Deafness, Autosomal Dominant 51 (DFNA51) via the TJP2 Gene

Autosomal dominant deafness 51 (DFNA51) is a postlingual, bilateral, progressive, nonsyndromic, sensorineural hearing loss disorder. Initial onset ranges from the second to sixth decade of life involving high frequencies and progressing to severe to profound at all frequencies (Walsh et al. 2010; Wang et al. 2015).

DFNA51 is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the tight junction protein 2 (TJP2) gene, which is located on chromosome 9q21.11 (Walsh et al. 2010; Kim et al. 2014). The TJP2 gene spans 81 kb and consists of 23 coding exons that produce a 1,190-amino acid protein that is a component of the tight junction barrier in epithelial and endothelial cells. In the mouse inner ear the TJP2 protein is localized in membranes connecting hair cells and supporting cells in the cochlea and is also expressed in cells of the vestibular system (Walsh et al. 2010).

The 4 TJP2 variants implicated to date in hearing loss consist of 3 missense (Kim et al. 2014; Wang et al. 2015) and 1 large duplication encompassing the entire TJP2 gene (Walsh et al. 2010). Additional missense, splicing, small and large deletion variants in TJP2 have been shown to cause cholestatic liver disease and hypercholanaemia not associated with hearing loss (Human Gene Mutation Database).

Pathogenic sequence variants in TJP2 have been reported to cause autosomal dominant nonsyndromic hearing loss in three Korean families and one Chinese family (Kim et al. 2014; Wang et al. 2015). Due to the limited number of known pathogenic variants the sensitivity of this test is currently unknown.

Only a single pathogenic copy number variant in TJP2 has been documented in association with autosomal dominant nonsyndromic hearing loss in a single family of Jewish ancestry (Walsh et al. 2010).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TJP2 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.