article · Human Mutation
Mutations in the transmembrane channel-like gene 1 (TMC1) are known to cause inherited forms of hearing loss. An investigation of a Sudanese family presenting with recessive, congenital nonsyndromic deafness mapped the condition to the DFNB7/B11 locus inside the TMC1 gene. Genetic sequencing of TMC1 identified two distinct variants segregating with deafness: a structural mutation leading to a premature stop codon and a separate splice-site alteration. Further screening identified the premature stop codon mutation in four out of 243 unrelated deaf Sudanese individuals, whereas neither mutation occurred in 292 individuals with normal hearing. These findings confirm the contribution of TMC1 mutations to recessive deafness within Sudan and indicate that pathogenic variants in this gene are distributed across diverse ethnic populations.
Congenital deafness significantly impacts early human development, yet understanding its genetic architecture requires data from diverse populations. Demonstrating that TMC1 variants cause deafness in Sudanese individuals broadens the known geographical and ethnic spectrum of hearing loss genetics. This aids researchers and medical professionals in building more representative reference data for inherited sensory disorders.
This discovery could inform the development of targeted diagnostic panels and screening tools for hereditary deafness, intended for use by clinical geneticists and diagnostic laboratories. Because the findings represent early-stage gene identification and linkage analysis, practical utility is currently limited to basic research and potential diagnostic design, leaving real-world clinical or commercial testing at an early stage.
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Mutations of the transmembrane channel-like gene 1 (TMC1) have been shown to cause autosomal dominant and recessive forms of congenital nonsyndromic deafness linked to the loci DFNA36 and DFNB7/B11, respectively. In a Sudanese pedigree affected by an apparently recessive form of nonsyndromic deafness, we performed a linkage analysis using markers covering the deafness loci DFNB1 - DFNB30. A two-point LOD score of 3.08 was obtained at marker position D9S1876, located within the first intron of the TMC1 gene at DFNB7/B11. By DNA sequencing of TMC1 exons 3-22, we identified the structural variant c.1165C>T in exon 13, leading to the stop codon p.Arg389X, and the splice-site variant c.19+5G>A, independently segregating with the deafness phenotype. The c.1165C>T [p.Arg389X] mutation was also observed in four out of 243 unrelated deaf Sudanese individuals, but none of the mutations was found among 292 normal hearing controls. The finding of TMC1 mutations contributing to deafness in Sudan confirms and extends previous reports on the role of TMC1 in recessive nonsyndromic deafness and shows that deafness-causing TMC1 mutations may occur in various ethnic groups.
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DOI: 10.1002/humu.9302
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