Document Type : Case Report(s)
Authors
- Fateme Zahedi Abghari
- Marzieh Mohseni
- Emran Esmaeilzadeh
- Hossein Ghasemi
- Hamid Reza Khorram Khorshid
- Reza Najafipour
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Abstract
Non-syndromic sensorineural hearing loss (NSHL) exhibits substantial genetic heterogeneity, and the identification of its causative variants remains an important challenge. The gap junction protein β-6 (GJB6), expressed in multiple tissues including the sensory epithelium of the inner ear, is essential for auditory function. Although large GJB6 deletions are well characterized, single-nucleotide variants (SNVs) have been reported infrequently, and their pathogenic significance remains insufficiently defined. In this study, we identified a novel homozygous missense variant in GJB6, NM_001110219.3:c.446C>T (p.Ala149Val), through whole-exome sequencing and confirmed it by Sanger sequencing in a 32-year-old Iranian female from a consanguineous family, presenting with prelingual bilateral sensorineural hearing loss without any additional phenotypes or syndromic features. She was referred to the Medical Genetics Laboratory in Tehran, Iran, in March 2025. In silico predictions, mammalian conservation, and structural modeling suggest that this substitution may disrupt normal GJB6 function. To contextualize this finding, we reviewed all reported SNVs in GJB6, identifying 20 distinct variants in 47 patients, with most mutations clustering in the extracellular loop 1, cytoplasmic loop, transmembrane domain 3, and extracellular loop 2. These results expand the mutational spectrum of GJB6 and highlight its critical role in NSHL pathogenesis. Collectively, this study presents the first comprehensive report of SNVs in GJB6 and supports their further investigation in the genetic architecture of hereditary hearing loss.
Highlights
Fateme Zahedi Abghari (Google Scholar)
Reza Najafipour (Google Scholar)
Keywords
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