Deafness, Autosomal Recessive 74 (DFNB74) via the MSRB3 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 MSRB3 gene is associated with prelingual, bilateral, profound sensorineural hearing impairment (Ahmed et al. 2011).

DFNB74 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the methionine sulfoxide reductase B3 (MSRB3) gene, which is located on chromosome 12q14.3. The MSRB3 gene spans 192 kb and consists of 6 coding exons that produce a 192 amino acid protein. The MSRB3 protein repairs oxidatively damaged proteins by catalyzing the reduction of oxidized methionine residues (Ahmed et al. 2011).

Only one missense and one nonsense variant in the MSRB3 gene have been reported as pathogenic for hearing loss in nine different consanguineous Pakistani families (Ahmed et al. 2011).

The clinical sensitivity of this sequencing test is not precisely known. Only one missense and one nonsense variant in MSRB3 have been reported as pathogenic for hearing loss in nine different consanguineous Pakistani families (Ahmed et al. 2011). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

No deletion or duplication variants associated with MSRB3 have been reported as pathogenic for hearing loss.

This test provides full coverage of all coding exons of the MSRB3 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).