Epigenetic study of the differential phenotypic expression of a hypertrophic cardiomyopathy-related pathological variant at MYBPC3 in a cohort of monozygotic twins

Abstract

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a inherited cardiac disease with a variable penetrance and expressivity. Epigenetics orchestrates the interplay between the environment and the molecular changes that lead to the development of the pathological phenotype. It is of great interest to identify the changes that determine the magnitude of left ventricular hypertrophy (LVH) in patients carrying a given pathogenic variant. Methods In this work, we used peripheral blood samples from a cohort of three homozygous twin pairs carrying the p.Gly263Ter pathogenic variant at MYBPC3 gene to suppress the underlying genetic effect and isolate the role of DNA methylation in its divergent phenotypic expressivity. Results We found a poorer life-style and a more anxious personality among the more severely affected patients. Using a pair-matched model corrected by cell type proportions, a total of 2486 differentially methylated positions (DMP) were extracted with moderate but proportional methylation changes to the LVH of the patients. DMP were enriched in functional regions controlled by repressor histone marks (H3K27me3, H3K9me3) and tended to colocalise forming differentially methylated regions (DMR) across genes mainly related to homophilic surface adhesion molecules and Ca2+ transport. Strikingly, many affected genes were found to be involved in LVH development, such as PLSCR2, ELMO3, TRIM68, HOXA5, UCN3, PCDHGA3, PAX8-AS1, suggesting that the analysis of blood samples could be able to recapitulate alterations at cardiac tissue level. Furthermore, the relationship of the observed changes with the development of the pathology was successfully validated with an external cohort of peripheral blood samples from healthy patients. Further studies are needed to validate the observed changes at cardiac tissue and to verify their causal role. Conclusions In this cohort of monozygotic twins we were able to identify promising epigenetic peripheral blood changes that relate to the expressivity of the HCM. Anxious personalities and lifestyle divergences could lie behind our findings. DNA methylation changes tend to locate at key positions related to cell-to-cell communication and Ca2+ metabolism, as well as at other loci already described to regulate LVH and stress.