Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing — including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials — provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.
Human genetic variation associated with severe forms of cardiomyopathy and arrhythmia has highlighted the crucial role of alternative splicing in myocardial health and disease.
Alternative splicing governs major adaptations in cardiac physiology and pathology, including the re-expression of fetal and perinatal isoforms in heart failure.
Up to 10% of mutations in cardiac disease-related genes affect splice sites.
Splicing factor mutations alter the global protein composition of cardiomyocytes, resulting in complex disease phenotypes.
Technical advances have enabled the global analysis of cardiac isoform expression through multiomics and single-cell approaches, with implications for improved clinical decision-making and patient care.
Cardiac splice regulators can be targeted therapeutically through small-molecule and antisense oligonucleotide approaches, whereas splice site mutations are now accessible to gene editing and trans-splicing.
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This work was funded by Leducq TAN CASTT grant 21CVD02. Jacobo Lopez Carballo (Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany) supported the data analysis and generation of the supplementary tables.
M. Gotthardt has a consultancy agreement with River BioMedics and has received speaker honoraria from Bayer. V.N.P. reports a sponsored research agreement with BioMarin and consulting relationships with Constantiam and viz.ai. E.A. reports sponsored research from Bristol Myers Squibb, has ownership interest in DeepCell, Nuevocor and Personalis, and is a board member of AstraZeneca. M.C.-F. is a cofounder and scientific adviser of GenoMed, a molecular diagnosis company. B.M. holds stocks in biotech and pharma, has received speaker honoraria from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Novartis and Pfizer, and is on the Scientific Advisory Boards of Bristol Myers Squibb/Myokardia and Fleischhacker. L.S. is a co-founder of SOPHiA Genetics, as well as co-founder and board member of LevitasBio and Recombia Biosciences, and receives research support from GlaxoSmithKline. L.L. has sponsored research agreements from Bristol Myers Squibb and Edgewise Therapeutics, and is on the scientific advisory boards of Bristol Meyers Squibb/MyoKardia and Edgewise Therapeutics. The other authors declare no competing interests.
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Alamut software: https://www.sophiagenetics.com/platform/alamut-visual-plus/
ClinVar database: https://www.ncbi.nlm.nih.gov/clinvar/
Gene Ontology: https://www.ebi.ac.uk/QuickGO/
Human Protein Atlas: https://www.proteinatlas.org/
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Gotthardt, M., Badillo-Lisakowski, V., Parikh, V.N. et al. Cardiac splicing as a diagnostic and therapeutic target. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-022-00828-0