype, including a prolonged QTc interval. Abnormal repolarization in arrhythmogenic cardiomyopathy may be an indicator of an increased risk of life-threatening arrhythmias. Cardiac arrest in a young individual is among the most challenging scenarios in clinical medicine. Finding the cause for such an event is of utmost importance so the correct approach to evaluate the individual and family members can be chosen.1 Plakophilin-2, found within desmosomes in cardiomyocytes, is encoded by the PKP2 gene, and defects in this gene have been associated with arrhythmogenic cardiomyopathy (ACM) and sudden cardiac death (SCD).2 Pathogenic heterozygous variants in PKP2 are the most frequently identified genetic cause of ACM although reduced penetrance and variable expressivity are reported, with wide intra-familial variability.3 We describe a complex phenotype, ACM with a prolonged corrected QT (QTc) interval, associated with a likely pathogenic frameshift variant in the PKP2 gene in a patient successfully resuscitated from cardiac arrest. These observations were further augmented by findings from the deCODE genetics database, with genetic information for a large fraction of the Icelandic population,4 and the extensive University Hospital electrocardiogram (EKG) database.5,6 The proband was a 16-year-old female (Figure 1, III-3) who suddenly lost consciousness, and became unresponsive after intense training. A witness immediately began cardiopulmonary resuscitation (CPR), called emergency services and she was successfully defibrillated from ventricular fibrillation by the emergency personnel from the ambulance. She was previously healthy, had no know cardiovascular disease and no family history of SCD. A family tree showing family members with the PKP2 variant (black dot) and ACM phenotype (proband in black and mother in grey). This shows variable disease penetrance in the affected family members. Cardiovascular exam was normal, but the initial EKG taken in the emergency room revealed a considerably prolonged QTc interval of 532 ms (normal