Abstract Body (Do not enter title and authors here): Introduction: Pathogenic variants (PVs) in the LMNA gene are associated with a range of diseases called laminopathies. While PVs in LMNA have diverse phenotypes, some of the most consequential are are observed in the heart. Cardiomyopathies associated with LMNA PVs may vary in terms of severity of mechaincal and electrical disturbance as well as age of onset and progression.
Methods: We examined the expression profiles of IPSC-derived cardiomyocytes (iCMs) and cardiac fibroblasts (iCFs) derived from patients with a several different LMNA PVs and variable clinical presentations. These allow us to explore the expression profiles of key cells involved in these diseases with te clinincally relevant gentic cause. The RNA seq data analyzed consists of three replicates each for three control lines and five patient-lines. We investigated differential gene expression for four clinical phenotypes of interest: atrial fibrillation, cardiac conductive disorder, striated muscle disease and ventricular arrythmia compared to control cell profiles in which these are absent using DESeq2.
Results: Each phenotype showed between 1300 and 2100 differentially expressed genes. Our exploration currently suggests a shared core of expression corresponding with the presence of exacerbated cardiomyopathy phenotypes. In iCMs 538 genes or 50% of differentially expressed upregulated genes were shared while in the downregulated pool 51% were common between phenotypes. This phenomenon was lower in iCFs with 43% of upregulation and 41% of downregulation being shared. These cores are distinct to each of the two cell types with little to no overlap in significantly up or downregulated genes. Gene Set Enrichment Gene ontology analysis on the shared cardiomyocyte cores revealed upregulation of genes in the system development and multicellular organismal process pathways. Enrichment gene ontology of the upregulated core for cardiomyocytes showed 102 enriched pathways with the top result of chromosome segregation.
Conclusion: We conclude that while these phenotypes have distinct outcomes and presentation, they share a core expression profile that could be indicative of overall severity. Having identified this shared core of expression will allow us to refine our search into potential genes and pathways to further target with drugs or gene therapy.