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Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score &gt; 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease.<\/jats:p>","DOI":"10.3390\/genes15010022","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T20:44:15Z","timestamp":1703450655000},"page":"22","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1027-8594","authenticated-orcid":false,"given":"Alba","family":"Escalera-Balsera","sequence":"first","affiliation":[{"name":"Otology & Neurotology Group CTS495, Instituto de Investigaci\u00f3n Biosanitaria, ibs.GRANADA, Universidad de Granada, 18071 Granada, Spain"},{"name":"Division of Otolaryngology, Department of 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Granada, Spain"},{"name":"Sensorineural Pathology Programme, Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Raras, CIBERER, 28029 Madrid, Spain"},{"name":"Meniere\u2019s Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Martin-Lagos","sequence":"additional","affiliation":[{"name":"Otology & Neurotology Group CTS495, Instituto de Investigaci\u00f3n Biosanitaria, ibs.GRANADA, Universidad de Granada, 18071 Granada, Spain"},{"name":"Division of Otolaryngology, Department of Surgery, Universidad de Granada, 18016 Granada, Spain"},{"name":"Department of Otorhinolaryngology, Hospital Clinico Universitario San Cecilio, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Rivero de 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