Deafness, X-linked 6 (DFNX6) via the COL4A6 Gene

X-linked deafness 6 (DFNX6) is a postlingual, progressive sensorineural type of hearing loss of variable severity that is responsible for around 1% of nonsyndromic hearing loss cases (ACMG 2002). Sensorineural deafness generally results from damage to the neural receptors of  the inner ear, the nerve pathways leading to the brain, or the region of the brain that receives sound information. To date, only one study has described DFNX6 in a three-generation Hungarian family with 4 males diagnosed with severe bilateral sensorineural hearing loss during infancy (Rost et al. 2014). Magnetic resonance imaging of the brain of the 3-year-old proband showed bilateral malformation of the cochlea, mainly presenting incomplete separation from the internal auditory canal. The proband was then subjected to cochlear implantation, which resulted in profuse release of cerebrospinal fluid after surgically opening the cochlea, which is also known as the 'gusher' phenomenon. The other 3 affected males presented with the same cochlear structural abnormality. Hearing loss in all four affected males was determined to be of prelingual onset. Four of the female family members developed mild to moderate hearing impairment during the third and fourth decades of life, whereas another female member developed mild hearing loss at age 9. The 46-year-old mother of the proband showed no hearing impairment nor cochlear malformation on brain imaging.

DFNX6 is an X-linked nonsyndromic, postlingual, sensorineural type of hearing loss caused by pathogenic sequence variants in the collagen type IV alpha-6 (COL4A6) gene. COL4A6 encodes a 1,678-amino acid collagen isoform that assembles in a head-to-head conformation with two collagen type IV alpha-5 chains, forming a triple-helical molecule that serves as a component of the cellular basement membrane (Zhou et al. 1994). The basement membrane plays a key role in the compartmentalization of tissues as well as in the transmission of molecular signals for cellular differentiation (Miner 1999; Thielen et al. 2003). Other members of the type IV collagen gene family include COL4A1, COL4A2, COL4A3, and COL4A4, with COL4A2 and COL4A4 showing the highest DNA sequence homology to COL4A6 (Oohashi et al. 1995). The COL4A6 gene is approximately 425 kb in length, consists of 45 exons, and has been localized to chromosomal region Xq22 (Oohashi et al. 1994).

To date, only one study has been conducted on DFNX6 via the COL4A6 gene. In a three-generation Hungarian family of 17 available members, all four affected males were determined to be hemizygous for the same causative missense variant in the COL4A6 gene (Rost et al. 2014). The four affected males were also pre-determined to have no pathogenic sequence variants in the other more common X-linked deafness genes such as PRPS1 and POU3F4. All four obligatory female carriers and one slightly affected female member were heterozygous for the same pathogenic sequence variant. All unaffected male family members did not harbor the causative missense substitution.

Because only one report has described a single COL4A6 pathogenic variant, it is difficult to estimate the clinical sensitivity of this test.

This test provides full coverage of all coding exons of the COL4A6 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).