Deafness, Autosomal Recessive 3 (DFNB3) via the MYO15A Gene

Autosomal recessive deafness 3 (DFNB3) is characterized by severe to profound, stable, prelingual, sensorineural nonsyndromic hearing loss. This disorder was initially reported in 1995 in a population of 2,200 villagers in Bengkala, Bali in Indonesia, in which 45 individuals were deaf (Winata et al. 1995). Due to the high incidence of deafness in this Balinese village for at least seven generations, the first cohort of deaf individuals developed a unique and complex sign language that is known by majority of the Bengkala community. Subsequent studies have identified individuals with DFNB3 hearing loss in various Asian, European, Middle Eastern, and South American countries (Lezirovitz et al. 2008; Duman et al. 2011; Fattahi et al. 2012; Ammar-Khodja et al. 2015).

DFNB3 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the MYO15A gene. MYO15A encodes a 3,530-amino protein called myosin-XV that plays a critical role in the formation of stereocilia in the cochlear hair cells (Anderson et al. 2000). This MYO15A protein comprises an N-terminal motor domain, two light-chain binding IQ motifs, and a tail region that consists of a MyTH4 and a line-like domain. The MYO15A protein is also expressed in the brain, ovary, testis, kidney, and pituitary gland. The MYO15A gene is 71 kb in size, located on chromosome 17p11.2, and consists of 66 exons (Liang et al. 1998). Functional studies have shown that the MYO15A protein interacts with the whirlin protein at the tips of stereocilia of the cochlear hair cells, which in turn regulates stereocilia elongation (Belyantseva et al. 2003). To date, about 100 pathogenic MYO15A sequence variants have been reported, which include missense/nonsense, splicing, small deletions, small insertions, small indels, and complex rearrangements (Human Gene Mutation Database).

The clinical sensitivity of this test ranges from 0.98% to 15%, depending on the ethnicity of the patient. For example, causative sequence variants in the MYO15A gene account for 0.98% (11/1,120) of Japanese patients with hearing loss (Miyagawa et al. 2015). Pathogenic sequence variants in the MYO15A gene are responsible for 1.5% (1/65) of Algerian families affected by autosomal recessive forms of nonsyndromic hearing impairment (Amman-Khodja et al. 2015). In Iran, 5.71% (8/140) families who were GJB2 variant-negative, mostly consanguineous, with at least two affected children, were determined to have pathogenic sequence variants in the MYO15A gene (Fattahi et al. 2012). A study involving Turkish families with at least three affected children born to consanguineous parents showed that 12.2% (6/49) of the families carried causative sequence variants in the MYO15A gene (Duman et al. 2011). In a collaborative research study involving Iranian and Turkish unrelated consanguineous families with autosomal recessive nonsyndromic hearing loss, 15% (3/20) of the families harbored pathogenic sequence variants in the MYO15A gene (Diaz-Horta et al. 2012).

This test provides full coverage of all coding exons of the MYO15A 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).