{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:59:52Z","timestamp":1783414792255,"version":"3.54.6"},"reference-count":28,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2024NSFSC1768"],"award-info":[{"award-number":["2024NSFSC1768"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2025ZNSFSC1749"],"award-info":[{"award-number":["2025ZNSFSC1749"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82030030"],"award-info":[{"award-number":["82030030"]}],"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":["82202046"],"award-info":[{"award-number":["82202046"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"1\u00b73\u00b75 project for the disciplines of excellence-Interdisciplinary innovation project, West China Hospital, Sichuan University","award":["ZYJC20002"],"award-info":[{"award-number":["ZYJC20002"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,9,4]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      A substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous\n                      <jats:italic>TBX2<\/jats:italic>\n                      frameshift variants that cause human HL, establishing a previously unrecognised genetic link.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Linkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of\n                      <jats:italic>TBX2<\/jats:italic>\n                      variants was performed through protein expression, localisation and transcriptional activity analysis\n                      <jats:italic>in vitro<\/jats:italic>\n                      , phenotypic analysis and mechanism study in knockout and knock-in mice model\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous\n                      <jats:italic>TBX2<\/jats:italic>\n                      variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described\n                      <jats:italic>TBX2<\/jats:italic>\n                      -associated disorders.\n                      <jats:italic>In vitro<\/jats:italic>\n                      assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , heterozygous\n                      <jats:italic>Tbx2<\/jats:italic>\n                      knockout mice (\n                      <jats:italic>\n                        Tbx2\n                        <jats:sup>+\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings establish\n                      <jats:italic>TBX2<\/jats:italic>\n                      as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-110997","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T17:20:40Z","timestamp":1758129640000},"page":"24-33","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Heterozygous\n                    <i>TBX2<\/i>\n                    frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus"],"prefix":"10.1136","volume":"63","author":[{"given":"Wan","family":"Hua","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Beijing Chao-Yang Hospital Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0098-9133","authenticated-orcid":false,"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"name":"Frontier Interdisciplinary Domain, Beijing Institute of Technology, Zhuhai, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilin","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxiao","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libo","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjun","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"name":"National Institute of Biological Sciences, Beijing and Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8746-0125","authenticated-orcid":false,"given":"Jing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"2026060805250933000_63.1.24.1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41586-022-04668-3","article-title":"Tbx2 is a master regulator of inner versus outer hair cell differentiation","volume":"605","author":"Garc\u00eda-A\u00f1overos","year":"2022","journal-title":"Nature New Biol"},{"key":"2026060805250933000_63.1.24.2","doi-asserted-by":"crossref","DOI":"10.1093\/nsr\/nwac156","article-title":"Development and transdifferentiation into inner hair cells require 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Ultrastructural findings","volume":"254","author":"Shnerson","year":"1981","journal-title":"Brain Res"},{"key":"2026060805250933000_63.1.24.28","first-page":"179","article-title":"Development of absolute auditory thresholds in the house mouse (Mus musculus)","volume":"1","author":"Ehret","year":"1976","journal-title":"J Am Audiol Soc"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2025-110997","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:26:08Z","timestamp":1780921568000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2025-110997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12,25]]},"published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1136\/jmg-2025-110997"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2025-110997","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,17]]}}}