Atlas of the clinical genetics of human dilated cardiomyopathy.

Aim Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts.We nowutilized next-generation sequencing toovercomethese limitations andscreenedallDCMdisease genes in a large cohort. Methods and results In this multi-centre, multi-national study,we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In thiswell characterized cohort,we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap betweenDCM,hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high.Ofnote,wefind that.38%of patients havecompoundor combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion This is to our knowledge, the first study thatcomprehensively investigated the genetics ofDCMin a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM. [ABSTRACT FROM AUTHOR]