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The age-related hearing loss allele (Cdh23 ahl ) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23 ahl allele to the wild-type Cdh23 + allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23 ahl allele to Cdh23 +, suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23 ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23 + allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss. • Outbred ICR mice develop early onset high-frequency hearing loss (HFHL). • Cdh23 ahl allele-specific genome editing ameliorated early onset HFHL in ICR mice. • Inbred NOD/Shi mice of ICR origin developed early onset severe hearing loss. • HFHL in NOD/Shi mice was not rescued by Cdh23 ahl allele-specific genome editing. [ABSTRACT FROM AUTHOR]