Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Area of Science:

• Genetics
• Otolaryngology
• Medical Diagnostics

Background:

• Congenital hearing loss significantly impacts quality of life, with over 50% of cases having a genetic origin.
• Despite available genetic testing, the cause of hearing loss remains unknown in some patients with a family history.
• Standard gene panel analysis may not identify all genetic causes of non-syndromic hearing loss.

Purpose of the Study:

• To optimize the diagnostic yield for genetic hearing impairment in patients with negative molecular diagnostics.
• To investigate the utility of whole exome sequencing in identifying genetic causes of hearing loss missed by gene panels.

Main Methods:

• Retrospective study of 21 patients (17 families) with a family history of hearing loss and negative gene panel results.
• Additional genetic testing using a whole exome sequencing (WESHL panel v2.0) was performed on four families.
• Analysis focused on identifying pathogenic copy number variants in the STRC gene.

Main Results:

• Moderate hearing loss was the most common severity (52%) in the studied cohort.
• Pathogenic copy number variants in the STRC gene were identified in two families through whole exome sequencing.
• This highlights the potential for advanced sequencing to detect genetic causes missed by initial testing.

Conclusions:

• Regular re-evaluation of patients with presumed genetic hearing loss is recommended after negative initial genetic testing.
• Switching from gene panel analysis to whole exome sequencing or whole genome sequencing shows promise for diagnosing congenital hearing loss.
• New deafness genes may be discovered through advanced genetic testing strategies.