Deafness, Autosomal Recessive 8 (DFNB8) and Deafness, Autosomal Recessive 10 (DFNB10) via the TMPRSS3 Gene

Autosomal recessive deafness 8 (DFNB8) and autosomal recessive deafness 10 (DFNB10) are characterized by progressive, sensorineural nonsyndromic hearing loss. The onset of DFNB8 is postlingual (age range: 10-12 years), whereas that of DFNB10 is prelingual (Wattenhofer et al. 2002). 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. DFNB8 patients generally show flat audiogram configurations, indicating hearing impairment at all frequencies, whereas DFNB10 patients have down-sloping audiogram configurations, demonstrating high-frequency impairment that later progresses to include low- and mid-frequency hearing loss (Weegerink et al. 2011). Patients diagnosed with DFNB8/10 are generally considered good candidates for electric acoustic stimulation (Miyagawa et al. 2015).

DFNB8/10 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the transmembrane protease, serine 3 (TMPRSS3) gene. TMPRSS3 encodes a 478-amino acid protein that is expressed in the hair cells of the cochlea, as well as in the brain, liver, spleen, lungs, and muscles (Guipponi et al. 2002). The TMPRSS3 gene has been localized to chromosome 21q22.3 and consists of 13 exons that span approximately 24 kb (Veske et al. 1993; Scott et al. 2001). The TMPRSS3 protein is structurally characterized by four domains, namely, an N-terminal transmembrane domain, a low-density lipoprotein (LDL) receptor A domain, a scavenger receptor cysteine-rich domain, and a C-terminal serine protease domain (Fasquelle et al. 2011). To date, a total of about 50 pathogenic sequence variants have been reported in the TMPRSS3 gene, which include missense/nonsense, splicing, regulatory, small deletions, small insertions, and complex rearrangements (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 0.1% to 5%. For example, pathogenic sequence variants in the TMPRSS3 gene accounted for 0.1%-2.8% of Japanese hearing loss patients (Miyagawa et al. 2013; Miyagawa et al. 2015; Nishio and Usami 2015). About 0.4% (2/448) of White deaf patients from Spain, Italy, Greece, and Australia who tested negative for GJB2 pathogenic sequence variants harbored causative variants in the TMPRSS3 gene (Wattenhofer et al. 2002). Approximately 0.8% (3/384) of Indian families with nonsyndromic hearing were determined to carry pathogenic TMPRSS3 sequence variants (Ganapathy et al. 2014). In Turkey, 2% (1/49) of deaf children born to consanguineous families and GJB2-, GJB6-, and MTRNR1-negative for pathogenic sequence variants were determined to harbor disease-causing sequence variants in the TMPRSS3 gene (Duman et al. 2011). In Palestine, 5% (1/20) of families with prelingual nonsyndromic hearing loss harbored causative TMPRSS3 sequence variants (Shahin et al. 2010).

This test provides full coverage of all coding exons of the TMPRSS3 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).