{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:43:14Z","timestamp":1780990994987,"version":"3.54.1"},"posted":{"date-parts":[[2026,4,1]]},"group-title":"Genetic and Genomic Medicine","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Oculopharyngodistal myopathy (OPDM) is a group of rare, hereditary myopathies characterized by ptosis, external ophthalmoplegia, facial, pharyngeal and distal limb weakness and classically with rimmed vacuoles and intranuclear inclusions on muscle biopsy. Heterozygous CCG-CGG repeat expansions in the 5\u2019 UTR of six genes are known to cause OPDM, only one of which (\n                  <jats:italic>ABCD3<\/jats:italic>\n                  ) has been reported in individuals of European ancestry. Here, we identify heterozygous CCG expansions in\n                  <jats:italic>TBC1D7<\/jats:italic>\n                  , ranging from 87-134 repeats, in three unrelated families of European and mixed African European descent, establishing\n                  <jats:italic>TBC1D7<\/jats:italic>\n                  as a new OPDM gene. Using integrated long-read and short-read sequencing technologies and large population datasets, we define the structure of the\n                  <jats:italic>TBC1D7<\/jats:italic>\n                  tandem repeat and show that this locus is strikingly variable in the control population \u2013 a recently recognized hallmark of pathogenic repeat loci. We furthermore investigate epigenetic regulation and repeat length variability at the repeat locus, demonstrating CCG repeat methylation as plausible mechanism for the observed non-penetrance in one unapected individual carrying a large repeat expansion, while in apected patients the repeat is unmethylated. Patient-derived fibroblasts show increased\n                  <jats:italic>TBC1D7<\/jats:italic>\n                  expression, and p62-positive intranuclear inclusions are observed on muscle biopsy, supporting a dominant toxic gain-of-function mechanism analogous to other CCG-expansion disorders. This study expands the known genetic architecture of OPDM and distal myopathies in general and reinforces the emerging paradigm in which the sequence motif and genomic context of repeat expansions, rather than gene function alone, are key drivers of disease. The identification of\n                  <jats:italic>TBC1D7<\/jats:italic>\n                  as a repeat-expansion myopathy gene further highlights the need for systematic interrogation of noncoding repeat loci in unresolved neuromuscular disease cohorts.\n                <\/jats:p>","DOI":"10.64898\/2026.03.27.26349107","type":"posted-content","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:55:35Z","timestamp":1775066135000},"source":"Crossref","is-referenced-by-count":2,"title":["A 5\u2019 UTR CCG expansion in\n                  <i>TBC1D7<\/i>\n                  causes oculopharyngodistal myopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2214-5908","authenticated-orcid":false,"given":"Liedewei","family":"Van de Vondel","sequence":"first","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA"},{"name":"Translational Neurosciences, University of Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Curro","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Facchini","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac R. L.","family":"Xu","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-6758","authenticated-orcid":false,"given":"Jonathan","family":"De Winter","sequence":"additional","affiliation":[{"name":"Translational Neurosciences, University of Antwerp, Belgium"},{"name":"Neuromuscular Reference Centre, Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Quartesan","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Monticelli","sequence":"additional","affiliation":[{"name":"Translational Neurosciences, University of Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Alonso-Jimenez","sequence":"additional","affiliation":[{"name":"Neuromuscular Reference Centre, Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"De Ridder","sequence":"additional","affiliation":[{"name":"Translational Neurosciences, University of Antwerp, Belgium"},{"name":"Neuromuscular Reference Centre, Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"},{"name":"Clinical Hospital of Ribeir\u00e3o Preto, Department of Neurosciences and Behaviour Sciences, University of S\u00e3o Paulo, Ribeir\u00e3o Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pizzuto","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermione","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pellerin","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"De Pooter","sequence":"additional","affiliation":[{"name":"Neuromics Support Facility, VIB Center for Molecular Neurology, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashirwad","family":"Merve","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, University College London Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Machado","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"},{"name":"Biomedical Research Centre, National Institute for Health Research, University College London Hospitals, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"OPDM study group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6754-3830","authenticated-orcid":false,"given":"Lydia","family":"Sagath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"Neveling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hoischen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6123-4551","authenticated-orcid":false,"given":"Robert D. S.","family":"Pitceathly","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Tucci","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bugiardini","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK"},{"name":"Biomedical Research Centre, National Institute for Health Research, University College London Hospitals, London, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefen","family":"Brady","sequence":"additional","affiliation":[{"name":"Oxford Neuromuscular Centre, Department of Neurology, John Radcl\u00ece Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt C.","family":"Danzi","sequence":"additional","affiliation":[{"name":"Dr. John T. 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