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The study combines linkage analysis with whole-genome sequencing in two unrelated Chinese families showing autosomal dominant progressive sensorineural HL with incompletely penetrant nystagmus. Functional work uses protein assays and cell-based transcription tests plus knockout/knock-in mouse models to define haploinsufficiency as the pathogenic mechanism.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/heterozygous-tbx2-frameshift-variants-cause-a-novel-syndromic-hearing-loss-with-incompletely-penetrant-nystagmus/440451/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/heterozygous-tbx2-frameshift-variants-cause-a-novel-syndromic-hearing-loss-with-incompletely-penetrant-nystagmus/440451.png","ImageObject",300,407,{"name":92,"@type":93},"PakDamar76","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What genetic cause is reported for the hearing loss in the study?","Question",{"text":112,"@type":113},"Heterozygous TBX2 frameshift variants are identified as causative for human hereditary hearing loss in two unrelated Chinese families.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were the TBX2 variants functionally evaluated?",{"text":117,"@type":113},"Variants were assessed using protein expression, localisation and transcriptional activity assays in vitro, along with phenotypic and mechanistic studies in knockout and knock-in mouse models.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism do the mouse models support?",{"text":121,"@type":113},"Heterozygous Tbx2 knockout mice develop progressive hearing loss and show developmental misexpression consistent with haploinsufficiency as the pathogenic mechanism.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},440451,1790982680,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Novel disease loci  \nOriginal research  \nHeterozygous TBX2 frameshift variants cause a novelsyndromic hearing loss with incompletely  \npenetrant nystagmus  \nWan Hua, 1,2 Yanfei Wang,3 Xiang Li  ,4,5 Wenyu Xiong,2 Lanchen Wang,2 Meilin Chen,2 Fengxiao Bu, 1,2 Libo Liu,2 Fangyi Chen,6 Mingjun Zhong,2 Yu Lu, 1,2 Zhiyong Liu,4,7 Jing Cheng  , 1,2 Huijun Yuan 1,2  \n► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/jmg-2025-110997](10.1136/jmg-2025-110997)) .  \nFor numbered affiliations see end of article.  \nCorrespondence to  \nDr Jing Cheng;  \nchengjing@wchscu.cnZhiyong Liu;  \n[liuzhiyong@nibs.ac.cn](liuzhiyong@nibs.ac.cn) and Huijun Yuan; [yuanhj301@wchscu.cn](yuanhj301@wchscu.cn)  \nWH, YW and XL contributed equally.  \nReceived 12 June 2025 Accepted 4 September 2025  \n© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.  \nTo cite: Hua W, Wang Y, Li X, et al. J Med Genet Epub ahead of print: [please include Day Month Year] . doi:10 . 1136/jmg-2025- 110997  \nABSTRACT  \nBackground 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 tobe documented. Here, we identified heterozygous TBX2 frameshift variants that cause human HL, establishing a previously unrecognised genetic link.  \nMethods Linkage analysis combined with wholegenome 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 TBX2 variants was performed through protein expression, localisation and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout and knock-in mice model in vivo.  \nResults Linkage analysis in Family 1 mapped SNHL to chr17q23 .2 (maximum logarithm of odds=3 .01), WGS identified two rare heterozygous TBX2 variants (c.977delA, p.Asp326Alafs*42 and c.987delC,  \np.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 TBX2-associated disorders. In vitro assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. In vivo, heterozygous Tbx2 knockout mice (Tbx2+/−) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.  \nConclusion These findings establish TBX2 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.  \nINTRODUCTION  \nTbx2 (MIM:600747), a member of the Tbox transcription factor family, orchestrates inner hair cells (IHCs) fate specification during murine cochlear  \nWHAT IS ALREADY KNOWN ON THIS TOPIC  \n\n| ⇒ Tbx2 is a transcription factor critical for inner hair cell specification and maintenance during murine cochlear development. However, its pathogenic role in genetic hearing loss (HL) in humans has yet to be documented.\u003Cbr>WHAT THIS STUDY ADDS |\n| --- |\n| ⇒ This study identifies heterozygous TBX2 frameshift variants as the cause of a novel autosomal dominant disorder characterised by progressive HL and variably penetrant nystagmus. Functional assays demonstrate that these variants result in stable but transcriptionally impaired pro","cbCairijkESr3coF","https://ap.wps.com/l/cbCairijkESr3coF","pdf",3711701,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusion\n# Introduction\n# What is already known on this topic\n# What this study adds\n# How this study might affect research, practice or policy","[{\"question\":\"What genetic cause is reported for the hearing loss in the study?\",\"answer\":\"Heterozygous TBX2 frameshift variants are identified as causative for human hereditary hearing loss in two unrelated Chinese families.\"},{\"question\":\"How were the TBX2 variants functionally evaluated?\",\"answer\":\"Variants were assessed using protein expression, localisation and transcriptional activity assays in vitro, along with phenotypic and mechanistic studies in knockout and knock-in mouse models.\"},{\"question\":\"What mechanism do the mouse models support?\",\"answer\":\"Heterozygous Tbx2 knockout mice develop progressive hearing loss and show developmental misexpression consistent with haploinsufficiency as the pathogenic mechanism.\"}]","Heterozygous TBX2 frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus | PDF",1790692253,25]