Deafness, Autosomal Dominant 4A (DFNA4A) via the MYH14 Gene

Deafness, autosomal dominant 4A (DFNA4A) is characterized by progressive, postlingual, sensorineural nonsyndromic hearing loss that begins in the first to third decades of life and eventually results in severe to profound deafness by the fourth decade (Mirgomizadeh et al. 2002; Zong et al. 2012). The audioprofile of most autosomal dominant 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 shows that DFNA4A individuals initially show a downsloping or U-shaped audiogram, indicating more severe hearing loss at high- or mid-frequency sounds, which then later becomes flat by age 40, when the individual progresses to all-frequency hearing loss (Zong et al. 2012; Qing et al. 2014).

DFNA4A is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the myosin heavy chain 14 (MYH14) gene, which is mainly expressed in the sensory area of the cochlea during embyronic development, as well as in the apical area of intestinal epithelial cells and skeletal muscles (Golomb et al. 2004; Choi et al. 2011). The MYH14 gene is located on chromosome 19q13.33, and consists of 42 coding exons that encode a 2,036-amino acid motor protein (Mirghomizadeh et al. 2002). The MYH14 protein belongs to the myosin II family of ATP-dependent molecular motor proteins that interact with actin microfilaments to regulate cytokinesis, as well as cell motility and polarity (Kim et al. 2005). This 228-kD protein is highly similar to the myosin heavy chain 9 (MYH9), MYH10, and MYH11 proteins based on its highly conserved myosin head domain (Golomb et al. 2004). To date, a total of about 15 pathogenic MYH14 sequence variants have been reported. Most are missense, but chain termination variants have also been reported (Choi et al. 2011; Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from about 2% to 9%. For example, 2.3% (5/216) of Japanese deaf patients tested positive for disease-causing MYH14 sequence variants (Miyagawa et al. 2013). In a German study, 3.3% (1/30) of patients with nonsyndromic hearing loss showed causative MYH14 sequence variants (Vona et al. 2014). In Korea, around 9.1% (1/11) of pediatric patients with sensorineural hearing loss harbored pathogenic sequence variants in the MYH14 gene (Kim et al. 2015).

This test provides full coverage of all coding exons of the MYH14 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).