{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T02:56:29Z","timestamp":1768013789750,"version":"3.49.0"},"reference-count":33,"publisher":"BMJ","issue":"8","funder":[{"name":"Guangzhou Science and Technology Planning Project","award":["202103000079"],"award-info":[{"award-number":["202103000079"]}]},{"name":"Guangdong Science and Technology Department","award":["2019A050509006"],"award-info":[{"award-number":["2019A050509006"]}]},{"DOI":"10.13039\/501100012678","name":"Young Teacher Foundation of Sun Yat-sen University","doi-asserted-by":"publisher","award":["20ykpy54"],"award-info":[{"award-number":["20ykpy54"]}],"id":[{"id":"10.13039\/501100012678","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203783"],"award-info":[{"award-number":["82203783"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273053"],"award-info":[{"award-number":["82273053"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFC1316903"],"award-info":[{"award-number":["2020YFC1316903"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFC2005204"],"award-info":[{"award-number":["2020YFC2005204"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,4,27]]},"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Variants in the human <jats:italic>SLC26A4<\/jats:italic> gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of <jats:italic>SLC26A4<\/jats:italic> gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In a cohort of 178 patients carrying <jats:italic>SLC26A4<\/jats:italic> variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent <jats:italic>SLC26A4<\/jats:italic> gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14\/323) of the variants within our cohort.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>By using the standard classification of <jats:italic>SLC26A4<\/jats:italic> variants, our results were able to interpret novel or uncertain <jats:italic>SLC26A4<\/jats:italic> gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying <jats:italic>SLC26A4<\/jats:italic> gene variants.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2024-110425","type":"journal-article","created":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T13:20:25Z","timestamp":1746969625000},"page":"516-522","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Reclassification of candidate splicing variants refines clinically conflicting interpretations in <i>SLC26A4<\/i>-associated hearing loss"],"prefix":"10.1136","volume":"62","author":[{"given":"Yue","family":"Liang","sequence":"first","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubin","family":"Fang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqing","family":"Cen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueying","family":"Wang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anhai","family":"Chen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lusha","family":"Huang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbin","family":"Lei","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanxia","family":"Xiong","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2927-4805","authenticated-orcid":false,"given":"Kaitian","family":"Chen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University First Affiliated Hospital Department of Otorhinolaryngology, Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,5,11]]},"reference":[{"key":"2025100510453123000_62.8.516.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00516-X"},{"key":"2025100510453123000_62.8.516.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-021-02311-1"},{"key":"2025100510453123000_62.8.516.3","doi-asserted-by":"crossref","unstructured":"Yuan Y , Guo W , Tang J , et al . 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