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However, the association between RNA mis\u2010splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighty\u2010two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]<jats:sub>inferred<\/jats:sub>, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]<jats:sub>inferred<\/jats:sub> using clinical outcome measures alone. Similar analyses were performed to predict 12\u2010month physical function using baseline metrics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Myotonia (measured via vHOT) was significantly correlated with RNA mis\u2010splicing in our cross\u2010sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis\u2010splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]<jats:sub>inferred<\/jats:sub> in our cohort of all DM1 individuals and when assessing children with CDM\u00a0independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]<jats:sub>inferred<\/jats:sub> from select clinical outcome assessments alone in all subjects\u00a0(adjusted <jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.6723) or exclusively in children with CDM (adjusted <jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.5875).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]<jats:sub>inferred<\/jats:sub>, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52224","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T12:13:42Z","timestamp":1729858422000},"page":"3175-3191","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>RNA<\/scp> mis\u2010splicing in children with congenital myotonic dystrophy is associated with physical function"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3610-0957","authenticated-orcid":false,"given":"Julia M.","family":"Hartman","sequence":"first","affiliation":[{"name":"Medical Scientist Training Program Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department of Neurology Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department for Human and Molecular Genetics Virginia Commonwealth University  Richmond Virginia 23298 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9159-063X","authenticated-orcid":false,"given":"Kobe","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department of Neurology Virginia Commonwealth University  Richmond Virginia 23298 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9781-1905","authenticated-orcid":false,"given":"Marina","family":"Provenzano","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department of Neurology Virginia Commonwealth University  Richmond Virginia 23298 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5409-3193","authenticated-orcid":false,"given":"Kameron","family":"Bates","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department of Neurology Virginia Commonwealth University  Richmond Virginia 23298 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1809-3341","authenticated-orcid":false,"given":"Amanda","family":"Butler","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Children's Hospital of Richmond at Virginia Commonwealth University Pediatric Therapy Services  Richmond Virginia 23220 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2882-3025","authenticated-orcid":false,"given":"Aileen S.","family":"Jones","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Children's Hospital of Richmond at Virginia Commonwealth University Pediatric Therapy Services  Richmond Virginia 23220 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6198-8153","authenticated-orcid":false,"given":"Kiera N.","family":"Berggren","sequence":"additional","affiliation":[{"name":"Center for Inherited Myology Research Virginia Commonwealth University  Richmond Virginia 23298 USA"},{"name":"Department of Neurology Virginia Commonwealth University  Richmond Virginia 23298 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanne","family":"Dekdebrun","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Rochester School of Medicine and Dentistry  Rochester New York 14642 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marnee J.","family":"McKay","sequence":"additional","affiliation":[{"name":"Sydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney  Sydney New South Wales 2006 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1604-1656","authenticated-orcid":false,"given":"Jennifer N.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Sydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney  Sydney New South Wales 2006 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9863-1040","authenticated-orcid":false,"given":"Kayla M. 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