Study On A Pedigree Of Inherited Cardiac Conduction Block Through The Whole Exome Sequencing

Background:Whole-exome sequencing(WES)is a next generation sequencing that uses sequence capture technology to catch and enrich the exome DNA,and then high-throughput sequencing.Compared with the traditional sequencing technology,whole-exome sequencing is more timesaving,cost-efficient and with high-throughout.To date,the pathogenic gene of several diseases have been found through whole exome sequencing.About 20 genes have been reported to be related with cardiac conduction block,including SCN5 A,HCN4,NKX2-5,LMNA and TRMP4.The goal of this article is to detect the causal gene of this hereditary cardaic conduction block by whole-exome sequencing,and explore the relevant mechanism.Object:To identify the causal variant in this pedigree with inherited cardiac conduction block.Method:According to medical history and electrocardiogram results,patients with cardiac conduction block were identified in this pedigree.The peripheral blood of 3patients and 3 normal members were collected to extract lymphocytes,and then extracted genomic DNA(gDNA)from lymphocytes.The gDNA of the 6 members was analyzed by Whole-exome sequencing.The variants which are shared by 3 patients but not found in normal members were selected as candidate variants.Analysis the candidate variants by online DAVID.The variants were screened by SIFT,PolyPhen.score and caseMutationFrq.Search the left variants for genes related in cardiac conduction block as the casual variant.Search the causal variant in PubMed and Google scholar to checked whether it has been reported before.Validated the causal variant by Sanger sequencing.Result: This inherited cardiac conduction pedigree with 3 patients was caused by autosomal dominant inherience.There are 186 variants including 162 genes shared in 3patients and not found in the 3 normal members.After analysis by SIFT,Polyphen.score and caseMutationFrq,18 variants were left,in which SCN5 A G3416A(R1139Q)and KCNJ12 A1289G(E430G)are related to cardiac conduction block.SCN5 A G3416A(R1139Q)in this pedigree was validated by Sanger sequencing.SCN5AG3416A(R1139Q)has not been reported to be related with cardiac conduction before.Conclusion:A rare inherited cardiac block pedigree including 3 patients is reported.The heterozygous variant SCN5 A G3416A(R1139Q)was found in this inherited cardiac conduction block pedigree.The SCN5 A G3416A(R1139Q)is associated with cardiac conduction block in this inherited pedigree.