Deafness, Autosomal Recessive 15 (DFNB15) via the GIPC3 Gene

Autosomal recessive deafness 15 (DFNB15) is characterized by prelingual, bilateral, severe to profound, nonprogressive, sensorineural nonsyndromic hearing loss that severely affects the development of speech and communication skills of an individual (Van Camp et al. 1997). Individuals diagnosed with DFNB15 do not show signs of vestibular dysfunction, ocular abnormalities, or other syndromic phenotypes (Charizopopulou et al. 2011). 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 DFNB15 individuals generally show a flat audiogram, indicating all-frequency hearing loss (Keller et al. 2011; Siddiqi et al. 2014). This disorder is also known as DFNB72 or DFNB95.

DFNB15 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the GIPC PDZ domain-containing family, member 3 (GIPC3) gene. The GIPC3 gene is located on chromosome 19p13.1 and consists of six coding exons. GIPC3 encodes a 312-amino acid protein with three domains, an N-terminal GIPC homology domain, a central PDZ doamin, and a C-terminal GH2 domain (Rehman et al. 2011; Sirmaci et al. 2012). The GIPC3 protein plays a major role in the postnatal maturation of the hair bundle of the outer and inner hair cells, as well as for the long-term survival of hair cells and spiral ganglion by facilitating cellular trafficking, signaling, and recycling of molecules and proteins across the cell membrane (Katoh 2013). Defects in the GIPC3 protein in mouse models have shown poor mechanotransduction in both the inner and outer hair cells, possibly due to defective activity of potassium channels (Charizopoulou et al. 2011). To date, a total of about 12 pathogenic GIPC3 sequence variants have been reported to cause sensorineural nonsyndromic hearing loss, which include 10 missense/nonsense, 1 splicing, and 1 small insertion (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 1% to 5%. For example, pathogenic sequence variants in the GIPC3 gene accounted for ~1.3% (2/160; Bademic et al. 2015) of families from a multiethnic cohort and 1.5% (1/65; Ammar-Khodja et al. 2015) of families affected by autosomal recessive nonsyndromic hearing impairment. In Iran, 5% (1/20) of consanguineous families with autosomal recessive nonsyndromic hearing loss harbored disease-causing GIPC3 variants (Diaz-Horta et al. 2012).

This test provides full coverage of all coding exons of the GIPC3 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).