Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Mutations in the TMPRSS3 gene are associated with non-syndromic hearing loss (DFNB8/10).
• Understanding genotype-phenotype correlations is crucial for predicting disease progression and guiding treatment.

Purpose of the Study:

• To investigate genotype-phenotype correlations in Dutch families with compound heterozygous TMPRSS3 mutations.
• To characterize the phenotypic spectrum associated with various TMPRSS3 variants.

Main Methods:

• Genetic analysis of eight Dutch families with DFNB8/10.
• Phenotypic assessment focusing on audiometric configurations, onset age, and progression rates.
• Comparison of phenotypes based on specific TMPRSS3 mutation combinations.

Main Results:

• Identified novel (p.Val199Met) and known pathogenic TMPRSS3 variants, including p.Ala306Thr, p.Thr70fs, p.Ala138Glu, p.Cys107Xfs, and p.Ala426Thr.
• Compound heterozygous mutations, particularly involving p.T70fs, p.Ala306Thr, or p.Val199Met, resulted in prelingual profound hearing impairment.
• Combinations with p.Ala426Thr or p.Ala138Glu showed milder, postlingual onset hearing loss, suggesting less detrimental effects on protein function.
• Progressive bilateral hearing impairment, often starting in high frequencies with eventual flat audiogram configuration, was observed.
• Ski-slope audiogram configuration was suggestive of TMPRSS3 involvement.

Conclusions:

• TMPRSS3 mutations exhibit variable expressivity, with specific variants correlating to distinct hearing loss phenotypes.
• Protein-truncating and certain missense mutations in TMPRSS3 lead to severe, early-onset hearing loss.
• Other missense mutations may result in milder, later-onset hearing loss.
• Cochlear implantation is a viable and effective treatment option for patients with TMPRSS3-related hearing loss, achieving satisfactory speech reception.