Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association

Area of Science:

• Genetics
• Molecular Biology
• Audiology

Background:

• The role of GJB2 noncoding regions in hearing loss (HL) remains underexplored.
• Previous studies identified limited noncoding mutations and an upstream deletion of uncertain pathogenicity.

Purpose of the Study:

• To comprehensively analyze GJB2 noncoding regions in Portuguese hearing loss patients and controls.
• To investigate the pathogenicity of the c.-684_-675del deletion and identify potential associations with hearing loss.

Main Methods:

• Sequencing of GJB2 basal promoter, upstream region, exon 1, and 3'UTR in HL patients and controls.
• Genotyping for the c.-684_-675del deletion and 14 single nucleotide polymorphisms (SNPs).
• Analysis of linkage disequilibrium (LD) between SNPs and potential association with HL.

Main Results:

• Novel variants (c.-731C>T, c.-26G>T, c.*45G>A, c.*985A>T) were identified in control subjects.
• A hearing individual homozygous for c.-684_-675del was identified, suggesting nonpathogenicity.
• Linkage disequilibrium between rs55704559 (c.*168A>G) and rs5030700 (c.*931C>T) was observed.
• The c.[*168G;*931T] allele is suggested to be associated with hearing loss.
• The c.*168A>G variant may affect mRNA folding and contribute to HL.

Conclusions:

• The study identified novel GJB2 noncoding variants and provided evidence against the pathogenicity of the c.-684_-675del deletion.
• A potential association between the c.[*168G;*931T] allele and hearing loss was indicated.
• The c.*168A>G variant warrants further investigation for its role in hearing loss pathogenesis.