{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:59:04Z","timestamp":1760147944323,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Jain Foundation focused research grant and Muscular Dystrophy Association Development","doi-asserted-by":"publisher","award":["MDA578400","SGZ-2017-11829"],"award-info":[{"award-number":["MDA578400","SGZ-2017-11829"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sanofi-Genzyme Investigator","award":["MDA578400","SGZ-2017-11829"],"award-info":[{"award-number":["MDA578400","SGZ-2017-11829"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>For inherited diseases, obtaining a definitive diagnosis is critical for proper disease management, family planning, and participation in clinical trials. This can be challenging for dysferlinopathy due to the significant clinical overlap between the 30+ subtypes of limb\u2013girdle muscular dystrophy (LGMD) and the large number of variants of unknown significance (VUSs) that are identified in the dysferlin gene, DYSF. We performed targeted RNA-Seq using a custom gene-panel in 77 individuals with a clinical\/genetic suspicion of dysferlinopathy and evaluated all 111 identified DYSF variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG\/AMP) guidelines. This evaluation identified 11 novel DYSF variants and allowed for the classification of 87 DYSF variants as pathogenic\/likely pathogenic, 8 likely benign, while 16 variants remained VUSs. By the end of the study, 60 of the 77 cases had a definitive diagnosis of dysferlinopathy, which was a 47% increase in diagnostic yield over the rate at study onset. This data shows the ability of RNA-Seq to assist in variant pathogenicity classification and diagnosis of dysferlinopathy and is, therefore, a type of analysis that should be considered when DNA-based genetic analysis is not sufficient to provide a definitive diagnosis.<\/jats:p>","DOI":"10.3390\/jpm13030520","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T03:04:46Z","timestamp":1678763086000},"page":"520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Utilization of Targeted RNA-Seq for the Resolution of Variant Pathogenicity and Enhancement of Diagnostic Yield in Dysferlinopathy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8208-0574","authenticated-orcid":false,"given":"Laura","family":"Rufibach","sequence":"first","affiliation":[{"name":"Jain Foundation, Inc., Seattle, WA 98115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiera","family":"Berger","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0236-3281","authenticated-orcid":false,"given":"Samya","family":"Chakravorty","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Emmons","sequence":"additional","affiliation":[{"name":"Jain Foundation, Inc., Seattle, WA 98115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurie","family":"Long","sequence":"additional","affiliation":[{"name":"Jain Foundation, Inc., Seattle, WA 98115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5352-5877","authenticated-orcid":false,"given":"Greg","family":"Gibson","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhuri","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"PerkinElmer Genomics, Global Laboratory Services, Waltham, MA 02451, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/1689","article-title":"A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B","volume":"20","author":"Bashir","year":"1998","journal-title":"Nat. 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