The mouse Cdh23 ^ahl allele drives early cochlear dysfunction and phenotypic heterogeneity before progressive hearing loss

The Cdh23 ^ahl allele is present in many commonly used inbred mouse strains and is known to cause progressive hearing loss. However, increasing evidence suggests Cdh23 ^ahl can also modify the severity and expressivity of other genetic phenotypes, extending its biological effects beyond the cochlea. Here, we define the phenotypic, physiological, and molecular consequences associated with Cdh23 ^ahl by comparing C57BL/6N mice with a co-isogenic strain in which the allele was repaired by genome editing. We find the auditory phenotype begins earlier and is more variable than generally appreciated, with significant threshold elevations at 36–42 kHz already present by 1-month of age and progressive involvement of lower frequencies thereafter. Before these threshold elevations, inner hair cells at postnatal day 14 (P14) exhibit tonotopically distinct alterations in mechanoelectrical transduction, with reduced maximal transduction currents apically, but increased currents basally, while resting open probability and adaptation kinetics remain preserved. Cochlear transcription is also altered shortly after hearing onset: by P16, Cdh23 ^ahl and repaired cochleae occupy distinct transcriptional states. By P30, transcriptional differences have expanded substantially, and Cdh23 ^ahl cochleae show significantly increased inter-individual transcriptomic dispersion coincident with the emergence of variable high-frequency auditory dysfunction. These findings demonstrate that Cdh23 ^ahl is not physiologically benign in young mice, but is associated with an altered cochlear state that precedes hearing loss. The early and variable consequences of this common allele provide a potential framework for understanding its effects on phenotype expressivity and have important implications for the design and interpretation of studies using mouse strains that carry Cdh23 ^ahl .