CDH23 – Autosomal Recessive Nonsyndromic Hearing Loss 12 (DFNB12)

CDH23 (HGNC:13733) is causally linked to autosomal recessive nonsyndromic hearing loss 12 (DFNB12; MONDO_0011067), presenting as congenital to progressive sensorineural hearing impairment without retinal or vestibular involvement. DFNB12 is distinguished by missense variants in CDH23, which disrupt tip‐link integrity in cochlear hair cells, leading to defective mechanoelectrical transduction.

Inheritance is autosomal recessive, with homozygous or compound heterozygous missense alleles segregating in multiple families. In a cohort of 38 unrelated DFNB12 probands, only missense substitutions such as c.7549A>G (p.Ser2517Gly) were observed, and these variants co-segregated with hearing loss in familial studies ([PMID:12075507]).

Genetic spectrum from multi-family screening (45 families) included 18 missense, 3 nonsense, 5 splice-site, 5 small deletions, and 2 insertions; however, missense mutations exclusively underlie DFNB12, whereas truncating and splice-site variants cause Usher syndrome type 1D ([PMID:12075507]).

Experimental evidence from the waltzer mouse model demonstrates that Cdh23 null alleles yield profound congenital deafness and hair cell degeneration, recapitulating DFNB12 pathology ([PMID:11386759]). Ex vivo splicing assays on noncanonical variants confirm aberrant transcript processing that impairs CDH23 function in hair cells ([PMID:20052763]).

Mechanistically, missense substitutions affecting calcium‐binding DXNDN motifs in extracellular cadherin domains compromise tip‐link stability, reducing mechanotransduction currents in outer hair cells. No studies have refuted this genotype-phenotype correlation; DFNB12 remains a well‐established recessive disorder.

Key Take-home: CDH23 missense variants define DFNB12 nonsyndromic hearing loss, and identification of alleles such as c.7549A>G (p.Ser2517Gly) is critical for accurate diagnosis, carrier testing, and genetic counseling.

References

• American Journal of Human Genetics • 2002 • CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. PMID:12075507
• Genomics • 2001 • Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. PMID:11386759
• Human Mutation • 2010 • Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes. PMID:20052763

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