Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype–phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural hearing loss were selected for exome sequencing. Mutational alleles in MYO7A were identified according to ACMG guidelines. Segregation analysis was performed to examine whether pathogenic variants segregated with affected status of families. All identified pathogenic variants were evaluated for a phenotype–genotype correlation. MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex. Five potentially pathogenic missense variants were identified. Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein. Missense variants in the motor domain caused late onset of hearing loss with ascending tendency. A severe audiological phenotype was apparent in individuals carrying tail domain variants. We report two new pathogenic variants responsible for DFNA11 in the Korean ADHL population. Dominant pathogenic variants of MYO7A occur frequently in motor and MyTH4 domains. Audiological differences among individuals correspond to specific domains which contain the variants. Therefore, appropriate rehabilitation is needed, particularly for patients with late-onset familial hearing loss.

Background: The vestibular phenotypes of patients with genetic hearing loss are poorly understood. Methods: we performed genetic testing including exome sequencing and vestibular function tests to investigate vestibular phenotypes and functions in patients with genetic hearing loss. Results: Among 627 patients, 143 (22.8%) had vestibular symptoms. Genetic variations were confirmed in 45 (31.5%) of the 143 patients. Nineteen deafness genes were linked with vestibular symptoms; the most frequent genes in autosomal dominant and recessive individuals were COCH and SLC26A4, respectively. Vestibular symptoms were mostly of the vertigo type, recurrent, and persisted for hours in the genetically confirmed and unconfirmed groups. Decreased vestibular function in the caloric test, video head impulse test, cervical vestibular-evoked myogenic potential, and ocular vestibular-evoked myogenic potential was observed in 42.0%, 16.3%, 57.8%, and 85.0% of the patients, respectively. The caloric test revealed a significantly higher incidence of abnormal results in autosomal recessive individuals than in autosomal dominant individuals (p = 0.011). The genes, including SLC26A4, COCH, KCNQ4, MYH9, NLRP3, EYA4, MYO7A, MYO15A, and MYH9, were heterogeneously associated with abnormalities in the vestibular function test. Conclusions: In conclusion, diverse vestibular symptoms are commonly concomitant with genetic hearing loss and are easily overlooked.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.