Heterozygous <i>TBX2</i> frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.
basic_science · Level V
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- Record sourced from PubMed, PMID 40962492.
- Also identified by DOI 10.1136/jmg-2025-110997 and PMC identifier 12772546.
- Licence recorded as CC BY-NC.
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Abstract
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. 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>. 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. 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.