Abstract
After excluding frequent mutations in common genes like GJB2, SLC26A4 and MT-RNR1 by straightforward Sanger sequencing in about 20 Polish families with hearing impairment, new and possibly pathogenic mutations were searched for by next-generation sequencing (NGS) screening using a specialised panel including more than 80 genes connected with hearing disorders. Due to high rates of false-positive pathogen predictions for newly discovered single-nucleotide polymorphisms (SNPs), different prediction models were combined to enhance the prediction power. In one family with a record of over four generations, II,3 and II,4 were suspected of hearing impairment without medical records. A male person (III,2) displayed hearing loss of 40 dB hearing level (HL) and his two sons, IV,1 and IV,2, were both affected; one with 90 dB HL and the other with 40 dB HL. Here, one heterozygous, non-synonymous variant was detected, with the SNP causing an amino acid substitution in TMC1 (transmembrane channel-like 1), a gene reported with many mutations in DFNA36 and DFNB7/11 (OMIM #606705 and #600974, respectively). Until now, the substitution p.S320R has not been described in any database. Instead of the significance of this mutation by bioinformatics tools, we confirmed the genotype–phenotype co-segregation in family members. The involvement of TMC1 in hereditary hearing impairment has not been observed in the Polish population so far.
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Acknowledgments
The authors wish to acknowledge the enthusiastic cooperation of the Wroclaw hearing impairment interest group. M.A.H. was supported by a fellowship from Africa City of Technology.
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The authors declare that they have no competing interests.
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Communicated by: Michal Witt
Mohamed Ahamed Hassan and Aftab Ali Shah contributed equally to this work.
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Supplementary data 1
DNA sequence variants and TMC1 mutation detected in patient IV in this study using NGS, where SNPs is single nucleotide polymorphism, Ref seq is reference sequence and chrom is chromosome. (DOC 287 kb)
Supplementary data 2
Known hearing impairment genes investigated by NGS in this study. (DOC 113 kb)
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Hassan, M.A., Shah, A.A., Szmida, E. et al. A TMC1 (transmembrane channel-like 1) mutation (p.S320R) in a Polish family with hearing impairment. J Appl Genetics 56, 311–316 (2015). https://doi.org/10.1007/s13353-014-0263-4
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DOI: https://doi.org/10.1007/s13353-014-0263-4