Deafness, Autosomal Recessive 59 (DFNB59) via the PJVK (DFNB59) Gene

Autosomal recessive deafness 59 (DFNB59) is a prelingual, severe to profound, stable, bilateral, nonsyndromic auditory neuropathy that is characterized by severely distorted or absent auditory brainstem responses but normal otoacoustic emissions from the outer hair cells of the cochlea (Borck et al. 2012). 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). The primary lesion of DFNB59 involves the inner hair cells, the auditory nerve, or the intervening synapse (Mujtaba et al. 2012). Individuals presenting with profound deafness for all frequencies may have impeded speech acquisition. Patients diagnosed with DFNB59 are generally compensated by hearing aids, whereas these individuals are strongly associated with poor cochlear implant performance (Ebermann et al. 2007; Wu et al. 2015).

DFNB59 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the PJVK gene. PJVK is located on chromosome 2q31.2 and consists of 6 coding exons that encode a 352-amino acid pejvakin protein, which is a member of the gasdermine family and expressed in inner and outer hair cells, a subset of supporting cells, the spiral ganglion, and the cell bodies of neurons of the afferent auditory pathway (Delmaghani et al. 2006; Collin et al. 2007; Schwander et al. 2007). Functional studies using mouse models indicate that the pejvakin protein controls the development and function of mechanosensory hair cells in signal propagation and amplification of acoustic signals (Schwander et al. 2007). To date, a total of about 15 pathogenic PJVK sequence variants have been reported, which include 8 missense/nonsense, 5 small deletions, and 2 small insertions (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 0.6% to 30%. For example, 0.6% (1/160) of families with autosomal recessive nonsyndromic deafness from Turkey, Iran, Mexico, Ecuador, and Puerto Rico were determined to have pathogenic PJVK sequence variants (Bademci et al. 2015). Another group reported that 1.3% (1/76) of patients with auditory neuropathy spectrum disorder showed causative sequence variants in the PJVK gene (Wang et al. 2011). Pathogenic PJVK sequence variants accounted for 2.9% (2/68) of Turkish deafness patients from consanguineous families and 2.4% (2/83) of Dutch patients with autosomal recessive hearing impairment (Collin et al. 2007). In two independent studies involving Iranian families with autosomal recessive nonsyndromic hearing loss, 1.4% (2/144; Babanejad et al. 2007) and 30% (9/30; Hashemzadeh Chaleshtori et al. 2007) were determined to harbor disease-causing sequence variants in the PJVK gene.

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