Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11

• Published in: Clinical genetics Vol. 74; no. 3; pp. 223 - 232
• Main Authors: Hilgert, N, Alasti, F, Dieltjens, N, Pawlik, B, Wollnik, B, Uyguner, O, Delmaghani, S, Weil, D, Petit, C, Danis, E, Yang, T, Pandelia, E, Petersen, MB, Goossens, D, Favero, JD, Sanati, MH, Smith, RJH, Van Camp, G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2008; Blackwell
• Subjects: Babies; Biological and medical sciences; Case studies; Deafness - genetics; DFNA36; DFNB7/11; DNA Mutational Analysis; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Exons; Family; Fundamental and applied biological sciences. Psychology; Gene Dosage; General aspects. Genetic counseling; Genetic disorders; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Hearing loss; Hearing Loss - genetics; Humans; Medical genetics; Medical sciences; Membrane Proteins - genetics; Molecular and cellular biology; Mutation; Non tumoral diseases; Otorhinolaryngology. Stomatology; sensorineural hearing loss; TMC1; Turkey; Human; TMC1; sensorineural hearing loss; Internal ear disease; Auditory disorder; DFNA36; Gene; DFNB7/11; ENT disease; Genetics; Perception hearing loss; Mutation; Locus; Sensory hearing loss
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2008.01053.x

Hearing loss is the most frequent sensorineural disorder affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait with about 100 gene localizations and 44 gene identifications for non‐syndromic hearing loss. Transmembrane channel‐like gene 1 (TMC1) has been identified as the disease‐causing gene for autosomal dominant and autosomal recessive non‐syndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, 2 dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non‐syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767delT and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene or alternatively at least one additional deafness‐causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.