Deafness, Autosomal Dominant 44 (DFNA44) via the CCDC50 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 sensorineural hearing impairment. The audioprofile may vary significantly, even among family members. Affected individuals have no other associated medical findings (Smith et al. 2013).

DFNA44 was found in a Spanish family segregating for progressive, postlingual, nonsyndromic sensorineural hearing loss. Initial hearing loss is moderate and affects mainly low to mid frequencies, progressing to involve all frequencies. Onset is typically 6-10 years of age with profound hearing loss by the 6th decade (Modamio-Hoybjor et al. 2007).

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. Nonsyndromic hearing loss and deafness via CCDC50 exhibits an autosomal dominant mode of inheritance corresponding to DFNA44.

The only documented DFNA44 causative variant is an 8 bp duplication (c.1394_1401dupCACGGCAT) in exon 11 of CCDC50. This variant results in a frameshift (p.Phe468Hisfs*37) replacing the last 15 aa of the CCDC50 protein with a novel 36 aa sequence (Modamio-Hoybjor et al. 2007).

The CCDC50 (coiled-coil domain containing 50) gene codes for the protein Ymer, a soluble, cytoplasmic, tyrosine-phosphorylated protein with multiple ubiquitin-interacting domains that is expressed in many different tissues (Tashiro et al. 2006; Modamio-Hoybjor et al. 2007). Ymer is involved with inhibition of EGF receptor down-regulation and regulation of NF-kB signaling (Tashiro et al. 2006; Tsukiyama et al. 2012). In the mouse inner ear Ymer is expressed in cochlear mesenchyme structures and nerve fibers during embryonic stages, as well as pillar cells, outer hair cells, Deiter’s cells and the stria vascularis during adult stages. Ymer colocalizes with microtubules of the cytoskeleton in the mouse inner ear, important structures for proper function of pillar cells and the stria vascularis. Destabilization of the cytoskeleton in these components of the inner ear over time may explain progressive hearing loss features of DFNA44 (Modamio-Hoybjor et al. 2007).

Clinical sensitivity cannot be estimated because only one pathogenic variant has been documented in a single Spanish family.

This test provides full coverage of all coding exons of the CCDC50 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).