[327A] Novel PKP2 Mutations in Sudden Death Due to Arrhythmogenic Right Ventricular Cardiomyopathy and Sudden Unexpected Death with Normal Cardiac Morphology.
Richard Zhang, Lauren F Xu, Ling Li, Bosco Oliveira, Allen P Burke. University of Maryland, Baltimore
Background: Sudden deaths in adults are often of cardiac origin and can be attributed to Arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden adult death syndrome (SADS). ARVC has been linked to mutations in Plakophilin2 (PKP2), which is a desmosome related protein with numerous armadillo repeats. SADS accounts for up to 30% of sudden death in adults, and a subset of cases has also been linked to ion channel mutations, but not to PKP2 thus far. We determined mutational status of PKP2 in a series of patients dying suddenly with ARVC and SADS.
Design: 33 cases of sudden unexpected death of cardiac etiology determined by full forensic autopsy were studied. 7 cases were witnessed sudden deaths in patients with normal hearts; 4 men (aged 32 ± 11) and 3 women (aged 24 ± 16). 26 cases had typical morphologic features of ARVC (fibrofatty infiltrates in the right ventricle and subepicardium of the left ventricle); 19 men (aged 35 ± 17 years) and 7 women (aged 33 ± 16 years). We sequenced all 14 exons of PKP2 in DNA extracted from post-mortem tissues of the 26 patients dying with ARVC and 7 with SADS. The primers used in this study were designed using the Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 Genetic Analyzer with SeqScape software.
Results: PKP2 mutations were identified in 7 of 26 DNA samples from patients with ARVC. Of the 7 mutations, 3 were likely significant, and two of which (L64PfsX22 and N642del) are novel mutations that has not been reported in patients with ARVC. PKP2 mutations were also identified in 3 of 7 cases of SADS, and one novel mutation (F339S) is likely significant.
Conclusions: PKP2 mutations are not specific for ARVC and may also be found in patients with sudden death without morphologic findings (SADS). Three new mutations of PKP2 are described (F339S,N642del,L64PfsX22) in patients with ARVC and SADS.
Monday, February 28, 2011 11:45 AM
Platform Session: Section G 2, Monday Morning