Abstract
Mutant alleles of
, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive
nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (
). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study's objective was to elucidate the role of
allelic variants of
in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in
were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in "Ca
" ion contact. In conclusion, our study identifies pathogenic
variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of
mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.