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Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA\u2010sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA\u2010sequencing data was retrieved from ENCODE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We generated new RNA\u2010seq data on TTN exons and identified genotype\u2013phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52189","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T04:31:14Z","timestamp":1724905874000},"page":"2745-2755","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Inferring disease course from differential exon usage in the wide titinopathy spectrum"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4090-9521","authenticated-orcid":false,"given":"Maria Francesca","family":"Di Feo","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI) University of Genoa  Genoa Italy"},{"name":"Folkh\u00e4lsan Research Center  Helsinki Uusimaa Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Oghabian","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center  Helsinki Uusimaa Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Nippala","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center  Helsinki Uusimaa Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Gautel","sequence":"additional","affiliation":[{"name":"Randall Division of Cell and Molecular Biophysics and Cardiovascular Division King's College London BHF Centre of Research Excellence  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Jungbluth","sequence":"additional","affiliation":[{"name":"Randall Division of Cell and Molecular Biophysics and Cardiovascular Division King's College London BHF Centre of Research Excellence  London UK"},{"name":"Paediatric Neurology Neuromuscular Service, Evelina's Children Hospital, Guy's and St Thomas' Hospitals NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Forzano","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department Guy's and St Thomas NHS Foundation Trust  London SE1 9RT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7871-8600","authenticated-orcid":false,"given":"Edoardo","family":"Malfatti","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Cr\u00e9teil, INSERM, U955, IMRB, and Reference Center for Neuromuscular Disorders, APHP Henri Mondor University Hospital  Cr\u00e9teil France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Castiglioni","sequence":"additional","affiliation":[{"name":"Clinica MEDS  Santiago de Chile Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Krey","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Hospitals and Clinics  Leipzig 4275 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gomez Andres","sequence":"additional","affiliation":[{"name":"Child Neurology Unit. 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