title: A TMC1 (transmembrane channel-like 1) mutation (p.S320R) in a Polish family with hearing impairment.
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.
authors.affiliation: Division of Molecular Genetics, University of Tuebingen, Tuebingen, Germany.
authors.forename: Mohamed Ahamed
authors.initials: MA
authors.lastname: Hassan
authors.forename: Aftab Ali
authors.initials: AA
authors.lastname: Shah
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Szmida
authors.forename: Robert
authors.initials: R
authors.lastname: Smigiel
authors.forename: Maria M
authors.initials: MM
authors.lastname: Sasiadek
authors.forename: Markus
authors.initials: M
authors.lastname: Pfister
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Blin
authors.forename: Andreas
authors.initials: A
authors.lastname: Bress
mesh_terms: D019943:Amino Acid Substitution; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D010375:Pedigree; D011044:Poland; D020641:Polymorphism, Single Nucleotide
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26