Deafness, Autosomal Recessive 35 (DFNB35) via the ESRRB Gene

Autosomal recessive deafness 35 (DFNB35) is characterized by prelingual, severe to profound, bilateral nonsyndromic hearing loss affecting all frequencies (Safka Brozkova et al. 2012). 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). DFNB35 individuals also do not elicit acoustic brainstem responses or transient otoacoustic emissions spectra, thereby indicating a disruption of outer hair cell function (Collin et al. 2008). Computerized tomography of the structures of the middle ear of DFNB35 individuals, particularly the temporal bone, is generally normal. Patients diagnosed with DFBN35 usually have no indications of visual problems, kidney failure, or any morphological features that are suggestive of syndromic hearing loss or history of environmental exposure to factors that may cause hearing loss (Lee et al. 2011).

DFNB35 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the estrogen-related receptor beta (ESRRB) gene, which is mainly expressed during inner ear development, as well as in the cochlea postnatally, particularly in the nerve fibers and spiral ganglion cells (Collin et al. 2008). The ESRRB gene is located in chromosome 14q24.3 and consists of 8 coding exons that encode a 508-amino acid protein that is highly similar to the estrogen receptor (Ansar et al. 2003; Misawa and Inoue 2015). The ESRRB protein is also expressed in embryonic stem cells and cancer cells (Ouyang et al. 2009; Amini et al. 2014) and is considered an orphan protein because its ligand is not known (Sanyal et al. 2002). Alternative splicing of the ESRRB gene gives rise to three major isoforms: one short and one long isoform are widely expressed in various human tissues, whereas the longer primate-specific isoform is highly expressed in the testis and cochlea (Zhou et al. 2006; Collin et al. 2008). The two main structures of the ESRRB protein include a ligand-binding domain and a DNA-binding domain (Moras and Gronemeyer 1998).

To date, a total of about 15 pathogenic ESRRB sequence variants have been reported, which include 12 missense/nonsense, 1 small deletion, and 1 small insertion causing hearing loss and 1 splicing variant that has been associated with dental decay (Human Gene Mutation Database; Weber et al. 2014).

The clinical sensitivity of this test has been reported to range from 1.3% to 1.9%. In a study involving Chinese patients diagnosed with sporadic sensorineural hearing loss, pathogenic sequence variants in the ESRRB gene were detected in 1.3% (1/79) of the patients (Ji et al. 2014). In a multiethnic cohort consisting of families with autosomal recessive nonsyndromic deafness, 1.3% (2/160) of the families were determined to have causative ESRRB sequence variants (Bademci et al. 2015). Approximately 1.9% (3/216) of Japanese patients diagnosed with hearing impairment showed disease-causing sequence variants in the ESRRB gene (Miyagawa et al. 2013).

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