MYO6 – DFNA22 Autosomal Dominant Nonsyndromic Hearing Loss

Myosin VI, encoded by the MYO6 gene, is a motor protein critical for inner ear hair cell function. Heterozygous variants in MYO6 cause DFNA22, an autosomal dominant nonsyndromic hearing loss, by disrupting cargo binding or motor activity. Early identification of pathogenic MYO6 alleles informs genetic counseling and auditory rehabilitation.

In a retrospective cohort of 81 AD NSHL families, MYO6 variants were identified in 5 families ([PMID:29607572]), corresponding to a 6.2% prevalence. Among these, a recurrent truncating mutation c.613C>T (p.Arg205Ter) was found in three of five DFNA22 pedigrees (60%) ([PMID:29607572]).

The variant spectrum includes one recurrent heterozygous nonsense change and two novel missense substitutions. The recurrent c.613C>T (p.Arg205Ter) occurs at the motor domain, while the novel c.667G>C (p.Gly223Arg) and c.474C>G (p.Thr158Arg) alter conserved residues in the head region, supporting a loss-of-function mechanism.

Segregation analysis across multiple pedigrees demonstrated cosegregation of MYO6 variants with bilateral, moderate-to-progressive sensorineural hearing impairment, with variable age of onset and intrafamilial phenotypic diversity, underscoring incomplete penetrance.

Functional studies reinforce pathogenicity: the splice acceptor mutation c.554-1G>A causes aberrant exon skipping and predicted protein truncation ([PMID:23635807]); the R1166X mutant exhibits loss of cargo adaptor binding and increased F-actin affinity in vitro ([PMID:27474411]); and zebrafish expressing the p.Glu60Gln variant develop otic vesicle and hair bundle defects recapitulating human hearing loss ([PMID:35328790]).

Collectively, genetic and experimental evidence supports a Moderate clinical validity classification for the MYO6–DFNA22 association. MYO6 should be included in diagnostic gene panels for AD NSHL to guide prognosis, counseling, and interventions such as hearing aids or cochlear implantation.

References

• The journal of gene medicine • 2018 • A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study. [PMID:29607572]
• Audiology & neuro-otology • 2013 • A novel MYO6 splice site mutation causes autosomal dominant sensorineural hearing loss type DFNA22 with a favourable outcome after cochlear implantation. [PMID:23635807]
• The Biochemical journal • 2016 • Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. [PMID:27474411]
• International journal of molecular sciences • 2022 • Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients. [PMID:35328790]
  

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