COCH-Related Hearing Loss in a French Cohort: Novel Variants and Genotype–Phenotype Correlations

Objectives: To characterize heterozygous pathogenic COCH variants in a French cohort with non-syndromic sensorineural hearing loss (NSHL) and assess genotype–phenotype correlations in autosomal dominant NSHL (DFNA9). Setting: National Reference Center for Genetic Hearing Loss, Necker–Enfants Malades Hospital, Paris, France. Methods: This retrospective observational study included 69 individuals from 20 unrelated families diagnosed with DFNA9 (2005–2025). All individuals underwent clinical and audiological evaluations and genetic testing via targeted COCH Sanger sequencing or next-generation sequencing (NGS) panels. Variants were interpreted according to ACMG guidelines. Audiometric profiles and vestibular data were collected. Results: Seven known pathogenic COCH variants were found in ten families, and ten novel likely pathogenic variants in the others. Variants in vWFA domains were associated with early or late onset, progressive, bilateral and symmetrical hearing loss. Three variants (p.Gln410Arg, p.Ile450Val, p.Cys542Arg) were associated with congenital or prelingual onset, an atypical DFNA9 presentation. Variants in the LCCL domain were associated with later-onset hearing loss and more frequent vestibular dysfunction. Vestibular abnormalities were observed in about half of early-onset cases. Conclusions:COCH-related hearing loss is a rare cause of autosomal dominant NSHL, with only 20 families identified over two decades within the French network. This study expands the mutational spectrum of COCH by reporting ten novel variants and supports a domain-specific genotype–phenotype correlation. These findings improve the understanding of DFNA9 variability and have direct implications for clinical diagnosis, prognosis, and genetic counseling.