DFNA9 is an autosomal dominant adult-onset form of progressive sensorineural hearing loss associated with variable vestibular dysfunction (summary by Robertson et al., 2006).
Manolis et al. (1996) reported results of a genetic linkage analysis in a family with nonsyndromic postlingual progressive sensorineural hearing loss. In this family hearing loss was inherited as an autosomal dominant trait which begins at approximately 20 ... Manolis et al. (1996) reported results of a genetic linkage analysis in a family with nonsyndromic postlingual progressive sensorineural hearing loss. In this family hearing loss was inherited as an autosomal dominant trait which begins at approximately 20 years of age and progresses to total deafness. Manolis et al. (1996) described unique temporal bone histopathologic findings in this family. Affected individuals were found to have mucopolysaccharide depositions in the channels of the cochlear and vestibular nerves. These depositions apparently caused strangulation and degeneration of dendritic fibers. Manolis et al. (1996) noted that others (Khetarpal et al., 1991; Khetarpal, 1993) had reported previous clinical evaluations of this family. Based on the findings in the 3 affected families, including the family of Manolis et al. (1996), Robertson et al. (1998) described the hearing loss as having its onset between 20 and 30 years of age. Initially it was most profound at high frequencies and displayed variable progression to anacusis by 40 to 50 years of age. Some DFNA9 patients had received cochlear implants and others used hearing aids. A spectrum of clinical vestibular involvement, ranging from lack of symptoms to presence of vertigo, vestibular hypofunction as assessed by electronystagmography and histopathology, had been found.
In the original family of Manolis et al. (1996) and 2 additional families with DFNA9 identified with the characteristic histopathologic findings of acidophilic ground substance in the cochlea and vestibular labyrinth, Robertson et al. (1998) described separate mutations ... In the original family of Manolis et al. (1996) and 2 additional families with DFNA9 identified with the characteristic histopathologic findings of acidophilic ground substance in the cochlea and vestibular labyrinth, Robertson et al. (1998) described separate mutations in the COCH gene (603196.0001-603196.0003), which is expressed almost exclusively in the inner ear. Fransen et al. (1999) identified a mutation in the COCH gene (P51S; 603196.0004) in 1 large Belgian and 2 small Dutch families with autosomal dominant nonsyndromic progressive sensorineural hearing loss associated with vestibular dysfunction. Greater than 25% of the patients affected with this mutation showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness, and hearing loss. Fransen et al. (1999) suggested that the COCH gene may be one of the genetic factors contributing to Meniere disease (156000) and that the possibility of a COCH mutation should be considered in patients with Meniere disease symptoms. From a study in a Japanese population, Usami et al. (2003) concluded that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominant inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction or sporadic Meniere disease. They identified a novel point mutation in the COCH gene (603196.0006) in a patient with autosomal dominant hearing loss and vestibular symptoms. Street et al. (2005) performed a genomewide scan and linkage analysis in an American pedigree with hearing loss and vestibular and oculomotor disturbances. A maximal pairwise lod score of 7.08 was obtained with marker D14S1021, and a mutation was identified in exon 12 of the COCH gene (603196.0007) that cosegregated with auditory dysfunction. Street et al. (2005) stated that this was the first mutation to be reported outside of the LCCL domain, which is encoded by exons 4 and 5. Hearing loss and vestibular dysfunction was present in a 17-year-old male in this family, the youngest reported age of onset in a DFNA9 family member. Yuan et al. (2008) reported a large Chinese family with DFNA9 confirmed by genetic analysis (603196.0008). Age at onset ranged from the second to fifth decade of life, and there was some evidence of genetic anticipation, although the findings may have been due to bias. Most affected family members (82%) had tinnitus at the onset of hearing loss. Hearing loss first affected the high frequencies and later involved all frequencies. Overall, the patients displayed a downward sloping audiogram contour. Although none had clinical vestibular complaints, detailed studies showed evidence for subtle defects. Hildebrand et al. (2009) reported a 5-generation American family in which members with nonsyndromic sensorineural deafness and vestibular impairment, excluding 2 thought to represent deafness phenocopies, had a P51S mutation in the COCH gene (603196.0004). In addition, 1 member with the P51S mutation had bilateral superior semicircular canal dehiscence (SCCD). The family was related to those reported by Fransen et al. (1999, 2001), providing further evidence of a founder mutation. Hildebrand et al. (2009) recommended high-resolution temporal bone CT in patients with DFNA9-related deafness and screening for COCH in sporadic or familial cases of superior semicircular canal dehiscence. In 3 unrelated patients with semicircular canal dehiscence and no family history of the disorder or of deafness, Crovetto et al. (2012) excluded mutations in the coding exons and intron-exon boundaries of the COCH gene.