{"id":1077,"date":"2025-09-17T16:00:47","date_gmt":"2025-09-17T16:00:47","guid":{"rendered":"http:\/\/sebigec.es\/blog\/?guid=91d13c3a5154c26117e9f36cf166ca59"},"modified":"2025-12-26T05:51:05","modified_gmt":"2025-12-26T05:51:05","slug":"heterozygous-tbx2-frameshift-variants-cause-a-novel-syndromic-hearing-loss-with-incompletely-penetrant-nystagmus","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2025\/09\/17\/heterozygous-tbx2-frameshift-variants-cause-a-novel-syndromic-hearing-loss-with-incompletely-penetrant-nystagmus\/","title":{"rendered":"Heterozygous TBX2 frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus"},"content":{"rendered":"\n<sec><st>Background<\/st>\n<p>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>\n<\/sec>\n<sec><st>Methods<\/st>\n<p>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>\n<\/sec>\n<sec><st>Results<\/st>\n<p>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>+\/&ndash;<\/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>\n<\/sec>\n<sec><st>Conclusion<\/st>\n<p>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>\n<\/sec>\n","protected":false},"excerpt":{"rendered":"<p>Background<br \/>\nA 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 &#8230;<\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,14,9],"tags":[83],"class_list":["post-1077","post","type-post","status-publish","format-standard","hentry","category-articulos","category-jmg","category-open-access","tag-jmedgenet"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/1077","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=1077"}],"version-history":[{"count":2,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/1077\/revisions"}],"predecessor-version":[{"id":4740,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/1077\/revisions\/4740"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=1077"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=1077"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=1077"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}