A Novel Cadherin 23 Variant for Hereditary Hearing Loss Reveals Additional Support for a DFNB12 Nonsyndromic Phenotype of CDH23

Background and objectives: Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported.

Methods: A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease.

Results: NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family.

Conclusions: The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families.