Abstract
BackgroundAlmost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness.MethodWhole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved.ResultsA biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8−/− mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia.ConclusionThis new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.
Highlights
In developed countries, congenital hearing impairment is thought to have a genetic origin in more than 70% of cases [1]
A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in Epidermal growth factor receptor pathway substrate 8 (EPS8) that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics
Mutant mice lacking EPS8 (Eps8−/− mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are profoundly deaf and have abnormally short hair bundle stereocilia
Summary
Congenital hearing impairment is thought to have a genetic origin in more than 70% of cases [1]. In about 90% of all cases of non-syndromic (i.e. isolated), severe to profound congenital inherited deafness, the defect is transmitted in an autosomal recessive manner (autosomal recessive non-syndromic deafness or DFNB forms) [2]. Forty-seven causal genes have been identified further analysis. We report here on one of these families, in which we identified a new causative deafness gene. Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness
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