PCDH15 – autosomal recessive nonsyndromic hearing loss 23

Protocadherin 15 (PCDH15) is a cadherin-superfamily cell-adhesion protein expressed in inner ear hair cells. Biallelic loss- or alteration-of-function variants in PCDH15 cause both syndromic (Usher syndrome type 1F) and nonsyndromic (DFNB23) congenital hearing loss. Nonsyndromic DFNB23 (MONDO:0012293) presents as prelingual, profound sensorineural hearing impairment without retinal degeneration. PCDH15 isoforms localize to hair-bundle tip links, essential for mechanotransduction and hair-bundle cohesion.

Genetic evidence for PCDH15 in DFNB23 includes at least two unrelated families with autosomal recessive inheritance. A homozygous missense variant, c.400C>G (p.Arg134Gly), segregated with prelingual nonsyndromic deafness in one Pakistani pedigree (PMID:18719945). More recently, a Chinese child with bilateral nonsyndromic sensorineural hearing loss was shown to carry compound heterozygous variants: a paternal nonsense variant c.733C>T (p.Arg245Ter) and a maternal deep‐intronic deletion, both disrupting PCDH15 function (PMID:37232061).

Variant spectrum in DFNB23 includes missense and truncating alleles affecting extracellular cadherin repeats and cytoplasmic domains. Reported variant classes are missense substitutions (e.g., p.Arg134Gly), nonsense (p.Arg245Ter), splice‐site, frameshift, and deep‐intronic changes. No recurrent or founder variants have been reported specifically for DFNB23 outside of those noted above.

Segregation data are limited: the original DFNB23 family demonstrated cosegregation of the homozygous missense allele with hearing loss, consistent with autosomal recessive inheritance. The second family displayed complete segregation of compound heterozygous PCDH15 variants with the affected proband and unaffected carrier parents.

Functional studies in Pcdh15-deficient Ames waltzer mice recapitulate the human DFNB23 phenotype. Multiple av alleles, including ENU-induced splice mutations and presumed null alleles, cause congenital profound hearing loss, abnormal stereocilia morphology, disorganized hair-bundle architecture, and absent auditory-evoked brainstem responses (PMID:15811708; PMID:16408167). The severity of hair-bundle and actin meshwork defects correlates with the extent of PCDH15 mutation, supporting a loss-of-function mechanism.

Integration of genetic and experimental data supports a ClinGen Moderate gene–disease association. Biallelic PCDH15 variants consistently segregate with DFNB23 in unrelated families, and Pcdh15 mutant mice faithfully model the hearing-loss phenotype. Additional case series and segregation studies would strengthen the evidence. Key take-home: PCDH15 sequencing is clinically useful for diagnosing autosomal recessive nonsyndromic hearing loss, guiding genetic counseling and potential future gene-based therapies.

References

• Human genetics • 2008 • Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome. PMID:18719945
• Molecular genetics & genomic medicine • 2023 • Case report: Compound heterozygous nonsense PCDH15 variant and a novel deep-intronic variant in a Chinese child with profound hearing loss. PMID:37232061
• Hearing research • 2005 • Characterization of a new allele of Ames waltzer generated by ENU mutagenesis. PMID:15811708
• Journal of the Association for Research in Otolaryngology : JARO • 2006 • Progression of inner ear pathology in Ames waltzer mice and the role of protocadherin 15 in hair cell development. PMID:16408167

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