Deafness, Autosomal Recessive 30 (DFNB30) via the MYO3A Gene

Autosomal recessive deafness 30 (DFNB30) is characterized by late-onset (postlingual), bilateral, progressive, sensorineural nonsyndromic hearing loss. This disorder was initially reported in 2002 in a Jewish community in Mosul, Iraq, which was established in 586 B.C. and underwent a high level of endogamy, considerable emigration, and minimal immigration in the past 2,500 years (Walsh et al. 2002). 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). Initial stages of DFNB30 generally involve moderate high-frequency hearing loss during the second decade of life, which then progresses to severe to profound high- and mid-frequency and moderate low-frequency hearing loss by the fifth decade of life (Walsh et al. 2002). DFNB30 individuals generally show normal vision and balance and are considered the most responsive to cochlear implants (Wu et al. 2015).

DFNB30 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the myosin IIIA (MYO3A) gene. MYO3A encodes a 1,616-amino acid actin-dependent motor protein that plays a critical role in the formation of stereocilia in the cochlear hair cells (Schneider et al. 2006). The MYO3A protein comprises an N-terminal domain, three 23-residue light-chain binding IQ motifs, and a C-terminal cargo-binding domain. The MYO3A protein is also expressed in the pancreas and retina (Quintero et al. 2010). The MYO3A gene is located on chromosome 10p12.1 and consists of 33 coding exons (Walsh et al. 2002). The MYO3A protein transports the actin-regulatory protein Espin 1 to the tips of stereocilia to increase its filament length, which is essential for hearing (Manor et al. 2012). The activity of the MYO3A protein is regulated through a mechanism involving concentration-dependent autophosphorylation (Quintero et al. 2013). To date, about 9 pathogenic MYO3A sequence variants have been reported to cause hearing loss, which include 3 chain termination (1 nonsense, 2 splicing) and 6 missense sequence variants (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 3% to 7%. For example, in two independent Korean research studies, pathogenic sequence variants in the MYO3A gene accounted for ~3.1% (1/32) of families with nonsyndromic hearing loss (Choi et al. 2013; Chang and Choi 2014). In Japan, 6.9% (15/216) of deafness patients harbored disease-causing sequence variants in the MYO3A gene (Miyagawa et al. 2013).

This test provides full coverage of all coding exons of the MYO3A 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).