Monogenic hearing loss

Gene: TBX2

Green List (high evidence)

Comment on list classification: As the article by Hua et al. has now been published (PMID: 40962492, Sep 2025), there is enough evidence to promote this gene to Green for Monogenic hearing loss (2 unrelated probands with nonsense variants in TBX2 & a supportive mouse model).

Created: 26 Nov 2025, 10:46 a.m. | Last Modified: 26 Nov 2025, 10:46 a.m.

Panel Version: 5.47

Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.

Created: 23 Sep 2025, 2:18 p.m. | Last Modified: 23 Sep 2025, 2:23 p.m.

Panel Version: 5.23

There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature

Created: 23 Sep 2025, 2:17 p.m. | Last Modified: 26 Nov 2025, 10:44 a.m.

Panel Version: 5.47

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hearing loss disorder, MONDO:0005365

Publications

• 15459098
• 20206336
• 21271665
• 22052739
• 35508658
• 40962492