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

Area of Science:

• Genetics
• Molecular Biology
• Audiology

Background:

• Familial autosomal recessive non-syndromic hearing loss (DFNB12) is a common form of hereditary hearing loss.
• Cadherin-related 23 (CDH23) gene mutations are a significant cause of DFNB12.

Purpose of the Study:

• To investigate the molecular basis and pathogenic mechanism of DFNB12 in a family.
• To identify disease-causing mutations in the CDH23 gene.

Main Methods:

• Family-based genetic study utilizing pedigree analysis.
• Clinical whole-exome sequencing to identify mutations.
• Structural bioinformatics (homology modeling, molecular dynamics) to assess functional consequences.

Main Results:

• The proband had compound heterozygous variants: one known pathogenic maternal variant and a paternal haplotype with two linked, individually benign variants (c.3262G > A and c.6911G > A).
• Pedigree analysis confirmed the paternal haplotype acted as a single pathogenic allele.

Conclusions:

• Two individually benign variants can form a novel pathogenic haplotype (c.3262A-c.6911A), a mechanism potentially missed in routine genetic analysis.
• Evaluating combined effects of linked benign variants is crucial for accurate genetic counseling in hereditary hearing loss.