Deafness, Autosomal Recessive 22 (DFNB22) via the OTOA Gene

Autosomal recessive deafness 22 (DFNB22) is a prelingual, bilateral, severe to profound, nonprogressive, nonsyndromic, sensorineural hearing loss disorder that involves disruption in the mechanotransduction of sound waves to the inner ear (Jovine et al. 2002; Zwaenepoel 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 (Hildebrand et al. 2008). Pure-tone audiometry of DFNB22 individuals generally show a flat audiogram, indicating all-frequency hearing loss (Lee et al. 2013).

DFNB22 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the otoancorin (OTOA) gene, which is located on chromosome 16p12.2 (Zwaenepoel et al. 2002). The OTOA gene is 86 kb in size and consists of 28 coding exons that produce a 1,139-amino acid predominantly helical, noncollagenous glycoprotein that is mainly expressed on the surface of the spiral limbus in the cochlea of the inner ear (Sathyanarayana et al. 2009; Lukashin et al. 2012). The OTOA protein mediates the attachment of the tectorial membrane to the sensory epithelium of the inner hair cells of the cochlea, thereby deflecting the stereociliary bundle for the mechanotransduction of sound (Jovine et al. 2002; Zwaenepoel et al. 2002). The 7 OTOA variants implicated to date in hearing loss consist of 4 missense, 1 splicing and 2 gross deletions (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range up to 5%. In a cohort of multiethnic families with autosomal recessive nonsyndromic deafness, 0.6% (1/160) harbored pathogenic sequence variants in the OTOA gene (Bademci et al. 2015). Around 1.5% (1/65) of Algerian families tested positive for disease-causing OTOA sequence variants (Ammar-Kodja et al. 2015). Causative OTOA sequence variants were detected in 5% (1/20) of Palestinian families with prelingual nonsyndromic hearing loss (Shahin et al. 2010).

This test provides full coverage of most coding exons of the OTOA 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).

Exons 20-28 of the OTOA gene have paralogy, or high levels of sequence similarity to a second genomic locus. Inherent limitations of NGS reduce the ability to detect sequence variants and CNVs in paralogous regions. For this reason the paralogous exons are Sanger sequenced to ensure full coverage of all coding exons. Detection of CNVs is performed using NGS, and is able to detect CNVs that involve exons of OTOA with and without paralogy. In summary, all exons of the OTOA gene are included in this sequencing and CNV test.

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).