GJB2 mutations: Genotypic and phenotypic correlation in a cohort of 690 hearing-impaired patients, toward a new mutation?

Objectives: To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with GJB2 mutations.

Design: Case series.

Setting: Collaborative study in referral centers, institutional practice.

Patients: A total of 690 hearing-impaired patients were genotypically and phenotypically described. The mutations of GJB2 and GJB6 were studied. Heterozygous patients were searched for another mutation by microsatellite approach.

Main outcome measures: Prevalence of GJB2 mutations, microsatellite approach, hearing-impairment.

Results: In 498 patients (72,17% of the cohort), no mutation was found. Homozygotous patients were 59 (8,55%), with 51 for c.35delG, 6 for p.M34T and 2 for GJB6. Compound heterozygous were 64 (9,28%) with 56 c.35delG-others mutations. Genotypes with biallelic non sense mutations had a high risk of severe to profound hearing impairment. It was frequently milder in compound heterozygotes than in c.35delG homozygotes. Heterozygous patients were 69 (10%) with 21 c.35delG, 20 p.M34T and 28 others mutations. We selected patients with a complete historical medical file (clinical and audiometric data). Then, we performed a microsatellite approach (multiplex PCR of short DNA fragments) to localize a new pathologic allele. Seventeen heterozygous patients were studied. Six patients (35%) showed the same haplotype. They were compound heterozygous bearing a new pathologic allele.

Conclusion: Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness. A new haplotype for GJB2 is described but the exact mutation remains unknown.