A Novel Pathogenic Haplotype in CDH23 Causing DFNB12: The Combined Effect of Two Individually Benign Variants

Aberrations in cadherin-related 23 (CDH23) account for a significant proportion of familial autosomal recessive non-syndromic hearing loss (DFNB12), a common subtype of hereditary hearing loss worldwide.

To elucidate the molecular basis and pathogenic mechanism of DFNB12 in an affected girl from a nine-member pedigree.

Family-based genetic study with pedigree analysis.

Clinical whole-exome sequencing combined with pedigree analysis was used to identify disease-causing mutations. The potential functional consequences of these mutations were investigated using structural bioinformatic approaches, including homology modeling, molecular dynamics simulations, and other relevant tools.

The proband carried compound heterozygous variants: a known pathogenic maternal variant (c.6049G > A) and a paternal haplotype comprising two linked variants (c.3262G > A and c.6911G > A), each individually classified as benign. Pedigree segregation analysis demonstrated that the paternal haplotype acts as a single pathogenic allele.

Two individually benign variants can combine to form a novel pathogenic haplotype (c.3262A–c.6911A). This mechanism may be under-recognized in routine variant interpretation pipelines. Our findings underscore the importance of evaluating the combined effects of linked benign variants to ensure accurate genetic counseling.