First clinical report of a rare PDZD7 nonsense variant and recurrent mutations in Iranian families with autosomal recessive non-syndromic hearing loss.

backgroundHereditary hearing loss (HHL) is a genetically heterogeneous disorder, with autosomal recessive non-syndromic hearing loss (ARNSHL) comprising a significant proportion of cases globally. To investigate its genetic basis, we performed whole-exome sequencing (WES) in four consanguineous Iranian families affected by ARNSHL.

methodsWES was performed for the proband of each family using an Illumina platform. Secondary analysis was conducted with the DRAGEN Bio-IT Platform, and variant annotation was performed using wANNOVAR. Variants were prioritized based on inheritance patterns and bioinformatic predictions. Selected variants were validated by Sanger sequencing and assessed according to American College of Medical Genetics and Genomics / Association for Molecular Pathology (ACMG/AMP) guidelines.

resultsThrough this approach, we identified a previously reported missense variant in CDH23:c.5908G > A (p.Glu1970Lys), a nonsense variant in PDZD7:c.175 C > T (p.Arg59Ter) with no prior clinical report, and a recurrent nonsense variant in CDC14A:c.1126 C > T (p.Arg376Ter) in two families, providing further support as a founder mutation in Iran.

conclusionThese findings illustrate the potential diagnostic value of WES in ARNSHL and report, for the first time, a clinical association of the PDZD7 variant (c.175 C > T) with hearing loss. Pathogenic variants in CDH23 and CDC14A are consistent with their established involvement in HHL. Overall, this study provides additional insights into the genetic landscape and genotype–phenotype correlations in ARNSHL.