Deafness, Autosomal Dominant 2B (DFNA2B) via the GJB3 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).

The clinical features of nonsyndromic hearing loss and deafness due to pathogenic variants in the GJB3 gene vary widely with autosomal dominant variants causing bilateral sensorineural hearing loss with a downsloping audiogram and moderate hearing loss at high frequencies (Xia et al. 1998). Autosomal recessive variants cause early-onset moderate to severe bilateral sensorineural hearing loss with flat audiograms and normal vestibular function (Liu et al. 2000).

The GJB3 gene encodes the gap junction protein beta 3, more commonly known as connexin 31. Connexins form gap junctions that facilitate metabolite and ion transport between adjacent cells. Connexin 31 is expressed in fibrocytes of the spiral ligament and spiral limbus of the mouse chochlea and auditory and peripheral nerves, although its role in auditory function remains unclear (Xia et al. 2000; López-Bigas et al. 2001).

The different gene loci for nonsyndromic hearing loss are designated DFN (for DeaFNess) and named on the mode of inheritance; DFNA for autosomal dominant, DFNB for autosomal recessive and DFNX for X-linked inheritance, respectively. The GJB3 gene is located in chromosomal region 1p34.3 and is associated with nonsyndromic hearing loss inherited in an autosomal dominant manner (DFNA2B), with some reports of autosomal recessive and digenic inheritance.

Autosomal dominant nonsyndromic hearing loss due to pathogenic variants in GJB3 has only been reported in two small Chinese families (Xia et al. 1998). However, these variants were found in both affected and unaffected individuals. Additionally, it is unlikely that hearing loss due to the nearby and at that time undiscovered KCNQ4 gene was excluded in these families. No subsequent reports have convincingly identified variants in GJB3 as causing autosomal dominant hearing loss in other families.

Autosomal dominant nonsyndromic hearing loss with peripheral neuropathy due to pathogenic variants in GJB3 has been reported in one multi-generation Spanish family (López-Bigas et al. 2001).

Autosomal recessive nonsyndromic hearing loss due to pathogenic variants in GJB3 has only been reported in two small Chinese families in which affected individuals were compound heterozygotes for two different missense variants (Liu et al. 2000). A Turkish family with one missense variant in GJB3 was reported to have autosomal recessive nonsyndromic hearing loss, although the second pathogenic variant was not identified (Uyguner et al. 2003).

Autosomal recessive nonsyndromic hearing loss has also been reported to be caused by digenic inheritance of variants in GJB3 and GJB2 (DFNA1A) in three Chinese families (Liu et al. 2009).

The role of GJB3 in causing nonsyndromic hearing loss is currently viewed as questionable due to limited evidence (Hilgert et al. 2009; Smith and Hildebrand 2015).

Heterozygous and homozygous variants in GJB3 are also known to cause erythrokeratodermia variabilis et progressiva, a skin disorder characterized by transient erythematous hyperkeratotic plaques (Gottfried et al. 2002).

The sensitivity of our sequencing assay for this gene is currently unknown. However, since only missense, nonsense and small deletion variants have been described for this gene in association with nonsyndromic hearing loss, we believe that our sequencing assay will be able to identify all of these variants. Overall, pathogenic variants in GJB3 are thought to play a small role in nonsyndromic hearing loss due to the limited number of families that have been identified (Hilgert et al. 2009; Smith and Hildebrand 2015).

No large deletions or duplications in GJB3 have been reported for nonsyndromic hearing loss.

This test provides full coverage of all coding exons of the GJB3 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).