Next-Generation Sequencing Identified Novel Desmoplakin Frame-shift Variant in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of ARVC. However, the specific etiology in individual families remains largely unknown. Methods A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmid containing the mutation and wild type (WT) was constructed, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. Results The proband, a 56-year-old female, presented with recurrent palpitation and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant ( c.832delG ) in Desmoplakin ( DSP ) among 5 family members. The variant led to a frame-shift and a premature termination codon, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of ARVC. HEK293T cells transfected with mutant expressed truncated DSP protein, upregulation of nuclear junction plakoglobin ( PG ) and downregulation of β-catenin, when compared with WT. Conclusion We infer that the novel c.832delG variant in DSP was associated with ARVC in this family, likely through Wnt/β-catenin signaling pathway.