{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:34:28Z","timestamp":1791952468929,"version":"4.3.4"},"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Open Access Publishing Fund of the University of T\u00fcbingen"},{"name":"Praxis f\u00fcr Humangenetik, T\u00fcbingen, and the CeGaT GmbH"},{"name":"entrum f\u00fcr seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augen\u00e4rztliches Diagnostik- und Therapiecentrum Siegburg GmbH"},{"name":"RetinaScience"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the\n                    <jats:italic>OPA1<\/jats:italic>\n                    gene: depending on the population studied, 32\u201390% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the\n                    <jats:italic>OPA1<\/jats:italic>\n                    gene in a large cohort of patients. Over a period of 20 years, 755 unrelated probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the\n                    <jats:italic>OPA1<\/jats:italic>\n                    gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the\n                    <jats:italic>OPA1<\/jats:italic>\n                    gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered\n                    <jats:italic>null<\/jats:italic>\n                    alleles. Variant c.2708_2711del\/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients\u00b4 blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0253987","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T14:13:03Z","timestamp":1625839983000},"page":"e0253987","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":34,"title":["Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1047-6227","authenticated-orcid":true,"given":"Nicole","family":"Weisschuh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Schimpf-Linzenbold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Mazzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinja","family":"Kieninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Kellner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Neuhann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Kelbsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Tonagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Wilhelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Kohl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Wissinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"pone.0253987.ref001","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.optom.2016.09.003","article-title":"A Review of Mitochondrial Optic Neuropathies: From Inherited to Acquired Forms.","volume":"10","author":"YL Pilz","year":"2017","journal-title":"J Optom."},{"key":"pone.0253987.ref002","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial optic neuropathies\u2014disease mechanisms and therapeutic strategies.","volume":"30","author":"P Yu-Wai-Man","year":"2011","journal-title":"Prog Retin Eye Res"},{"key":"pone.0253987.ref003","first-page":"1190","article-title":"Linkage analysis in dominant optic atrophy","volume":"35","author":"JD Kivlin","year":"1983","journal-title":"Am J Hum Genet"},{"key":"pone.0253987.ref004","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1600-0420.1996.tb00672.x","article-title":"Dominant optic atrophy mapped to chromosome 3q region II. 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