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Exon 5 of\n              <jats:italic>TNNT1<\/jats:italic>\n              is alternatively spliced, and retention of the 3\u2019 region of intron 11 (exon 12\u2019) has also been described. Variants in\n              <jats:italic>TNNT1<\/jats:italic>\n              are known to cause nemaline myopathy (NM).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>To identify and further investigate the disease-causing variant in a patient with lethal NM.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              The genetic analyses included a gene panel, Sanger sequencing, whole-exome sequencing, and targeted array-CGH. Muscle biopsy was analyzed using routine histopathological methods. The alternative splicing of\n              <jats:italic>TNNT1<\/jats:italic>\n              exon 12 in patient muscle was quantified from RNA sequencing data, and the protein expression was confirmed by western blot. Expression of ssTnT in patient muscle was studied by immunohistology.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              The patient presented with arthrogryposis, stiffness, respiratory insufficiency, and minimal spontaneous movements. Histopathology showed hypotrophy and predominance of type II fibers, perimysial connective tissue accumulation, and nemaline bodies. The patient was homozygous for the\n              <jats:italic>TNNT1<\/jats:italic>\n              missense variant (NM_003283.6:c.653C\u2009&gt;\u2009G, p.(Pro218Arg), NM_ 001126132.3:c.612-7C\u2009&gt;\u2009G), predicted to disrupt splicing. RNA-seq revealed inclusion of exon 12\u2019 in 49.85% of transcripts, whereas in controls exon 12\u2019 was not expressed. Exon 12\u2019 expression on the protein level was confirmed by western blot. Immunohistology showed strong ssTnT expression in remaining type I fibers, and low expression in type IIA fibers.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The c.653C\u2009&gt;\u2009G variant was shown to alter\n              <jats:italic>TNNT1<\/jats:italic>\n              splicing. The results suggest a novel pathogenetic mechanism involving abnormal expression of a troponin T isoform.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1177\/22143602251339569","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T10:43:04Z","timestamp":1747824184000},"page":"689-698","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A homozygous single-nucleotide variant in\n            <i>TNNT1<\/i>\n            causes abnormal troponin T isoform expression in a patient with severe nemaline myopathy: A case report"],"prefix":"10.1177","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-4779","authenticated-orcid":false,"given":"Milla","family":"Laarne","sequence":"first","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, 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