Frameshift variants in TBX2 underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

PurposeThe transcription factor TBX2 plays a critical role in inner hair cells development in mice. Yet, the link between TBX2 malfunction and human hearing-related disorders remains unexplored. MethodsLinkage analysis combined with whole genome sequencing was applied to identify the causative gene in two autosomal dominant Chinese families characterized by late-onset progressive sensorineural hearing loss and incomplete penetrance of horizontal oscillatory nystagmus. Functional evaluation of TBX2 variants was performed through protein expression, localization, and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout mice model in vivo. ResultsMultipoint parametric linkage analysis of Family 1 revealed a maximum LOD score of 3.01 on chromosome 17q23.2. Whole genome sequencing identified distinct TBX2 variants, c.977delA (p.Asp326Alafs*42) and c.987delC (p.Ala330Argfs*38) in each family, co-segregating with hearing loss. These variants resulted in premature termination and the generation of a new peptide segment, reducing transcriptional activity. Further, heterozygous Tbx2 knockout mice exhibited late-onset progressive hearing loss, along with ectopic expression of Prestin in IHCs and a gradual decrease in expression from P7 to P42. ConclusionOur findings indicate that heterozygous TBX2 frameshift variants are the genetic cause of late-onset progressive hearing loss and incomplete penetrance of nystagmus. The heterozygous Tbx2 knockout mouse model mirrored the human hearing loss phenotype, further validating TBX2s role in auditory function. These insights enhance our understanding of TBX2 in the auditory system, providing valuable information for molecular diagnostics and genetic counseling in related hearing disorders.