Deafness, Autosomal Dominant 12 (DFNA12) and Deafness, Autosomal Recessive 21 (DFNB21) via the TECTA Gene

Autosomal dominant deafness 12 (DFNA12) is characterized by mid- to high-frequency, mild to moderately severe, stable to progressive, prelingual, sensorineural nonsyndromic hearing loss (Bai et al. 2014). The degree of hearing impairment in DFNA12 is generally similar among all affected members of the family, regardless of age or sex. DFNA12 generally has a childhood onset (Iwasaki et al. 2002). Autosomal recessive deafness 21 (DFNB21) is characterized by low- to mid-frequency, severe to profound, stable, prelingual, sensorineural nonsyndromic hearing loss (Naz et al. 2003). Varying degrees of residual hearing can also be observed in a subset of hearing loss patients (Kim et al. 2015). 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).

DFNA12, an autosomal dominant hearing disorder, and DFNB21, an autosomal recessive hearing disorder, are caused by pathogenic sequence variants in the alpha tectorin (TECTA) gene, which is one of the major noncollagenous components of the tectorial membrane of the inner ear. This membrane lies above the stereocilia of sensory hair cells, inducing fluctuations in its membrane potential, thereby transducing and amplifying sound into electrical signals (Legan et al. 2000). The TECTA protein is a large modular glycoprotein that consists of three distinct modules: the entactin G1 domain, the zonadhesin domain, and the zona pellucida domain (Alloisio et al. 1999). The TECTA gene is 88 kb in size, located in chromosome 11q23.3, and consists of 23 coding exons (Hughes et al. 1998). To date, a total of about 70 pathogenic TECTA sequence variants have been reported, which include missense/nonsense, splicing, small deletions, small insertions, small indels, gross deletions, gross insertions/duplications, and complex rearrangements (Human Gene Mutation Database). Most missense variants in the TECTA gene are causative for DFNA12, whereas truncated mutations, including nonsense, frameshift, and splicing, generally result in DFNB21.

The clinical sensitivity of the TECTA test ranges from 0.2% to 10%. For example, pathogenic TECTA sequence variants were detected in 0.2% (2/1,120) of Japanese patients with nonsyndromic hearing loss (Nishio and Usami 2015). In China, 0.8% (1/125) of deaf probands who did not have pathogenic sequence variants in the GJB2, SLC26A4, and MT-RNR1 genes were determined to carry causative TECTA variants (Yang et al. 2013). Disease-causing TECTA variants were responsible for 1.07% (9/73) of American patients and 4.03% (15/372) of Spanish patients with DFNA12 (Hildebrand et al. 2011). On the other hand, pathogenic sequence variants in the TECTA gene accounted for 3.2% (2/62 and 1/32, respectively) of Korean patients with nonsydromic hereditary hearing loss (Sagong et al. 2010; Choi et al. 2013). In Iran, 3.3% (1/30) of patients with DFNB21 harbored causative TECTA variants (Diaz-Horta et al. 2012). In Japan, 5.8% (13/216) of deaf patients presented with causative sequence variants in the TECTA gene (Miyagawa et al. 2013). Pathogenic TECTA sequence variants were observed in 8.3% (1/12) of deaf families coming from Italy and Qatar (Vozzi et al. 2014). In another Korean study, 9.1% (1/11) of children with mild to moderate sensorineural hearing loss were determined to carry pathogenic TECTA sequence variants (Kim et al. 2015). Approximately 10% (2/20) of Palestinian families with prelingual nonsyndromic hearing showed causative TECTA sequence variants (Shahin et al. 2010).

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