Deafness, Autosomal Recessive 9 (DFNB9) via the OTOF Gene

Autosomal recessive deafness 9 (DFNB9) is characterized by two major features: prelingual, bilateral nonsyndromic hearing loss and less frequently, tempeture-sensitive nonsyndromic auditory neuropathy (TS-NSAN) (Iwasa et al. 2013). DFNB9-related deafness generally appears during the first two years of life as an auditory neuropathy, which is detected by electrophysiologic testing, wherein auditory brainstem responses (ABRs) are absent and otoacoustic emssions (OAEs) are present (Madden et al. 2012). However, OAEs eventually disappear, resulting in electrophysiologic testing that indicates a cochlear defect. It is important to distinguish auditory neuropathy from a cochlear defect because cochlear implants may be of marginal value in individuals with auditory neuropathy. TS-NSAN pertains to normal-to-mild hearing loss in the absence of fever or severe to profound hearing loss in the presence of fever. Hearing often returns to normal as fever resolves (Shearer et al. 2008). The global prevalence rate of DFNB9 remains unknown.

DFNB9 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the otoferlin (OTOF) gene, which is mainly expressed in the inner hair cells of the cochlea and the brain, and plays a major role in synaptic exocytosis at the auditory ribbon synapse (Roux et al. 2006). The OTOF gene is 21 kb in size, located in chromosome 2p23.1, and consists of 48 coding exons that encode two isoforms. The long isoform contains six C2 domains and a C-terminal domain, whereas the short isoform comprises only the last three C2 domains (Chaib et al. 1993; Yasunaga et al. 1999, 2000). To date, a total of about 110 pathogenic OTOF sequence variants have been reported, which include missense/nonsense, splicing, small deletions, small insertions, small indels, and gross deletions (Human Gene Mutation Database).

The clinical sensitivity of this test ranges from 2.3% to 10%, depending on the ethnicity of the patient. For example, pathogenic sequence variants in the OTOF gene account for 10% (16/160) of Japanese patients with severe to profound recessive nonsyndromic hearing loss who did not harbor causative variants in the GJB2 and SLC26A4 genes (Iwasa et a. 2013). On the other hand, pathogenic sequence variants in the OTOF gene may be responsible for 7% (7/52) of Brazilian families with prelingual autosomal recessive hearing loss (Romanos et al. 2009). In China, 6.8% (5/73) of families with temperature-sensitive auditory neuropathy were determined to have pathogenic sequence variants in the OTOF gene (Wang et al. 2010). In Turkey, 6.1% (3/49) of families with prelingual deafness and no detected pathogenic variants in the GJB2, GJB6, and MTRNR1 genes harbored disease-causing variants in OTOF (Duman et al. 2011). In Algeria, 6% (2/33) of families with recessive nonsyndromic hearing loss and no detected pathogenic variants in the GJB2 and TMC1 genes showed causative variants in the OTOF gene (Ammar-Khodja et al. 2015). In Korea, 3.2% (1/32) of families with nonsyndromic hearing loss and did not carry pathogenic sequence variants in the GJB2, SLC26A4, and POU3F4 genes or mitochondrial DNA were determined to have causative sequence variants in the OTOF gene (Choi et al. 2013). In Pakistan, disease-causing OTOF sequence variants have been detected in 2.3% (13/557) of patients with recessive congenital/prelingual severe to profound deafness (Choi et al. 2009).

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