COCH – nonsyndromic genetic hearing loss

COCH encodes cochlin, an extracellular matrix protein critical for inner ear homeostasis. Variants in COCH are established causes of autosomal dominant nonsyndromic sensorineural hearing loss (DFNA9) and have recently been implicated in adult-onset nonsyndromic genetic hearing loss. Genetic screening in a Spanish cohort confirmed the gene’s relevance beyond classic DFNA9 phenotypes.

An observational study of 248 Cantabrian patients with postlingual nonsyndromic sensorineural hearing loss identified a heterozygous COCH c.263G>C (p.Gly88Ala) variant in 7 index cases (2.8 %) (PMID:39666779). Familial segregation encompassing 22 genetically and clinically studied individuals revealed 19 affected relatives with bilateral progressive SNHL beginning in adulthood; 13 reported vestibular instability without meeting Menière’s criteria (PMID:39666779).

Inheritance is autosomal dominant, with multiple families showing co-segregation of the c.263G>C variant and late-onset SNHL. The spectrum of COCH variants includes missense changes concentrated in the LCCL and vWFA domains; c.263G>C (p.Gly88Ala) represents a recurrent LCCL domain allele in this population.

Functional studies of DFNA9-associated COCH missense mutations demonstrate that mutant cochlins misfold, form stable dimers/oligomers, and aggregate in the extracellular matrix, disrupting inner ear structure and function (PMID:12843317; PMID:20228067). These results support a gain-of-function/dominant-negative mechanism consistent with the progressive SNHL phenotype seen in heterozygous carriers.

No conflicting studies have been reported for the c.263G>C variant. Taken together, the genetic segregation and mechanistic data provide strong evidence linking COCH to adult-onset nonsyndromic genetic hearing loss. Integration of COCH sequencing in hearing loss panels enables precise diagnosis, prognosis, and genetic counseling.

Key Take-home: Heterozygous COCH c.263G>C (p.Gly88Ala) causes autosomal dominant, adult-onset nonsyndromic SNHL with vestibular hypofunction through a dominant-negative misfolding mechanism.

References

• Otolaryngology--head and neck surgery • 2025 • Hearing and Vestibular Impairment Related to a Variant (c.263G>C) of the COCH Gene. PMID:39666779
• Journal of medical genetics • 2003 • Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. PMID:12843317
• The Journal of biological chemistry • 2010 • Role of protein misfolding in DFNA9 hearing loss. PMID:20228067

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