Novel Mutation Of DSP Gene In Arrhythmogenic Right Ventricular Cardiomyopathy Identified By Next Generation Sequencing

BackgroundArrhythmogenic right ventricular cardiomyopathy(ARVC)is an inherited myocardial disease,characterized by fibrofatty replacement of the right ventricular myocardium in pathology.Ventricular arrhythmias and sudden cardiac death(SCD)could occur before the development of any overt abnormality of cardiac structure and function.One of the main molecular mechanisms of ARVC is that dysfunction of desmosomes lead to loss of electrical coupling between cardiomyocytes.5 genes encoding desmosomal proteins have been identified in approximately half of the patients with ARVC.However,disease related genes or mutations remain undetected.ObjectivesThe aim of the present study is to explore the new genes or the new mutations of genes related to the disease by screening the mutations of the genes in one family with SCD and detect the potential patients with disease related gene mutations.MethodsWe reviewed medical records of the SCD family proband and other family members,and obtained their genomic DNA from peripheral blood samples.Next generation sequencing(NGS)was used to screen mutations of the proband in genes associated with SCD.The results associated with clinical phenotype were verified by Sanger Sequencing.Then,we sequenced the relevant mutation sites of other family members.Results10 family members were recruited in this study.Genetic analysis of the proband revealed two mutations,neither of which have been reported before.The proband was heterozygous for the c.832delG change in exon 7 of the desmoplakin(DSP)gene.And a heterozygous missense mutation was found in exon 44 of the A-kinase anchoring protein 9(AKAP9)gene.Genetic analyses of other family members revealed that 6 members carried mutations detected in the proband,of them,2 with the DSP mutation,2 with the AKAP9 mutation and 2 with both.The frame-shift mutation of DSP gene can change the reading frame,and the amino acid sequence of the encoded protein,which is predicted to be pathogenic for ARVC.The disease likelihood of AKAP9 mutation is unclear since different bioinformatic missense prediction tools had different results.The cardiac magnetic resonance results of 2 DSP mutation carriers fulfilled the characteristic features of ARVC.We reviewed and summarized the DSP and AKAP9 mutations and clinical phenotypes of the patients described in the literature.ConclusionsWe report one family with yet unreported DSP frameshift mutation(c.832delG).We infer that the heterozygous mutation of DSP is causal for ARVC in the patient,and it has an autosomal dominant inheritance pattern.These findings add to our knowledge of this genetic heterogeneity in inherited cardiac disease and highlight the need for genetic testing in patients with malignant ventricular arrhythmia and their families.