Deafness, Autosomal Dominant 9 (DFNA9) and Autosomal Recessive Hearing Loss via the COCH Gene

Deafness, autosomal dominant 9 (DFNA9) is characterized by high-frequency, progressive, postlingual (adult-onset) sensorineural nonsyndromic hearing loss that is associated with variable vestibular dysfunction associated with histological alterations in the temporal bone as well as mucopolysaccharide deposition in the cochlear channels and vestibular nerves. This can result in vestibular hypofunction, vertigo or tinnitus (Robertson et al. 1998. PubMed ID: 9806553, Robertson et al. 2006. PubMed ID: 16481359).

Hearing in individuals with DFNA9 generally deteriorates at age 20 and progresses to anacusis (total deafness) by the age of 50 (Hildebrand et al. 2009. PubMed ID: 19161137). The progression of deafness is often slow. The most pronounced hearing loss in DFNA9 involves high-frequency sound. By age 30, DNFNA9 individuals may develop a sudden drop in word recognition, which in turn corresponds to a sharp decline in communication ability, yet can be resolved to a certain degree using cochlear implants (Manolis et al. 1996. PubMed ID: 8817345).

Autosomal recessive inheritance has also been reported in two individuals from a single family with moderate prelingual sensorineural hearing loss with vestibular dysfunction (JanssensdeVarebeke et al. 2018. PubMed ID: 29449721).

Pathogenic variants in the cochlin (COCH) gene cause autosomal dominant (DFNA9) and autosomal recessive hearing loss. The COCH gene is located in chromosome 14q11.2-13, and consists of 11 coding exons that encode a 550-amino acid cochlin protein (Robertson et al. 2001. PubMed ID: 11709536). The COCH gene is mainly expressed in the spiral ligament, limbus, and channels of the osseous spirallamina, which are components of the cochlea (Robertson et al. 1998. PubMed ID: 9806553).

To date, a total of ~25 pathogenic COCH sequence variants have been reported to cause DFNA9, all of which are missense and small in-frame deletions (Human Gene Mutation Database), suggestive of a dominant negative or gain-of-function effect. Autosomal recessive hearing loss has been described in one family with a homozygous premature termination variant, suggestive of a loss-of-function effect (JanssensdeVarebeke et al. 2018. PubMed ID: 29449721).

The clinical sensitivity of this test has been reported to range from about 1% to 6%. For example, an investigation conducted in China indicated that pathogenic sequence variants in the COCH gene accounted for ~1% (1/125) of families with nonsyndromic hearing loss that tested negative for causative variants in the GJB2, SLC26A4, and MT-RNR1 genes (Yang et al. 2013. PubMed ID: 23767834). In a study involving Japanese deafness patients, 0.09% (1/1,120) harbored causative COCH sequence variants (Nishio and Usami. 2015. PubMed ID: 25788563). In two independent studies, disease-causing COCH variants were detected in ~3% (1/32) and ~6% (2/32) of Korean patients with nonsyndromic sensorineural hearing loss (Chang and Choi. 2014. PubMed ID: 25279224; Choi et al. 2013. PubMed ID: 23990876).

No large deletions or duplications involving COCH have been reported (Human Gene Mutation Database).

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