GJB2 mutations and degree of hearing loss: a multicenter study

Area of Science:

• Genetics
• Audiology
• Otolaryngology

Background:

• Hearing impairment (HI) is the most common congenital sensory impairment, affecting 1 in 650 newborns.
• Mutations in the GJB2 gene, encoding connexin 26, are responsible for up to 50% of autosomal recessive nonsyndromic hearing loss.
• GJB2 mutation analysis is a common diagnostic test due to its high frequency.

Purpose of the Study:

• To assess the association between GJB2 genotype and the degree of hearing loss in individuals with HI.
• To analyze genotype-phenotype correlations in a large cohort with biallelic GJB2 mutations.

Main Methods:

• Cross-sectional analysis of GJB2 genotype and audiometric data from 1,531 individuals with autosomal recessive nonsyndromic HI.
• Participants were from 16 countries, with a median age of 8 years (90% aged 0-26 years).
• Identified 83 different mutations (47 nontruncating, 36 truncating) and 153 distinct genotypes.

Main Results:

• The degree of HI was significantly more severe with biallelic truncating GJB2 mutations compared to biallelic nontruncating mutations (P<.0001).
• Specific genotypes, such as 35delG/R143W and 35delG/dela(GJB6-D13S1830), were associated with significantly more severe HI than 35delG homozygotes.
• Common mutations like M34T, V37I, and L90P were linked to mild-to-moderate HI (median 25-40 dB).

Conclusions:

• The specific GJB2 genotype is a significant determinant of hearing loss severity in individuals with autosomal recessive nonsyndromic HI.
• Understanding these genotype-phenotype correlations can aid in predicting hearing loss progression and guiding clinical management.
• This study highlights the genetic heterogeneity within GJB2-related hearing loss and its impact on audiometric outcomes.