Intronic OTOF mutation causes an atypical splicing defect resulting in auditory neuropathy spectrum disorder

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Pathogenic variants in the OTOF gene are a known cause of auditory neuropathy spectrum disorder (ANSD).
• ANSD encompasses conditions like prelingual nonsyndromic ANSD and temperature-sensitive ANSD (TS-ANSD).

Purpose of the Study:

• To identify the genetic cause of OTOF-related ANSD in a specific family.
• To investigate the molecular mechanism by which the identified OTOF variant leads to ANSD.

Main Methods:

• Genetic analysis and whole-exome sequencing of study subjects.
• RNA extraction and analysis of OTOF messenger RNA (mRNA) to assess splicing.
• Characterization of an intronic mutation (NM_194248: c.2406>4A[G) in the OTOF gene.

Main Results:

• A novel intronic mutation in OTOF was identified as the cause of ANSD in the studied family.
• This variant was demonstrated to cause a splicing defect, leading to the exclusion of exon 20 in OTOF mRNA.
• The mutation is located four nucleotides upstream of the canonical splicing site.

Conclusions:

• The identified OTOF intronic mutation disrupts normal mRNA splicing, resulting in ANSD.
• This study underscores the critical role of splicing mechanisms and the impact of intronic variants on gene function.
• Further research into splicing intricacies and the influence of neighboring DNA regions is warranted for understanding genetic hearing loss.