Deafness, Autosomal Dominant 10 (DFNA10) via the EYA4 Gene

Autosomal dominant deafness 10 (DFNA10) is a late-onset, progressive nonsyndromic hearing loss disorder that begins in the second to fifth decades, often resulting in severe-to-profound hearing impairment that requires the use of sound amplification. 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 DFNA10 generally involve hearing impairment for middle frequency sound, followed by flattening of the audiogram over time that is more pronounced in high-frequency sound (Pfister et al. 2002; Huang et al. 2015). By the sixth decade of life, DFNA10 patients present with severe hearing loss across all frequencies (Tan et al. 2014; Liu et al. 2015). The majority of patients with DFNA10 are equipped with hearing aids by the third or fourth decade. DFNA10 individuals are considered the least responsive to cochlear implants (Hildebrand et al. 2007).

DFNA10 is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the eyes absent 4 (EYA4) gene, which is located on chromosome 6q23.2 (O'Neill et al. 1996; Borsani et al. 1999). The EYA4 gene consists of 19 coding exons that encode a 639-amino acid transcription factor, which interacts with specific protein families that are involved in early embryonic development, including that of the organ of Corti, tympanic membrane, and the Eustachian tube (Depreaux et al. 2008; Wayne et al. 2001). Disease-causing sequence variants in the EYA4 gene have also been implicated in two other disorders, namely, holoprosencephaly (a birth defect characterized by malformation of the forebrain), and syndromic hearing loss (with dilated cardiomyopathy and mental retardation (Schonberger et al. 2000; Abe et al. 2009). To date, a total of about 20 pathogenic EYA4 sequence variants have been reported, which include 8 missense/nonsense, 2 splicing, 2 small deletions, and 5 small insertions that cause DFNA10, and 1 gross deletion that causes holoprosencephaly, and 2 gross deletions that cause syndromic hearing loss (with dilated cardiomyopathy and mental retardation) (Human Gene Mutation Database).

The clinical sensitivity of this test has been reported to range from 1% to 12%. For example, three independent research studies conducted in Korea indicated that pathogenic sequence variants in the EYA4 gene accounted for ~1% (1/87) of patients (Kim et al. 2015) and ~12% (1/8) of families (Baek et al. 2012) with autosomal dominant nonsyndromic hearing loss, and in ~3% (1/32, 1/32, and 1/30) families with nonsyndromic hearing loss (Choi et al. 2013; Chang and Choi 2014. Vona et al. 2014).

No large-scale studies have been conducted on gross rearrangements involving the EYA4 gene, thus the clinical sensitivity for these mutations is unclear. One gross deletion (~10.4-Mb in size, which included the promoter and exons 1 and 2 of the EYA4 gene) was detected in a patient with holoprosencephaly (Abe et al. 2009). In another study, one of two families with syndromic sensorineural deafness and dilated cardiomyopathy harbored a 4.8-Mb deletion that overlaps the EYA4 gene (Schonberger et al. 2000).

This test provides full coverage of all coding exons of the EYA4 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).