Deafness, Autosomal Dominant 40 (DFNA40) via the CRYM 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 CRYM gene is associated with pre- or postlingual, bilateral, moderate to severe, nonprogressive or progressive sensorineural hearing impairment affecting all frequencies. No visual, vestibular or temporal bone abnormalities are present (Abe et al. 2003).

DFNA40 is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the crystallin mu (CRYM) gene, which is located on chromosome 16p12.2. The CRYM gene spans 48.6 kb and consists of 8 coding exons that produce a 314 amino acid protein that is expressed in human inner ear, retina, heart, brain, muscle and kidney (Abe et al. 2003; Kim et al. 1992). In the mouse inner ear the CRYM gene is expressed in fibrocytes of the lateral wall of the cochlea, but not in the inner or outer hair cells (Abe et al. 2003; Oshima et al. 2006).

Only one missense and one nonsense variant in CRYM have been reported to date as pathogenic for hearing loss in two different families of Japanese origin (Abe et al. 2003).

The clinical sensitivity of this sequencing test is difficult to predict because only one missense and one nonsense variant in CRYM have been reported as pathogenic for hearing loss in two different families of Japanese origin (Abe et al. 2003). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

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

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