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Genet."],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9\u201310% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, <jats:italic>OTOG<\/jats:italic> being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an <jats:italic>OTOG<\/jats:italic>-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of <jats:italic>OTOG<\/jats:italic> rare variants across different populations. For this purpose, the\u00a0coding regions with high constraint (low density of rare variants) were retrieved\u00a0in\u00a0the <jats:italic>OTOG<\/jats:italic> coding sequence in Non-Finnish European (NFE).. Missense variants (AF\u2009&lt;\u20090.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of <jats:italic>OTOG<\/jats:italic> rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that\u00a0could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they\u00a0may have a founder effect and explain the burden of FMD in the European population.<\/jats:p>","DOI":"10.1007\/s00439-024-02643-8","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T17:02:31Z","timestamp":1711126951000},"page":"423-435","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population"],"prefix":"10.1007","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1208-8348","authenticated-orcid":false,"given":"Alberto M.","family":"Parra-Perez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-8965","authenticated-orcid":false,"given":"Alvaro","family":"Gallego-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-1430","authenticated-orcid":false,"given":"Jose A.","family":"Lopez-Escamez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"issue":"2","key":"2643_CR1","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3390\/genes14020399","volume":"14","author":"ET Aboagye","year":"2023","unstructured":"Aboagye ET, Adadey SM, Wonkam-Tingang E, Amenga-Etego L, Awandare GA, Wonkam A (2023) Global distribution of founder variants associated with non-syndromic hearing impairment. 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