{"title":"杂合TBX2移码变异引起一种新型综合征性听力损失伴不完全渗透性眼球震颤。","authors":"Wan Hua, Yanfei Wang, Xiang Li, Wenyu Xiong, Lanchen Wang, Meilin Chen, Fengxiao Bu, Libo Liu, Fangyi Chen, Mingjun Zhong, Yu Lu, Zhiyong Liu, Jing Cheng, Huijun Yuan","doi":"10.1136/jmg-2025-110997","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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 <i>TBX2</i> frameshift variants that cause human HL, establishing a previously unrecognised genetic link.</p><p><strong>Methods: </strong>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 <i>TBX2</i> variants was performed through protein expression, localisation and transcriptional activity analysis <i>in vitro</i>, phenotypic analysis and mechanism study in knockout and knock-in mice model <i>in vivo</i>.</p><p><strong>Results: </strong>Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous <i>TBX2</i> 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 <i>TBX2</i>-associated disorders. <i>In vitro</i> assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. <i>In vivo</i>, heterozygous <i>Tbx2</i> knockout mice (<i>Tbx2<sup>+/-</sup></i> ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.</p><p><strong>Conclusion: </strong>These findings establish <i>TBX2</i> 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.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Heterozygous <i>TBX2</i> frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.\",\"authors\":\"Wan Hua, Yanfei Wang, Xiang Li, Wenyu Xiong, Lanchen Wang, Meilin Chen, Fengxiao Bu, Libo Liu, Fangyi Chen, Mingjun Zhong, Yu Lu, Zhiyong Liu, Jing Cheng, Huijun Yuan\",\"doi\":\"10.1136/jmg-2025-110997\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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 <i>TBX2</i> frameshift variants that cause human HL, establishing a previously unrecognised genetic link.</p><p><strong>Methods: </strong>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 <i>TBX2</i> variants was performed through protein expression, localisation and transcriptional activity analysis <i>in vitro</i>, phenotypic analysis and mechanism study in knockout and knock-in mice model <i>in vivo</i>.</p><p><strong>Results: </strong>Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous <i>TBX2</i> 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 <i>TBX2</i>-associated disorders. <i>In vitro</i> assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. <i>In vivo</i>, heterozygous <i>Tbx2</i> knockout mice (<i>Tbx2<sup>+/-</sup></i> ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.</p><p><strong>Conclusion: </strong>These findings establish <i>TBX2</i> 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.</p>\",\"PeriodicalId\":16237,\"journal\":{\"name\":\"Journal of Medical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jmg-2025-110997\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2025-110997","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Heterozygous TBX2 frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.
Background: 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 TBX2 frameshift variants that cause human HL, establishing a previously unrecognised genetic link.
Methods: 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 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.
Results: 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, 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 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.
Conclusion: 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.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.