Deafness, Autosomal Recessive 91 (DFNB91) via the SERPINB6 Gene

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the SERPINB6 gene is associated with postlingual, bilateral, moderate to severe, progressive sensorineural hearing impairment. Onset is in the first or second decade and is characterized by downsloping audiograms. No vestibular abnormalities are present (Sirmaci et al. 2010; Kim et al. 2015).

DFNB91 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the serpin family B member 6 (SERPINB6) gene, which is located on chromosome 6p25.2. The SERPINB6 gene spans 28 kb and consists of 6 coding exons that produce a 376 amino acid protein. The SERPINB6 protein is expressed in mice in the crista ampullaris hair cells of the inner ear as well as inner and outer hair cells in the cochlea during embryonic development and postnatally (Sirmaci et al. 2010). SERPINB6 is thought to counteract cytotoxic components of leaking lysosomal proteases caused by normal physiological hearing processes and stress inducing external stimuli to the hair cells of the inner ear (Sirmaci et al. 2010).

Only one nonsense, one splicing and one small deletion variant in the SERPINB6 gene have been reported as pathogenic for hearing loss, all predicted to result in premature protein termination and found in the homozygous or compound heterozygous state in affected individuals (Sirmaci et al. 2010; Kim et al. 2015).

The clinical sensitivity of this sequencing test is not precisely known. Only one nonsense, one splicing and one small deletion variant in the SERPINB6 gene have been reported as pathogenic for hearing loss, all predicted to result in premature protein termination and found in the homozygous or compound heterozygous state in affected individuals (Sirmaci et al. 2010; Kim et al. 2015). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

No large deletion or duplication variants associated with SERPINB6 have been reported.

This test provides full coverage of all coding exons of the SERPINB6 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).