CDH23 – Usher Syndrome Type 1D

CDH23 encodes cadherin-23, a calcium-dependent adhesion protein expressed in cochlear hair cells and photoreceptors. Biallelic CDH23 variants underlie autosomal recessive Usher syndrome type 1D (USH1D), characterized by congenital profound sensorineural hearing loss, vestibular areflexia, and prepubertal retinitis pigmentosa (PMID:11386759). The inheritance is autosomal recessive, with loss-of-function alleles typically causing the syndromic USH1D phenotype and hypomorphic missense alleles causing DFNB12 nonsyndromic hearing loss.

Multiple family and cohort studies have confirmed CDH23’s role in USH1D. A mutation screen in 56 USH1 probands identified 18 patients with two pathogenic CDH23 alleles, including 21 distinct variants in 32.1% of cases (PMID:18429043). In a consanguineous Dutch pedigree, six USH1D patients harbored splice-site mutations, whereas four DFNB12 relatives carried missense alleles, demonstrating genotype–phenotype correlation (PMID:15353998). A novel nonsense variant, c.6562G>T (p.Glu2188Ter), was reported in two Iranian siblings with atypical USH1D, expanding the mutational spectrum (PMID:37088079). Segregation of biallelic CDH23 mutations in at least three multiplex families supports pathogenicity.

The variant spectrum includes >30 alleles: 15 missense, 8 splice-site, 5 nonsense, and 3 frameshift variants. Truncating and canonical splice-site mutations correlate with the full USH1D phenotype, whereas missense changes in conserved extracellular cadherin (EC) repeats often cause DFNB12 or atypical USH1D. The intronic NCSS variant c.6050-9G>A recurs in East Asian patients (PMID:17850630), suggesting a population-specific founder effect.

Functional studies provide concordant evidence. Waltzer mouse alleles of Cdh23 produce deafness, vestibular defects, and stereocilia degeneration, modeling USH1D (PMID:11386759). In vitro thermal scanning assays reveal that pathogenic EC1+2 variants disrupt cadherin-23 binding to protocadherin-15, impairing tip-link formation (PMID:29261728). Ex vivo splicing assays confirm that silent and missense NCSS variants, such as c.7872G>A (p.Glu2624=), induce aberrant transcripts in patient cells (PMID:20052763).

No compelling conflicting evidence has been reported. All pathogenic alleles demonstrate recessive segregation, consistent audiovestibular and retinal phenotypes, and functional impairment in model systems. Further deep-intronic and regulatory variants remain to be characterized but likely contribute marginally beyond ClinGen scoring caps.

Integration of genetic and experimental data establishes CDH23 as a definitive USH1D gene. Genetic testing for CDH23 variants provides definitive diagnosis, guides auditory and ophthalmologic management, and informs family counseling. Key Take-home: CDH23 genetic screening is clinically actionable for AR Usher syndrome type 1D.

References

• Genomics • 2001 • Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. PMID:11386759
• Otology & neurotology • 2004 • Variable clinical features in patients with CDH23 mutations (USH1D-DFNB12). PMID:15353998
• Human Mutation • 2008 • Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. PMID:18429043
• Clinical Genetics • 2007 • Distribution and frequencies of CDH23 mutations in Japanese patients with non-syndromic hearing loss. PMID:17850630
• Progress in retinal and eye research • 2022 • Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions. PMID:35066146
• PLoS One • 2017 • Using thermal scanning assays to test protein-protein interactions of inner-ear cadherins. PMID:29261728
• Human Mutation • 2010 • Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes. PMID:20052763
• Audiology & neuro-otology • 2023 • A Novel Biallelic Variant in CDH23 Gene in a Family with Atypical USH1D Manifestation... PMID:37088079

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