Molecular Genetics of Dilated Cardiomyopathy

Abstract

Abstract Dilated cardiomyopathy (DCM) is an autosomal dominant disease characterised by dilation of the left ventricle and reduced systolic function. Although hundreds of mutations in more than 40 genes have been attributed to DCM, affecting a wide variety of structural proteins, conduction pathways and contraction mechanisms, this accounts for approximately 40% of familial genetic causes. Additionally, due to low prevalence of any particular single gene mutation in the population, as well as genetic overlap with other cardiomyopathies and diagnostic technology limitations, the diagnosis of DCM remains difficult. The introduction of high‐throughput deoxyribonucleic acid (DNA) sequencing through multigene testing panels has improved diagnostic sensitivity. Furthermore, functional studies have provided innovative approaches to advance collective understanding of DCM aetiology, pathogenesis and diagnosis. Key Concepts: DCM is an autosomal dominant disease affecting 1 in 2500 individuals with up to 50% of cases attributed to genetic causes. Approximately 40 genes have been discovered as part of DCM aetiology, but this accounts for only 40% of genetic cases. Mutations causing DCM have been discovered in multiple cardiomyocyte proteins and pathways, with most mutations representing a rare cause of DCM and each contributing a low frequency of DCM cases. Mutated genes involved in DCM include those encoding sarcomeric, cytoskeleton, nuclear membrane and ion channel proteins; most mutations leads to a similar DCM phenotype. DCM‐associated rare gene variants found both in research and clinical settings require confirmatory and follow‐up studies, because some of them may eventually result in benign common variations. Functional studies model systems and animal models, such as in zebrafish, are useful for clearly observing the heart, and these studies have been successful in demonstrating distinct cardiac phenotypes for DCM‐related gene mutations.