Deafness, Autosomal Recessive 28 (DFNB28) via the TRIOBP Gene

Autosomal recessive deafness 28 (DFNB28) is characterized by prelingual, bilateral, symmeterical, stable, severe to profound, sensorineural nonsyndromic hearing loss (Shahin 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 audiometery of DFNB28 individuals are usually flat, indicating hearing loss at all frequencies (Riazuddin et al. 2005). Individuals diagnosed with DFNB28 generally do not present any signs of syndromic deafness, which include facial dysmorphology, night blindness, structural abnormalities involving the vestibutle, goiter, and kidney disease.

DFNB28 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the trio- and F-actin-binding protein (TRIOBP) gene. The TRIOBP gene is located in chromosomal region 22q13.1 and consists of 23 coding exons (Hirosawa et al. 2001). The TRIOBP gene undergoes alternative splicing, which results in three isoforms, of which the longest isoform encodes a 2,365-amino acid protein that is expressed in the cochlea, retina, and fetal brain (Riazuddin et al. 2006). Previous studies have shown that the TRIOBP protein is particularly expressed at the base of stereocilia rootlets of the outer hair cells of the cochlea and is involved in mechanoelectrical transduction of sound waves (Kitajiri et al. 2010). The TRIOBP protein directly binds to F-actin, which in turn induces actin remodeling (Seipel et al. 2000). This particular interaction provides flexibility to the stereocilia bundle by reducing structural rigidity, thereby facilitating in the transmission of mechanoelectrical signals for the perception of sound (Shahin et al. 2006). To date, about 18 pathogenic TRIOBP sequence variants have been reported, which include 15 missense/nonsense, 2 small deletions, and 1 small insertion (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 0.5% to 5%. For example, in Japan, pathogenic sequence variants in the TRIOBP gene were detected in 0.5% (7/216) of deaf patients (Miyagawa et al. 2013). In three independent research studies conducted in Iran, pathogenic sequence variants in the TRIOBP gene accounted for ~0.6% to 5% (1/20, Diaz-Horta et al. 2012; 1/144, Babanejad et al. 2012; 1/160, Bademci et al. 2015) of families with autosomal recessive nonsyndromic hearing loss.

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