TBC1D24 – Autosomal Recessive Nonsyndromic Hearing Loss 86

TBC1D24 encodes a TBC domain–containing protein implicated in synaptic vesicle trafficking and neuronal development. Pathogenic variants in TBC1D24 cause a spectrum of recessive disorders, including autosomal recessive nonsyndromic hearing loss 86 (DFNB86).

Whole-exome sequencing in three consanguineous families mapped DFNB86 to 16p13.3 and identified homozygous missense variants c.208G>T (p.Asp70Tyr) and c.878G>C (p.Arg293Pro) in TBC1D24 segregating with profound congenital deafness ([PMID:24387994]). Sanger sequencing in a fourth large family confirmed segregation of c.208G>T (p.Asp70Tyr) with DFNB86. Neither variant was observed in 634 ethnically matched control chromosomes, supporting rarity and pathogenicity.

Inheritance is autosomal recessive, with segregation demonstrated in at least four unrelated families and multiple affected siblings per pedigree. To date, only two missense variants have been reported: c.208G>T (p.Asp70Tyr) and c.878G>C (p.Arg293Pro). Both affect residues conserved from Drosophila to human and are absent from population databases.

Functional assessment localized TBC1D24 in the mouse inner ear predominantly to spiral ganglion neurons, suggesting a neuropathic mechanism of hearing loss. No variant-specific biochemical or in vivo rescue studies have been reported for DFNB86.

Collectively, genetic and expression evidence support a moderate clinical validity for TBC1D24 in DFNB86. Inclusion of TBC1D24 in diagnostic gene panels can facilitate early genetic diagnosis and counselling for AR nonsyndromic hearing loss. Key Take-home: Screening for TBC1D24 variants improves molecular diagnosis of DFNB86 and guides patient management.

References

• American journal of human genetics • 2014 • Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. PMID:24387994

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