Hearing loss is one of the most common sensory disorders and, currently, approximately 120 genes have been reported as causative for non-syndromic hearing loss (The Hereditary Hearing Loss Homepage). TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL) as first reported by Kurima et al (2002). The encoding protein transmembrane channel-like protein 1 is highly expressed in the tips of stereocilia and plays a crucial role in mechano-electro-transduction (Liu et al., 2020).
TMC1 variants are a relatively common genetic cause of non-syndromic hearing loss, and accounts for 3.4% of Pakistani ARNSHL (Kitajiri, McNamara, et al., 2007), 4.3 to 8.1% of Turkish (Kalay et al., 2005; Sirmaci et al., 2009), 5.9% of Tunisian (Tlili et al., 2008), 4.2% of European (Schrauwen et al., 2013), and 2.3% of American (Sloan-Heggen et al., 2016) hearing loss patients. Most cases of TMC1-associated hearing loss are identified from autosomal recessive inherited hearing loss, and only limited cases are identified as autosomal dominant. The clinical phenotypes of TMC1-associated hearing loss differ according to the inheritance mode. TMC1-associated ARSNHL cases show congenital severe-to-profound hearing loss, whereas ADSNHL cases show late-onset progressive hearing loss with predominant deterioration in the higher frequencies. To date, 125 pathogenic variants in TMC1 have been reported (HGMD Professional). Among the 125 pathogenic variants, only 8 variants were reported as causative for ADNSHL (DFNA36). The TMC1 gene variants associated with ADNSHL are p.I266T (Sloan-Heggen 2016), p.S320R (Hassan et al., 2015), p.Y381N (Likar et al., 2018), p.G417R (Yang et al., 2010), p.M418K (Zho et al., 2014; Wang et al., 2018), p.D543N (Moteki et al., 2016), p.D572N (Kurima et al., 2002; Wang et al., 2018; Ramzan et al., 2019), and p.D572H (Kitajiri et al., 2007). However, there is some conflict regarding the pathogenicity of the p.D572H variants (Azaiez et al., 2018). In addition, the p.I266T variant and p.Y381N variant were also reported as causative for TMC1-associated ARSNHL (Wang et al., 2018; Sommen et al., 2016). So, only five variants identified from 8 families are reliably known to be the genetic cause of TMC1-associated ADNSHL. Based on this limited number of cases, the overall picture regarding the clinical phenotypes of TMC1-associated ADNSHL remains unclear.
Recently, autosomal dominant TMC1-associated hearing loss has received special attention as a candidate for gene therapy. A mouse model of TMC1-related hearing loss (Beethoven mice), which are generated by ENU mutagenesis, showed autosomal dominant inherited progressive hearing loss (Vreugde et al., 2002). This mouse model carries the Tmc1:c. 1235 T > A:p.M412K variant and, subsequent to this report, ADNSHL patients with an orthologous TMC1 variant (TMC1 c.1253T > A:p.M418K) were reported (Zhao et al., 2014). As the Beethoven mice showed a similar phenotype (progressive hearing loss with predominant deterioration in the higher frequencies) to human patients and carried the orthologous mutation identified in human ADNSHL patients, this mouse model is widely used for translational research for gene therapy (Askew et al., 2015; Shibata et al., 2016; Yoshimura et al., 2018; Gao et al., 2018; Nist-Lund et al., 2019; György et al., 2019; Wu et al., 2021). However, prior to the clinical application of gene therapies, the detailed phenotypes and prevalence information are essential.
In this study, we sought to (1) elucidate the prevalence of HL caused by TMC1 variants in a large cohort of non-syndromic hearing loss patients, (2) analyze the rate of HL deterioration in TMC1-associated ADNSHL patients, and (3) carry out haplotype analysis of the TMC1: NM_138691:c.1627G > A:p.D543N variant identified from 11 unrelated ADNSHL families to confirm whether the mutation occurred by founder mutation or in a mutational hotspot.