Deafness, Autosomal Recessive 6 (DFNB6) via the TMIE Gene

Autosomal recessive deafness 6 (DFNB6) is a prelingual, severe to profound, stable nonsyndromic hearing loss disorder (Santos et al. 2006). The audioprofile of most nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008). Pure-tone audiometry of DFNB6 individuals generally shows downsloping to flat audiograms, indicating all-frequency hearing loss, with more severe impairment at high frequencies (Chaïb et al. 1996). Affected individuals also do not generate an auditory brainstem response up to 100 decibels. DFNB6 individuals do not have balance problems, nor severe motor dysfunction. Parents of DFNB6 patients are obligate carriers, often showing normal audiometric tests (Chaïb et al. 1996).

DFNB6 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the transmembrane inner ear-expressed gene (TMIE) gene, which is located on chromosome 3p21.31 (Fukushima et al. 1995). The TMIE gene consists of four coding exons that encode a 154-amino acid peptide that consists of at least one transmembrane domain (Mitchem et al. 2002). The mature TMIE protein has been localized to the plasma membrane of cochlear cells and serves as a site of interaction for other molecules via its highly charged C-terminal domain (Shin et al. 2010). Previous investigations have also suggested that the TMIE protein plays an important role in signal trafficking between cells, as well as in signal tranduction in the auditory system (Karuppasamy et al. 2011). Functional studies using animal models have shown that pathogenic changes in the TMIE protein result in alterations in sensory hair cells in the cochlea, including defects in stereocilia, which are the apical projections that are involved in mechanoelectrical transduction of sound, thereby resulting in hearing loss (Mitchem et al., 2002; Shen et al. 2008; Gleason et al. 2009; Zhao et al. 2014). To date, a total of about 10 pathogenic TMIE variants have been reported. These variants include both missense and chain termination (nonsense, frameshift and splicing) (Naz et al. 2002; Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range up to 8%. In India, 0.09% (1/1,120) of nonsdynromic hearing loss cases harbored disease-causing variants in the TMIE gene (Nishio and Usami 2015). In another study from India, 0.8% (3/374) of families with autosomal recessive, nonsyndromic hearing loss tested positive for disease-causing TMIE variants (Ganapathy et al. 2014). In Iran, 0.7% (1/144) of families with autosomal recessive nonsyndromic hearing loss presented with pathogenic sequence variants in the TMIE gene (Babanejad et al. 2012). In two independent studies conducted in Turkey, 3.4% (1/29; Atik et al. 2015) of families with autosomal recessive nonsyndromic hearing loss and 8.2% (4/49; Duman et al. 2011) of families with nonsyndromic deafness and consanguineous parents were determined to have causative TMIE sequence variants. Approximately 4.1% (7/172) of Jordanian and Pakistani families with autosomal recessive nonsyndromic hearing loss who tested negative for pathogenic sequence variants in the GJB2 gene harbored disease-causing variants in the TMIE gene (Santos et al. 2006).

This test provides full coverage of all coding exons of the TMIE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).