{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:53:25Z","timestamp":1781196805947,"version":"3.54.1"},"reference-count":27,"publisher":"Georg Thieme Verlag KG","issue":"05","funder":[{"name":"Elterninitiative Kinderkrebsklinik e.V"},{"DOI":"10.13039\/100000065","name":"NIH National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropediatrics"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n          Introduction\u2003Arthrogryposis is characterized by the presence of multiple contractures at birth and can be caused by pathogenic variants in TTN (Titin). Exons and variants that are not expressed in one of the three major isoforms of titin are referred to as \u201cmetatranscript-only\u201d and have been considered to be only expressed during fetal development. Recently, the metatranscript-only variant (c.39974\u201311T\u2009&gt;\u2009G) in TTN with a second truncating TTN variant has been linked to arthrogryposis multiplex congenita and myopathy.<\/jats:p><jats:p>\n          Methods\u2003Via exome sequencing we identified the TTN c.39974\u201311T\u2009&gt;\u2009G splice variant in trans with one of three truncating variants (p.Arg8922*, p.Lys32998Asnfs*63, p.Tyr10345*) in five individuals from three families. Clinical presentation and muscle ultrasound as well as MRI images were analyzed.<\/jats:p><jats:p>\n          Results\u2003All five patients presented with generalized muscular hypotonia, reduced muscle bulk, and congenital contractures most prominently affecting the upper limbs and distal joints. Muscular hypotonia persisted and contractures improved over time. One individual, the recipient twin in the setting of twin-to-twin transfusion syndrome, died from severe cardiac hypertrophy 1 day after birth. Ultrasound and MRI imaging studies revealed a recognizable pattern of muscle involvement with striking fibrofatty involvement of the hamstrings and calves, and relative sparing of the femoral adductors and anterior segment of the thighs.<\/jats:p><jats:p>\n          Conclusion\u2003The recurrent TTN c.39974\u201311T\u2009&gt;\u2009G variant consistently causes congenital arthrogryposis and persisting myopathy providing evidence that the metatranscript-only 213 to 217 exons impact muscle elasticity during early development and beyond. There is a recognizable pattern of muscle involvement, which is distinct from other myopathies and provides valuable clues for diagnostic work-up.<\/jats:p>","DOI":"10.1055\/a-1859-0800","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T23:30:22Z","timestamp":1653348622000},"page":"309-320","source":"Crossref","is-referenced-by-count":9,"title":["Recognizable Pattern of Arthrogryposis and Congenital Myopathy Caused by the Recurrent TTN Metatranscript-only c.39974-11T\u2009&gt;\u2009G Splice Variant"],"prefix":"10.1055","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0719-1607","authenticated-orcid":false,"given":"Luisa","family":"Averdunk","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, University Hospital, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Horn","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Waldm\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safoora","family":"Syeda","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah B.","family":"Neuhaus","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Chao","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"van Riesen","sequence":"additional","affiliation":[{"name":"Center for Chronically Sick Children, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"Department of Pediatric Neurology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darja","family":"Gauck","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Haack","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Japp","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unaa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, University Hospital, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ertan","family":"Mayatepek","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and 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titinopathy","volume":"6","author":"M Yu","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"issue":"12","key":"ref25","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.nmd.2004.08.006","article-title":"Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations","volume":"14","author":"H Jungbluth","year":"2004","journal-title":"Neuromuscul Disord"},{"issue":"02","key":"ref26","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/jmri.20804","article-title":"Muscle MRI in inherited neuromuscular disorders: past, present, and future","volume":"25","author":"E Mercuri","year":"2007","journal-title":"J Magn Reson Imaging"},{"issue":"04","key":"ref27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.nmd.2005.01.004","article-title":"Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy","volume":"15","author":"E Mercuri","year":"2005","journal-title":"Neuromuscul Disord"}],"container-title":["Neuropediatrics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1859-0800.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T23:30:52Z","timestamp":1665531052000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1859-0800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,23]]},"references-count":27,"journal-issue":{"issue":"05","published-online":{"date-parts":[[2022,10,11]]},"published-print":{"date-parts":[[2022,10]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1859-0800","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0174-304X","1439-1899"],"issn-type":[{"value":"0174-304X","type":"print"},{"value":"1439-1899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,23]]},"published":{"date-parts":[[2022,5,23]]}}}