Deafness, Autosomal Dominant 3A (DFNA3A) and Deafness, Autosomal Recessive 1A (DFNB1A) via the GJB2 Gene

Hereditary or familial hearing loss (HL) and deafness can be prelingual (before language develops) or postlingual (after language develops) and may be conductive, sensorineural, or a combination of both. Causes for hereditary HL can be syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (no associated visible abnormalities of the external ear or any related medical problems). Familial forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss (such as environmental effects or mechanical stress) and are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (e.g., CT examination of the temporal bone), and molecular genetic testing. Molecular genetic testing is possible for many types of syndromic and nonsyndromic deafness and plays a prominent role in diagnosis and genetic counseling (Smith et al, 2013).

Nonsyndromic hearing loss and deafness is characterized by childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment. The audioprofile may vary significantly, even among family members. Affected individuals have no other associated medical findings (Smith et al, 2013).

Nonsyndromic hearing loss and deafness via GJB2 exhibits two modes of inheritance. 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. GJB2 mediated deafness and hearing loss are inherited in both autosomal dominant (DFNA3A) and autosomal recessive (DFNB1A) modes.

The GJB2 gene codes for the gap junction beta 2 protein, more commonly known as connexin 26. Connexins form gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells that are in contact with each other. Connexin 26 transports potassium ions and certain small molecules. GJB2 gene mutations probably alter gap junctions, which may disturb the level of potassium ions in the inner ear. Levels of potassium ions that are too high may affect the function and survival of cells that are needed for hearing. Connexin 26 also plays a role in the growth, maturation, and stability of the outermost layer of skin (the epidermis).

Mutations in GJB2 account for >90% of all DFNA3 cases and ~98% of DFNB1 cases. Mutations include single nucleotide deletions and missense variants. Mutations in GJB6 (Connexin 30) account for the remaining cases of DFNA3 and DFNB1.

GJB2 mutations account for 60-70% of nonsyndromic hearing loss cases (Smith et al, 2013). The most common mutations in GJB2 are single nucleotide deletions, c.35delG in particular. Our sequencing assay is able to detect >90% of mutations associated with this gene.

This test provides full coverage of all coding exons of the GJB2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.