Recessive variants in plakophilin-2 contributes to early-onset arrhythmogenic cardiomyopathy with severe heart failure

Aims Plakophilin-2 (PKP2) is the most prevalent mutant gene causing arrhythmogenic cardiomyopathy (ACM) and PKP2 carriers are prone to develop ventricular arrhythmic events. The objective of this study is to use integrated analysis of whole genome sequencing (WGS) and transcriptome sequencing (RNAseq) to identify deep intronic and/or coding variants that cause aberrant splicing events in ACM patients, and hence, to test the hypothesis that recessive variants in PKP2 may lead to early-onset ACM with severe heart failure. Methods and results We performed WGS and RNAseq in 27 heart transplanted ACM patients. By integrated analysis of WGS/RNAseq, we discovered that two patients with PKP2 variants were affected in recessive pattern. One patient had aberrant splicing arising from two intronic variants that led to exon skipping and exon retention. We screened three additional recessive PKP2 variants in 47 non-heart transplanted ACM patients. We compared the clinical characteristics of recessive PKP2 (n = 5) and heterozygous PKP2 carriers (n = 18), and found that recessive PKP2 variant carriers all had early-onset ACM with left ventricular dysfunction. We examined truncating PKP2 variants in explanted hearts and confirmed that truncated PKP2 was not translated. Moreover, the morphology of intercalated disc in recessive PKP2 variants carriers was similar to normal heart suggesting little intercalated disc remodelling. Conclusion By using combined implementation of WGS RNAseq, we were able to demonstrate that recessive variants in PKP2 may contribute to early-onset ACM with severe heart failure. These findings may play a role in risk stratification of ACM based on genetic testing in clinical practice.