Abstract
BackgroundVariants in TMC1 (transmembrane channel‐like 1) can cause both autosomal dominant and recessive hearing loss in human population. Mice with Tmc1 variants have been shown to be ideal animal models for gene therapy. In this article, we report four TMC1 variants in four different Chinese families and the follow‐up auditory phenotype of a previously reported family.MethodsFour families with TMC1 variants, as well as a previously described family with TMC1 variant orthologous to the Beethoven mouse, were recruited in this study. A comprehensive auditory evaluation was performed on all ascertained family members. High‐throughput sequencing was conducted using genomic DNA from the probands and other family members to identify probable deafness genes.ResultsWe identified four TMC1 (NM_138691.2) variations, including two pathogenic variants, c.1714G>A, and c.1253T>A, one likely pathogenic variant, c.[797T>C];[797T>C], and one single nucleotide polymorphism (SNP), c.2276G>A. Among these variants, c.[797T>C];[797T>C] is a novel likely pathogenic variant, and c.1714G>A and c.1253T>A are known pathogenic variants at the DFNB7/11 (DFNA36) locus. Phenotype‐genotype correlation analysis of TMC1 variants showed that the TMC1 dominant variation‐related phenotype was late‐onset, progressive, high frequency to all frequency sensorineural hearing loss, while the TMC1 recessive variant was related to congenital all frequency sensorineural hearing impairment.ConclusionsTwo pathogenic, one likely pathogenic variants and one SNP of TMC1 were identified in four Chinese families with hereditary hearing loss, indicating that TMC1 may be a more frequent cause of hearing loss than expected. TMC1 variants related to hearing loss result in specific phenotypes. The TMC1 c.1253T>A (p.M418K) variation, homologous to the Tmc1 c. 1235 T> A (p.M412K) variant in Beethoven mice, was the second report of this variant in human patients with hearing loss, suggesting the possibility to translational gene therapy from Beethoven mice to human patients.
Highlights
Hearing loss is one of the most common sensorineural defects in humans worldwide
At least 50% of hearing impairment cases are caused by genetic factors and are classified as syndromic and nonsyndromic hearing loss, which can be subclassified to autosomal recessive nonsyndromic hearing loss (ARNSHL, accounts for 77%), autosomal dominant nonsyndromic hearing loss (ADNSHL, 22%), X-linked hearing loss, Y-linked hearing loss, and mitochondrial hearing loss
The transmembrane channel-like 1 (TMC1, OMIM: 606706) gene is the sixth most frequent cause of hereditary hearing loss among the ARNSHL-related genes based on worldwide case studies, following GJB2, SLC26A4, MYO15A, OTOF, and CDH23 (Hilgert, Smith, & Van Camp, 2009)
Summary
Hearing loss is one of the most common sensorineural defects in humans worldwide. The prevalence is 1/1,000 in newborns and increases to 2.7/1,000 before 5 years old and to 3.5/1,000 during adolescence (Morton & Nance, 2006). TMC1 variants at the DFNB7/11 and DFNA36 locus are implicated in the pathogenesis of both ARNSHL and ADNSHL respectively The former appears primarily as congenital or prelingual severe/ profound hearing impairment, while the latter shows postlingual progressively aggravated hearing loss. The Beethoven (Bth) mouse is a natural model with hearing impairment that carries the Tmc (NM_028953.2) missense variant (p.M412K, c.T1235A), which is orthologous to that found in Family 1304, a DFNA36 family we previously described (Zhao et al, 2014). This dominant variant can cause progressive and profound hearing loss in humans. We performed audiology follow-up in Family 1304 (c.1253T>A p.M418K) to evaluate the progression of hearing loss (Zhao et al, 2014)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
