Deafness, Autosomal Dominant 10

A number sign (#) is used with this entry because autosomal dominant deafness-10 (DFNA10) is caused by heterozygous mutation in the EYA4 gene (603550) on chromosome 6q23.

Clinical Features

O'Neill et al. (1996) reported a large multigenerational family from the U.S. with progressive sensorineural hearing loss beginning in the second to fifth decades and leading ultimately to severe to profound hearing impairment requiring the use of amplification.

Verhoeven et al. (2000) reported a Belgian and a Norwegian family with nonsyndromic deafness similar to that in the American family reported by O'Neill et al. (1996). Hearing loss in all 3 families began with the middle frequencies and later involved the low and high frequencies.

Mapping

O'Neill et al. (1996) mapped a locus for autosomal dominant late-onset progressive nonsyndromic hearing loss, designated DFNA10, to chromosome 6q22.2-q23.3 on the basis of linkage analysis in a large multigenerational family from the U.S. The markers D6S472 and D6S407 yielded 2-point lod scores of 4.44 and 4.0 at theta = 0, respectively. Multipoint linkage analysis of DFNA10 within a 5-marker linkage map yielded a maximum lod score of 5.27 with marker D6S407.

By extending the American pedigree in which linkage of DFNA10 to 6q was first demonstrated (O'Neill et al., 1996), and by study of a Belgian and a Norwegian family with DFNA10, Verhoeven et al. (2000) corroborated and narrowed the linkage to a 3.7-cM region.

Hildebrand et al. (2007) performed a genomewide scan on 10 affected members of a 5-generation Australian family with nonsyndromic sensorineural hearing loss and obtained a maximum lod score of 2.5 for an 8-cM critical region on chromosome 6 containing the DFNA10 locus.

Molecular Genetics

Wayne et al. (2001) identified 'eyes absent' 4 (EYA4; 603550), a member of the vertebrate Eya family of transcriptional activators, as the causative gene of autosomal dominant postlingual progressive hearing loss at the DFNA10 locus. In affected members of 2 unrelated families from Belgium and the U.S. segregating for deafness, previously studied by Verhoeven et al. (2000) and shown to link to this locus, Wayne et al. (2001) identified heterozygosity for 2 different mutations in EYA4 (603550.0001 and 603550.0002, respectively), both of which create premature stop codons. Although EYA proteins interact with members of the SIX (601205) and DACH (603803) protein families in a conserved network that regulates early embryonic development, this finding shows that EYA4 is also important postdevelopmentally for continued function of the mature organ of Corti.

In affected members of a family segregating autosomal dominant postlingual progressive sensorineural hearing loss, Makishima et al. (2007) identified heterozygosity for a 2-bp insertion (603550.0004) in the EYA4 gene. Comprehensive cardiac evaluation of 9 affected individuals revealed no evidence of dilated cardiomyopathy. Noting that the 3 known EYA4 mutations causing nonsyndromic SNHL are predicted to encode truncated EYA proteins with a deleted Eya domain but an intact variable domain, whereas the EYA4 deletion (603550.0003) causing syndromic hearing loss with dilated cardiomyopathy (CMD1J; 605362) partially truncates the variable domain of the protein as well, Makishima et al. (2007) proposed a correlation between EYA4 mutation position and the presence or absence of DCM.

In affected members of a 5-generation Australian family with nonsyndromic sensorineural hearing loss mapping to the DFNA10 locus, Hildebrand et al. (2007) identified heterozygosity for a splice site mutation (603550.0005) in the EYA4 gene.