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Most <jats:italic>DMD<\/jats:italic> missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether <jats:italic>DMD<\/jats:italic> missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of <jats:italic>dystrophin<\/jats:italic> and <jats:italic>sarcoglycan<\/jats:italic> genes were performed in them.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted <jats:italic>DMD<\/jats:italic> missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of <jats:italic>sarcoglycan<\/jats:italic> genes didn\u2019t reveal any aberrant transcripts in them. <jats:italic>Dystrophin<\/jats:italic> mRNA studies confirmed that 3 predicted <jats:italic>DMD<\/jats:italic> missense variants (c.2380G\u2009&gt;\u2009C, c.4977C\u2009&gt;\u2009G, and c.5444A\u2009&gt;\u2009G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 <jats:italic>DMD<\/jats:italic> variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with <jats:italic>DMD<\/jats:italic> splicing variants and 6 patients with confirmed <jats:italic>DMD<\/jats:italic> missense variants were diagnosed with DMD and BMD, respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain <jats:italic>DMD<\/jats:italic> missense variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03128-7","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T14:02:32Z","timestamp":1710424952000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies"],"prefix":"10.1186","volume":"19","author":[{"given":"Zhiying","family":"Xie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihao","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luhua","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanyu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunlong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoxia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingchao","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3282-9123","authenticated-orcid":false,"given":"Yun","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"key":"3128_CR1","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S1474-4422(03)00585-4","volume":"2","author":"F Muntoni","year":"2003","unstructured":"Muntoni F, Torelli S, Ferlini A. 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