{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:20:54Z","timestamp":1779175254386,"version":"3.51.4"},"reference-count":59,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T00:00:00Z","timestamp":1578441600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neuromuscular Diseases"],"published-print":{"date-parts":[[2020,1,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene ( TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OBJECTIVE:<\/jats:title>\n                    <jats:p>To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-\/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3233\/jnd-190423","type":"journal-article","created":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T14:55:06Z","timestamp":1581087306000},"page":"153-166","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies"],"prefix":"10.1177","volume":"7","author":[{"given":"Marco","family":"Savarese","sequence":"first","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mridul","family":"Johari","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Johnson","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meharji","family":"Arumilli","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalaura","family":"Torella","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina di Precisione, Universit\u00e1 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Naples, Italy"},{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"T\u00f6pf","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Rubegni","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marius","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Genetikum, Neu-Ulm, 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Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sini","family":"Penttil\u00e4","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Center, Department of Genetics, Fimlab Laboratories, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Lehtinen","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Center, Department of Genetics, Fimlab Laboratories, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Gibertini","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Ruggieri","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico 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Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ami","family":"Mankodi","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, Unites States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders, Medical Center \u2013 University of Freiburg, Faculty of Medicine, Freiburg, Germany"},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain"},{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada"},{"name":"Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, 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