Deafness, Autosomal Recessive 29 (DFNB29) via the CLDN14 Gene

Autosomal recessive deafness 29 (DFNB29) is characterized by prelingual, bilateral, severe to profound, nonprogressive, sensorineural nonsyndromic hearing loss affecting all frequencies, with more severe impairment at high frequencies (Bashir et al. 2010, Bashir et al. 2013). The audioprofile of most nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008). Pure-tone audiometry of DFNB29 individuals generally show a downward sloping audiogram (Lee et al. 2012).

DFNB29 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the claudin 14 (CLDN14) gene, which is located on chromosome 21q22.13n (Hattori et al. 2000). The CLDN14 gene consists of one coding exon that encodes a 239-amino acid protein that constitutes the fibrils of tight junctions and mainly functions in selective paracellular permeability (Wattenhofer et al. 2005). The claudin-14 protein is mainly expressed in the inner ear and plays a major role in decreasing cellular permeability to cations, particularly potassium. Claudin-14 is also expressed in the liver and kidney (Ben-Yosef et al. 2003). Pathogenic sequence variants in the CLDN14 gene result in impairment of the ability to form tight junctions, which is crucial for maintenance of an eletrochemical gradient between the endolymph and the surrounding tissues of the inner ear for proper hearing (Wilcox et al. 2001; Chiba et al. 2008). Gene knockout studies using mouse models have shown that deletion of the CLDN14 gene results in the rapid degeneration of the outer hair cells of the cochlea (Ben-Yosef et al. 2003). To date, a total of about 8 pathogenic CLDN14 sequence variants have been reported, which include 6 missense, 1 frame shift, and 1 truncation sequence variant that generates a non-functional claudin-14 protein (Lee et al. 2012; Human Gene Mutation Database). The CLDN14 gene has also been associated with susceptibility to kidney stones (Thorleifsson et al. 2009).

The clinical sensitivity of this test has been reported to range from 2% to 3%. For example, in two separate studies conducted in Pakistan, 1.9% (15/800) of families with hearing loss (Bashir et al. 2013) and 2.2% (2/88) of families with moderately severe to severe hearing loss (Bashir et al. 2010) showed disease-causing CLDN14 sequence variants. In Iran, 2.8% (4/144) of families with autosomal recessive nonsyndromic hearing loss that tested negative for pathogenic variants in the GJB2 gene showed disease-causing variants in the CLDN14 gene (Babanejad et al. 2012).

This test provides full coverage of all coding exons of the CLDN14 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).